World Health Strategy Ebook for Happier Longer Lives

World Health Strategy eBook For Happier Longer Lives

Edited By Renata G. Bushko

Editor of Strategy for the Future of Health, Future of Intelligent and Extelligent Health Environment & Future of Health Technology

Table of Contents Strategic Directions in Future of Health

Chapter 3: From Artificial Intelligence to Intelligent Health...... 8

Chapter 4: Welcome to the Future of Medicine...... 10

Chapter 5: A Strategy for Staying Young ...... 17

Chapter 6: Defining Future of Health Technology...... 32

Chapter 7: Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology...... 49

Chapter 8: Strategy for the Future of Health...... 73

Chapter 9: Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law...... 90 Revolution in Public Health with Big Data Analytics and Reality Mining

Chapter 10: Big Data and Health...... 102

Chapter 11: Using Reality Mining to Improve Public Health and Medicine...... 114 Unsolved Problems and Technology Map and Evaluation

Chapter 12: 45+ Big Questions of the 20th FHTI Summit...... 125

Chapter 13: Emerging technology areas that will have a profound impact on the entire economy including healthcare sector...... 128

Chapter 14: Unsolved Health Problems...... 130 Patient Empowerment, Consumerism, and Self-care

Chapter 15: Inventing the Future – Tools for Self Health...... 137

Chapter 16: How Do We Treat Patients Like Valued Customers?...... 146

Chapter 17: How should we Communicate to the Public about Health Technology? ...... 161

Chapter 18: Evaluating New Health Information Technologies: Expanding the Frontiers of Health Care Delivery and Health

Promotion...... 172

Chapter 19: Flexibility and Constraints in Patient Interviews...... 181

Chapter 20: The Value of Impermanence in Design...... 192

Integrative Medicine – Prevention and Cure Without Toxic Side-effects

Chapter 22: Can Chinese Herb-based Medicines Heal the Immune System and Cure Allergies?...... 198

Chapter 23: Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine...... 206

Chapter 24: RAGE Control: Regulate and Gain Emotional Control ...... 218

Chapter 25: Shaping a Healthy Future: Megabyte, Not Mega bite!...... 228 Healthy, Caring Cities and Homes – Preventive Behavioral Changes

Chapter 27: Future of Diagnostics for Personalized Medicine...... 239

Chapter 28: Designing and Evaluating Home-Based, Just-in-Time Supportive Technology ...... 252 Nanomedicine - Maintaining Health from Within: Chromallocyte by 2039

Chapter 29: The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine...... 264

Chapter 30: Can we build Chromallocyte by 2039?...... 283

Chapter 31: Nanotechnology and its Impact on Medicine...... 293

Chapter 32: Diamond Bio Electronics...... 323

Chapter 34: Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids...... 335 Staying Young – Life Extension Technologies

Chapter 35: Fantastic Voyage: Live Long Enough to Live Forever The Science Behind Radical Life Extension Questions and

Answers...... 347

Chapter 36: What are Similarities and Differences between the Singularity and Methuselarity? ...... 355 Regenerative Medicine: 3D Printing and Stem Cell Engineering

Chapter 38: Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing ...... 365 Artificial Intelligence Decision Support as a Dominant Force in Health

Chapter 39: Future of Medical Knowledge Management and Decision Support...... 373

Chapter 40: AI Introduction to Healthcare...... 390

Chapter 41: Artificial-Intelligence-Based Hospital-Acquired Infection Control ...... 395

Digital Medicine- Caring Machines and Applications

Chapter 44: Doctor of the Future with Knowledge of 1000 Best Physicians and Medical Traditions from 50 Cultures...... 401

Chapter 45: What is Digital Medicine? ...... 403

Chapter 46: How Can We Build Trustworthy, Secure and Transparent Health Apps? ...... 415

Chapter 47: Future of Computer Implant Technology and Intelligent Human-Machine Systems...... 423

Chapter 48: Healthwear: Medical Technology Becomes Wearable...... 432

Chapter 49: Health. Care. Anywhere. Today...... 444

Chapter 50: How Can We Avoid Individual and Inter-generational Medical Errors?...... 476 Brain-Computer Interfaces

Chapter 51: Thought to Computer Communication...... 487

Chapter 52: Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body...... 495 Emotional, Conversational Caring Machines, Health Apps, and Robots

Chapter 53: Affective Medicine: Technology with Emotional Intelligence...... 506

Chapter 54: Future of Caring Machines...... 523

Chapter 55: Cyber-anthropology: A New Study on Human and Technological Co-evolution...... 538

Chapter 56: Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals,

Communities and Homes...... 550 Future of Addiction and Disability Management

Chapter 57: Therapeutic Robotics for Children with Disabilities:...... 565

Chapter 58: Future of Anti-addiction Vaccines...... 580

Chapter 59: Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future...... 591 Impact of Information Technology on Health in Developing Countries

Chapter 60: The Future of Information Technology for Health in Developing Countries...... 615

Chapter 61: Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa...... 628

Videos from the 20th Future of Health Technology Summit

About 20th Anniversary Future of Health technological revolution in healthcare Technology Summit® which is manifesting itself in the convergence of molecular biology, s we reflect upon the 20th Future computer and medical science, of Health Technology Summit, many electrical, mechanical, genetic and Athanks to Professor Marvin Minsky, biomedical engineering. Health Dr. Gloria Rudisch, Dr. Danuta Glowacka, professionals look towards a future Professor Alex (Sandy) Pentland, Dr. Tracy where caring machines will assist them Heibeck, Professor Rosalind Picard, Dr. in much of their work and consumers Aubrey de Grey, Dr. Ray Kurzweil, Dr. Craig will diagnose and treat themselves Feied, Dr. Gary Kreps, Dr. Joseph Kvedar, with self-health tools, personalized Dr. Michael McDonald, Glenn Fields, and designer drugs and automatic surgery Dr. Zbigniew Glowacki for their guidance in bubbles. Such developments will lead the development and their participation in to dramatic shift towards consumer- Future of Health Technology Summits since driven healthcare, cost reduction and 1996. happier, longer lives for all. At FHTI 2016 we honored and 2016 FHTI Summit begun with remembered great scientist and mentor the presentation of art works by Marvin Minsky 1927-2016. Renata Bushko, photographic artist and Nobel Marvin Minsky’s student, led a session “From Laureate Wally Gilbert, Christopher Artificial Intelligence to Intelligent Health” MacDonald and Jehan Said of on how to build upon his work while Henry New England Institute of Arts. Then Lieberman discussed the importance of Renata Bushko discussed New World Minsky’s ideas to medicine. Ray Kurzweil, Health Strategy shifting from supply- and panel with Aubrey de Grey, Michael side to demand-based R&D and McDonald, Glenn Fields and Joshua Feast healthcare and the need for major remembered him as well. R&D changes in US to keep up with Bringing together most prominent voices accelerating and already dominating in the field of medicine and technology, medical technology innovation in East 20th Future of Health Technology Summit and South Asia and Latin-America. examined the constantly changing horizon Future of Health Technology Summit of ideas and technologies which must be mobilizes to action and sets a new addressed by decision makers involved in direction to international cooperation. health-related investments. Future progress The opening talk on treating depends on the decisions to invest in patients as valued customers was research, development, education and delivered by innovative co-founder strategic repositioning today of Prosperata LLC Sanjay Sarma who 2016 FHTI Summit touched upon all shared his expertise in customer- aspects of the health system to provide centric design helping healthcare direction for those making investment organizations transform the patient decisions. It addressed the unprecedented experience and evolve patient

About 20th Anniversary Future of Health Technology Summit® 1 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

transactions into enduring relationships. Health by looking into how it can help Then keynote by leading computational us in work and life. Creator of Wolfram biologist and statistician Dr. Tom Chittenden Alpha, Dr. Stephen Wolfram spoke of WuXi NextCODE Genomics uncoverd about the future of computation with “Novel Strategies for Enhanced Predictive Big Data. Healthcare innovator Shari Modelling and Deep Learning in the Heath of Medalogix, provided an Biosciences” – a scientific development of example of how Big Data can make a immense importance to the world health big difference in the end-of-life care. strategy. An intriguing and far reaching Congratulations to Dr. Xiu-Min Li, honoree question: “How to cure almost of the 2016 Future of Health Technology, everything in brain disorder with light?” for turning her love for traditional herbal was asked by Dr. Newton Howard, remedies into science-based medicines. Professor of Oxford University and The title of her Award Lecture was “Can it was the title of his distinguished Chinese Herb-based Medicines Heal the lecture. The author of “Ending Immune System and Cure Allergies?”. Aging” Dr. Aubrey de Grey of SENS Renown leader Barbara Winston of Foundation uncovered secrets of Bruce Winston Gem Corporation, familiar staying young in addition to an update with Dr. Li’s excellent clinical outcomes on his progressive longevity research and patient care spoke at the Award while Dr. Lorraine Gudas of Weill Ceremony representing Dr. Li’s patients and Cornell Medical College and Sveikatal, symbolizing patient empowerment era. The Inc. unveiled new innovative offerings immensely important topic of herbal science to the consumer in the cancer was continued with insights from renown treatment area. scientist Dr. Jing-Ke Weng of MIT and Doctor of the future debate started Whitehead Institute for Biomedical Research at FHTI 20 years ago by Renata - “How can we harness healing power from Bushko was reignited by the paper plants?” and presentation by Rennna Bushko by Dr. Urs-Vit Albrecht from Hannover of Smith College on the important role of Medical School who explained how scientific herbal medicine in combatting we can build trustworthy, secure and inflammation. transparent health-apps so essential Keynote by Sylvia Hobbs of in consumer empowerment and self- Massachusetts Center for Health Information care movement. Leader of affective and Analysis, “Can Terabytes of new Data computing, Professor Rosalind Picard Deepen our Knowledge of the state of of MIT Media Lab and Affectiva Health Care in the Commonwealth of Inc. introduced intelligent, affective Massachusetts?” opened a discussion applications by asking if “we can on the role of BIG data in health. Most forecast changes in mood and mental quoted computational scientist in the world, health, like we forecast a storm”. A Professor Alex (Sandy) Pentland of MIT theme of technological innovation in Media Lab, further explored Big Data and mental health was continued by Dr.

About 20th Anniversary Future of Health Technology Summit® 2 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Skyler Place of Cogito Health who explained by futurist and healthcare strategist how our smartphones may know more Renata Bushko of FHTI included about our mental health than our doctors. remarks by Dr. Xing Jijun, Counselor That trend may continue into fashion so Consul for Science and Technology, a session led by Renata Bushko on how Consulate General of P.R. China in high-tech fashion and wearable technology New York focusing on the future of would impact consumers’ health addressed healthcare in China. Visionary talk by high-tech fashion 5.8 billion market. Creative Dr. Nick van Terheyden of Dell – “Will and artistic Dr. Katia Vega of MIT media Lab healthcare be delivered by George investigated Beauty Technology: “When Jetson in the future?” completed this Technology meets Cosmetics” presenting topic. Critical importance of renewable among other topics conductive makeup energy distributed collectively through including eyelashes than can turn on the intelligent grids globally was explored lights for disabled. by public health strategist, Dr. Michael TI 2016. FutureofHealth.org McDonald, of Global Health Response Innovative technologies may also help in and Resilience Alliance. reduction of fast growing opioid Nanomedicine revolution was misuse among chronic pain patients be outlined by Dr. Guillermo Ulises according to Dr. Robert Jamison of Harvard Ruiz Esparza and Dr. Yu Shrike Medical School who led session on that Zhang of Harvard-MIT Division of topic while Dr. Darin Correll of Brigham and Health Sciences and Technology. Women’s Hospital chaired the panel on They described what’s next in the the future of pain management and urgent application of Nanotechnology-based need for more consumer education around Molecular Delivery Systems (Sr. the world with Dr. Daniell Carr of Tufts Esparza) and how Google Glass can University School of Medicine and Dr. Navil remotely integrate with microfluidic Sethna of Harvard Medical School. Health biosensors and actuators (Dr. Zhang). communications expert, Shelagh Maloney of Professor Hermano Igo Krebs of Canada Health Infoway presented on how MIT unveiled methods to repair a we should communicate to the public about broken brain with movement therapy the health technology revolution to assure while Professor Ernesto Rodriguez Leal progress. of Tecnologico de Monterrey outlined The path of this revolution was charted strategy for building exoskeletal body by prominent healthcare leader Dr. Gary support to avoid physical disparity and Kreps of George Mason University and ten demonstrated his prototype. further described by Dr. Joe Kvedar of Two essential financial questions Partners HealthCare, Dr. Guergana Savova (1) What are the new possible ways to of Harvard Medical School and Dr. Robert fund basic bio-medical research? and Teague from Quorum Health Resources in (2) How can we accelerate formation a session on future of healthcare in 10-20 and success of biotechnology years. This Future of Care panel moderated startups? were discussed by the

About 20th Anniversary Future of Health Technology Summit® 3 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

group leading into strategic links between a question posed and discussed by inventors and investors. Albert di Rienzo of Ian Pentland of Northeastern University Radicle Innovation LLC moderating a panel and Dr. Todd Reid, of Massachusetts on ways to increase success of bio-tech General Hospital and MIT Connection startups was joined by two renown experts Science. Dr. Eric Elenko of Pure Tech and Dr. Adam Dr. Luis Alonso Pastor of MIT Greenspan of Business Incubation University Media Lab partnering with the City Science Center in Philadelphia. team from Schepens Eye Research New generation of talented researchers Institute and Massachusetts Eye and and students unveiled bold ideas leading Ear, Department of Ophthalmology, to happier longer lives in the FHTI poster Harvard Medical School, discussed session. Dr. Agnes Stibe of MIT Media how 3-D printing can help with Labs Changing Places Group helped us epithelial wound healing. imagine cities that feel, understand, and take Talented dancer and care of our wellbeing. Dr. Brittany Seymour choreographer, Maria Caruso of of Harvard School of Dental Medicine Bodiography and La Roche College explained how network science can be of Performing Arts prepared original applied for an expanded understanding of dance performance illustrating ideas in large online network information structures the summit. Renown Violinist, Yuan Mei and behaviors to modernize public health Xing celebrated her 20th performance communication strategies for improved at the Future of Health Technology health outcomes. Institute’s summits by playing with The future of depression prediction pianist, Steven Jackson Member of the based on self-report diary via smartphone orchestra, Boston Lyric Opera applications was discussed by Yoshihiko Suhara of MIT Media Lab. Psychology 20th FHTI Summit resulted in the World topic was continued by another amazing Health Strategy eBook (Ed.) Renata G. MIT Media Lab student Sooyeon Jeong Bushko www.futureofhealth.org. Both presenting on the topic of: “How can we chapters and video-lectures from the implement personalized positive psychology eBook provide an excellent roadmap interventions in the form of interactive to plan the future of healthcare journaling?” Renna Bushko of Smith College globally. and Research Intern at Ichan School of Medicine at Mount Sinai talked about the 50+ Luminaries Asking and Answering role of Arctigenin isolated from Arctium Most Pressing Questions of our Times: lappa L. in inhibiting IgE production and reducing inflammation, providing hope to The best way to progress with health treat IgE associated inflammatory diseases. investments to assure best outcomes “How can we reduce the economic burden for humanity. 2016 BIG Questions of Type 2 Diabetes management through selected by FHTI are: smartphone technology and Big Data?” was

About 20th Anniversary Future of Health Technology Summit® 4 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

1. How can we honor and build upon 10. Can we forecast changes in mood Marvin Minsky’s work? and mental health, like we forecast a Aubrey de Grey, Joshua Feast, Glenn Fields, storm? Renata Bushko, Mike McDonald Rosalind Picard

2. What should the new world health 11. What is the healing story of Dr. strategy be? What fundamental changes Xiu-Min Li? and dramatic shifts do we need to prepare Barbara Winston for? Renata Bushko 12. How should we remember Marvin Minsky? 3. How do we treat patients like valued Ray Kurzweil customers? Sanjay Sarma, Rahul Ghate 13. How can we chart the future for digital health information systems? 4. Can terabytes of new data deepen our Gary Kreps knowledge of the state of health care in the Commonwealth of Massachusetts? 14.What are seven secrets to staying Sylvia Hobbs young? Aubrey de Grey 5. What are novel strategies for enhanced predictive modelling and deep learning in 15. What is the future of pain the biosciences? management? Tom Chittenden Darin Correll

16. What is the future of 6. How will health care look like in 20 computation? Stephen Wolfram years? Renata Bushko, Xing Jijun, Joseph Kvedar, 17. Why Minsky’s ideas are important Guergana Savova, for medicine? Henry Lieberman 7. How can Big Data help you in work and life? Alex (Sandy) Pentland 18. How can we reduce opioid misuse among chronic pain patients and 8. How to cure almost everything in brain what is the role of risk assessment disorder with light? Newton Howard and innovative technology? Robert Jamison 9. Can Chinese herb-based medicine heal the immune system and cure allergies? 19. Will healthcare be delivered by Xiu-Min Li George Jetson in the future? Nick van Terheyden

About 20th Anniversary Future of Health Technology Summit® 5 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

20. What are new innovative offerings 30. How can we build trustworthy, to the consumer in the cancer treatment secure and transparent health-apps? area? Urs-Vit Albrecht Lorraine J. Gudas 21. Are exoskeletons a solution to physical 31. How will health care look like in disparity? 20 years? Ernesto Rodríguez Leal Renata Bushko, Guergana Savova, Joseph Kvedar 22. What would best catalyze 100% renewable energy distributed collectively 32. What are the new possible ways through intelligent grids globally? to fund basic bio-medical research? Michael McDonald Renata Bushko

23. How can we harness healing power 33. How can we accelerate formation from plants? and success of biotechnology Jing-Ke Weng startups? Eric Elenko, Albert Di Rienzo, Tanveer 24. How should we communicate to the Patel, Adam Greenspan public about health technology? Shelagh Maloney 34. How can Big Data make a big 25. Is hospital a place? difference in the end-of-life care? Robert Teague Dan Hogan

26. What is the future of international 35. Does your smartphone know cooperation in health research, more about your mental health than development and commercialization? your doctor? Renata Bushko Skyler Place

27. Can art inspire? 36. Is violin music healing? Wally Gilbert Yuan Mei Xing

28. What is the best way to communicate 37. What is the road from Artificial ideas through graphic design and media Intelligence to Intelligent Health? arts? Renata Bushko Christoper MacDonald, Jehan Said, Lauren Callahan, Dianna Cox, Tania Saade, Marisa 38. Can we repair a broken brain Campbell, Andrew R Emery, Charles Searle with movement therapy approach? Hermao 29. What is the future of eHealth? Claudia Igo Krebs Pagliari

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39. How can Google Glass remotely 47. How can we implement integrate with microfluidic biosensors and personalized positive psychology actuators? interventions in the form of Yu Shrike Zhang interactive journaling? Sooyeon Jeong 40. What’s next in the application of nanotechnology-based molecular delivery 48.How will fashion industry change Systems? healthcare? How will high-tech Guillermo Ulises Ruiz Esparza fashion and wearable technology market impact consumers’ health? 41. Can you imagine cities that feel, Will garment be a new health app understand, and take care of your development platform? wellbeing? Agnis Stibe Renata Bushko

42. How Can 3-D printing help with epithelial wound healing? Louis Alonso Pastor

43. Can Arctigenin reduce inflammation giving hope to treat igE related inflammatory diseases? Renna Bushko

44. What is the future of depression prediction based on self-report diary via smartphone applications? Yoshihiko Suhara

45. How can we reduce the economic burden of Type 2 Diabetes management through smartphone technology and Big Data? Todd Reid, Ian Pentland

46. How can network science be applied for an expanded understanding of large online network information structures and behaviors to modernize public health communication strategies for improved health outcomes? Brittany Seymour

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Renata G. Chapter 3: From Artificial Intelligence to (2)The Health Information Bushko / From Artificial Intelligent Health Infrastructure. Intelligence to Renata G. Bushko Intelligent Health in “World Health September 17, 1995 (3)Advancing Intellectual Strategy” eBook, “If you understand something one way you Leadership (Ed.) Renata.G. Bushko do not understand it at all.” FHTI, 2016. Marvin Minsky (1) Advancing medical technologies. Futureofhealth. org n 1956, a meeting at Dartmouth initiated a Many advances in health services new field of science, Artificial Intelligence. have come from technical innovations, IThe goal of that meeting of the minds was such as: to discover the unknown and mysterious machinery of the mind. We could consider *New Genetic knowledge. this to be a model of leadership and innovation--skills that will surely be essential *Non-invasive Visualization: for dealing with the problems of the 21st CAT, PET, MRI, Ultrasound, etc. century. How can we exploit that successful example to deal with the new complexities *Virtual Reality that lie ahead? The world has changed in forty years *Telemedicine since Marvin Minsky, John McCarthy, Allen Newell, Herbert Simon and other inquisitive *Designer Drugs, minds met at Dartmouth to begin the field of Radiopharmaceuticals Artificial Intelligence. In the same forty years, the world of *Intelligent Networks, biology and medicine saw equally radical Collaborative Work changes. Few workers had as much effect Environments in that period as did Dr. C. Everett Koop, who pursued the goal of improving health. The *Electronic Medical Records, 1996 Future of Health Technology meeting and new methods of analysis. will address achievements of the last forty years in both those realms, and try to map *Transplants, prosthetics, artificial out how those fields might come closer organs. together in the future. Etc. A major problem is that we now see a widespread fear that these These fields could merge in several ways: wonderful innovations are coming to have a dreadful side effect: relentlessly (1).Advancing Medical increasing costs. Most observers see Technologies. that as inevitable. However, one of our goals should be to show how that

could be stopped, and even reversed. In the field of computers, we’ve seen just the opposite: the cost of computers has decreased exponentially! Why should not that be the case, as well, in the domain of health. Why can’t we exploit the new techniques that will come in AI to make those procedures less costly? Perhaps it is merely a matter of vision and leadership.

(2) The Health Information Infrastructure. According to Dr. C. Everett Koop two revolutions are taking place: (1) health systems transformation (2) global presence of intelligent networks. The Health Information Infrastructure (HII) lies at the “volatile intersection” of these two revolutions. HII has the potential for substantially improving health of Americans even within the next decade. How shall we proceed with its development, so that the developing countries are included? (3) Advancing Intellectual Leadership. Professor Minsky’s book, The Society of Mind, provides a new agent-based model of the mind. There is a convergence between new ideas about minds and machines and the focus on adaptiveness in current research on leadership. The future merger between new ideas about technology, leadership, and science of the mind will make it possible to create intelligent health systems much faster. September 17, 1995; Reviewed by Marvin Minsky 1/19/1996

Renata Bushko Tel: 508-497-2577, Fax: 508-497-2518

Robert A. Freitas Chapter 4: Welcome to the Future of Irving’s passing was a great Jr./ Welcome to the Future Medicine hardship on the family, which now of Medicine in Robert A. Freitas Jr. consisted solely of my mother and “World Health Strategy” eBook, Senior Research Fellow, Institute for grandmother. The Great Depression, (Ed.) Renata Molecular Manufacturing you may recall, hit bottom in 1935, the G. Bushko, FHTI, 2016. Palo Alto, California USA year Irving died. My scrappy Futureofhealth. grandmother, who had never worked, org From Strategy for the Abstract managed to find a job and held on to Future of Health his chapter describes the negative the house. She and my mother burned (Ed.) Renata G. Bushko, IOS consequences of medical technology player piano rolls in the fireplace that Press 2009 Tdevelopment and commercialization winter, to keep warm. The piano had that is too slow, and makes the case for an been delivered just days before Irving immediate large scale investment in medical fell ill. As a matter of fact, I still have nanorobots to save 52 million lives a year. It that once-prized piano, and the last also explains the essence of two surviving rolls, in my own house nanotechnology, its life-saving applications, today. the engineering challenges, and the What Irving’s wife and daughter did possibility of 1000-fold improvement over not know, what none of Irving’s doctors our current human biological abilities. Every knew, what almost no one in the entire decade that we delay development and world knew, was that almost a decade commercialization of medical nanorobotics, earlier, in 1928, an obscure Scottish half a billion people perish who could have microbiologist named Alexander been saved. Fleming had first reported the antibacterial activity of a common Introduction blue-green mold. By 1929, Fleming I never met my maternal grandfather, Irving had isolated the antibiotic substance Lincoln Smith. I understand he was a good and named it: “penicillin”. Tests man, a kind and loving father, a hard worker. showed that penicillin was not toxic to He died in 1935, at the age of 39, when my humans. mother was only 12. But that was 1929. Irving died in Irving died of encephalitis, or “sleeping 1935, six years later. Almost nothing sickness.” It is a horrible disease with many was done to promote the use or possible causes which has up to a 50% production of penicillin until 1938. untreated mortality rate in some population That’s when two British biochemists, subgroups. Encephalitis is an inflammation Florey and Chain, began an intensive of the brain. Prolonged fevers over 106 study to define the range of bacteria Fahrenheit are not uncommon. There is a affected by penicillin. They pounding headache, unending nausea, stiff discovered, among other things, that muscles, then drowsiness, coma, and penicillin was an effective treatment for sometimes death. some bacterial forms of encephalitis.

By 1941-44, in cooperation with American consistent with natural laws, thus industry and the War Department, up to a permitting the manufacture of artificial ton of penicillin was being manufactured objects of surpassing beauty and and distributed to Allied troops fighting in strength that are far more valuable World War II. Penicillin, a true wonder in its than diamonds. This is the essence of day, saved millions of wounded soldiers nanotechnology: the control of the from dying of gangrene and other common composition and structure of matter at battlefield bacterial infections that just a few the atomic level. The prefix “nano-“ years earlier would have been fatal. But all refers to the scale of these this good news came a decade too late for constructions. A nanometer is one- Irving. billionth of a meter, the width of about My grandfather may have died, not 5 carbon atoms nestled side by side. because the cure he needed had yet to be Nanomedicine is the application of discovered, and not because the FDA had nanotechnology to the field of taken too long to approve a new drug, but medicine. simply because the development and commercialization of a new technology took 2. Nanorobotics too long. As a result, I never knew my In decades to come, grandfather, and my life has been forever nanotechnologists will build nanoscale impoverished as a result. molecular parts like gears, bearings, Each of us similarly has friends and loved and ratchets. Each nanopart may ones we care deeply about – children, comprise a few thousand precisely spouses, parents and friends. Two of them placed atoms. These mechanical die every second, somewhere on Earth, nanoparts will then be assembled into totaling 52 million worldwide annually. But larger working machines such as almost all of these deaths are, in principle, nanopumps, nanocomputers, and medically preventable – not by the methods even complete nanorobots. With of present-day medicine, but by a new form medical nanorobots in hand, doctors of medicine, called nanomedicine, that now will be able to quickly cure most lurks on the technological horizon. diseases that hobble and kill people today, rapidly repair most physical 1. What is Nanomedicine? injuries our bodies can suffer, and What is nanomedicine? The concept is fairly vastly extend the human healthspan. easy to understand. The only important This application of nanotechnology to difference between the carbon atoms in a the improvement of human health is plain lump of coal and the carbon atoms in a the most visionary branch of stunning crystal of diamond is their nanomedicine, called medical molecular arrangement, relative to each nanorobotics. other. Future technology currently Microscale robots are already being envisioned will allow us to rearrange all investigated for in vivo medical use. In atoms exactly the way we want them, 2002, researchers at Tohoku

University tested magnetically-driven nanorobots, could be constructed. spinning screws intended to propel drug This technology, said Feynman, payloads through veins and into infected “suggests a very interesting possibility tissues, or even to burrow into tumors and for relatively small machines. Although destroy them with heat. In 2005 a team at it is a very wild idea, it would be the Swiss Federal Institute of Technology in interesting in surgery if you could Zurich fabricated a similarly-powered swallow the surgeon. You put the microrobot small enough to be injected into mechanical surgeon inside the blood the body through a syringe. The team vessel and it goes into the heart and hopes their device might be used to deliver looks around. (Of course the drugs or to perform minimally invasive eye information has to be fed out.) It finds surgery. Moving still smaller in scale, out which valve is the faulty one and experimentalists have used a rapidly takes a little knife and slices it out. ... vibrating micropipette to slice individual [Imagine] that we can manufacture an dendrites from single neurons without object that maneuvers at that level!... damaging cell viability. Other researchers Other small machines might be have wielded tightly focused femtosecond permanently incorporated in the body lasers as nano-scissors to perform to assist some inadequately nanosurgery on individual chromosomes functioning organ.” inside a live cell nucleus, and have What is a medical nanorobot? Like dissected the cell wall of a single bacterium, a regular robot, a nanorobot may be layer by layer, using an atomic force made of many thousands of microscope. mechanical parts such as bearings and Medical nanorobots would be even gears composed of strong diamond- smaller and would be constructed entirely of like material. A nanorobot will have atomically precise mechanical components. motors to make things move, and The first and most famous scientist to voice perhaps manipulator arms or the possibility of nanorobots traveling mechanical legs for mobility. It will through the body, searching out and have a power supply for energy, clearing up diseases, was the late Nobel sensors to guide its actions, and an physicist Richard P. Feynman. In his onboard computer to control its remarkably prescient 1959 talk “There’s behavior. But unlike a regular robot, a Plenty of Room at the Bottom,” Feynman nanorobot will be very small. A proposed employing machine tools to make nanorobot that would travel through smaller machine tools, these to be used in the bloodstream must be tiny enough turn to make still smaller machine tools, and to squeeze through even the so on all the way down to the atomic level, narrowest capillaries in the human noting that this is “a development which I body. Such machines must be smaller think cannot be avoided.” than the red cells in our blood. A With these small machine tools in hand, convenient measure of size is the small mechanical devices, including micron, or one-millionth of a meter. A

red cell is about 7 microns wide. A molecule, using mechanical pumps on bloodborne medical nanorobot will typically the device’s surface. This simple be no larger than 2-3 microns in its largest nanorobot is regulated by onboard dimension. The mechanical parts that make computers, powered by glucose fuel up a nanorobot will be much smaller still, cells, and controlled by a physician typically 1-10 nanometers in size. who communicates with the device via ultrasound signals beamed into the 3. Nanorobotics Revolution by 2020s body from outside. A therapeutic 5-cc We cannot build such tiny robots today. But injection of respirocytes, just 1/1000th perhaps by the 2020s, we will. These future of total blood volume, duplicates the devices may be made of rigid diamondoid oxygen-carrying ability of the entire nanometer-scale parts and subsystems human blood mass. Such a dose including onboard sensors, motors, could instantly revive emergency manipulators, and molecular computers. victims of carbon monoxide poisoning They will be fabricated in a nanofactory via at the scene of a fire. positional assembly: picking and placing Artificial mechanical white blood nanoscale parts one by one, then moving cell devices called microbivores are them along controlled trajectories much like nanorobots that would seek and digest the robot arms that manufacture cars on harmful bloodborne pathogens automobile assembly lines. These steps will including bacteria, viruses, or fungi. be repeated over and over with all the The pathogens are completely different parts until the final product, such as digested into harmless sugars, amino a medical nanorobot, is fully assembled. acids and the like, which are the only The ability to build nanorobots cheaply effluents from this 3-micron nanorobot. and in therapeutically useful numbers will No matter that a bacterium has revolutionize the practice of medicine. acquired multiple drug resistance to Performance improvements up to 1000-fold antibiotics or to any other traditional over natural biological systems of similar treatment – the microbivore will eat it function appear possible. For example, the anyway. Microbivores would respirocyte is an artificial mechanical red completely clear even the most severe blood cell just 1 micron in diameter having bloodborne infections in hours or less, 1/100th the volume of a natural red cell. Red then be removed from the body. This cells carry oxygen to our tissues and is 1000 times faster than the weeks or remove carbon dioxide. Respirocytes do months often needed for traditional too, but would be made of much stronger antibiotic-based cures. diamond-like materials, not floppy lipids and proteins as we find in living cells. This Related medical nanorobots with allows respiratory gases to be safely stored enhanced tissue mobility could within the respirocyte at tremendous similarly consume tumor cells with pressures – up to 1000 atmospheres – and unmatched speed and surgical to be loaded or unloaded, molecule by precision, eliminating cancer. Other

devices could be programmed to remove restored once a year to a more or less circulatory obstructions in just minutes, constant physiological age that you quickly rescuing even the most select. Nanomedicine thus may permit compromised stroke victim from near-certain us first to arrest, and later to reverse, brain damage. the biological effects of aging and The most advanced types of most of the current medical causes of nanomedical devices could perform surgery natural death, severing forever the link on your individual cells. In one procedure, a between calendar time and biological nanorobot called a chromallocyte, controlled health. by a physician, would extract existing This sounds almost miraculous, but chromosomes from a diseased tissue cell in getting there is primarily an a living patient, then insert fresh new ones in engineering and R&D challenge. their place. This process is called Building nanorobots requires the ability chromosome replacement therapy. The to fabricate strong, rigid, nanoscale replacement chromosomes would be diamond or diamond-like machine manufactured earlier, outside of the patient’s parts that are atomically precise, and body, by a desktop nanofactory that then to assemble them into working includes a molecular assembly line, using machinery. Reminiscent of Alexander the patient’s individual genome as the Fleming’s early experiments with blueprint. If the patient chooses, inherited blue-green mold in 1928, an obscure defective genes could be replaced with Japanese research group led by nondefective base-pair sequences, Oscar Custance at Osaka University in permanently curing any genetic disease and Japan reported, in 2003, the first permitting cancerous cells to be atomically precise bonding and reprogrammed to a healthy state. Each unbonding of a single silicon atom, on chromallocyte is loaded with a single copy a single spot on a silicon surface, using of the digitally-corrected chromosome set. purely mechanical forces. This was After injection, each device travels to its the first laboratory demonstration of a target tissue cell, enters the nucleus, mechanically-forced chemical reaction replaces old worn-out genes with new – called mechanosynthesis – in history. chromosome copies, then exits the cell and And mechanosynthesis is the key is removed from the body. manufacturing technology that must be The implications for extension of healthy developed in order to build medical lifespan are profound. Perhaps most nanorobots, atom by atom. importantly, chromosome replacement Several years ago, Ralph Merkle therapy could be used to correct the and I founded the Nanofactory accumulating genetic damage and Collaboration to coordinate a mutations that leads to aging in every one of combined experimental and theoretical your cells. With annual checkups and R&D program to design and construct cleanouts, and some occasional major the first working diamondoid cellular repairs, your biological age could be nanofactory, which could then build

medical nanorobots. This long-term effort capital is unquestionably the greatest must start by developing the initial catastrophe that humankind has ever technology of positionally controlled faced. This catastrophe continues mechanosynthesis of diamondoid structures tormenting us year after year. We have using engineered tooltips and simple a moral obligation to minimize the molecular feedstock. Our Collaboration has number of people who die led to continuing efforts involving direct unnecessarily between now and the collaborations among more than two dozen day that nanorobotic medicine is first researchers at a dozen organizations in 5 introduced for therapeutic purposes. countries – the U.S., U.K., Russia, Australia, Let’s not repeat the mistakes of the and Belgium. A dozen peer-reviewed past. Let’s not take too long to papers are published or in progress as of develop this important new medical 2008. technology. I’m sure – though I never Most recently, after working closely for had the pleasure of meeting him – that three years with Philip Moriarty, one of the my grandfather Irving Smith would leading scanning probe microscopists in the have heartily agreed. U.K., in 2008 our international colleague received a five-year $3M grant to undertake Web References direct experiments to build and validate 1.Personal website of Robert A. Freitas several of our proposed mechanosynthesis Jr. http://www.rfreitas.com tooltips in his laboratory. We’re also 2.Nanomedicine website http://www. preparing a separate research program nanomedicine.com proposal of our own to solicit additional 3.Nanofactory Collaboration website funding from various U.S. public or private http://www.MolecularAssembler.com/ sources to support further Nanofactory mechanosynthesis-related experimental and 4.Nanomedicine Art Gallery http:// theory work on a greatly accelerated www.foresight.org/Nanomedicine/ schedule. We expect these efforts will Gallery/index.html ultimately lead to the design and manufacture of medical nanorobots for life Literature References (popular) extension, perhaps during the 2020s. 1.Robert A. Freitas Jr., “Say Ah!” The Sciences 40(July/August 2000):26-31. Conclusions This new medical technology needs to be 2.Robert A. Freitas Jr., “Death is an moved forward as quickly as possible. Outrage!” Invited Lecture delivered at Every year we delay, 52 million of our fellow the Fifth Alcor Conference on Extreme travelers on the river of life fall overboard Life Extension, 16 November 2002, and are lost forever to the rest of us. Every Newport Beach, CA. decade that we delay, half a billion people perish who could have been saved. The 3. Robert A. Freitas Jr., “Nanomedicine,” stupendous loss of knowledge and human KurzweilAI.net, 17 November 2003.

Literature References (technical) NASA feasibility analysis of self- 1. First book on nanomedicine ever replicating space factories and in 1996 published: Robert A. Freitas Jr., authored the first detailed technical Nanomedicine, Volume I: Basic Capabilities, design study of a medical nanorobot Landes Bioscience, Georgetown, TX, 1999, ever published in a peer-reviewed see also: Robert A. Freitas Jr., mainstream biomedical journal. Freitas Nanomedicine, Volume IIA: Biocompatibility, is the author of Nanomedicine, the Landes Bioscience, Georgetown, TX, 2003, first book-length technical discussion of the potential medical applications 2. First medical nanorobot design of molecular nanotechnology and paper ever published: Robert A. Freitas medical nanorobotics; the first two Jr., “Exploratory Design in Medical volumes of this 4-volume series were Nanotechnology: A Mechanical Artificial Red published in 1999 and 2003 by Landes Cell,” Artificial Cells, Blood Substitutes, and Bioscience. His research interests Immobil. Biotech. 26(1998):411-430. include: nanomedicine, medical nanorobotics design, molecular 3. Published design paper on the machine systems, diamondoid microbivores: Robert A. Freitas Jr., mechanosynthesis (theory and “Microbivores: Artificial Mechanical experimental pathways), molecular Phagocytes using Digest and Discharge assemblers and nanofactories, Protocol,” J. Evol. Technol. 14(April 2005):55- and self-replication in machine and 106. factory systems. He has published 4.First technical description of a cell repair 35 refereed journal publications nanorobot ever published: Robert A. and contributed book chapters, co- Freitas Jr., “The Ideal Gene Delivery Vector: authored Kinematic Self-Replicating Chromallocytes, Cell Repair Nanorobots Machines (Landes Bioscience, 2004), for Chromosome Replacement Therapy,” J. and co-founded the Nanofactory Evol. Technol. 16(June 2007):1-97. Collaboration. His home page is at www.rfreitas.com. Bio on Freitas Robert A. Freitas Jr. is Senior Research Fellow at the Institute for Molecular Manufacturing (IMM) in Palo Alto, California, and was a Research Scientist at Zyvex Corp. (Richardson, Texas), the first molecular nanotechnology company, during 2000- 2004. He received B.S. degrees in Physics and Psychology from Harvey Mudd College in 1974 and a J.D. from University of Santa Clara in 1979. Freitas co-edited the 1980

Aubrey de Grey./ Chapter 5: A Strategy for Staying Young 1. Introduction A Strategy for Staying Young Aubrey de Grey, Ph.D. The approach to postponing aging that in “World Health Department of Genetics, University of I shall describe in this essay is one of Strategy” eBook, (Ed.) Renata Cambridge, Cambridge, UK maintenance and repair. Those who G. Bushko like to claim that aging is intrinsically FHTI, 2016. Futureofhealth. Abstract immutable are often inclined to start org, From Future t may seem premature to be discussing by asserting, ex cathedra, that living of Intelligent and Extelligent approaches to the effective elimination organisms are qualitatively unlike Health (Ed.) of human aging as a cause of death at machines and therefore cannot be Renata G. I Bushko, IOS a time when essentially no progress has maintained beyond their “warranty Press 2005 yet been made in even postponing it. period” in the way that typical However, two aspects of human aging machines can. Even leaving aside combine to undermine this assessment. the absence of any justification of the The first is that aging is happening to us “therefore” in that assertion, there is a throughout our lives but only results in conspicuous fragility in the idea that appreciable functional decline after four or organisms (even humans) are in any more decades of life: this shows that we relevant way unlike machines. The can postpone aging arbitrarily well without property of living organisms that is knowing how to prevent it completely. The most often suggested as distinguishing second is that the typical rate of refinement them from machines is their capacity of dramatic technological breakthroughs is for self-repair, and indeed that is rather reliable (so long as public enthusiasm undoubtedly something at which for them is abundant) and is fast enough organisms are vastly superior to any to change such technologies (be they machine currently in existence. But to in medicine, transport, or computing) consider it a qualitative difference is almost beyond recognition within a clearly incorrect: as a simple example natural human lifespan. Here I explain, one need only consider household first, why it is reasonable to expect that robots that plug themselves into the (presuming adequate funding for the initial mains when their batteries run low, or preclinical work) therapies that can add photocopiers that suspend operation 30 healthy years to the remaining lifespan to clean their wires when they of healthy 55-year-olds will arrive within automatically detect the need. the next few decades, and, second, why The pessimist often retorts those who benefit from those therapies that, even if this is not a qualitative will very probably continue to benefit difference, the difference of degree from progressively improved therapies is so astronomical that the practical indefinitely and thus avoid debilitation or feasibility of maintaining an organism death from age-related causes at any age. as one does a machine is far too distant to be worth considering. But here again we see a crass logical error, because the idea is to augment

our natural maintenance systems: thus, 2. The Lag Phase of Aging: Our the fact that they are so good already Window of Opportunity means that there is that much less for us What is aging, actually? It is often to do to make them good enough to work suggested that aging is very hard to indefinitely. There is much more to this define. That is true if one requires a question, as will emerge below, but the crux definition that suits all purposes, but of the argument is as just stated. when discussing interventions an In the next section I will describe in rather altogether uncontroversial definition abstract terms the sort of maintenance that is easily found. A typical one is as I believe we should be working towards follows: in the quest to postpone aging as much as possible as soon as possible. In the Aging is the set of side-effects of following section I will go into more concrete metabolism that alter the composition biological detail, giving an overview of the of our bodies over time to make it specific types of maintenance and repair progressively less capable of self- that humans need to do better in order maintenance and thereby, eventually, to maintain our health and youth for a lot less functional. longer and the methods already under development to implement those required This definition allows us to identify improvements. The concrete and detailed three very distinct strategies for nature of those prospective interventions postponing aging and thereby leads me to the view that we are potentially extending healthy and total lifespan. within only a decade of developing them Curiously (at least in retrospect), only all in laboratory mice, and that once we two of them have historically been have done so we have perhaps a 50% pursued. They are depicted in figure chance of developing them in humans 1, in which the flat-headed arrows are within only 15 years thereafter. Then, in the used in the conventional genetics final section I will explain why this should sense to mean “inhibits”. be enough to put us beyond “life extension escape velocity” – the point at which we are improving these technologies faster than the remaining imperfections in them are catching up with us. Once we reach that point, and presuming we can stay there (which, I will argue, is virtually certain), no one need die of old age ever again, whatever age they attain.

down, such as whether it could reasonably be called “wear and tear”. What is the prognosis for the gerontology and geriatrics Figure 1. The two traditional approaches to postponing aging. approaches, in the foreseeable future? It is easy to see that the Putting Figure 1 into words: the geriatrics approach is short- gerontology approach is pre-emptive, termist almost by definition: as seeking to diminish the side-effects damage accumulates, its natural of metabolism mentioned above and pathological consequences thereby to slow down the rate at which become progressively harder to metabolism changes the composition avert. Besides, even if we could in of our bodies, whereas the geriatrics principle develop geriatric medicine approach is reactive, seeking to delay so sophisticated that pathology was the functional decline (i.e., pathology) slowed, that would be a somewhat that those changes in composition mixed blessing, as it would cause. The changes in composition constitute an extension of the frail themselves, in Figure 1, are simply period of life. denoted by the term “damage”: they are The gerontology approach no more nor less than the accumulation initially seems much more of that damage. It is important to stress promising. If one can retard the that I will use the term “damage” in rate at which metabolism lays down this very precise sense throughout damage in the first place, one this essay: for present purposes it is will certainly extend the healthy defined as the entire set of changes part of life, which would seem of bodily composition that (a) are side- unambiguously desirable. (Possibly effects of metabolism and (b) are the frail part would be extended eventually pathogenic. In particular, the too, but probably less so.) However, reader should not infer any implication it has two daunting shortcomings. concerning how this damage is laid Firstly, damage that has already

been laid down before the treatment the only way to extend mammalian begins will not be affected: hence, those lifespan is to elicit a response that who already have enough of it to be metabolism already has available to starting to suffer functional decline will it, namely the intensification of repair not have that loss of function restored and maintenance that results from by such therapies. Secondly, the moderate deprivation of nutrients practicality of the gerontology approach [2]. (This is no longer the only way is determined by the extent to which to elicit that response – genetic we understand metabolism, because manipulation has done it too [3,4] altering the workings of a system that – but it is still essentially the same we understand only very poorly tends response.) either to have no effect at all on its If we wish to postpone aging behaviour or to do more harm than any time soon, therefore, it seems good. And unfortunately, that is the case clear that we must seek a third with metabolism: though we certainly way – something radically different understand far more about it than we from the gerontology and geriatrics did only a few decades ago, we are approaches. Just such an approach regularly reminded by the discoveries of has been the focus of my work fundamental new aspects of metabolism since 2000 and has become known (such as RNA interference, discovered as “Strategies for Engineered only a few years ago [1]) that in reality we Negligible Senescence” or SENS have still hardly scratched the surface of [5,6]. It can best be explained by its complexity. This bleak conclusion is embellishing Figure 1, as shown in reinforced by the failure of the rational Figure 2. but evidently over simplistic approaches to extending mammalian lifespan that gerontologists have attempted over the past 50 years: it remains the case that, apart from a scattering of reports Figure 2. How the engineering (SENS) that were never reliably reproduced, approach to postponing aging relates to the two traditional approaches.

The key feature of the SENS approach is Perhaps the most obvious initial that it intervenes early enough to avoid objection to the SENS approach, and being a “losing battle” like the geriatrics certainly a common one heard from approach, but at the same time it does not biogerontologists, is that it “must” be attempt to improve the already indescribably impossibly infeasible simply because it complex and well-honed machine that is seeks to reverse age-related decline. our metabolism, but rather to clean up after The idea here is that reversing a it. In short, the SENS approach does not process is intuitively far harder than attempt to interfere in processes – neither slowing it down, and we have made the process whereby metabolism causes precious little progress (even in mice, damage, nor that by which damage causes let alone humans) in slowing aging pathology. Rather, it seeks to remove the down. There are two main errors in damage that metabolism lays down, at this logic. The first is that reversing least as fast as it is laid down, and thereby a process is only necessarily harder to prevent it from ever translating into than retarding it if one restricts oneself pathology at all. to using the same methods for The SENS approach relies on a reversal as one would for retardation frequently overlooked aspect of aging and doing them so well that the which is mentioned in the definition I gave retardation outstrips the progression. earlier: that even though metabolism In reality, there are other approaches causes damage all the time, throughout to reversing a process that do not act our whole life, damage only eventually in this “head-on” way. Consider the causes functional decline. If you live and predicament of a person in a small eat essentially as your mother told you to, rowing-boat in the centre of a large and if you are not particularly unlucky in lake, which has sprung a leak. The terms of genetics, you will probably be able person has two fundamentally different to run and think more or less as fast at the options for keeping afloat until rescue age of 40 as you could when you were 20. arrives: he can try to plug the leak, This tells us that there is a threshold level thereby retarding the rate at which of damage beyond which trouble starts but water enters, or he can bail water below which metabolism copes without over the side, counterbalancing the degradation of performance, rather as a influx. The latter process constitutes roof carries on keeping the rain out if only a a reversal of the accumulation of the couple of isolated slates are dislodged, or problem, but by a method that (unlike as a car continues to work if it has acquired forcing the water back through the just the odd patch of rust. A machine is hole!) is technologically no more only as dependable as its weakest link, of challenging than plugging the leak. course, so there may be a variety of types of The other error in the idea that damage, all of which must be kept below the reversal is inherently far harder than threshold, but that does not alter the logic. retardation is equally important. If one has few tools available, one may only

be able to plug the leak rather imperfectly, Table 1. The seven “deadly things”: types so that some water continues to enter of damage that SENS seeks to combat and one will prolong one’s survival but and the dates when they were first not indefinitely. In the case of bailing, by suggested by gerontologists to contribute contrast, a sufficient but finite rate of removal to mammalian aging. of water will suffice to keep one afloat for as long as may be required. This has especially profound implications in the longer term, as Type of age-related Suggested by, in will be explained below. damage

Cell loss, cell Brody, 1955 [7] 3. From Boats to Biology: Is the Analogy Valid? atrophy Analogies are all very well for showing Senescent/toxic Hayflick, 1965 [8] that an idea makes sense in principle, but cells what about putting it into practice? In order Oncogenic Szilard, 1959 [9]; to demonstrate that the SENS approach is truly foreseeable, it is necessary to describe nuclear mutations/ Cutler, 1982 [10] in concrete terms what the “damage” is epimutations that SENS must repair, and also to propose Mitochondrial Harman, 1972 [11] specific biotechnological approaches to that repair for each type of such damage. mutations Moreover, the proposed approaches must Intracellular Strehler, 1959 [12] embody sufficient detail to give confidence aggregates that we can get there from here in a Extracellular Alzheimer, 1907 [13] meaningfully predictable timeframe. Without further ado, then, I offer in Table aggregates 1 what I claim is an adequately complete list Extracellular Monnier and of the types of side-effect of metabolism crosslinks Cerami, 1981 [14] that can be considered to qualify as “damage” by the definition being employed The suggestion that this list is indeed in this essay – that is, changes that there adequately complete is a bold one and is is some reason to believe contribute to routinely challenged. However, there are age-related pathologies of one sort or two strong arguments for this contention. another. By “adequately complete” I mean The first concerns the dates noted in the that it includes all types of change in our right-hand column, the most recent of molecular and cellular composition that which is 1982. The analytical sophistication may contribute to tissue dysfunction in a available to biologists has advanced currently normal lifetime; I acknowledge very considerably since then, so the fact that other types of such change, such as that this list has not been extended as a nuclear mutations that do not affect the cell result constitutes a strong circumstantial cycle, may be pathogenic when we reach argument that no “eighth sin” will be ages considerably exceeding our existing discovered in the future either (except, as lifespan. noted above, in those who reach ages that

the seven problems listed above currently So far, so good: we have a prevent anyone from attaining). satisfactorily complete description of The second argument that the above is the problem. What about solutions? a complete list is perhaps more attractive Table 2 summarises the current state to the biologist: it is that the list can be of play as I see it. derived from first principles by examining our biology systematically. The starting- Table 2. Foreseeable approaches to repair or point for doing this is to note (a) that the list obviation of the seven types of damage listed is of types of damage, not of processes in Table 1. that cause that damage (which would be a much longer one – indeed, one that Type of damage Proposed repair certainly could not be confidently completed (or obviation) with current knowledge) and (b) that, by Cell loss, cell Stem cells, definition, damage can only accumulate in atrophy growth factors, long-lived structures. Intracellular proteins, exercise [15] for example, vary somewhat in half-life but Senescent/toxic Ablation of never survive for more than a small fraction cells unwanted cells of the human lifespan: thus, any deleterious [16] modifications that they suffer are eliminated when they are destroyed. With these two Oncogenic “WILT” (Whole- points in mind, we can then ask: what are nuclear body Interdiction we made of? The first-level answer is: cells mutations/ of Lengthening of and stuff between cells. Cells of a given type epimutations Telomeres) [17,18] can become more or less numerous with Mitochondrial Allotopic age: when this is deleterious we have the mutations expression of 13 first two of the seven types of aging listed proteins [19] in Table 1. Within cells there are only two Intracellular Microbial types of long-lived molecule – DNA (which aggregates hydrolases [20,21] of course is long-lived in an unusual way, because it is synthesised by replication) and Extracellular Immune- garbage, i.e. indigestible substances that aggregates mediated are sequestered indefinitely, usually in the phagocytosis [22] lysosome. That accounts for items 3, 4 and 5 Extracellular AGE-breaking in Table 1. In the extracellular space, similarly, crosslinks molecules [23] there are just two types of long-lived The first point to emphasise about molecule: complex proteinaceous structures Table 2 is that, of the seven therapies such as the lens of the eye and the artery listed, two are not strictly repair wall that can become chemically and thus strategies (reversing the accumulation physically modified over time (item 7), and of the specified type of damage) but garbage, again of different composition rather obviation strategies that make in different tissues but collectively termed the phenomenon no longer capable of amyloid (item 6). causing pathology, and thus make it

cease to classify as “damage”. These are How far away are the therapies items 3 and 4 in the list, addressing nuclear listed in Table 2? In order to answer and mitochondrial mutations respectively. that question one must ask it For nuclear mutations, the proposal is a somewhat more precisely, by treatment for cancer that does not stop cells specifying two additional things: how from accumulating the mutations that allow well the therapies must work, and in them to divide uncontrollably, but instead what organism. Here we encounter an gives them a time-bomb – telomere slightly paradoxical pair of shortening – which they cannot defuse even comparisons: initial, relatively modest by the hypermutation that makes cancers so progress will certainly occur sooner in versatile in eluding all contemporary shorter-lived mammals (specifically therapies. For mitochondrial mutations the mice) than in the relatively long-lived suggested strategy is to make such human, but longer-term and more mutations harmless by allotopic expression dramatic advances will occur in –introducing copies of the 13 protein-coding humans first – indeed, they will quite genes of the mitochondrial DNA into the probably never occur in mice. The nucleus, with modifications such that they latter will be the topic of the next will still encode the correct amino acid section; in this section we consider sequence when translated on cytosolic more modest, more near-term ribosomes and will then be targeted to and advances. imported into mitochondria by the pathway There are two main reasons why already employed by the thousand-odd the first substantial steps in extending naturally nuclear-coded mitochondrial healthy lifespan with late-onset proteins. These proteins would maintain interventions will occur in mice sooner mitochondrial function in the presence of than in humans: firstly there is the any mitochondrial mutation. biological reality that organisms with How far away are the therapies listed in longer lifespans are already avoiding Table 2? In order to answer that question aging rather well and thus are harder one must ask it somewhat more precisely, to improve by copying ideas (genes, in by specifying two additional things: how well particular) from even longer-lived the therapies must work, and in what species, and secondly there is the organism. Here we encounter an slightly sociological reason that society mostly paradoxical pair of comparisons: initial, considers the deaths of rather large relatively modest progress will certainly numbers of mice in the quest to perfect occur sooner in shorter-lived mammals a therapy to be much more acceptable (specifically mice) than in the relatively long- than the death of even one human in lived human, but longer-term and more that quest. Neither is likely to change dramatic advances will occur in humans first any time soon, so we first address the – indeed, they will quite probably never extension of mouse lifespan. occur in mice. The latter will be the topic of As noted, we must also specify a the next section; in this section we consider degree of progress that can be more modest, more near-term advances. considered an appropriate milestone.

The one that I have championed in recent tissue, will address a sufficient years, with the moniker “Robust Mouse proportion of their respective Rejuvenation” (RMR) [24], is to treble the categories of damage to deliver RMR remaining average lifespan of a cohort of (so long, of course, as the therapies for naturally long-lived mice that are already 2/3 the other five classes of damage are through their natural lifespan before any also up to scratch). intervention (whether genetic, Compensation for cell loss is also pharmacological or dietary) is begun. Long- going rather well. Many tissues that lived mouse strains typically live to three lose cells during normal aging or in the years of age on average, so this means context of disease are the subject of initiative a protocol on such mice at the age intensive research into cell of two years and giving them an average replacement using growth factors or age at death of five years. stem cell therapy, some of which has So to the timeframe for interventions. The also reached the clinic [26-28]. This last two items in Table 2 are the ones in work lags behind the two SENS strands which we are furthest advanced at present. just discussed only insofar as the In 1996, a small molecule was revealed differences between therapies for which restored elasticity of rat tail tendons to different tissues are probably more a remarkable degree [25]; subsequent work challenging, relying as they currently from the same group has demonstrated the do (at least in the case of stem cell restoration of youthful elasticity in a therapies) on rather precise ex vivo biomedically more significant tissue, the “pre-differentiation” of initially over- artery wall [23]. Likewise, in 1999, a mouse versatile stem cells that are otherwise model of Alzheimer’s disease was shown to prone to develop not only into the exhibit a dramatic reversal of the desired cell type but also into a variety accumulation of senile plaques, the main of unwanted ones. extracellular feature of the disease, in Elimination of supernumerary cells response to vaccination against their major in rodents varies greatly in difficulty constituent, the Abeta peptide [22]. Both depending on the type of cell to be these discoveries are only the start in eliminated. The simplest is visceral fat, developing comprehensive reversal of their which can be surgically removed from respective “sins”, but they are both the abdominal cavity of rats and results promising enough to have progressed in in the abrupt alleviation of previously only a few years to clinical trials. In both advanced diabetes [16]. Potentially cases the main work remaining to be done there is also the possibility of in mice is to apply the same principles to converting the cells in question to a other major types of (respectively) crosslink benign form, but no systematic method and amyloid than the ones which these to identify such an intervention is yet pioneering therapies address, but in fact it evident. There are two attractive may transpire that these initial treatments, options that do qualify as “rationally though currently restricted to one category designed”, however, both exploiting of crosslink and one amyloid-accumulating the identifiability of the problematic

cells by their excessive expression of process efficiently. An approach to this particular genes. In the first method, “suicide” problem that I introduced in 2002 [20] genes [29] are introduced by somatic gene and which has since enjoyed therapy: these typically enter cells of many increasing interest [21] is to identify cell types, but the gene is placed under the microbial enzymes that can break promoter of the excessively-expressed down such compounds (or convert gene so that it is only expressed in the cells them to ones that mammalian that one wishes to eliminate. In the second metabolism already handles). approach, the undesired cells are removed Exploration of the microbial ecology of by the immune system as a result of contaminated environments has stimulation by appropriate vaccines and proven so extraordinarily successful in adjuvants [30]. However, none of these bioremediation that there is strategies has yet reached the clinical trial widespread optimism for the stage. corresponding strategy in respect of The remaining three SENS strands may material that accumulates in the be considered the “critical path” towards environment of our bodies. However, RMR, as they are all some way from the challenges that will arise in the later implementation even in mice. Allotopic stages of implementing such a therapy expression of the mitochondrial proteins – such as the avoidance of toxicity, the from nuclear transgenes may be closer than retention of function in the mammalian it seems in vitro, as recent work gives cell and the management of any considerable confidence that the only immune response – mean that remaining requirement is to identify amino “lysosomal enhancement” is acid changes to these proteins’ realistically up to a decade away even transmembrane domains which makes them in mice. a little less hydrophobic and thus more Finally we come to nuclear readily importable by the mitochondrial mutations, and specifically those which protein import apparatus [19,31]. The promote cancer. The energy with remaining issue for RMR in regard to which cancer has been fought by the mitochondrial mutations is delivery of these biomedical research community over genes to affected cells, and the current state recent decades, especially since of somatic gene therapy in mice is such that Nixon’s initiation of the “War on this may be only moderately challenging, Cancer” in 1971, is matched only by that especially in view of the fact that introduction effort’s lack of success in coming close of these genes into mitochondrially healthy to the rate of progress predicted by cells should be harmless many leading cancer specialists at that The runner-up in the difficulty stakes for time. This sobering reality led me to RMR is probably the removal of intracellular introduce recently [17,18] a proposed aggregates. Indigestible material anti-cancer strategy, termed WILT progressively impairs cell function, not least (Whole-body Interdiction of by impairing the degradation of other Lengthening of Telomeres) that is as substances that the cell was hitherto able to ambitious as it is audacious: the use of

both ex vivo and somatic gene therapy to have therefore predicted that there is a delete the genes for telomerase and (as and 50% chance of our achieving a when they are identified) ALT (Alternative comparable advance in human life Lengthening of Telomeres) from as many of extension within 15 years after we our cells as possible. This will have achieve RMR. This human milestone, deleterious side effects that are obvious and which I rather unimaginatively term daunting: telomere shortening will irresistibly “Robust Human Rejuvenation” or RHR, eliminate the stem cell pools that maintain all is not in my formulation precisely our continually-renewing tissues, such as the proportional to RMR: rather than a blood, the gut and the skin. My proposal is trebling of the remaining lifespan of to avert these consequences by periodic people who are already 2/3 of the way replenishment of our stem cell pools with to the prevailing average age at death, new cells that also lack genes for telomere I define it as only a doubling. This elongation but have had their telomeres means roughly 25-30 years of extra extended ex vivo to normal lengths with healthy life for people who are exogenous telomerase. This is a decidedly perhaps 55 when treatment begins. tall order, and is only even worthy of Why have I chosen a relatively contemplation because it appears that the toned-down version of RMR to define frequency of such replenishment may not as RHR? Simply, because 25-30 years need to exceed once a decade in humans. is a familiar duration in the history of However, WILT is for many reasons technology, and specifically in that part exceptionally difficult to test in mice and may of the history of many technologies thus need to be developed in less which, in respect of life extension, I will convenient species. It is this, above all, that now discuss. How long does it take, makes it the hardest SENS strand to following some fundamental develop. In a sense this could be argued to technological breakthrough, for that be irrelevant to RMR, because many of the technology to progress by incremental anti-cancer therapies that have had such refinements to a stage beyond that modest success in humans actually work which the architects of the original extremely well in mice, quite possibly well breakthrough could reasonably have enough to achieve the RMR milestone. contemplated? The answer seems However, ultimately the purpose of working rather reliably to be in the 20-30 year towards RMR is to achieve the range. Lindbergh flew the Atlantic 24 corresponding advance in humans years after the Wright brothers’ first thereafter, so there is a certain inadequacy flight. Commercial jetliners first flew 22 in that line of reasoning. years after that, and supersonic airliners 20 years after that. In 4. Escape Velocity: When Humans Become computing, the personal computer Easier Than Mice arrived about 28 years after the first Once RMR is achieved, I am convinced that electronic computer and the first society’s attitude to the postponement of convenient laptops arrived about 20 human aging will become unrecognisable. I years later. In medicine, the discovery

of antibiotics followed the publicising of the discovered, too quickly for those germ theory by about 30 years and was in problems to be addressed by scientific turn followed, after another 25 years, by the advances. development of methods to manufacture What does this add up to for vaccines specific for a particular disease. lifespan? Clearly the life spans of those The implications of this pattern for the who live their entire lives in a period lives of people who are in middle age or when progress is faster than LEV will younger at the time that RHR is achieved is be indefinite, since a given individual’s clear, but no less dramatic for that. Put risk of death at any adult age will be simply, there is a very high probability that less than at earlier adult ages. What is the 25-30 years of good health conferred less immediately clear is how to on its recipients by the first-generation panel estimate the life spans of those already of rejuvenation therapies (defined as those alive (and at various ages) at the time which achieve RHR) will suffice for the RHR arrives. My estimates are depicted development of much more thorough and (for actual numbers are too speculative comprehensive therapies, capable of to estimate) in Figure 3. To summarise: I delivering more like a century of extra life to estimate that 50-year-olds who are in those who are in relatively good health at average health at the arrival of RHR the time those therapies arrive. This is where and who are, thereafter, able to benefit the longevity escape velocity (LEV) concept from the latest and best rejuvenation [24] arises. The recipients of the first- therapies, will have at least a 50/50 generation therapies – the ones that gave chance of reaching their own personal only around 30 years of extra healthy life – escape velocity – that is, of being will, at least if sociopolitical pressures do not restored to a truly youthful state with a intervene, mostly also be among the very low mortality risk. Most of those beneficiaries of the second-generation who are only 30 at that time will never ones, since they will be in the same degree reach a state of age-related frailty. of health at that time as they were when the Moreover, elite individuals – those who first-generation therapies arrived. The same would naturally live to 100 or more logic of course applies indefinitely into the even in the absence of these therapies future, just so long as the rate of progress in – will have that 50/50 chance even if improving the comprehensiveness of the they are already in their 70’s when RHR therapies continues to outstrip the rate at arrives. A key corollary of the above which the remaining imperfections in those considerations is that there will be a therapies allow the accumulation of stunningly sharp “cusp” in the increase eventually pathogenic damage. It should in life spans of those born in now be clear why the correspondingly successive years. One way to quantify dramatic extension of mouse lifespan may in this is that the first 1000-year-old is fact be much harder than for humans probably only about ten years younger (indeed, maybe impossible) – since mice than the first 150-year-old. Another, age so fast, new age-related problems will possibly of more relevance to those kill mice rather soon after they are who do not consider themselves

nothing can be done about aging and thus do not agitate for efforts to hasten progress, and that will only change if their sights are raised [33]. Accordingly, I have no compunction in setting out (here and elsewhere) a scenario that, after much consideration, I consider the most likely way in which, and rate Figure 3. Plausible trajectories of “biological age” for at which, we will move to a post-aging typical individuals of the specified ages at the time RHR arrives, presuming access to the best therapies world. at any time. References inherently likely to live exceptionally long, is [1] A. Fire A et al., Potent and specific that a whole generation will be, in the words genetic interference by double- of the Australian writer Damian Broderick stranded RNA in Caenorhabditis [32], the “last mortal generation” – a cohort who live roughly as long as those born in elegans, Nature 391 (1998) 806-811. 1900, but whose offspring mostly live [2] A.D.N.J. de Grey, The unfortunate indefinitely and die only of causes unrelated influence of the weather on the rate to age. The sociopolitical implications are of aging: why human caloric restriction highly unpredictable but it seems or its emulation may only extend life inescapable that they will be unprecedentedly profound. expectancy by 2-3 years, Gerontology 51 (2005) 73-82. 5. Conclusion: We know not what the future [3] K.T. Coshigano et al., Deletion, but brings, but we must hasten it anyway. not antagonism, of the mouse growth I have attempted in this essay to outline the hormone receptor results in severely methods by which humanity will in due course defeat its greatest remaining decreased body weights, insulin, and scourge. Much of what I have written is insulin-like growth factor I levels and plainly speculative in the extreme, yet I have increased life span, Endocrinology 144 stuck my neck out and given estimates of (2003) 3799-3810. timeframes, with probabilities attached to [4] M. Holzenberger et al., IGF- them. Some feel that speculations of this sort are irresponsible, engendering unwarranted 1 receptor regulates lifespan and optimism about the rate of progress. I take resistance to oxidative stress in mice, the diametrically opposite view: I am Nature 421 (2003) 182-187. convinced that it is irresponsible to remain [5] A.D.N.J. de Grey et al., Time to talk silent on such matters, because doing so SENS: critiquing the immutability of engenders unwarranted pessimism: the public are predisposed to presume that human aging, Annals of the New York

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Renata G. Chapter 6: Defining Future of Health Poland. Through my experiences with Bushko/ Defining Future of Health Technology these healthcare programs I realized Technology in Renata G. Bushko, M.S. that we needed to spend more time “World Health Strategy” eBook, Founder, Future of Health Technology on long-term planning. We needed (Ed.) Renata Institute, Hopkinton, MA, US an independent agency to discuss G. Bushko, FHTI, 2016. and oversee long-term issues of Futureofhealth. Abstract health technology. This agency would org From Future of Health (Ed.) uture progress in healthcare and prepare for a future society where Renata G. medicine depends on today's computers might outsmart people, Bushko, IOS Press 2002 Finvestment in research, development, where we might be able to stop and education. We cannot leave such diseases before they begin, where urgent issues to determine themselves, Affective Intelligent Caring Creatures but rather must actively collaborate to [3] will aid physicians in 90% of their ensure a stable healthcare system. This work and individuals can diagnose and chapter describes efforts made by cure themselves with self-health tools leading experts in industry, government, and designer drugs. Such an agency and academia to better ascertain future would prepare the medical community healthcare management. Such collaboration and consumers for inevitable has occurred during a series of Future technological changes and advances. Healthcare Technology Summits [1] helping in planning investments in health technology. 2. Agency To Look At Long-Term Deliberating and reviewing plans before Issues Of Health Technology taking action will accelerate progress as it The Future of Health Technology will (1) save costs, (2) encourage compliance, Institute (FHTI) was founded in 1996 (3) improve clinical outcomes, and (4) to address the long-term issues of ensure greater patient satisfaction [2]. What health technology [4]. FHTI is a think- we must resolve is: How can we invest tank aimed at defining an agenda for a couple billion dollars to save hundreds health technology development and of billions and, most importantly, increase determining the most critical focus human health in the future. A new branch areas for health technology investment of science, Biomechatronics, with millions of in the new century. Founded on the Intelligent Caring Creatures– is the answer. 40th anniversary of the field of Artificial Intelligence, FHTI found inspiration 1. Introduction in the intellectual legacy of Professor In early 1990’s I worked on national Marvin Minsky. He is one of the healthcare programs organized by Vice founders of Artificial Intelligence and President Gore, Dr. C. Everett Koop, and one of the most creative minds of our former secretary of Health and Human times. I became his student in 1985 Services Dr. Louis Sullivan. I advised on when he was working on the Society health technology investment issues in US, of Mind theory. UK, Puerto Rico, Australia, New Zealand, and

Since its foundation in 1996, FHTI has How can we use this successful been doing what Professor Dertouzos example to address emerging describes as: complexities that lie ahead? The "Put in a salad bowl the wildest, most world has changed in forty years since forward-thinking technological ideas that you Marvin Minsky, John McCarthy, Allen can imagine. Then add your best sense of Newell, Herbert Simon and other what will be useful to people. Start mixing inquisitive minds met to design the the salad. Something will pop up that begins field of Artificial Intelligence. In the to qualify on both counts" [5]. Professor same forty years the world of biology Dertouzos suggests that we should then and medicine faced equally radical "Grab it and run with it," which agrees with changes. FHTI summits address the paradigm that the best way to define the achievements of the last forty years in future is to invent it. both medicine and medicine, trying to Unfortunately this optimistic model map out how those fields might come leaves a lot to random chance. The salad- closer and merge in the future. bowl approach is a good start, but each With the development of new idea should be attributed impact value and technological innovations, people compared against alternative ideas. The naturally fear that increased costs are ideas rely on both technological novelty inevitable. FHTI, however, believes and human usefulness. The process that increased expenses can be of comparing various ideas can be an stopped or even reversed. For efficient way to save time and money. FHTI example, while computer technology proposes to manage the coordination of the continues to expand, computer costs most promising ideas in health technology have decreased exponentially. Why using top-level experts from the industry, should technological improvements government and academia during Future in healthcare not follow the same of Health Technology Summits 1996-2001 progression? How can we take [1]. The most investment-productive health advantage of new technologies technology areas are presented in this to improve the quality of life and chapter (Tables 2-9). simultaneously reduce procedure and treatment costs? Perhaps it is a matter 3. Background: Thinking Model from the of vision and leadership. Field of Artificial Intelligence In 1956 a diverse group of scientists Specific goals of the Future of Health consolidated various studies into a new Technology Institute are: field of science: Artificial Intelligence. They aimed to discover the unknown and 1.Develop a vision of future health mysterious machinery of the mind. Future of care supported by current and future Health Technology Institute considers their efforts a model of leadership and innovation, health technologies. representing skills essential in facing the problems of the 21st century.

2. Define distinct promising health problem itself”. [6] “A problem is hard if technology research areas. it requires common sense knowledge in addition to specialized knowledge 3. Demonstrate that technology driven and a set of non-obvious to the non- cost increases in healthcare can be expert heuristics in order to be solved stopped and possibly reversed by a new effectively and accurately. A body of allocation of research and development knowledge required to solve a hard resources. problem is not algorithmical but it is not totally intuitional either” [7]. A difficult 4.Define productive areas for research (hard) problem manifests itself by the and development that will have potential following facts: impact on healthcare. (1)There exist experts that can solve 5.Identify new technologies that are that problem better (significantly practical faster, with better accuracy) than an and necessary in health and wellness average human maintenance. (2)Providing solution involves some 6.Identify research and development symbolic reasoning and some needed to meet future health challenges. common sense reasoning that is perceived as intuition 7.Identify current products best for preparing 21st century healthcare. (3)Training humans to solve this kind of problem is a long-lasting, difficult, 4. Health Challenges – Need for Common and not always successful process Sense (4)Even single experts accuracy 4.1 Dare to Guess – Dealing with Hard leaves some space for improvement Problems Defining the future of health technology Hard problems require making is difficult and requires both common educated guesses and then sense and intuition. “Common sense is an verifying that hypothesis. We do immense society of hard earned practical not know the algorithm generating ideas – of multitudes of life-learned the solution but we can verify the rules and exceptions, dispositions and positive solution once a guess tendencies, balances and checks.”[6] These is provided [7]. The best way to balances and checks are especially useful make some progress in defining when performing estimation tasks, where the future of health technology is we deal with incomplete information. “For a to work with a group of experts in hard problem, it may be almost as difficult related fields and also reach out to to recognize progress as to solve the other industries to transfer relevant

knowledge and know-how (e.g. hotel 15 Effective Knowledge management industry’s customer satisfaction model at 16 Providing relevant health information to the FHT99) [7, 8]. people who most need it 4.2 Define Health Challenges 17 Creating happy environment for being sick The first step is to define challenges 18 Emotional aspects of getting over ahead of us. A group of experts was healthcare problem and death asked to define health challenges of the 19 Assuring medical data integration 21st. Century using survey method. The 20 Improving healthcare workflow results are listed in Table 1. Experts were 21 Patient-omic data management and energized and inspired to action by the analysis (patient genomic, proteomics, approaching Future of Health Technology physiomics) and patient cross-comparisons Summit. 22 Expanding use of body-pervasive monitoring devices

Table 1. Health challenges of the 23 Personalized drug design new century. Order does not reflect 24 Improved gene repair importance. 25 Providing high quality health care services to all people, regardless of where they reside, what their socioeconomic status is, 1 Poverty or what their cultural characteristics is 2 Hunger 26 Reducing healthcare disparity 3 Escalating costs of drugs 27 Maintaining high levels of health services (with tight budgets) 4 Escalating costs of technology 28 Inter-disciplinary issues related to the 5 Engaging people to be responsible for human element, not technology their health and their family's health 29 Aging population explosion 6 Empowering consumers with better information and self help tools 30 Healthcare access, especially preventive care, for the large number of the uninsured 7 Expanding & improving access to quality services including advanced diagnostic/ 31 Shortage of nurses therapeutic technologies while maintaining 32 Appropriate selection and use of or reducing costs healthcare resources by clients, self- 8 Improving medical informatics literacy care, and healthy habits through the among medical staff dissemination of quality health information 9 Reengineering the medical visit 33 Establishing cost-conscious evidence- based practice 10 Establishing Internet electronic medical record 34 Stop rising cost of healthcare 11 Better monitoring and treatment of 35 Increasing expenses and demand for chronically ill patients away from the services with decreasing reimbursement hospital 36 Eliminating medical errors (estimated 12 Finding cure for cancer and heart disease 40,000-98,000 inpatient deaths annually in US1) 13 Finding cure for paralysis 37 Extending human lifespan 14 Coordination of services, transfer of information between providers and 1 Institute of Medicine report released on November 29, provider /patients 1999

4.3 Most Promising Health Technologies – 4.4 Most Promising Health Brainstorming Method Technologies – Survey Method Seven technology areas listed in Table In order to approximate seven most 3 were selected as most promising promising health technology areas, the using the survey method. None of list of most promising health technologies these lists or any other lists should be generated by the before-summit survey, was taken as the only lead to follow. They presented to experts for prioritization. Then, are only useful to attune our common seven most promising areas were selected sense and to turn into the right during the brainstorming session. Results direction in the specific technology are presented in Table 2. investment process.

Table 2. Seven most promising health Table 3. Seven most promising health technology areas. Brainstorming method. technology areas selected by experts. Summarized by Dr. Gary Kreps [9]. Survey method.

1 Instant Medical Data Collection 1 (A) Tissue Bioengineering & (B) and Knowledge Dissemination Nanotherapeutic Technologies Technologies and Standards 2 Knowledge Management 2 Decision Making and Support Technologies (including decision Technology (personal and point of support and data mining) care) 3 Electronic Health Record in a Standard Format with Unique 3 Individualized Diagnosis and Patient Identifier Treatment (e.g. real time protein 4 (A) Powerful yet easy to use Self- synthesis, real time genetic diagnostic Technologies & (B) testing) Vaccine Biology 4 Health Systems Methodologies 5 Affordable information system 5 High Tech Intervention (e.g. access with decision support for Robotic Surgery, Sensors, healthcare professional Teleconsultations) 6 Internet-driven Technologies 6 Information Access and Feedback 7 Voice Recognition, (B) Technologies Psychological Aids & 7 New Technologies Evaluation (C) Artificial Intelligence & (D) Controlled Medical Vocabularies Methodologies

4.5 Seven Health Technology Areas with the lists obtained from survey and Highest ROI brainstorming method but all experts As the last step, experts were asked to involved in prioritization heard a prioritize technologies given that “most detailed explanation of Professor promising” meant technology producing the Pentland’s selection just before their highest impact with the lowest investment brainstorming session. (technologies with highest return on investment - ROI). ROI was evaluated Table 5. Seven most promising health intuitively based on the diverse knowledge technology research areas as defined of the experts involved. FHTI’s graphical by Professor Alice Pentland. Common Sense Squares Method was used 1 Memory Assistance Aids in the ranking process. 2 Tissue Bioengineering and Gene Therapy Table 4. Seven health technology areas 3 Perceptual Prostheses with the highest return on investment. Survey method and FHTI’s ”Common Sense 4 Vaccine Biology Squares Method” method. 5 Rapid Diagnosis 6 3D Mapping 1 Internet-driven Technologies 7 Psychological Aids 2 Electronic Health Record in a Standard Format with Unique 5. Rapid and Cost-effective Patient Identifier Technology Impact Assessment 3 Psychological Aids Technology impact study is an important next step after selection of 4 Vaccine Biology most promising health technologies. 5 Powerful yet easy to use Self- An example of a cost-effective impact diagnostic Technologies study is presented in the chapter 6 Intelligent Agents (Intelligent “Impact of Voice and Knowledge- Caring Creatures) enabled Clinical Reporting – US 7 Affordable information system Example“ in this book. It uses Unified access with decision support for Quality Framework [2, 11, 12] that healthcare professional & patient helps to examine technology impact on quality of healthcare using four 4. 6 Most Promising Health Technology qualitative and quantitative dimensions: Research Areas - Insight To balance group thinking (Table 3 and 4) 1)Process Quality as measured by FHTI asked one of the leading thinkers, cost Professor Alice Pentland, to propose a separate list of seven most promising 2)Organizational Quality as health technology research areas [10]. This measured by compliance list was generated independently from

3)Clinical Quality as measured by clinical Figure 1. National quality cube in the outcomes Unified Quality Framework. Example of a component of the Unified Quality 4)Service Quality as measured by patient Framework. Top corners illustrate and staff satisfaction types of quality and bottom corners show the measure of quality. It is important that we try to maximize the use of Unified Quality Framework and FHTI’s 6. Important Challenges and common sense methodology to evaluate Technologies in Genetics and quality impact of various technologies. Bioengineering The goal is to generate studies that are Because of the importance of genetic not expensive and comparable with engineering, a survey regarding each other. We could learn a lot faster if most important health challenges health technology assessment studies, and technologies was conducted performed by 160 different nations were on a focused group of experts with easily comparable. We would be much genetics background. The results are closer to the goal of making the process of listed in Table 6 and Table 7. Table investment in new technologies less of a 8 shows a list of most promising random chance. Then one might say – let’s bioengineering areas as defined by leave it all to the market forces. May be it the American Medical Association for would be a good idea? But then, let’s ask comparison [13]. ourselves what would have happen if we invested in nanotechnology 20 years ago Table 6. Health challenges in the when Dr. Eric Drexler and others uncovered beginning of the new millennium. its potential. How many lives and how much Survey method used on experts with human suffering could we spear? Maybe background in genetics. cancer would be a history by now. 1 Understanding the genetics of complex traits 2 Curing and preventing disease onset 3 Preventing healthcare and insurance discrimination 4 Delivering mental health focused care (major consumer of healthcare in 2010) 5 Shifting paradigm from reactive to proactive

6 Constraining technology lacking 24 Predictive therapeutic sufficient positive predictive technologies value for treatment/diagnosis 25 True connectivity for medical 7 Food delivery professionals and consumers 8 Preventing cost increase in 26 Antibiotic-resistant national healthcare systems microorganisms 9 Working out disease pathways 27 Auto-immune diseases 10 Development of disease 28 Allergic variations in CYT-P4O phenotype (different individuals respond 11 Establishing interaction of differently to the same drug) environment and genetics as 29 Protein folding – function causes of cancer, diabetes and heart diseases Table 7. Technologies that can meet 12 Individualized medicine health challenges listed in Table 6. 13 Lifestyle awareness Order does not reflect importance

14 Wider variety and less expensive drugs 1 Genetic mapping: Genome-wide SNP association studies 15 Understanding complex molecular networks involved in 2 Diagnostic SNP chips human diseases 3 Gene Therapy 16 Extending medical advances to 4 New antigen delivery systems developing countries (molecular biology of peptide 17 Global minimum standards for expression on cell surfaces) health 5 Genome analysis/Genomics 18 Conquering bacterial resistance 6 Structural genomics towards antibiotics 7 Cost-effectiveness analysis 19 Developing cost-effective cures technology for TB, Malaria, AIDS 8 Bioinformatics 20 Deconvolution of clinical 9 Structural biology and drug disease in terms of genes and design function 10 Pharmacogenomics 21 Developing of therapeutics 11 Gene/Protein chips through knowledge of genes 12 Genomic profiling and proteins involved 13 Accurate annotation of genes 22 Personalized genetic diagnosis and prediction of functions and treatment 23 Predictive diagnostic It is also important to keep track of advances in biomedical engineering, especially in the technologies seven areas listed in Table 8.

Table 8. Important areas of biomedical Haptics engineering; Order does not reflect II Machine Intelligence importance Processing Requests 1 Molecular Engineering Data Mining 2 Cell Engineering Common Sense Reasoning 3 Tissue Engineering Reasoning by Analogy 4 BioMEMS and Microfluidics Flexible Transistors (e.g. on plastic) 5 Virtual Surgery and Nanoinstrumentation Responding to Requests Organic Light Emitting Displays (data 6 Imaging glasses, e-paper, smart windows) 7 Bioinformatics Speech Generation 7. Technology Areas Important for All Affective Computing (emotional Sectors of Economy Including Healthcare communication) We should never treat healthcare as a Visualization of Data separate island, isolated from other parts of Automatic Summarization / the economy. Thus, it is important to keep Abstracting track of technologies that will change entire Triggering Action economy. Emerging Technology Areas that Decision Triggers will soon have a profound impact on the Biomechatronic Interfaces (to cells entire economy including healthcare sector and biomechanical devices) are listed in Table 9. Electronic Skin (e.g. triggering Table 9. Emerging technology areas that payment transaction on the way out will soon have a profound impact on the of supermarket with no cashiers) entire economy including healthcare sector. III Preservation of Individuality and Order does not reflect importance. Security I Human-Machine Interaction - Digital Rights Management Requesting Things from Machines Biometrics (Face, Voice, DNA, finger Hybrid Brain-Machine Interfaces print, behavioral pattern recognition) (HBMI) – Thought to Computer Biometronics Ethics and Law Communication IV Human-Machine Global Network Natural Language Processing Microphotonics (all optical Internet Automatic Voice Recognition with super high bandwidth) Mobile, wireless, wearable, and High-temperature Superconductivity textile computing (inexpensive power quality devices Computer Implants (connected to SMES2) tagged smart environment) Infinite High-density Data Storage 2Superconducting Magnetic Energy Storage

Restructuring Code (Software computer weighted 30 tons and had Engineering) less computing power than a digital watch; In 2010 one computer could V Intelligent Creatures have the same power as all computers Mobile Mechanical Machines on earth in 1999 and it will be printed Nanorobots (Microfluidics) on plastic with flexible organic light Humanoids (Cyborgs) emitting display so we can roll it like Machine Vision a piece of old-fashioned paper. It Machine Learning will be small enough to work inside our bodies powered by molecular Robot Design chemical reactions (E.g., ATP) or on our VI Sources of Energy bodies as sensors powered by our Body-heat Batteries body-heat. In 2020 computers will be Chemical Molecular Energy (e.g. ATP) smarter than people and we’ll have a Earth tides (Geothermal Energy) choice to augment ourselves to extend Solar Energy our cognition or not. By 2050 most of us will become cyborgs with implanted Superconductive Generators computers that extend our cognitive powers and give us extra senses (e.g., 8. Defining the Future by Vision ultrasonic sense). Statements, Insights and Scenarios

Another way to uncover the future is to 8.1.2 Light-Flexibility Perspective – envision it and create scenarios. Most of From 1880 to 2006 chapter authors whom I invited to focus Electric light, one of the most visible on specific issues in this book did just that inventions of the 20th Century, was brilliantly. The most convincing vision will first featured on a steam ship Columbia have an impact on decision makers and that traveled from port to port, making thus on resource allocation decisions today. headlines by showing the light of Selection of topics covered in the book is a 150 light bulbs produced by four result of five years of research by the Future generators. The new Millennium has of Health Technology Institute to define started with a similar story: In May health technology agenda for the new 2000, Quinn Mary in Long Beach century. California became the showing place for what will become one of the most 8.1 Integrative Vision from Future of visible technologies of the 21st Century Health Technology Summits – technology that will allow flexible,

paper-thin, bendable computer and 8.1.1 Weight-Power Perspective - From video displays. Future of Health 1946 to 2050 Technology Institute’s Cruise to the In 1946 – ENIAK – the first electronic Future™ planned for the year 2006 will continue Columbia’s and Quinn

Mary’s tradition with specific focus on health (facts and relationships). Machines technologies. involved will be both software agents Organic light emitting diodes combined (ICCs) and robots. Intelligent Health with polymer transistors will evolve into Environment will utilize biosensors electronic paper, personalized hardware and machine learning techniques. that one can print at home, personalized With time it will lead to the Affective disposable computers woven into textiles, Intelligent Caring System embracing wallpaper that is also a control center of other aspects of our lives like a hospital or electronic skin that is able childcare, homes, relationships, to respond mechanically to changing finance, shopping, work and pleasure conditions. This means that making activities. healthcare paperless does not make sense anymore and that there is hope for rapid 8.1.5 From Knowledge Management computerization of medicine because to Self-Health Tools the biggest obstacle to computerization Intelligent Health Environment will – computer itself (the way it looks in early involve wearable, wireless and 2001) – will change dramatically. implantable self-health tools based on personal genomic information and 8.1.3 From Electronic Care to Smart Care linked to tags and geographic We should reformulate “electronic health positioning system for ongoing record” goal in order to make faster monitoring of people’s vital signs and progress in technology introduction to location. Fast progress in healthcare. Framing this problem as microphotonics leading to all optical “electronic patient record” suggests that the Internet with huge bandwidth will allow only thing that we are striving for is moving real time video links to every home, information about patient and care from school and workplace making paper to electronic format. This is not our telemedicine and telepresence a primary goal. We do not want electronic common place. care – we want smarter and more sensitive care (high tech combined with high touch). 8.1.6 From Doctor, Nurse and Pharmacists to Affective Intelligent 8.1.4 From Electronic Health Record to Caring Creature Intelligent Health Environment In an Intelligent Health Environment We should use a term:“Intelligent Health each person will have a personal Environment” instead of “Electronic Health distributed Affective Intelligent Caring Record” to embrace the generative aspect Creature (ICC) – a hybrid physician/ of modern computer technology. Health nurse/pharmacist that processes all the record in an Intelligent Health Environment data from biosensors, genomic data will also include not only a mere record sources, medical science and other of human interactions and health metrics ICCs. Affective Intelligent Caring but also machine-generated knowledge Creature has many helpers embedded

in our homes and also in our bodies, year 2070 we will have direct brain- showers, cars, beds, toothbrushes, and surgical-tools interface where surgeon kitchen counters. ICCs use Inter-ICC operates using her/his thoughts not language that allows them to communicate hands. Thought operated surgical effectively, interlink facts and predict equipment will be as common as emergency situations that will reduce to the thought operated cars for disabled minimum need to have emergency rooms (eventually we will all want to use as they are today. them). Some helpers are embedded in robots We will not use surgery bubble a lot equipped with computer vision and natural though because nanorobots will do language understanding for remote most of the surgical jobs for us – presence. For example, your ICC starting before our birth. Chromosome embedded in a robot may go through the replacement and nanocytosurgery will house of your elderly mother to check on save us from surgeries that are her when you are away. Since you can currently necessary. Nanorobots will navigate the robot through the Internet you voyage through our bodies to repair will be able to see her and talk to her. damage, treat tumors, attack viruses, Yet, another ICC may specialize in repair cell walls, deliver drugs, and monitoring products on international markets remove blockages. The first that may have impact on your health and nanotweezers and rotating, chemically well-being. This ICC – health purchasing powered nanomotors were agent – may suggest that you buy a car that successfully built in 1999. The year uses video cameras to eliminate the blind 2000 brought the first molecular spot and that automatically adjusts car seat switches – a great step towards for your 5-year old child, when the car turns nanocomputers. into an airplane. It may then call your financial ICC to prepare savings strategy to 8.1.8 From Pharmaceutical Lab to buy that “healthy car” resulting in the Cellular Drug Invention and cancellation of your virtual trip to Mars in Distribution 2058. By 2020 personalized drug design and production in Intelligent Caring 8.1.7 From Robotic Surgery to Nanosurgery Centers will be a common place. We will also have private tele-surgery Mergers between pharmaceutical bubble as a mobile attachment to our companies, health information systems homes and cars. Intelligent Caring Creature vendors, and providers will be long will schedule surgery for us with the surgeon forgotten by then. or a surgical robot most experienced with By 2050 we will have our particular condition. Telesurgeon will nanopharmacies – tiny cellular see the operating field through virtual retinal pharmacies that produce a drug, store display goggles. With rapid progress in it, and release it when needed inside hybrid-brain-machine interfaces (HBMI) in the our bodies. They will replace drug

prescriptions, lengthy lab design, clinical telehealth tool at any time since Dr. trials and eventually mixing procedures. Zuzu understands 105 human Drugs produced by nanopharmacies and languages and 1005 machine designed by Intelligent Caring Creatures will languages. Another communication be personalized to a single individual option will be hybrid brain-machine avoiding any adverse reactions and interface allowing a patient to send a delivered directly to locations in our bodies request to Dr, Zuzu just by thinking that need them. As a new form of about requesting an extraordinary entertainment we’ll watch on VRDs how pleasant virtual experience such as cancer cells are eliminated because petting a rabbit on the skyglide to nonorobots will have tiny video transmitters. ULURU, or getting rid of terrible nightmares about spiders. 8.2 Closer Look at the Doctor of the It is important to note that Dr. Zuzu Future – Affective Intelligent Caring will be prepared to respond to many Creature requests related to maximizing joy and In 2057 your personal pharmacists/nurse/ pleasures of life not reducing pain physician - Dr. Zuzu - will not be a human but because most of the diseases were an ICC, a distributed Intelligent Caring eliminated and probability of the rest of Creature, with the knowledge of 1000 best them was minimized in the neonatal physicians, pharmacists, and nurses from phase through chromosome different specialties, traditional medicine replacement. Effective preventors from 50 cultures and an office in the (stress reducers) helping ICCs also Cyberspace. contributed to low-sickness levels. All Dr. Zuzu’s patients will be equipped Dr. Zuzu will always listen to all its with computers in their homes and cars in patients (no limit on amount) and will the form of data glasses, windows, mirrors process their vital signs and test and e-wallpaper. In addition, they will have results, relating all the findings and on-body sensors and nanocomputers inside looking for unusual patterns. Dr. Zuzu their bodies allowing continuous screening, will be able to warn patients about monitoring and data collection about their incoming health problem (e.g., pain) physical and emotional state (e.g. EKG, GSR). using its case-based and memory- They will also have bathroom MRI machines, based predictive engine: for example, shower skin mole detectors, toothbrush it could warn you “Please, call your protein analyzers, smart beds monitoring surgery robots before leaving for work, sleep pattern, and sensors equivalent to a to remove a splinter that will cause hospital pathology lab, checking daily basic pain in 3 hour and 15 min – just when lab results. you have to change plains in Denver, Their on and in-body sensors will be able Colorado.” to report pain or any unusual physical or Dr. Zuzu’s will have a rich library of emotional state directly to Dr. Zuzu. They health stories extracted from life-long could also do it via a voice-enabled medical data. These stories will be

parsed and represented in the knowledge environment when you are ill. It will base for further retrieval and then turned have millions of stories of other people into video scripts out of which context- going through a given condition specific educational health movies will be including: assembled for other patients in need. To facilitate ease of patient-physician () Encoded mental states communication, Dr. Zuzu will have multiple personalities, sex, age, voice and cognitive () Most common thoughts they style depending on the situation and the thought and patient. This includes the ability to become a humanoid version of the best friend from () Activities and words that helped high school in order to maximize its them to make it through the rough convincing power and emotional closeness. experience. This way Dr. Zuzu will be able to relate well to emotional states of its young and elderly Dr. Zuzu’s collective common sense patients in a close and friendly manner. knowledge will allow it to always say What if Dr. Zuzu gets sick itself? Dr. Zuzu the right thing or to produce a right will use self-treatment through knowledge virtual companion, that you can interact injections. Another option is to call on other with through direct retinal projection, in Intelligent Caring Creatures and get a byte difficult cases. of support. Most of the time Dr. Zuzu is in Dr. Zuzu will charge its patients perfect shape – never tired like its human per knowledge injection and per predesesors, never competitive or jealous, successful interaction that will be never anxious or annoyed. automatically recorded based on Based on the genetic profile of each your positive response recorded patient Dr. Zuzu will develop a long-term in your data stream. The payment educational and care plan based on will be expected also in the form personalized interactive movies, illustrating of knowledge – your permission to major behavioral points that should be use your data to further improve Dr. reinforced to maximize life’s capacity, length, Zuzu’s common sense and medical and pleasure. Dr. Zuzu’s ability to annotate knowledge. This way your personal and retrieve from image and video libraries ICC will revitalize its curing and allows a just-in-time health education or educational ability. compliance program. Dr. Zuzu will also be able to prescribe and then develop (in its virtual R&D lab) personalized drugs just for its patient. Dr. Zuzu will help its patients not only to maintain good health but also deal with bad health in a compassionate and emotional way. With Dr. Zuzu you will have a happy

8.3 The Integrating Power of Insight – is generated by an observer, relative Biomechatronics to his point of view, in the process of Future of Health Technology Summit thinking making sense (modeling)” [15]. It is sessions generate knowledge waves the same with knowledge in health present long after the event. 6th Summit, technology – it should be an adaptive, FHT2001, confirmed that an unprecedented dynamic process not a one-time revolution is taking place: molecular biology, event or publication. Current rate of computer and medical science, electrical, innovation and product creation makes mechanical, genetic and biomedical the process of defining what to invest engineering, are merging into one field best in similar to seating on a raft on a fast, described as Biomechatronics. infinite, mountain river trying to decide To make progress we need to have not where to stop. “Knowledge about only manageable models of the future but [healthcare] cannot be captured in a also of the science and technology behind finite structure” [14] – it has to be an it. Biomechatronics brings together tissue ongoing dialog. Results of that dialog engineering, robot design, information could be used by decision makers technologies, knowledge management, in different situations and different pharmacogenomics, biometrics, places on earth as hints and general nanotechnology, and bioinformatics. direction in their own problem solving One reason that back in 1996 I focused processes. on health technology in the era of booming More than forty years of research healthcare informatics was an observation on learning, problem solving, and that health-related information comes from intelligence conducted by the field of and is embedded in biological, electronic Artificial Intelligence brings hope of and mechanical artifacts – it is an integral making that process more effective. part of Biomechatronics not an independent Realizing that information becomes island. On-going symbolic reasoning on knowledge when it starts guiding health data and tools helping humans or decision making, makes it even cyborgs to make sense out of the multi- more obvious that defining future of layered biomedical, organizational and health technology involves on-going, mechanical processes is an important adaptive dynamic learning by industry, goal. Creating meaning out of petabytes governments and academia. of personal information requires the same Seven Strategies to Leadership [2] common sense capabilities as generating based on forty years of knowledge smart medical advice. science provide a guiding structure.

9. Defining the Future of Health 1. Sustained Renewal & Growth Technology as a Dynamic Learning Treat Sustained Growth as a final Process goal;You do not want to be successful According to Allan Newell, knowledge can only once - only be created dynamically in time [14]. “It you want to be continuously successful

2. Situated Adaptability the future is an ongoing effort to point Change your organization in a specific in the right direction. According to situation and problem solving context; 21st opinions gathered at Future of Health Century requires ongoing situated Technology Summits (1) Instant Medical adaptability Data Collection and Knowledge Dissemination Technologies, (2) Tissue 3. Sociotechnological Responsibility Bioengineering & Nanotherapeutic Learn and use new technologies and do not Technologies, (3) Internet-driven delegate it to others - “I am non- Technologies and (4) Brain-Machine technical” syndrome; Think about your goal Interfaces are the key investment in a context of sociotechnological areas for the next 10 –20 years. process; technology and organizations Unprecedented technological cannot be separated revolution manifests itself in convergence of molecular biology, 4. Strategic Repositioning computer and medical science, Look outside your organization and ahead electrical, mechanical, genetic and in time; Use Unified Quality Framework biomedical engineering (including cell, molecular and tissue engineering) 5. Simplification into biomechatronics. It will play an Avoid bureaucracy and look for integrative role in the future of health unconventional shortcuts technology accelerating the speed of discoveries leading to dramatic cost 6. Self-Reinventing reduction. It is necessary to maintain Keep learning and developing leadership an ongoing watch of new technologies and innovation skills and revisit the issue of resource allocation periodically with different 7. Strength, Savings, Satisfaction groups of experts. We have a unique Spend time absorbing results of work; Bring chance to define the future not to back child-like joy and celebration spirit observe it; to say what should happen instead of saying what will happen if 10. Conclusions we do not change anything. Future progress in healthcare and medicine depends on the investments in research, development and education made today. Defining most promising health technology areas by the group of experts from industry, government and academia may help in planning investments in health technology. The answer to the question of how to invest a couple of billion dollars to save hundreds of billions and increase human health in

References [11]G. Edwards, R. Bushko; Business [1]Future of Health Technology Summits 1996- Modeling Tools for Decision Support 2000, www.fhti.org Systems (Quality Impact on Hospitals), [2]R.G. Bushko, Leadership Challenges in Proceedings of the 8th International the 21st Century: 7 Strategies to Leadership, Medical Informatics Congress, in Robert Workshop P-6, Healthcare Executiveâ€™s Greenes (Ed.); Challenges in the 21st Century: Leadership, 7/1995, Vancouver, Canada. Quality, Technology, and Innovation-driven [12]R. G. Bushko, Poland: Socio- Process Management, IMIAâ€™95, Vancouver technological Transformation â€“ its Canada, 1995. Impact on Organizational, Process, [3]R. G. Bushko, Doctorâ€™s Office of the Clinical and Service Quality of Health Future, presentation at the Future of Health Care. In: W. Wieners (Ed.), Global Technology Summit 1998, Cambridge, MA. Healthcare Markets. [4]R. G. Bushko, From Artificial Intelligence to Jossey-Bass Publishers, John Wiley & Intelligent Healthcare; Position paper for the Sons, Inc. 2000, pp. 194-201. initiation of the Future of Health Technology [13]L. G. Griffith, A.J. Grodzinsky, Summit series, Future of Health Technology Advances in Biomedical Engineering, Institute, internal document, 1996. JAMA, Vol. 285 No. 5, 2001, p 556-561 [5]M. Dretouzos, Kurzweil vs. Dretouzos, [14]A. Newell, The Knowledge Level, Technology Review Vol. 104/NO. 1 (2001) 81-84. Artificial Intelligence 18, 87-127, 182. [6]M. L. Minsky, The Society of Mind, Simon [15]W. Clancey, The Knowledge Level and Schuster Inc., New York, NY, 1986. Reinterpreted: Modeling How Systems [7]R. G. Bushko, â€œKnowledge-Rich Interact, Machine Learning, 4, 285-291, Analogy: Adaptive Estimation with Common 1989. Senseâ€, thesis, Massachusetts Institute of [16]M. Minsky, The Future of Artificial Technology, Cambridge, MA USA, 1991 Intelligence Technology, Forum, Risk [8]R. G. Bushko, Wake-Up USA: Accelerated Management Foundation of the Harvard Cross-Domain Knowledge Transfer Medical Institutions, Volume 17, Number 1, to Healthcare, Research proposal; April 1996. 8/1994,Updated 1996, 7SL International [17]M. L. Minsky, Framework for and Future of Health Technology Institute, Representing Knowledge, MIT AI Memo Hopkinton, MA No. 306, 1974. [9]G. L. Kreps, B. Glassman, FHT99 Synthesis, [18]M. L. Minsky, The Future of Artificial in R. G. Bushko (Ed.), Future of Health Intelligence Technology, Is there a Virtual Technology Summit 1999 CD-ROM, Future of Doctor in the House?Forum, Volume 17, Health Technology Institute, Hopkinton, MA, Number 1, April 1996. 1999. [19]R. G. Bushko, Situated, Strategic, and [10]A. P. Pentland, Seven Most Promising AI-Enhanced Technology Introduction Health Technology Research Areas in R. G. to Healthcare; Proceedings of the Bushko (Ed.), Future of Health Technology Workshop on the Medical Knowledge Summit 1999 CD-ROM, Future of Health Representation, International Joint Technology Institute, Conference of Artificial Intelligence, Hopkinton, MA, 1999, www.fhti.org 8/1991, Sydney, Australia.

Craig F. Feied, Chapter 7: Indistinguishable From Magic: advanced that we can’t even begin Jonathan A. Handler, Health and Wellness in a Future of to understand it; a future in which Michael Gillam, Sufficiently Advanced Technology everybody is automatically well, all the Mark S. Smith / Indistinguishable Craig F. Feied, M.D. time, and everybody lives forever, or from Magic: Health Strategy Officer, Microsoft Health Solutions as long as they want to. Some sort of Health and Group and Professor of Emergency Medicine at Wellness in incomprehensible machine repairs us a Future of Georgetown University when necessary – or perhaps billions Sufficiently Jonathan A. Handler, M.D. of tiny machines live inside our bodies Advanced Chief Deployment Architect, Microsoft HSG and Technology in and spend all their time repairing “World Health Clinical Associate Professor of Emergency Medicine Strategy” eBook, at Northwestern University us from the inside out. The resulting (Ed.) Renata population problem is resolved in G. Bushko, Michael Gillam, M.D. FHTI, 2016. Director, Advanced Development Lab, Microsoft some ingenious manner – perhaps Futureofhealth. HSG and Clinical Associate Professor of Emergency through an arrangement whereby org From Medicine at Northwestern University. Strategy for the having children requires giving up your Future of Health Mark S. Smith, M.D. own opportunity to “live forever.” (Ed.) Renata G. Professor & Chair of Emergency Medicine at MedStar A more difficult problem is how to Bushko, IOS Health and Georgetown University Press 2009 imagine a series of futures leading Abstract up to that one; a series in which the e describe a future in which health technologies in use are sufficiently and wellness are transformed by advanced to make a real difference in (1) the availability of definitive and health, but not so advanced that they W become indistinguishable from magic. unambiguous tests to prove or disprove each diagnosis, (2) new methods based in We believe five identifiable forces systems biology to help unravel the web will shape a future of healthcare that is of messages transmitted across cellular quite different from that of today. and subcellular networks, and (3) universal access to data that has been freed from 1. True data liquidity – bringing data silos to produce true data liquidity for together all existing data and a constellation of purposes ranging from allowing it to be combined and personal health management to population queried in real time and in ways that health research. We believe the resulting were never before possible. “connected health” environment will have a profound impact on every aspect of modern 2. Truly definitive tests for an life. increasingly large percentage of known ailments, through positive 1 Imagining the future identification of pathogens on the Clarke’s Third Law states that “Any basis of their genomic makeup and sufficiently advanced technology is proteomic activity. indistinguishable from magic” [1] and in truth it is relatively easy to imagine a future in which health technology is so

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 49 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

3. Systems biology approaches to unravel incomplete, and the tools used to the complexity of biological interactions investigate are insufficient to the and identify patterns of gene activation need. Healthcare is flawed because in a variety of disease states and altered people have flawed ways of thinking states of wellness. about the underlying problems and no readily available mechanism by 4. Improved imaging techniques and the which to improve this. In some sense, fusion of image and non-image data. healthcare is not better because people are incapable of making it 5.Human clinicians abandoning a flawed better within the current technology dependence on clinical judgment and framework. adopting diagnostic and therapeutic Fundamental problems in methodologies that are based in fact and healthcare include lack of knowledge, anchored by definitive tests. information hiding, poor management of existing data, inadequate analysis, A host of other technological advances self-deception, over-reliance on will also help to establish a world in which flawed clinical judgment, failure to we have very different expectations about compensate for cognitive bias, lack of health and sickness, and very different sufficient context to permit informed approaches to our daily lives. decision-making, and a near-universal emphasis on localized short-term gain 2 Fundamental problems in healthcare rather than optimization against a set of Envisioning the future does not require us larger imperatives. to think mechanistically about what is wrong today and how to fix it, yet there is value 2.1 Hidden knowledge: Physicians in recognizing the underlying gaps that bury their mistakes prevent us from enjoying a life of health and That physicians bury their mistakes is wellness today. Although this begins with both literally and figuratively true, and human failings, in the end it is viewed as it is one of the fundamental problems a pure technology problem. It has nothing that must be addressed. The problem to do with politics, or economics, nor is it comes in two parts. brought about or perpetuated by any payor system or system of incentives. In our view 2.1.1 Cause of death healthcare is not worse because some cabal has elected to place profit over people, The first half of the problem is that nor because clinicians systematically deny we often do not know why a patient their patients life-saving treatments in order really died. Hospital records and to navigate some system of incentives. death certificates are notoriously Healthcare is worse than it should be incorrect when it comes to cause because true knowledge is scant or absent, of death. [2] Even with the patient’s the underlying concepts are wrong or dead body in front of us we often

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 50 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

can’t make a definitive and unambiguous any feedback loop telling us whether diagnosis: autopsy studies routinely identify we have got it wrong? discordance between clinical and autopsy Part of the reason autopsy rates diagnoses in the range of 40%. [3] Some have been declining is the fact that autopsy studies have found that half of many people find the notion of an cancer diagnoses were missed during autopsy abhorrent, whether due to the patient’s life, while half of the cancer religious convictions or personal diagnoses that were made were wrong. [4] squeamishness. However, it is now A review of more than 120,000 published possible to acquire post-mortem 3-D autopsy cases shows that when patients radiographic images of precision die from pulmonary thromboembolism – sufficient to permit a virtual autopsy [7; blood clots that occlude the lungs and 8] that presumably will not violate most stop the heart – the diagnosis had been sensibilities. Add to that a detailed unsuspected in 80% of cases. If it requires analysis to detect pathogens and a an autopsy to even suspect the correct proteomic sweep to identify patterns of diagnosis in patients who die, how can gene activation, and we will be well on we begin to expect proper diagnoses in our way to confirming a positive cause patients who are alive? of death in each case so evaluated. Historically, autopsy was both an Whether autopsy is virtual or essential part of medical training and a physical, there would be transformative routine opportunity to confirm or disprove power in a unified database of detailed clinical diagnoses, with roughly half of all post mortem examinations on every deaths going to autopsy. Unfortunately person who dies while undergoing the autopsy rate has been dropping for medical care. Rather than abstracting decades: today fewer than 6% of non- only a few data points of general forensic deaths proceed to autopsy, [5] and interest, banked data should include more than half of all hospitals in a recent everything that can be determined study had performed no autopsies during about the cause and mechanism of the prior year. [6] In fact, in the absence death, in as much detail as science will of a suspected crime, there is absolutely permit at the time. no rigor associated with any assertion as to the cause of death: when patients die, 2.1.2 Hiding data the vast majority do not undergo any sort The second half of the problem relates of post-mortem examination whatsoever. to data hiding. In a situation bizarrely How can we draw any conclusions about similar to that faced by the United the efficacy of our treatments when we Nations nuclear weapons inspectors, can’t even tell what kind of cancer a patient hospitals and clinicians spend a has, or recognize when a person is dying significant amount of time and energy because their heart and lungs are full of attempting to hide information about blood clots? How can we expect to make the care they provide and to keep out better diagnoses if there is no possibility of inspectors who would like to sunshine

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 51 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

the data. [9; 10; 11] Patients also participate complexity of dataflows, with no sign in this data-hiding exercise, fearing that a that the rate of increase will slacken. breach of privacy will bring them personal In addition to growth in traditional harm. Vendors exacerbate the problem with clinical and operational data sources business models based on keeping data (radiology, EKG, labs, meds, monitoring, captive in silos often referred to as “data MD notes, nurse observations, and jails.” billing) many new sources have This state of affairs has often been become available, including such contrasted to the situation in the aviation things as: industry, where it is universally recognized that information-hiding cannot lead to better • Real-time biosensors in more and outcomes. So long as vendors, clinicians, different clinical situations departments, hospitals, payors, and entire countries believe that restricting the flow • Continuous location tracking of of information is a path to success over every person and thing in a health their competitors, we can never achieve setting the clarity of understanding we need. The path to value involves making all data and • Constant vital signs monitoring metadata about every case constantly and automatically available both for clinical • Transcutaneous monitoring of care and for cross-institutional research. glucose, ETOH, etc. Some of this could be accomplished with a policy shift to require that if hospital care • Testing to maintain wellness, rather is subsidized in any way by federal dollars, than only in response to sickness pseudo-anonymized data from that hospital must be shared for the common good. • Image utilization for new purposes Some of it depends on enterprise adoption of a new class of data management systems • Genomics and proteomics designed from the ground up to facilitate data liquidity. • Personalized pharmacy

2.2 The Data Explosion New data sources emerge with In addition to the challenges of sunshining alarming frequency, and new sources previously hidden information and liberating can produce data of new types that data from data silos, medical decision- cannot easily be accommodated by makers must also somehow cope with most current data stores. The volume explosive growth in the number and kind of of new data alone can be a problem, clinically relevant data sources, and in the and the full integration of medical volumes of data being produced by each images adds a special challenge due one. The past few decades have seen a to the extremely large size of current massive increase in the number, size, and images.

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 52 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Medical imaging still is in its infancy, more often than not the diagnostic with most of its growth ahead of it, yet the and treatment approach for a disease explosion is already underway. Utilization are not based on much valid data at of existing modalities is increasing rapidly, all. Some of this is due to fuzziness in and new imaging modalities already our definitions of disease. demonstrate applicability for disease For example, we often are told states that previously did not benefit that a drug or treatment “is effective from imaging. 3D rendering and fusion of in 15% of cases,” but it seems different image types are just beginning unlikely that we should ever have to become widely available, and the accepted this concept of sporadic or medical imaging landscape will continue occasional efficacy. Of course what’s to grow and diversify for the foreseeable really happening is that the drug or future, improving diagnostic accuracy treatment works in 100% of patients and elucidating disease entities in ways who actually have the disease for that were never before possible. At the which the treatment is effective – same time, the challenges of acquiring, taking the patient’s internal milieu transforming, transporting, storing, as part of the “disease” definition. analyzing, fusing, and displaying such What we have today is a stewpot massive image datasets will require new of diseases with similar signs and techniques in health data management. symptoms, all stirred together in a Future analytical methods will need to common diagnosis. Penicillin works in take into account a lot more data of more 5% of patients with pneumonia – but diverse types, aggregated and sliced in in 100% of patients with pneumococcal many more different ways than ever before pneumonia of a serotype sensitive to possible. Systems will need to work with penicillin. bigger aggregates as data is rolled up With increasing clinical availability across departments, hospitals, enterprises, of genomic and proteomic testing regions, and entire countries. Clinicians (of both patients and pathogens) will also need to work with smaller atomic we are beginning to make progress slices, drilling down from summary data to in separating out false disease individual events that can be combined in cognatesi, or “bucket” diagnoses that many different ways. And all of this needs conflate distinct medical conditions to make sense in the context of traditional simply because they share a common belief, newly published information, and presentation and common clinical emerging best practices. Traditional clinical data management systems are wholly inadequate to the challenge. i False cognates in linguistics are pairs or groups of words that are similar in form and meaning but have completely different linguistic roots. We use the term false disease 2.3 Definitions of disease cognates to refer to diseases or syndromes that appear The primary value of data is to aid in the to be the same and may share a common diagnosis, but diagnosis and treatment of a disease, yet have completely different pathogenic roots.

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 53 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

findings. Just as the nineteenth century • Gulf War Syndrome and many related false disease cognate “consumption” has ailments (infectious disease, toxic been resolved into a group of distinct exposures, psychological illness) diagnoses (including tuberculosis, cancer, viral illness, anorexia, and a variety of 2.4 Diverse treatment approaches degenerative diseases) we are now on for imprecise diagnoses the verge of making definitive sense of The bluntness of our instruments is these and many other conditions that may reflected in the medical adage used represent false disease cognates. Among to guide treatment of dermatologic the common diagnostic entities that stand problems by those outside the ready to be transformed, we may find: specialty: “If it’s wet, dry it; if it’s dry, wet it; if neither approach works then • Chronic fatigue syndrome (chronic viral apply steroids.” That may sound like infections of various types, along with a joke, but it is a recipe that quite adrenal and pituitary malfunctions from a accurately describes the approach variety of etiologies) to treatment of lesions about whose diagnosis a clinician hasn’t a clue. • Cancer (etiologic and subtype diagnosis Part of the challenge is in sunshining based on cell surface proteins and the data needed to identify best receptors; many viral etiologies) practices and decide among different approaches to the same problem. • Flu (multiple disease entities, mostly not Ten orthopedic surgeons perform influenza) knee surgery in ten different ways. They have different preferences • Gastroenteritis (multiple viral, bacterial, toxic, for equipment, prostheses, surgical and parasitic etiologies) approach, sequence of steps, and so forth. They take different amounts • Obesity (many different etiologies) of time and have different amounts of standard blood loss, which they • Coronary artery disease (many subtypes, cope with in different ways. Their including infectious and hereditary versions) patients have different lengths of hospital stay, different rehabilitation • Arthritis (various infectious and immune- courses, different complication rates, mediated etiologies) and different overall outcomes. They cannot all be correct – yet we defend • All “idiopathic” diseases (mostly the heterogeneity as necessary unrecognized infectious etiologies) and unavoidable, citing “surgeon’s preference” and other intangibles. In • Dementia of all types (injury, infection, prion fact – in medicine as in surgery – it disease) seems increasingly clear that when the disease is fully characterized, one

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 54 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

treatment approach must be demonstrably trying to make a definitive diagnosis. superior to the others, and we should be The vast majority of the time we able to identify that superiority through choose to operate by inference and analysis of the data. guesswork even when a definitive Certainly there are situations so diagnostic test does exist. The complex that predicting the outcome of an problem is not confined to rare or intervention is impossible – yet in the vast subtle diagnoses: tests exist that majority of situations, we don’t even try to can reliably detect or rule out use existing data or available tests to fully appendicitis, yet the initial diagnosis characterize the starting point and to define is missed in up to 57% of children the planned intervention. We start from a and nearly 100% of infants with position so impoverished of data that our the disease, leading to significant predictive and analytic capacity is severely morbidity and mortality. [17] Test constrained, and we act as if the resulting avoidance often is encouraged in an uncertainty is somehow a fundamental law effort to secure cost savings; this is a of the universe. false economy but a seductive one: the costs of diagnostic testing are 2.5 Miracle cures and bad diagnoses immediate, explicit, and isolated to a Simply getting the diagnosis right on single payer, while the true costs of a consistent basis may be sufficient to incorrect diagnosis, although massive, underwrite a transformation of our entire are hidden, spread over time, and healthcare system, because most of what often spread over multiple payers. we have taken for expensive variability in Medicine today is not so advanced the natural history of disease and variable that we can afford to optimize for false human response to treatment (requiring savings or individual profits at the human judgment to navigate the protean expense of universal knowledge. The pathways of disease management) is cost of being wrong in each individual actually simply a problem with diagnostic diagnosis may be a raindrop, but ability. There are no miracle cures, there are the aggregate downstream flood only bad diagnoses. is strong enough to wash away the very foundations of our medical 2.5.1 Clinical judgment and other forms of system. Simply put, we are chronically guesswork underinvested in diagnosis. Absent a definitive test, most diagnoses are incorrect, yet most diagnoses are 2.5.2 Knowledge gaps made without any definitive test ever being Medicine enjoys a long history performed. [12; 13; 14; 15; 16] The problem of technological advances is not that we have a ineffectual method that completely transform our for escalating the diagnostic process for understanding of a disease and its unusual problems – it’s that we routinely, diagnosis and treatment. For most every day, manage patients without even of the past century, even the best

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 55 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

clinicians could not come to agreement • Is the patient in shock due to in distinguishing between pairs of cardiogenic or septic causes? common clinical perturbations, simply (Swan-Ganz catheterization) because there was no readily available At one time these were considered to or convenient method by which to test be disputed diagnoses, but they were their clinical observations. A number of never actually diagnoses in the sense these confounding pairs are listed below, of carrying any understanding of together with the technological advance causation. These were really just that ultimately resolves the confusion. arguments about simple observations at a time when the observations could • Does the patient have pneumonia? not be made directly, but were (chest x-ray) imputed from indirect effects and subtle findings. In each case a simple • Is the patient hyperglycemic, application of technology is sufficient euglycemic, or hypoglycemic? (blood to resolve a century of disputation. sugar measurement) Pride in the advanced state of our medical system notwithstanding, the • Are the oxygen or carbon dioxide same situation holds today for the low, normal, or high? (blood gas majority of situations in which a patient measurement) is not well. Excepting trauma and proven infectious disease, most • Is the patient euthyroid, hypothyroid, or current “diagnoses” do not imply any hyperthyroid? (thyroid function tests) real understanding of causation, nor do they necessarily imply the kind of • Is the sodium or potassium high, low, or understanding that would lead to a normal? (serum electrolytes) definitive or even normative approach • Is the spleen or liver enlarged? to treatment. We perceive merely the (ultrasound; CT scan) shadows of reality, and not reality itself. It remains for us to create the • Are the kidneys normal, large, small or is technology that will resolve this one absent? (ultrasound; CT scan) century’s dogmatic and diagnostic disputes. • Is the patient acidotic or alkalotic? If we are to make progress it is (blood gases and serum electrolytes) essential that we be clear about what it means to make a definitive • Does the patient have seizures, or are diagnosis and explicit about our they pseudo seizures? (EEG) (statistically defensible) level of confidence in each unproven • Has the patient had a myocardial diagnosis. With that clarity and infarction? (EKG, enzymes, transparency, we may confidently set echocardiogram) forth a series of best practices against

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 56 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

which to drive iterative improvement in our 1%). In a population of 1 million people diagnostic and therapeutic processes. where the true incidence of the disease is 1 in 100 (10,000 people 2.5.3 Diagnostic testing and reasoning have the disease and 990,000 do not) through uncertainty the test will detect 9,900 of those The first branches of traditional diagnostic with the disease, but will also be decision-making depend on time-tested falsely positive in 9,900 of those who (i.e. primitive) approaches based on our five do not have the disease – so only half senses – focusing on the patient’s of those with a positive test actually description of his or her subjective have the disease, and the other half experience and combining it with findings do not. Yet in a different community on inspection, palpation, auscultation, where half the people carry the olfaction, and even gustation. At the next disease, 99% of those with a positive layer we add a series of crude tests test do have the disease, and 99% of intended to confirm or deny our initial those with a negative test do not.ii guesses through the detection of non- For tests of this kind, “prior specific changes in the body. For example, probability” dominates the equation so the white blood count is generally elevated much as to make the test very difficult to fight disease or in response to a variety to apply rationally in practical of stresses; we attempt to use this finding in situations. Many currently available an attempt to verify or deny the existence tests are of this sort when used to of a disease as specific as appendicitis. help diagnose a specific disease. Although tests of this kind are necessary They give evidence that can support for many diagnoses today, the or weigh against an inference, but discriminative power of most tests is very they cannot prove or disprove a low for any specific disease, and much of specific diagnosis. the diagnostic decision remains bound up For all its uncertainties, current in what we refer to as “prior probability” – diagnostic evaluation at least follows a essentially the weighted sum of our deterministic branching path that does guesses before we add in the results of the not require any bizarre creative leaps test. This leads to an odd reality in which a to achieve its goals. Although our test interpretation changes depending not concept of a gold standard is soft, on whether a specific patient actually has the disease, but rather on how common the disease is in the population. Imagine a test that reliably detects 99% ii 500,000 people do have the disease. The test detects 99%, or 495,000 of those with the disease, and gives of cases of a disease (missing 1% of those false negatives to 1%, or 5000 people. The other 500,000 who really have the disease) and that also people do not have the disease. The test gives a true negative in 99%, or 495,000 people, and gives a false reliably screens out 99% of those who do positive result to 1%, or 5000 people. Of all the people not have the disease (giving both a false- who had a positive test result, 495,000 are true positives and 5000 (1%) are false positives. The same ratio holds for positive rate and a false-negative rate of those with a negative test.

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 57 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

being rooted in a historical dependence on be required. With a new generation of expert opinion, it is nonetheless possible to unified intelligence systems managing model current diagnostic approaches all data, every clinician will have the effectively in software. Where this has been same universal view of the patient’s done it has often been possible to exceed data. With no data gaps and no the diagnostic accuracy and consistency of ambiguity about the diagnosis, there human clinicians. [18] will be nothing to fall through the Fortunately, another class of diagnostic cracks and no cracks for it to fall tests exists that is capable of proving or through. When we know the exact disproving specific diagnoses within the pathogen and the biochemical limits of certainty, and it is growth in this behavior of the host, we will know class of test that will help reduce the overall whether a given drug is going to work uncertainty in medical diagnosis over time. or not, without guessing. When we The ability to positively identify the genetic know the exact anatomy of the patient material of a pathogen is one such test that and the precise motions of the robotic has already made a dramatic difference in surgeon, we will know whether the our approach to certain diseases. The surgery is going to work without positive identification of specific molecular guessing. There will be very little room receptors in biopsy specimens is another remaining for what today is called example of a test that has transformed our clinical judgment. approach to certain types of cancer. 2.6 Information overload 2.5.4 Diagnostic certainty and new care Many people believe that the root of models our collective diagnostic When it becomes possible to have a incompetence is somehow associated correct diagnosis 100% of the time, and with the phenomenon of information when complete data aggregation and overload, and that “there’s just too constant analysis produce data and much to know.” The problem of understanding to underlie all treatment information overload is often regarded protocols, the interaction between patients as a modern phenomenon. After all, and the medical system may be completely one hundred years ago, a physician different from today’s limited set of could reasonably expect to learn offerings. For one thing, the traditional role everything that was believed to be of a primary care clinician may be true in the field of medicine. As it subsumed into the system as a whole. After happens, most of what was then all, there will be no ambiguity about whether believed has since been proven false a patient needs to see a specialist: an – yet we cannot help but imagine how absolutely definitive diagnosis will either much happier a clinician must have respond to a specific pharmaceutical been in an era when it was still regimen, or it will require some other possible to “know everything,” even if intervention, in which case a specialist will it was all wrong. Today a primary care

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 58 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

doctor is expected to somehow stay minutiae of every disease entity and abreast of approximately 10,000 named to bring all that detail together in order diseases and syndromes, 3,000 to exercise clinical judgment in every medications, and 1,100 laboratory tests. We case. When a diagnosis can be made can only speculate as to how much of this unambiguously, keeping up may only will later be proven false. require each clinician to have some It is true that the biomedical literature reliable mechanism by which to now contains more than 18 million indexed always find and use a valid approach articles, that more than 800,000 new for making each definitive diagnosis, articles are published each year, and that and then to follow the most current the rate of growth is doubling every 20 accepted treatment protocol for each years. Clearly no individual can read and proven disease state. digest all the new raw information created The poet Edna St. Vincent Millay each year even within their own area of [20] captured this sense most specialization. Research librarians have beautifully in 1938, writing: estimated that a physician may need to spend 21 hours of study per day in order to Upon this age, that never speaks its mind, remain current. [19] Of course this is This furtive age, this age endowed with power To wake the moon with footsteps, fit an oar impossible, and clinicians invariably fall Into the rowlocks of the wind, and find behind. What swims before his prow, what swirls behind --- In fact, the sense of information overload Upon this gifted age, in its dark hour, in medicine has been present for many Rains from the sky a meteoric shower Of facts . . . they lie unquestioned, uncombined. years. Henry D. Noyes, the great oculist of Wisdom enough to leech us of our ill the 19th century, opined in 1865 that “… Is daily spun; but there exists no loom medical men strive…to keep up their To weave it into fabric; undefiled knowledge…but the preparatory work in the Proceeds pure Science, and has her say; but still Upon this world from the collective womb study of medicine is so great that if Is spewed all day the red triumphant child. adequately done…few can spare time…”. As Millay correctly perceived, the 2.6.1 Distilling knowledge for wayfinding problem is not so much an overload It is not surprising that clinicians are of information as it is a need for inadequately prepared to navigate a knowledge synthesis – the weaving formless sea of information, and that current of facts into a fabric of knowledge. medical systems are incapable of aiding in Why worry about information that navigation, because we have defined overload in the midst of a shortfall the problem at entirely the wrong scale. A of understanding? Information is flood is indisputably made up of a trillion merely a distraction if it cannot lead raindrops, but nobody thinks it essential to to deterministic solutions to practical track all the raindrops in order to manage problems. Even if it were possible for the flow of water. Keeping up does not clinicians somehow to keep up with require each clinician to understand all the the rapid pace of new developments

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 59 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

in their own narrow fields, the simple reality is that relying on the judgment of a small number of hyper-educated human clinicians is not a viable long-term basis for achieving widespread excellence in healthcare. There is too much to know in too many areas, and the raw knowledge grows and changes too Figure 1: Time to widespread adoption of new quickly for humans to keep up. medical knowledge - 2500 years.

2.6.2 Translational science and medicine Yet even as it swamps an individual clinician, the increasing rate of growth of information in the biomedical literature seems to be associated with an overall increasing rate of adoption of the medical breakthroughs described in that literature. Figure 2: Time to widespread adoption of new It’s difficult to predict breakthroughs in medical knowledge - 150 years. terms of content -- most real breakthroughs 2030 has been proposed as ripe arise from the recognition of an unexpected for a “healthcare singularity” in which occurrence or happy accident, making it the instantaneity of adoption of new unlikely that we can project the world of knowledge causes the entire class of tomorrow simply by tracing the vectors of medical technologies to undergo a today. However, if we cannot tell what the fundamental shift to a simpler form. A future will hold, we can at least tell when post-singularity health era would imply it is likely to arrive; the pace of innovation a world where health discovery and has been increasing at a predictable rate practice are seamlessly meshed in for many centuries, in a sort of “Moore’s a virtuous cycle of ever-accelerating law” of medical innovation. Gillam et al. [21] improvement. Not coincidentally, Ray have remarked on the increasing pace with Kurzweil has identified the year 2040 which new medical knowledge becomes as a potential time of “Technologic adopted, from the 2500 years needed to Singularity” [22] during which bring knowledge of cardiac angina into computers become able to recursively common clinical care to the mere decades improve themselves in an explosion required for adoption of antibiotics in of intelligence that could transform the treatment of helicobacter pylori, the every aspect of human culture and recently-discovered etiologic agent for technology. gastric and duodenal ulcers. Figures [1] and

[2] graph the pace of adoption for longer- 2.7 Cognitive gaps and bias term and shorter-term time scales (reprinted Our healthcare challenge is a by permission). daunting one: we begin with a fuzzy Based on these trends, the decade after and incomplete concept of disease,

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 60 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

add an abridged and inconsistent approach rather than making decisions based to making any diagnosis, stir in a vast and on evidence and rational thought. increasing number of facts embedded in a Each of these leads to flawed clinical literature that is overwhelming in its decision-making in real-world volume, and layer on a vast and increasing clinical settings, and in some cases amount of clinical data and an increasingly it is possible to count the bodies of complex and detailed set of images. Finally those who have died after decisions we attempt to glue all this together with the driven by some of the more common human mind, relying on clinical judgment, cognitive biases. experience, and intuition to bridge any gaps in knowledge and evidence. Unfortunately, 2.7.1 Logical fallacies and cognitive the human mind appears to be hard-wired blind spots for susceptibility to a series of cognitive Many logical fallacies, cognitive biases, blind spots, and logical fallacies. biases, and blind spots seem to This susceptibility renders human clinicians be based in mental heuristics that uniquely unsuited to make unaided represent shortcuts in problem- diagnoses or to design treatment plans solving; some are so deeply-rooted under any but the least complicated of that it can be extremely difficult scenarios. to think about them clearly, even Researchers have identified more than after they have been exposed and a hundred common and replicable ways elucidated. One of the best-known in which human judgment and decision- examples is a veridical paradox making differ from what we would predict known as the “Monty Hall Paradox,” on the basis of rational choice. [23] For given here as it was understood by example, the availability heuristic causes readers when it appeared in Parade us to consider things more likely if they are magazine a few years ago: more readily available in memory, resulting in a bias toward vivid or emotionally Suppose you’re on a game show, and charged examples. The confirmation bias you’re given the choice of three doors: leads us to have greater confidence in Behind one door is a car; behind the evidence that supports a previously made others, goats. You pick a door, say No. 1, decision than in evidence that contradicts and the host, who knows what’s behind it. The self-serving bias allows us to feel the doors, is compelled to open one of the responsible for desirable outcomes but remaining doors and show you a goat (if not for undesirable ones, and intervention both remaining doors contained goats he bias causes us to feel responsible for bad will choose one at random). Say he opens outcomes following an active intervention door No. 3 and shows you a goat. He then but not for bad outcomes following a willful must say to you, “I’ll give you the option to withholding of treatment. Wishful thinking switch your choice from door No. 1 to door causes us to prefer decisions that lead to No. 2.” Is it to your advantage to switch your a less likely but more pleasing outcome, choice?

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 61 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Obviously the open door contained a goat, or re-derive the understanding that and one of the two remaining unopened was previously attained. doors also contains a goat while the other This cognitive shortfall seems to be contains a car. Since the assignment of associated with a predisposition for goats and car was random, most people evenly distributed probabilities, and assume that each of the remaining doors many other problems with uneven has an equal probability (50/50) of probability distributions can command containing the car. In fact, although it seems the same sort of logical errors. For counter-intuitive, the door originally chosen example, if a patient is equally likely to by the contestant has only a 1/3 chance of have any of three combinations of containing the car, while the door being health markers A and B (AA, BB, or AB) offered as an option now has a 2/3 chance and a test detects that our patient has of containing the car. Switching your choice at least one A marker, what is the doubles the probability of winning.iii likelihood that the other marker is also The paradox has been known for many A (for a combination of AA)? Most years, but when the problem and solution people reason that the patient cannot appeared in Marilyn Vos Savant’s column in have BB, so must have either AA or Parade, some 10,000 readers (reportedly AB, thus has a 50% likelihood of 1,000 claimed to have PhD degrees) wrote having AA – however, that answer is to the magazine insisting the published incorrect.iv solution was wrong. Professors of In many settings it’s merely mathematics declaimed their credentials amusing to note that humans are and publicly staked their reputations on the heavily predisposed to get this sort of true probability distribution being 50-50. thing wrong, and even more amusing This is a common response: even in the to watch them defend their wrongness face of a wholly unambiguous problem with their credentials as a shield. statement offered with complete However, getting even this one simple explanations and mathematical proofs, by thing wrong in a medical setting can an authoritative source, many people still lead to a significantly increased risk of refuse to believe the correct answer. There are many ways of demonstrating iii One way of thinking about this is to consider that when the correct solution – from simulation to first choosing a door, we have a 1/3 chance of getting the car, but a 2/3 chance of having selected a goat. When actually working through a number of trials Monty later shows us a goat and offers us the remaining with playing cards, to traditional probabilistic closed door, he really is offering us the opportunity to swap our single door for both of the doors not originally and even Bayesian arguments. With a little chosen. Our original door has a 2/3 chance of having a effort it is reasonably straightforward to goat, and the other two doors (together) had a 2/3 chance of having the car. Together, they still have that 2/3 chance convince oneself of the correctness of the of having had the car – even though one of the doors is true answer – yet this paradox has the open (showing a goat) and the other remains closed. If offered, take the switch. peculiar quality that when re-introduced at another time, the result is so counter- iv In reality, there are three A markers in the mix and only one of them is opposite a B – so our patient has a 2/3 intuitive that it is very difficult to remember chance of being AA and only a 1/3 chance of being AB.

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 62 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

death, and it’s a more serious problem if the the pathogen can be guaranteed to clinician not only can’t perceive the correct be susceptible. Similarly, the answer, but refuses to believe it even when opportunity to distinguish different it is pointed out. There are hundreds of biochemical and metabolic pathways examples of this sort of logical fallacy, in different patients allows us to adjust probability conundrum, and cognitive bias. medication dosing in such a way as to These problems are not just the stuff of ensure that each patient gets riddles and game researchers. They are therapeutic levels of the drug real and pervasive and affect thousands of prescribed. These new approaches medical decisions each day. are just beginning to be available to According to Crosskerry [24], in order to clinicians, and the impact on our make progress in managing cognitive bias, understanding of disease is already “medical decision makers and educators enormous. have to do three things: (1) appreciate the full impact of diagnostic errors in medicine 3.2 Systems Biology and the contribution of cognitive errors in Today’s best candidate for a particular; (2) refute the inevitability of completely transformative approach to cognitive diagnostic errors; and (3) dismiss diagnostics may lie in the area of the pessimism that surrounds approaches systems biology, a new and rapidly for lessening cognitive bias.” advancing field that attempts to understand complex biological and 3 Solutions for the future physiological phenomena through a From this sea of challenges and change mesh of empirical, mathematical and emerge a few trends that seem to offer computational techniques. Systems hope as solutions for our most pressing biology explicitly addresses the fact problems. Some of these relate to new and that hundreds of distinct proteins are better types of data that can help reduce involved in information exchange the uncertainty in today’s system. Others even for a single cellular process, and relate to new and better ways to aggregate, that even minor defects in this web of share, analyze, and present information, information exchange can result in with an emphasis on data re-use and on chronic illnesses such as diabetes new computational techniques that can mellitus, or in the development of augment or replace human effort, certain types of cancer. particularly where we are at our weakest. Traditional tools in the biological sciences can only focus on the 3.1 Genomics and proteomics activities of a single cell or a single The opportunity to definitively identify a biochemical pathway, and cannot pathogen through detection of its genome capture or represent the mesh of offers an incredible opportunity to reduce interactions that exists in real life. the overall level of uncertainty in medical Treatments designed by changing a diagnosis and to provide a therapy to which single path within this mesh of

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 63 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

interactions carry a high likelihood of system. Small technological advances unintended consequences and a high that create simplification and shorten likelihood that a disease will escape the feedback loops in a complex adaptive treatment by following alternate biochemical system can have dramatic effects on pathways – problems that bedevil disease the overall behavior of the system. research and the new drug development Systems biology also recognizes process today. the need to capture information along Systems biology attempts to produce many different axes in order to detailed route maps of the subcellular and characterize the state of a system in extracellular networks that are activated in a terms of its envelope and its network particular state of the system (either in of interactions. With this approach it is health or in a disease state) in order to possible to examine, for example, the allow perturbations to be modeled in a way patterns of protein expression over that reflects the real biological world . Early time in order to determine which results suggest that when sufficient human and pathogen genes have quantitative data is available, even simple been activated in a specific disease mathematical models can produce results state. Laboratories today have of immediate practical use. successfully used this approach – Systems biology implicitly recognizes a using proteins circulating in the blood fundamental reality: that the human body is to track the activation of many a complex adaptive system in which a very different genes in brain tissue – to large number of inputs obey a large differentiate such things as prion number of rules in a system with a high disease and Alzheimer’s disease from dependence on initial conditions and a high other causes of dementia that degree of nonlinearity, with feedback loops previously could be distinguished only passing through many levels. In a complex through brain biopsy or (worse) only at adaptive system our ability to autopsy. [25; 26] deterministically predict the results of a perturbation may be fundamentally limited 3.3 Data Liquidity and re-use by emergent behaviors. However, it is not Traditionally, healthcare data is necessary to predict all aspects of system created within a data silo, used for a behavior to exert control; many complex single purpose, and discarded or adaptive systems can be effectively (if not archived when that purpose is deterministically) controlled so long as the complete. However, in an organization right subsystem can be identified and that has invested in data liquidity, data controlled. Furthermore, just as a few simple from all sources is brought together in rules and a small number of variables can one place and made available for a create a complex adaptive system, small wide variety of current and future reductions in the number of variables and purposes. Data is stored with an rules can have dramatic and nonlinear extensive list of attributes and impact in reducing the complexity of a metadata so it can be repurposed

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 64 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

easily. All types of data are made “instantly can deliver unprecedented universal and ubiquitously” available through multiple access to all existing data across an cycles of creation, capture, storage, entire enterprise. Today this can be purposing, and presentation. This kind of readily achieved across the medical data re-use can bring a tremendous amount enterprise and even across a region. of new value at low cost. Ultimately it will lead to pertinent One source of value comes from using information being instantly and data from multiple sources to drive ubiquitously available throughout the predictive analysis both at the operational entire life of any individual. level and at the personal health level. The analogy is to an “air-traffic control system” 3.3.1 Connected Health for health in which a “flight plan” may be With the advent of true data liquidity filed and deviations from a normal course we are beginning to move from a detected early enough to permit course world of data fragmentation towards a correction. Such predictive systems will be world of Connected Health, in which highly dependent on the constant health information from any source availability of rich real-time datasets, forcing can become part of a personal health a gradual migration away from an data asset that is available wherever environment in which data is highly and whenever needed. Connected restricted and hard to obtain, and towards Health moves data freely from an environment in which data is highly enterprise to consumer and from mobilized and readily available where datacenter to desktop, with solutions needed (“data liquidity”). for trust, authentication, identity, In traditional environments (dominated encryption, security, transmission, by hard-coded point solutions for a small presentation, delivery, rights number of old, known problems) it can be management, and other utility difficult even to perceive newly emerging functions. problems, let alone to solve them. The future depends upon a data-centric 3.3.2 Decision support environment in which many points of view New approaches are challenging the (many purposes) are equally enabled perception that a doctor’s art is always through late binding of structured displays better than the computer’s algorithm. and functional modules, all using a unified In many areas, even simple computer- data resource to create enterprise aided decision-making approaches intelligence. have been shown to be better and Just as tools like Visicalc and Excel more consistent than an unaided wiped out legacy approaches to centralized clinician. Newer decision support reporting and analysis by empowering offerings are based on Bayesian and individual workers in unprecedented ways, multiple regression approaches, legacy approaches to information hoarding expert systems using rule-driven are being challenged by new systems that approaches, and more exotic methods

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 65 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

such as evolutionary algorithmic design and Technological solutions already fuzzy logic. exist to provide significant benefits through improved management of 3.3.3 Creating Context for Health Data clinical data and shared knowledge. Context matters. For example, the current For example, clinicians today choose weight taken in isolation is all but an antibiotic from handbooks listing meaningless for the management of a drugs-of-choice for presumed and patient with congestive heart failure. proven infectious diseases. These However, with the added context of the handbooks are published via patient’s baseline dry weight, the current traditional methods and do not reflect weight becomes the single strongest the situation or condition of a specific predictive factor for fluid overload and hospital or a specific patient. Such impending cardiovascular collapse. The recommendations could and should same requirement for context will be true be made by clinical systems capable for hundreds of different measures that can of drawing upon all known data about and will be tracked on a regular basis, at the situation. At a minimum, initial home – and not just for disease entities that treatment recommendations may be we can name and diagnose today. based upon recent trends in antibiotic In many cases, the meaning of medical susceptibility in the local population, data depends not only on historical context and with genomic characterization of about that data element itself, but also on a pathogens there is no reason why systems context – on all the data about there should be any ambiguity other things that are going on in the whatsoever in the optimum person’s body and life. A blunted morning therapeutic regimen. cortisol surge after a 30-hour plane ride There are many other examples of means jet lag, and the balance is restored ways in which existing data can be by restoring a normal sleep cycle for some mobilized to provide guidance that is period of time. However, a blunted morning sorely needed. One that has obvious cortisol surge that arises out of the blue appeal involves the creation of a may mean pituitary or adrenal dysfunction, government-sponsored exhaustive list and the balance is restored in quite a of diagnoses together with current different way. recognized best practices for ruling in/ It’s also likely that the context for ruling out each disease, along with understanding individual daily health data some uniform mechanism by which to will also include some population and communicate our statistical cohort data. If a patient feels terrible and confidence in a diagnosis, based on has a fever during the flu season when 20% how the diagnosis was made. of people in the community also feel terrible and have fevers, the implications may be 4 Health and the spectrum of quite different from a scenario where only wellness one person feels bad and has a fever. Over time, health data of various types

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 66 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

will play an ever-increasing role in daily life, standard regimen invariably have initially by improving our ability to reduce hormone levels that are at times too sickness and manage chronic conditions, high, and at other times too low: real and later by improving our ability to balance cannot be achieved through enhance wellness. Over time, the false such crude “one size fits all” separation between wellness and sickness manipulations. For many of these will become blurred and eventually deficiency states, tests are now forgotten. available that can be performed by the patient at home – and as more 4.1 Reducing sickness frequent and more granular data Worldwide, 170 million people have elements become the norm, health diabetes, and the number is expected to data management needs will continue double by the year 2030. Today, most to develop in interesting ways. diabetics in developed countries perform a blood test on themselves multiple times 4.2 Enhancing wellness daily. They use the data in a crude way to How many people now think about guide their diet and activity, and in a more their health every day? Hint: it’s not direct way to make specific metabolic just people who are sick. How many adjustments, calculating how much of a people do something on a regular medication is needed to maintain the basis to deliberately adjust their balance of a single substance – glucose - physiology and biochemistry? Hint: it’s within their body. Today, the data most often not just those taking medication for a is used as a snapshot and then discarded; it chronic disease. In actuality, most is difficult or impossible to perceive patterns people already take actions to or trends for a single patient or across a optimize some aspect of their health population of patients. Tomorrow a every single day, and this will only snapshot approach will be unthinkable. increase in the future. Today, a few people take hormone How many people have a scale replacements – thyroid, testosterone, and step on it regularly? How many estrogen – to restore a natural homeostatic adjust their fitness regimen based on balance that has been lost through illness, a target heart rate? How many people accident, or aging. Dosing is static, based count calories or follow a diet of any on a small number of crude tests that may kind? How many read the ingredients be performed a single time or may be on food labels in order to avoid repeated annually. However, the hormonal something they don’t wish to ingest? ecology of the human body is extremely How many know their waist size, dynamic and tremendously complex, and height, and other body hormonal requirements can change measurements, and use that data to significantly on a daily basis in response to guide clothing purchases? diet, activity, and other environmental How many have performed a home factors. For this reason, patients on a pregnancy test or an ovulatory cycle

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 67 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

test? How many have used a home test for How many people use mouthwash occult blood in the stool? How many have or brush their teeth with a cavity- checked their own blood pressure? These preventing formulation? Today, those kinds of diagnostic activities once required measures are moderately effective, a visit to a doctor’s office. Today they but it’s already possible to analyze are self-provisioning activities that affect the flora of the mouth environment, personal decision-making, and leave a data and people will regularly adjust trail that has value when integrated into a their biochemistry (and that of their longitudinal record – or when aggregated bacterial colonies) to eliminate such across entire populations. things as bad breath and tooth decay How many people drink coffee? completely. How many take a vitamin? These are How many “healthy” people take biochemical manipulations based on regular medications of any kind? Oral sensory feedback (coffee) or global contraceptives? Allergy medications? beliefs about metabolic needs (vitamins), Headache remedies? Bone density rather than based on measurements and formulations? calculations of personal needs at a specific These are all activities that involve time. Today there is no rational basis for gathering health-related biometric and customizing a vitamin regimen, yet many bio-environmental data and using it people have developed closely-held to affect decision-making and modify beliefs about their own specific vitamin daily activities. These activities involve needs, and an entire industry has arisen to people engaging with their own health help people select specific combinations data to try to improve their wellness of vitamins and other dietary supplements. in some way. Today the data is crude Today those selections are based solely and episodic, and isn’t integrated upon belief, but tomorrow they will be with other data sources – it is used in based on data from personal testing. In snapshot form and then discarded – the future, each person will adjust their but when specific tests with sufficient own biochemistry periodically based on granularity can make the spectrum personal health data-points and complex of wellness a reality, the entire calculations involving many sources of data. population will be engaged with their How many people use a cleanser, personal longitudinal health datastore antibiotic, or other treatment for acne or in a meaningful way, every day. other skin problems? Today these are Even sophisticated test-based generic approaches to the health of a adjustment of essential hormonal and specific organ system – the skin. It’s already metabolic systems may not remain possible to do DNA analysis on the bacteria confined to people who today have a that colonize your skin, and feasible to recognized chronic deficiency state: adjust the mix with antibiotics and probiotics there are biochemical reasons why that are tailored to your own specific needs people sometimes wake up feeling as they evolve over time. great, and other times wake up

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 68 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

feeling rotten, and it may soon be possible A clinician today applies a relatively to measure and correct those problems crude set of screening capabilities to just as we’re able to measure and correct try to diagnose why a patient does blood sugar or blood pressure today. At not feel well. Even if tests are ordered, some future time – probably not far off – the tests themselves can only detect each person will have the opportunity to a small number of conditions that assess his or her metabolic balance and have been labeled as disease states. make daily or even continuous adjustments If a patient meets the criteria for a on not one, but multiple different axes. named illness, he or she most often is Naturally these aren’t going to be single- classified into one of a series of false factor tests that exist at a single point in disease cognates. Even when two time – they will be systems biology data people with similar findings do have elements that will connect to a live mesh of exactly the same disease, they may health data to give them meaning. not respond to treatment in the same Today we think health means “getting way because of differences in genes, treated,” “avoiding illness,” or “managing lifestyle, diet, or concomitant illness. chronic disease.” Tomorrow we will use And for those who do not meet the quantitative measures of the full spectrum criteria for a named diagnosis, there of wellness, and will make data-based is little to offer. Patients are told “there decisions about health that will affect every is nothing wrong with you,” or “there part of our lives. In a very fundamental way, is something wrong with you, but we the future of health is the future of beauty, don’t know what to do about it.” fitness, and happiness. The house of medicine today has very little to offer people who 4.3 Spectrum of wellness are “not sick” – yet are not as well Dynamic change along a functional as they used to be, not as well as continuum is the normal human condition; they want to be, and not as well as against that background there are they could be. However, a multi- periods of time when a person has clearly billion dollar neutraceutical industry recognizable problems due to injury or thinks it has something to offer, and illness, and there are also times when a large number of fringe and quack a person has some level of dysfunction offerings have arisen to address that doesn’t meet the current threshold of the problems of those who are not what’s called illness or injury. Eventually well, yet not sick with an identifiable our concept of wellness will converge with disease. Fortunately, new advances in our concept of sickness, so that not only genomics, proteomics, metabolomics, can we use health data to manage daily and systems biology combine with activities for enhanced wellness, but we can advances in data management to also manage our trajectory into a future that improve the granular detail of our includes overt illness at some future time, in data, the level of complexity with ways that simply are not possible today. which we can reason, and our

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 69 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

ability to make definitive diagnoses. As we have the tools to help us see we progressively redefine the baseline and understand exactly how an early of wellness, we will soon find ourselves health disturbance today will lead to able to define exactly what pathogens are a bad outcome ten years later, we active in a patient’s body – and exactly will have much better arguments to what they are doing at any moment. In the support investing in an individual case of an injury we will be able to measure today to achieve better outcomes what the body is doing to repair the injury, later in life. Most importantly, instead because we will know which genes are of top-down population arguments, turned on and what proteins are being these will be real individual arguments elaborated. When a patient doesn’t feel with real biochemistry for a specific well, more often than not we will be able to person behind each one – and in see and understand that process in terms the aggregate they will add up to the of biochemical activities and a pattern population argument. of genomic activation and proteomic expression, making a definitive diagnosis 5 Conclusions where today we cannot even identify a To be directionally correct in our patient as “sick.” headlong rush to the future requires When we can routinely measure these from us only a small number of kinds of things, the clear threshold between positive actions. We must stop hiding “well” and “sick” will simply vanish, and information and begin to share data we will see each individual very clearly widely, even if this requires changes in positioned somewhere along a very broad health data policy. We must embrace spectrum of wellness that extends from data liquidity and make all existing “perfectly well” all the way to “very sick,” data available for clinical care and for with a granularity as fine as we care to subsequent analysis using systems make it. approaches. We should establish Today we are just at the point where we definitive clearinghouses for each can make not only a statistical argument, disease entity that is under study. but a direct personal argument that a Important progress may result simply person who is going to work every day and from placing a strong emphasis on generally feeling well – but has a slowly making a definitive and unambiguous rising serum creatinine – actually is on a diagnosis, and clearly distinguishing trajectory to end up with renal failure. We those cases where the diagnosis can show that if we intervene immediately, is suspect so we do not continue in many cases we can prevent that patient to contaminate our reasoning with from ever progressing to need dialysis. We data from false disease cognates. can imagine that with the right data and Genomic, proteomic, and systems the right modeling tools, we may soon be biology approaches should be able to say the same kind of thing about encouraged and supported. We must a vast number of health situations. When assiduously apply the best available

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 70 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

analytical tools to the data at hand. And May 23, 2009. finally, we must empower the individual 8. Virtopsy, a new imaging horizon as a full partner in his or her health and in forensic pathology: virtual autopsy wellness, with unfettered access to the by postmortem multislice computed data necessary to make informed health tomography (MSCT) and magnetic decisions. Thus, we begin, in the greenish twilight of the past. resonance imaging (MRI)--a feasibility study. Thali MJ, Yen K, Schweitzer W, References et al. 2, Mar 2003 , J Forensic Sci, Vol. 1. Clarke, Arthur C. Hazards of Prophecy. Profiles 48, pp. 386-403. of the Future. s.l. : Warner Books, 1973. 9. When Doctors Hide Medical Errors. 2. Discrepancies in initial death certificate New York Times. September 9, 2006, pp. diagnoses in sudden unexpected out-of- http://www.nytimes.com/2006/09/09/ hospital deaths. Tavora, F, et al. 3, 2008, opinion/09sat4.html?_r=2&oref=slogin Cardiovasc Pathol, Vol. 17, pp. 178-182. May 23, 2009. 3. Autopsy diagnoses of malignant 10. Medical error disclosure among neoplasms: how often are clinical pediatricians: choosing carefully what diagnoses incorrect? Burton, E C, Troxclair, we might say to parents. Loren DJ, D A and Newman, W P. 14, 1998, JAMA, Vol. Klein EJ, Garbutt J, et al. 10, Oct 2008, 280, pp. 1245-1248. Arch Pediatr Adolesc Med, Vol. 162, 4. Misdiagnosis of lung cancer in 2000 pp. 922-927. consecutive autopsy study in Budapest. 11. Buntin, J. Plague of Errors. Kendry, G, Szende, B and Lapis, K. 3-4, Governing. Aug 2005, Vols 1996, General & Diagnostic Pathology, Vol. http://www.governing.com/archive/ 141, pp. 169-178. archive/2005/aug/medical.txt, May 24, 5. Medical error and outcomes measures: 2009. where have all the autopsies gone? Burton, E C 12. Relative contributions of history- and Nemetz, P N. 2000, MedGenMed, Vol. 2. taking, physical examination, and 6. Institutional characteristics associated laboratory investigation to diagnosis with hospital autopsy performance. and management of medical Burton, E C, et al. 2001, Am J Clin Pathol, outpatients. Hampton JR, Harrison MJ, Vol. 116, p. 590. Mitchell JR, Prichard JS, Seymour C. 1975, Br Med J, Vol. 2, pp. 486-489. 7. Virtual Autopsy: Supporting Clinical Practice and National Policy. Satava, R. 68, November 2004, US Medicine, pp. http://www.usmedicine. com/column.cfm?columnID=186&issueID=68.

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 71 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

13. Diagnostic yield of the autopsy in a university 21. Gillam M, Schneiderman B, hospital and a community hospital. Landefeld Feied CF, Handler JA, et al. The CS, Chren MM, Myers A, Geller R, Robbins S, Healthcare Singularity and the Age of Goldman L. 1988, N Engl J Med, Vol. 318. Semantic Medicine. [book auth.] Ben 14. Changes in rates of autopsy-detected Schneiderman. The 4th Paradigm. diagnostic errors over time: a systematic Baltimore : TBD Books, 2010. review. Shojania KG, Burton EC, McDonald 22. Kurzweil, Ray. The Singularity Is KM, Goldman L. 2003, JAMA, Vol. 289, pp. Near. s.l. : Viking Press, 2005. 2849-2856. 23. Kahneman, D, Slovic, P and 15.A prospective study of 1152 hospital Tversky, A. A judgment under autopsies: II. Analysis of inaccuracies in uncertainty: Heuristics and biases. clinical diagnoses and their significance. New York : Cambridge University Cameron HM, McGoogan E. 1981, J Pathol, Press, 1982. Vol. 133, pp. 285-300. 24. The Importance of Cognitive 16. Contributions of the history, physical Errors in Diagnosis and Strategies to examination, and laboratory investigation in Minimize Them. Crosskerry, P. s.l. : diagnoses. Peterson MC, Holbrook JH, Von Acad Med, 2003, Vol. 78, pp. 775-780. Hales D, et al. 1992, West J Med, Vol. 156, 25. A landmark systems analysis of pp. 163-165. prion disease of the brain. Omenn, 17. Acute appendicitis in children: GS. Mol Sys Biol, Vol. 5, p. 254. emergency department diagnosis and 26. A systems approach to prion management. Rothrock, Steven G and disease. Hwang D, et al. Mol Sys Biol, Pagane, Joseph. 1, July 2000, Annals of Vol. 5, pp. 252 -. Emergency Medicine, Vol. 36, pp. 39-51. 18. Clinical versus mechanical prediction: A meta-analysis. Grove WM, Zald DH, Lebow BS, Snitz, BE, Nelson, C. 1, Mar 2000, Psychological Assessment, Vol. 12, pp. 19-30. 19. How much effort is needed to keep up with the literature relevant for primary care? Alper BS, Hand JA, Elliott SG, et al. 4, 2004, J Med Libr Assoc, Vol. 92, pp. 429-437. 20. Millay, Edna St. Vincent. Upon This Age. Huntsman, What Quarry? s.l. : Harper & Brothers, 1939.

Indistinguishable From Magic: Health and Wellness in a Future of Sufficiently Advanced Technology 72 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

R.G. Bushko / Chapter 8: Strategy for the Future of personalized designer drugs, and Strategy for the Future of Health Health automatic surgery bubbles. FHTI is a in “World Health Renata G. Bushko, M.S.* think-tank aimed at defining strategy Strategy”, Renata G. Bushko Founder, Future of Health Technology for health technology development (Ed.) eBook Institute, Hopkinton, MA, US and determining the most critical FHTI 2016. FutureofHealth. focus areas for health technology org Abstract investment in the new century. FHTI his article shows the importance of shares Schrodinger’s optimism goal setting in strategy development expressed in his seminal paper “What Tand presents the Future of Health is Life”: Technology Institute’s www.fhti.org goals as an example of goals that have How can the events in space and time transformative power. It also provides which take place within spacial boundary synthesis and developmental history of the of living organism be accounted for by “Strategy for the Future of Health” book physics and chemistry?[…] The obvious while examining collective book design as inability of present-day physics and a strategy development tool. It emphasizes chemistry to account for such events is unprecedented technological revolution no reason at all for doubting that they can manifesting itself in the convergence of be accounted for by these sciences. molecular biology, computer and medical Erwin Schrodinger, 1944 science, electrical, mechanical, genetic and biomedical engineering (including cell, We will be able to watch, to explain molecular and tissue engineering) resulting and to control not only events in in the merger of information technology (IT) space and time in a living organism with medicine and the formation of “ITicine”. but also events that connect this organism to a multitude of other 1. Introduction organisms. In order to successfully I have spent last twenty years running an achieve this, however, but we need to independent agency – Future of Health outline a concrete strategy. Technology Institute (FHTI) www.fhti.org – to oversee long-term issues of health *Please send correspondence to technology and to strategize and set goals [email protected] for the future. This agency prepares for a future society where computers might 2. Strategy Development outsmart people, where we might be Defining strategy for the future of able to stop diseases before they begin, health involves on-going, adaptive where caring machines will aid physicians dynamic learning by industry, in 90% of their work and connected government, and academia. This caring consumers will diagnose and involves ultimate goal setting and the cure themselves with self-health tools, definition of strategy equations.

2.1 Setting High Level Goals • Demonstrate that technology The most important part of strategy driven cost increases in healthcare development is goal setting. High-level can be stopped and possibly goals provide distinct direction and sense reversed by a new allocation of purpose and can assist large groups of of research and development people in creating a coordinated effort. resources. Without these high level goals international, national and organizational operational • Define productive areas for strategic plans often fail because of lack of research and development that stamina and perseverance. Future of Health will have potential impact on Technology Institute’s goals listed below healthcare. provide direction and inspiration to search for and develop a better future: • Identify new technologies that are practical and necessary in health FHTI’s Strategic Goals: and wellness maintenance. • Stop disease before it even begins • Stop suffering before tears occur • Identify research and • Stop symptoms before they hurt development needed to meet • Stop medical errors before they kill future health challenges • Stop cyborgs before they control us . • Stop aging before it disables us • Identify current products that will best prepare for 21st century On the operational level these goals mean: healthcare. • Beginning to seriously think about and invest in long-term solutions

• Beginning to manage and organize Figure 1. The the unpredictability of the technology Future of Health creation and adoption process Technology Award (© 2006-9 FHTI) - a sculpture of • Beginning to address health crisis Pegasus with situations as national and international crystal eyes, and a third eye (for seeing emergencies the future) created from a nano- It also means that we have to: made diamond. It is a symbol of inspiration to • Develop a vision of future health care save lives, reduce supported by current and future health suffering and enhance human potential with technolog. Winners include Marvin Minsky, Lorraine Gudas, Gary technologies. Kreps, Eric Dishman, Michael McDonald, Kevin Warwick, • Define distinct promising health Xiu-Min Li, Craig Feied, Danuta Glowacka, Ray Kurzweil, technology research areas. Barry Robson, Benjamin Miller.

In this book we will touch upon all aspects of conversion of old-fashoned medicine healthcare system (Figure 2) and the with human doctor in the center to underlying science and technology that will IT-centered medicine with caring inspire healthcare leaders responsible for machine or healthmatician as a main resource allocation to make decisions that delivery vehicle.

best serve both their immediate goals, as Information Technology(IT) + Medicine = ITicine well as the human race as a whole. Future 3. Book Design as a Strategy progress in healthcare and medicine Development Tool depends on the investments in research, In 2002, thirty-two experts contributed development and education made today. to the “Future of Health Technology”, and in 2005, thirty-three experts expressed their thoughts in the second book “Future of Intelligent and Extelligent Health Environment”. As editor, I have named the third volume produced in 2009, “Strategy for the Future of Health” to provide an inspiration to “think big”, to build upon strategic nature of two previous volumes, and to provide Figure 2. National quality cube in the Unified Quality a link between IT, medicine, and Framework (©FHTI 2002). Top corners illustrate types of nanotechnology communities. The quality and bottom corners show the measure of quality. idea of developing high level goals, 2.2 Simple Strategy Equation an underlying theme in all three Unprecedented technological revolution volumes is similar to that expressed manifests itself in the convergence of by Thomas Edison: “My philosophy of molecular biology, computer and medical life is work – bringing out the secrets science, electrical, mechanical, genetic of nature and applying them for the and biomedical engineering (including cell, happiness of man. I know of no better molecular and tissue engineering). This service to render during the short time convergence will led to new life forms and we are in this world.” human-machine merger. All three volumes segment health Simple Strategy Equation: technology in different ways to Life Science + Computer Science = New Synthetic Life Form assure that we capture multiple and Another version of the above simple constantly developing dimensions strategy equation, shown below, of the subject matter as presented demonstrates complete conversion below. of health information technology with medicine resulting in a new field that could be called ITicine. This reflects the

3.1 Future of Health Technology - Book #1 from electric light to electronic paper, 2002 windows, mirrors and wallpaper. In the first Future of Health Technology In the next century most current book the following four areas of diseases will be history and medicine advancement were considered as strategic: will be focused on maximizing joy 1. Looking into the Future and pleasures of long lives of humans 2. Advancing Medical Technologies augmented with biomechatronics. 3. Advancing Intellectual Leadership Most healthcare cost will be shifted 4. Advancing Global Health Information from end-of-life to prenatal care. Infrastructure Since everybody will be augmented Health technology becomes the center with biomechartonics, the word of healthcare systems’ strategic planning “disabled” will not exist anymore – we process. Developing a clear vision of the will all have the same chance to be future of health technology and smart truly human. investment in technology are the critical The “Future of Health Technology” success factors. Healthcare leaders book provides a comprehensive need to develop a vision of future health vision of the future ofhealth technology to lead effectively in the new technology by looking at the ways century. The social and economic issues to advance (1) medical technologies, surrounding health care will be inextricably (2) health information infrastructure, linked to the technological aspects of and (3) intellectual leadership. It also medicine in the next century. Given rapid explores new technology creation progress in nanomedicine, the pressure and adoption processes including towards detailed outcomes analysis, the impact of rapidly evolving growing use of Internet, robotic surgery, technologies. People discover and genetic therapy, telemedicine, on-line respond to the future as much as they consumer education, and bioinformatics plan it. Health systems and societies health technology becomes the key with the clear vision of future health to intelligent health care. To embrace technology will have a better chance technology is the only way health systems of reducing human suffering. can assimilate with the technologically advanced society. On-going massive 3.2 Future of Intelligent and medical data collection, instantaneous Extelligent Environment – Book #2 analysis, affective computing with emotional 2005 intelligence, and nanosurgery will be In the “Future of Intelligent and possible soon. Extelligent Environment” book there Last century took us from the first are eight strategic areas selected as electric switch back in 1880s to the first outlined below: nanomotor’s switch in the year 2000; from • Goals and Unsolved Problems 30 ton computer to polymer transistors on a plastic that one can print at home;

• Consumers Era - Sociotechnological enhances our health and wellbeing Environment from conception to death. This environment is emerging now with • Healthons Era – Technology On our intelligent caring machines, cyborgs, Body, in our Body and All Around Us wireless embedded continuous computing, healthwear, sensors, • Cyborgs Era – Implants, Merging of healthons, nanomedicine, adaptive Men and Machine & Caring Machines process control, mathematical modeling, and common sense • Long Life Era - Extending Human Life- systems. span and Future of Caring for Elders Human body and the world in which it functions is a continuously • Hi-Tech Cure and Care Era – changing complex adaptive system. Examples: Future of Cancer and We are able to collect more and Addiction Control more data about it (wearable body monitors will be soon in each • Global Healthcare Era - Enhancing household just like toothbrushes) Healthcare with Soft Technologies but the real challenge is to infer local dynamics from that data. Intelligent • Adaptive and Errorless Era - Adaptive Caring Biomechatronic Creatures Healthcare Process Management and Healthmaticians (mathematicians serving human health) have a better The cover design of this edition reflects the chance of inferring the dynamics that unsurpassed drive to understand health on needs to be understood than human the molecular level as well as a conviction physicians. that this is the only way to hope to Humans can only process eradicate major diseases and have control comfortably three dimensions over mental health. It also reflects the need (max 22) while computers can see to connect traditional IT with Life sciences, infinite number of dimensions. Will and especially, with nanomedicine. In 1996, we enjoy doing medical science I focused on health technology in the era of if computers become better at it booming healthcare informatics due to my than us? We will need to trust the observation that health-related information distributed network of healthons, comes from and is embedded in biological, Intelligent Caring Creatures, and electronic and mechanical artifacts – it is an NURSES (New Unified Resource integral part of Medicine and does not exist System Engineers) - designers who as an independent and isolated island. inbuilt medical intelligence in our “The Future of Intelligent and Extelligent external environment - creating Health Health Environment ” book brings you Extelligence (ubiquitous computing). closer to the world where technology on At Future of Health Technology our body, in our body and all around us Summit™ 2003 Space Elevator

example was used to show how seemingly impossible conceptual designs could become real. Celestial hospitals and errorless healthcare are possible. We may need to use bionic arms and extended cognition to do that but if we spend as much time designing our preferred future as we do researching the past we can get there in no time. Developments like robo-docs, robo- Figure 3. Original picture of a “background cats, and space elevators are not just neuron” (© 2002, FHTI) from the cover of exotic; they are a reaffirmation that with “Future of Intelligent and Extelligent Health Environment” book taken by Danuta Glowacka creative thinking we can go a long way to Ph.D. during her research on morphological the discoveries that will allow us to fix our differentiation of PC12 Cells; Journal of Neuroscience Research 25:453-462 (1990). healthcare system and set it on a high road for the future. The dream of an intelligent caring machine is closer to reality considering that Timothy Bickmore’s relational agent can help you with your fitness training, Yulun Wang’s robotic doctor can help you even from a remote location (remote presence); BodyBug™ can collect your lifestyle data and tell you what to eat and how much to sleep. We are closer and closer to the world with healthons on your body, in your body and all around you; where not a doctor but your primary care healthmatician warns you about an approaching headache; and where NURSE programs Figure 4. Connecting Neurons. Cover your intelligent caring machines so they illustration of Future of Intelligent and Extelligent Health Environment, Ed. R. Bushko, can talk to your cells and stop disease in its IOS Press 2005. Image (©2005, R. Bushko,) tracks. based on pictures of neurons grown by Danuta Glowacka Ph.D. 1990.

4. “Strategy for the Future of Health” and “World Health Syrategy” – Book #3 2009 and eBook #4 2016 - Book Synthesis “Among the noblest aspirations of humanity are the development of advanced technologies for the conquest of aging and medically preventable causes of death, and the launching of a new era of personal choice in medicine. Strategy for the Future of Health gives us a solid push in the right direction.” Robert A. Freitas Jr., Author of “Nanomedicine”

Defining the future of health is difficult and requires both common sense and intuition. Attempts to find solutions for difficult problems require educated guesses and subsequent efforts to verify any hypothesis Figure 6. Cover page illustration of the that is made. The best way to strategize ”Strategy for the Future of Health” book by Egg Design www.egg-design.com (© Renata for the future is to collaborate with experts Bushko, 2008-9) based on the above neuron in diverse fields and to then employ their picture by Danuta Glowacka Ph.D. shows future collective knowledge and common sense to of medicine where we communicate with our dare to guess. nanorobots (artist’s conception) to stop disease before it even produces any symptoms. Figure 5. Original 4.1 Health Care Strategy for the picture of a Future - General Directions “background The most important part of strategy neuron” (© 2009, FHTI) development is goal setting. High- from the cover level goals provide direction and of “Strategy sense of purpose. Without these high for the Future level goals international, national and of Health” book taken organizational operational strategic by Danuta plans often fail because of lack of Glowacka Ph.D. stamina and perseverance. “Health during her Care Strategy for the Future - General research on morphological Directions” segment describes the differentiation of PC12 Cells; Journal of Neuroscience environment in which technology will Research 25:453-462 (1990). be functioning, as well as its broader

social ramifications in an attempt to create where science and technology have errorless healthcare. brought healthcare closer to an ideal As described by David Gruber, the form and where design can even American health care system is in crisis. further progress the field. Such Gruber begins to address the economic design issues can be examined in problems enveloping the field, describing the context of pilot projects, such as a future environment where professionals, that described by Julia Royall in her providers and policy experts holistically chapter that examines the progress care for their patients, where technology of the employment of a malaria plays an enormous role in increasing electronic tutorial in Mifumi village, engagement, the personalization of the use of a mental health electron healthcare, the sharing of experiences, tutorial in northern Uganda and the and increase convenience as well as development of a health management better choice making and where a cost system in Tororo Hospital. Through effective primary care navigator becomes IT and medical informatics, these pilot the central component of public policy. projects demonstrate the possibilities Robert Greenes echoes the concerns of that exist, in an African setting, when Gruber regarding the current state of the interdisciplinary teams employ health American healthcare delivery, discussing informatics to enhance community issues of availability, access, quality and collaboration and overall health. cost that afflict current models of health As it may be seen, the first step to care delivery. strategizing about the future is to Craig Feied et al, in their visionary paper, envision a holistic picture regarding “Indistinguishable From Magic: Health the social environment of health and Wellness in a Future of Sufficiently care. Next, specific examples may be Advanced Technology”, assert that the role explored in order to understand what of informatics is to act as a “key enabler” may be possible. to address these problems through the availability of definitive and unambiguous 4.2 Strategy for Future of e-Health: tests, new methods of analyzing messages Technologically Connected from cellular and subcellular networks and Consumers & Machines universal access to data in order to create In this segment, experts describe “connected health” and to improve all various concrete examples of aspects of health and modern life. technologies and currently available Gianfranco Zaccai adds to the prototypes that will have great discussion regarding a better future transformative power on healthcare by suggesting the use of a holistic and the progression towards errorless design process in order to address the and perhaps, eventually, doctorless multifaceted problems that affect our healthcare. healthcare system, boldly asserting his goal Klaus Peter Adlassnig et al. in creating an ideal customer experience describe the first of these

technologies in a paper regarding the use another alternative to the traditional of Artificial Intelligence to control hospital- patient-health care provider based (nosocomial) infections, a system that relationship in which a system, named will expand upon the computerization of “I’m Listening” can work in patient records. They describe fuzzy and conjunction with a human doctor to knowledge based systems of identification more efficiently and effectively and monitoring employing medical conduct triage care to best take knowledge packages (MKPs) in a system advantage of time and resources, as named Moni that may be incorporated into well as to reduce errors in preexisting medical information systems communication and diagnosis. leading to unparalleled nosicomial infection James DelloStritto introduces surveillance. One can imagine the wide innovative concept of “spontaneous variety of uses such technology could be interoperability” with his chapter on used for. adaptive information networks in In “ Innovations in Connected Health,” health. Creating a model based upon Kanwaljit Singh and Joseph Kvedar assert biological frameworks, DelloStritto that recent technological advances make describes memory maps that facilitate new innovations that lead to the concept of adaptability and interoperability with Connected Health feasible. Like Gruber the transference of evolutionary and Greenes in Section 1, Singh and Kvedar history and meta-data associated with remark that the crisis status of the current information. Despite challenges, this health care system provides a unique system will allow for greater opportunity and avenue for reform in using availability of information which will technology to increase quality and access lead to better prevention of disease, while simultaneously decreasing cost with patient outcomes and fewer medical hardware and software technology errors. innovations. Rather than a holistic system In the paper “Can Consumers Cure reform, Alex Pentland et al. suggest Themselves?” Renata Bushko examines the that current technologies and their future of e-Health within the context of a transaction “breadcrumbs” be used to newly evolved field of “ITicine” which fuel Reality Mining, which has the equally merges the more traditional medical capability to use statistical analysis discipline with Information Technology (IT) in and machine learning methods to order to improve medical diagnosis. This provide individually and collectively field would employ the use of caring comprehensive pictures of our lives. machines as well as a sophisticated expert Employed in fields of diagnosis, system by consumers themselves in order patient treatment and monitoring, to analyze and reason with physiological health service planning, surveillance and molecular data. These technologies of disease and risk factors, and public will drastically reduce errors in medicine. health investigation and disease John Moore and Henry Lieberman suggest control, Reality Mining will use raw

data provided by everyday devices such as progression towards immortality and mobile phones, cars and security cameras. that eliminating human aging is Pentland et al., address the potential legal becoming a reality through what they and privacy ramifications, yet clearly refer to as “Fantastic Voyage.” This demonstrate the value of such technology. Program includes the aggressive As these various technologies are application of current knowledge, the developed, we must stop to consider the use of biotechnologies such as gene retributions of inventing and using such technologies and the use of technology with a large segment of the nanotechnology to rebuild bodies and population, as described in Section I of this brains in order to slow aging and book. Barry Robson addresses just this, disease process. Aubrey deGrey exploring issues of privacy, security, addresses aging in terms of molecular bandwidth and computational power that and cellular decay, a process that can require roaming agents of analysis that incrementally be defeated. He send only conclusions rather than full predicts a threshold on the reports of primary data. He suggests the succession of advances deemed use of best practice in inference and the “Methuselarity” that will follow a future necessity for a universal agreement decreased rate of improvement in regarding the treatment of probabilistic anti-aging technologies required as higher order logic. According to Robson, we age. He compares and contrasts quantum mechanics may provide such a this to the concept of “singularity,” and system, one with emergent properties that makes interesting predictions might allow for understanding of the nature regarding the future of this field. of thought, an issue he addresses in In his chapter titled “Of Mice and Chapter 18 in as well. Men,” Kevin Warwick provides a concrete link between biology and 4.3 Life Extension Strategy: Longer Lives technology in reference to the brain. and New Life Forms Examining a laboratory cultured brain This segment delves into the current efforts linked to and controlling a physical towards the extension of human life and the robot, Warwick explains his interesting maintenance of high quality throughout life. insight regarding fundamental It examines ways in which existing human features of neural disease and the life may be extended, as well as how new mechanisms of neural signal transfer. or artificial life may be used in field such as Examining a similar technology- organ regeneration in order to further biology link, S. Adam Hacking et al. improve existing and future human life. explore the issue of tissue Issues of new machines and subsequent regeneration of artificial organs. They machine-human interactions and relations address the limits to such are also addressed technological progression but also In Chapter 14, Raymond Kurzweil and the emerging approaches that may be Terry Grossman demonstrate the brought about in the near future

regarding control of stem cell a discussion regarding the differentiation, microscale control of local consequence of slow technology tissue and the generation of organs that development, demonstrating the vast contain multiple cell types. effects that an immediate and large- In Chapter 18, Robson again investigates scale investment in nanorobots could the connection between quantum make. Renata Bushko expands on mechanics (QM) and thought, suggesting the importance of recent ways in which QM can be used to decipher technological events, describing patterns of human thought and to aid in the chromallocyte, designed by Freitas. communication between humans and This nanorobot, capable of in vivo machines. These papers provide but a chromosome replacement, would simple snapshot of current ideas and reverse the effects of genetic disease despite the absence of a comprehensive and damage, preventing infirmity and picture, it can be surmised that we are well aging. She also stresses the on our way to a different and better future. importance of timely investment and The next section furthers this conclusion, delivery. Rob Burgess addresses the addressing the extension of human health medical applications of nanoparticles and life with the use of nanotechnologies. and nanomaterials and the current limitations of diagnostics and 4.4 Nano-Strategy: Extending Human therapeutics that function without such Potential with Nanomedicine technologies. He argues that in order This segment focuses on current to improve the sensitivity and efficacy technology designed on a nanoscale to of health care interventions, a new extend human life and to reduce suffering generation of technology will be through non-invasive interventions, a required. technology that will vastly revolutionize the In Chapter 21, Robert Linares et al way we think about healthcare delivery and discuss the recent advances made in the acceptable levels of human suffering diamond technologies as well as the inflicted by surgery. In order to better various ways in which diamonds, as a understand the implications of bio-compatible material, may be used, nanomedicine, one can consider the use of including quantum computing, nanotechnology to be as significant as the molecular imaging and perhaps even invention of anesthesia, an analogy that eventually diamond nano-bots. The may be extended to understand the chapter asserts that a new generation subsequent drastic reduction in suffering. of diamond based bio-electronic This is an idea that must be kept in mind devices could usher in a paradigm when considering the implications of the shift for medical science. Benjamin technologies related in the following Miller explores other revolutions in chapters. healthcare, examining the streamlining Welcoming us to the future of medicine, and simplification of detection and Robert A. Freitas Jr. begins the section with quantification capabilities regarding

molecules of biomedical relevance. Tod autism. Rather than a diagnosis Hogg looks how molecular electronics and based upon behavioral measures, nanoscale chemical sensors will be able to Rembrand demonstrates technologies detect chemical pattern as they flow in a that can diagnose and treat those with passive solution, demonstrating how autism on the basis of Otoacoustic information acquired from a large number Emissions (OAE) and Attention Shift of sources will allow for precise drug Delay (ASD) to improve quality of life. delivery as well as the increased speed Cindy Mason et al. discuss another and accuracy of microsurgery. Each of field of soft medicine: haptic these chapters demonstrate an example of medicine. As healthcare based on a branch of nanotechnology that when the effects of loving touch on disease combined, will revolutionize modern prevention, haptic medicine has been healthcare. shown to have positive outcomes on over forty health conditions. Mason et 4.5 Strategy for Wellness: Emotional and al. describe two web-based education Physical Fitness and media projects that will expand This section of the book introduces the the field of haptic medicine, thus concept of soft technology and a more improving and extending human life. qualitative improvement of human life. It As a concluding chapter, Caroline describes examples of current M. Apovian and Rosane Ness- technologies used for mental health Abramof’s “Future of the Fight with applications as well the training of Obesity” addresses a modern emotions, as described by Jason Kahn et epidemic and the ways in which soft al. Their chapter presents a computer- technology may be used to alleviate based intervention called RAGE (Regulate its consequences on both individual And Gain Emotional Control) which employs health and the health of society as a the paradigm of biofeedback and requires whole. relaxation during a quick reactive pulse in As it may be seen, technology, order to train children to focus, react, inhibit both hard and soft, provides us with impulses and control their own heart rate the tools for an unimaginable number during stressful circumstances in order to of solutions for issues in healthcare increase emotional control. ranging from aging to obesity, James Drane et al. and Raffi Rembrand diagnosing and treating learning focus more upon learning disabilities and disabilities and autism to unraveling the secrets of thought employing autism, respectively. Drane et al. examine quantum mechanics. By discussing the profound effects of technology on and outlining strategies in e-health, quality of life improvement for children with life extension, nanomedicine, and disabilities, looking at the benefits of general wellness, we can begin to robotics in eduation and rehabilitation. address the crisis of the current Rembrand looks towards technology as healthcare system as well as the more of a diagnostic tool, particularly for endless possibilities for our future.

5. Conclusions Appendix Goal setting is the most important part of strategy development. The Future of Health Table 1. Future of Health Technology Book Ed. Technology Institute’s www.fhti.org goals Renata G. Bushko, IOS Press 2002 are an example of goals that have transformative power: (1) stop disease Part I: Looking into the Future before it even begins, (2) stop suffering before tears occur, (3) stop symptoms • Defining the Future of Health Technology – Biomechatronics before they hurt, (4) stop medical errors before they kill, (5) stop cyborgs before • Inventing the Future - Tools for Self- they control us, and stop aging before it health disables us. Part II: Advancing Medical Technologies These goals can be realized because of • Future of Medical Knowledge unprecedented technological revolution Management and Decision manifesting itself in the convergence of Support molecular biology, computer and medical science, electrical, mechanical, genetic and • Future of Nanofabrication and biomedical engineering (including cell, Molecular Scale Devices in molecular and tissue engineering). Nanomedicine Resulting merger of information technology (IT) with medicine and the formation of • Thought to Computer Communication “ITicine” is a major strategic development. It will play an integrative role in the future of • Affective Medicine: Technology health technology, accelerating the speed with Emotional Intelligence of discoveries leading to dramatic cost reduction and eventually to errorless • Future of Medical Computing healthcare. According to Aubrey de Grey, author of “Ending Aging”, like all technology, • Intelligent Agent Software in health technology can only proceed so far Medicine by small incremental steps; every so often it • Speech and Language needs vision, lateral thinking, the Technologies, Intelligent willingness to step back and consider Content Management and radical new approaches. Renata Bushko's Intelligent ([email protected]) annual conference and associated books are a tremendous focus • Assistants for this crucial long-term thinking.” We have Part III: Advancing Global Health a unique chance to define the future rather Information Infrastructure than to simply observe it, and we must take absolute advantage of this opportunity. “Strategy for the future of Health” book is the nano-step in that direction. Most of the work is ahead of us and it will continue at annual Future of health technology summits: FHT2010 9/26-27/2010 and FHT2011 9/27-28/2011.

Table 2. Future of Intelligent and Extelligent Health Environment Ed. Renata G. Bushko, IOS Press 2005 • Developing the Health Information Infrastructure in the United States Goals and Unsolved Problems

• Future of Telemedicine • Healthons: Errorless Healthcare with Bionic Hugs • Advanced Technology Program: and no Need for Quality Information Infrastructure for Health Control Focused Program Consumers Era - • Quality Enhancing Conceptual Sociotechnological Environment Tools for Medical Decision Making • The Prospects for Medical • The Future of Highly Personalized Technology in the Next Health Care Decade

• Developing E-Commerce and • Innovation in Telehealth and Improving Resource Management the Role of the Government • The Future of Information Technology for Health in • Present and Future Developing Countries Challenges in Medical Data Part IV: Advancing Intellectual Leadership Management: Economics, Ethics, and the Law • What is Digital Medicine? Healthons Era – Technology On our Body, in our Body and All • Evaluating New Health Information Technologies: Around Us Expanding the Frontiers of • Healthwear: Medical Health Care Delivery Technology Becomes Wearable • Future of Security and Privacy in Medical Information • Interfacing Biology and Computing for Health: The • Future of Health Technology Future of Home Diagnostics to Augment Patient Care in the Hospitals • Designing and Evaluating • Your Wealth Your Health – Home-based, Just-in-Time Bellweather Industries for Supportive Technology Decision Tools and Symbiotic Stewardship • Health. Care. Anywhere. Today. • Impact of Voice-enabled Clinical Reporting – US • How Do We Get The Medical Example Intelligence Out?

Cyborgs Era – Implants, Merging Global Healthcare Era - of Men and Machine & Caring Enhancing Healthcare with Soft Machines Technologies • Future of Computer Implant • Global Medicine Technology and Intelligent Technology Human-Machine Systems • Shaping a Healthy • Future of Caring Machines Future: Megabyte, Not Mega bite! • Cyber-anthropology: A New Study on Human and • Digital Literacy in a Technological Co-evolution Landscape of Data: Hi-Tech Cure and Care Era – A Plea for a Broader Examples: Future of Cancer and Definition for Citizens Addiction Control and Patients • Harnessing the Power Adaptive and Errorless Era - of an Intelligent Health Adaptive Healthcare Process Environment in Cancer Management Control • Situated, Strategic and AI- enhanced Introduction of • Future of Anti-addiction Technology to Health Care Vaccines • Towards an Intelligent • Automating Addiction Hospital Environment: Treatment:Enhancing the Operating Room of the Human Experience and Future Creating a Fix for the Future Long Life Era - Extending Human • Framework for Measuring Life-span and Future of Caring Adaptive Knowledge-Rich for Elders Systems Performance • A Strategy for Postponing Aging Indefinitely

• Future of Caring For An Aging Population:Trends, Technology, and Caregiving

• Promoting Safe and Comfortable Driving for Elders

Table 3. Strategy for the Future of Health, Ed. Renata Life Extension Strategy – Longer, Happier Lives G. Bushko, IOS Press 2009 and New Life Forms • Fantastic Voyage: Live Long Enough to Live Goals and Synthesis Forever – The Science Behind Radical Life Extension • Strategy for the Future of Health – Goal Formation & ITicine • The Singularity and the Methuselarity: Health Care Strategy for the Future - General Similarities and Differences Directions • Indistinguishable From Magic: Health • Of Mice and Men and Wellness in a Future of Sufficiently Advanced Technology • Future Approaches to Organ Regeneration: Microscale Environments, Stem Cell • Informatics and a Health Care Strategy for Engineering, and Self-assembly of Living the Future - General Directions Tissues

• Designing the Future of Healthcare • Links Between Quantum Physics and Thought Nano-Strategy - Extending Human Potential • Can Consumers Cure Healthcare? with Nanomedicine • Welcome to the Future of Medicine • Strategies for Positive Outcomes: Can Information Technology Make a • Medical Applications of Nanoparticles Difference in Health in Africa? and Nanomaterials Strategy for Future of e-Health: Technologically Connected Consumers & Machines • Diamond: A Bioelectronics Platform • Using Reality Mining to Improve Public Health and Medicine • Diagnostics for a Personalized Medical Future: Extending our Senses to the • Artificial-Intelligence-Based Hospital- Molecular Scale Acquired Infection Control • Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids • Adaptive Information Networks in Healthcare: Spontaneous • Fight for Chromallocyte Interoperability Strategy for General Wellness - Emotional and Physical Fitness • Innovations in Connected Health • RAGE Control: Regulate And Gain Emotional Control • Talking About Painful Subjects: Flexibility and Constraints in Patient • Therapeutic Robot for Children with Interviews Disabilities: Case Study

• Towards Intelligent Internet-Roaming • Sound of Hug Agents for Mining and Inference from Medical Data • Haptic Medicine

• Can Consumers Cure Themselves? • Future of Obesity Prevention and Treatment

Acknowledgements [4] M. L. Minsky, The Society of Mind, The author would like to thank Danuta Simon and Schuster Inc., New York, Glowacka, Angela Fiori, Timothy Preston NY, 1986. and John Jackson for cover illustrations, [5] L. G. Griffith, A.J. Grodzinsky, and “Strategy for the Future of Health” Advances in Biomedical Engineering, chapter authors: Klaus-Peter Adlassnig, JAMA, Vol. 285 No. 5, 2001, p 556-561 Caroline M. Apovian, Alexander Blacky, [6] A. Newell, The Knowledge Level, Devon Brewer, Rob Burgess, Aubrey Artificial Intelligence 18, 87-127, 182. D.N.J. de Grey, James DelloStritto, Patrick [7] W. Clancey, The Knowledge Level Doering, James Drane, Peter Ducharme, Reinterpreted: Modeling How Systems Craig F. Feied, Robert A. Freitas, Michael Interact, Machine Learning, 4, 285-291, Gillam, Joseph Gonzalez-Heydrich, Robert 1989. A. Greenes, Terry Grossman, David Gruber, [8] M. Minsky, The Future of Artificial S. Adam Hacking, Jonathan A. Handler, Intelligence Technology, Forum, Tracy Heibeck, Tad Hogg, Jason Kahn, Ali Risk Management Foundation of the Khademhosseini, Nezamoddin Kachouie, Harvard Medical Institutions, Volume 17, Walter Koller, Raymond Kurzweil, Joseph C. Number 1, April 1996. Kvedar, Corinna Lathan, David Lazer, Won [9] M. L. Minsky, Framework for Gu Lee, Henry Lieberman, Bryant Linares, Representing Knowledge, MIT AI Robert Linares, Cindy Mason, Earl Mason, Memo No. 306, 1974. John Moore, Benjamin Miller, Rosane Ness- [10] M. L. Minsky, The Future of Artificial Abramof, Alex Pentland, Raffi Rembrand, Intelligence Technology, Is there a Barry Robson, Julia Royall, Charlotte Safos, Virtual Doctor in the House?Forum, Kanwaljit Singh, Mark S. Smith, Brian Travers, Volume 17, Number 1, April 1996. Kevin Warwick, Gianfranco Zaccai. [11] Future of Health Technology, Ed. Renata. G. Bushko, IOS Press 2002. References [12] Future of Intelligent and Extelligent [1] Future of Health Technology Summits Health Environment, Ed. Renata G. Proceedings 1996-2008, www.fhti.org Bushko, IOS Press 2005. [2] Renata G. Bushko, Leadership [13] Strategy for the Future of Health, Challenges in the 21st Century: 7 Strategies Ed. Renata G. Bushko, IOS Press 2009. to Leadership, Workshop P-6, Healthcare [14] Robert A. Freitas Jr., The Ideal Executive’s Challenges in the 21st Century: Gene Delivery Vector: Chromallocytes, Leadership, Quality, Technology, and Cell Repair Nanorobots for Innovation-driven Process Management, Chromosome Replacement Therapy, J. IMIA’95, Vancouver Canada, 1995. Evol. Technol. 16(June 2007):1-97. [3] M. Dretouzos, Kurzweil vs. Dretouzos, Technology Review Vol. 104/NO. 1 (2001) 81- 84.

Salil H. Patel Chapter 9: Present and Future of novel modalities for practice, / Present and Future Challenges in Medical Data treatment, and payment. Challenges in Management: Economics, Ethics, and Concomitantly, the pervasive adoption Medical Data Management: the Law of an Internet infrastructure, Economics, Salil H. Patel underpinned by a host of standardized Ethics, and the Law in Johns Hopkins School of Medicine open protocols (e.g., TCP/IP, SSL, “World Health Departments of Urology and Radiology DICOM, and VPN), served as a means Strategy” eBook, (Ed.) Renata The Johns Hopkins Hospital, Baltimore, MD, for convergence of these G. Bushko, USA technologies. Electronic medicine FHTI, 2016. Futureofhealth. generates economic activity on the org From Abstract order of hundreds of millions each Intelligent and Extelligent lectronically-linked knowledge plays an year, at levels ranging from individual Health increasingly central role in the delivery private practices to comprehensive Environments (Ed.) Renata G. of health services worldwide. Medical provider networks. According to the Bushko, IOS E data collection, archival, and analysis are all 2002 American Medical Association Press 2005 increasing in both rate and volume; large, Study on Physicians’ Use of the World cohesive collections of personal health Wide Web, nearly 80% of American information are emerging rapidly. Factors physicians use the Web as part of their driving this integration include value-added practice. One-third of surveyed methods of diagnosis and therapy, interest doctors are affiliated with a website for in evidence-based practices, safety promotional or public-education concerns, and increased consumer demand purposes. The era of information has for personalized, comprehensive medical indeed altered the behaviors of services. Practitioners, businesses, patients, individual consumers of medical goods and the public at large would be well-served and services, with nearly one-half of all to develop and sustain a dialogue adults in America using the Web as a addressing these phenomena, including source of healthcare information [1]. assessments their of economic, ethical, legal On larger scales, companies such as implications. Healtheon have already begun to offer commercial solutions for patient data, 1. Introduction prescription, and claims management Since Watson and Crick’s elucidation of the [2]. The implementation of electronic structure of DNA in 1953, a revolutionary tide patient record systems such as has swept across the fields of biology and Siemens SIENET’s MagicWeb, which chemistry, profoundly affecting the practice claims a user-base of 25,000 of clinical medical care. The era of the clinicians, has increased the degree of 1990’s marked the inception of a second enterprise-wide data aggregation and major shift in the practice of medicine: the communication among care providers, informatics wave. Seminal developments in diagnostic facilities, and insurers. the domains of data collection, manipulation, Greater centralization of health and distribution have potentiated the spread information in databases, according to

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 90 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

industry commentator Lawrence Gostin, is needs for knowledge-based “already under way” and carries with it “an information” [3]. The advantage of this aura of inevitability.” Although a monolithic, early investment is a large projected cross-industry and nationwide system might return in terms of economic efficiency maximize the level of aggregation, it is and effectiveness. perhaps more feasible that existing Inefficiencies in administration may databases and information streams will be reduced through improved interoperate by leveraging the current reach consistency in billing and data transfer of open standards and Internet practices. Such savings have already technologies. In light of these dramatic been demonstrated in the changes, it is possible to envision that the northeastern U.S., where the storage and manipulation of personal data establishment of the New England such as medical histories, genetic profiles, Healthcare Electronic Data and treatment delivery in novel paradigms, Interchange Network is currently facilitated by information technology, may reducing costs to care providers due occur within a comprehensive electronic to reduced administrative overhead network established within our lifetimes. and is forecasted to lead to annual Such integration must proceed with careful savings on the order of 66 million consideration of issues such as economics, dollars [4]. Furthermore, it is public health, and civil rights. conceivable that an information- systems facilitated reduction in 2. Economic Considerations preventable medical errors, to be Linked information technology systems addressed shortly, and the potentially bear a major impact upon the employment of intelligent decision medical field in the realm of costs. Although support systems may reduce exposure the initial adoption of any new system entails to malpractice suits, which have been some investment, in the long term, the partly responsible for dramatic savings to the health care system over a increases in physician insurance prolonged deployment period may be premiums since 1999 [5]. In addition, significant. In terms of startup expenditures, the establishment of a “computerized the major areas for investment will include decision support model” which software and hardware development and analyzes care efficacy and alerts installation, as well as the creation of a providers to treatment alternatives has robust services model to exploit fully the been demonstrated empirically to capabilities of the new system. The latter reduce total expenditures and to may entail changes in medical and decrease the length of hospital stays consumer education methods, as well as [6]. Even these models, however, must training of librarians and data custodians to account for changes in the final assist in data manipulation and storage. As “product” of quality of care delivered, Jones, et al. note, “Services are the most as initial parameters of the treatment important factor in meeting organizational process are altered. Witness the

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 91 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

enactment of an 80 hour work-week encourage developing countries to limitations for residents in accredited training make use of a “leapfrog” model of programs at U.S. hospitals, a response to healthcare development – i.e., the claims that fatigued residents are more likely directed and proactive integration of to commit errors. One consequence of current information technology in these regulations is that the care of a patient nascent public health systems. This may be passed among several separate same leapfrogging process has care teams within an initial span of 24-48 already been demonstrated in the hours; the demands of multiple transfers of telephony sector in countries such as recent patient information may lead to China, India, and the former Soviet altered content, granularity, and quality of Republics, where high-capacity these findings, and unintentionally wireless cellular services in some compromised quality of care. Retrospective areas are being deployed in lieu of studies and randomized controlled trials are traditional land-lines [13]. Thus, cost especially indicated in order to assess the savings issues may provide an impetus response of the healthcare delivery system for the adoption of electronic medicine to such perturbations. internationally. Tele-health services, involving remote diagnosis and supervision of care, may 3. Ensuring Public Health facilitate cost savings by increasing access The convergence of personal data and decreasing utilization of inpatient and delivery systems presents myriad services [7]. The potential of using the potential boons and challenges to the nascent Internet II, with its high-bandwidth health of both the individual and infrastructure, combined Quality of Service population levels. Hospitals are assurances and high network availability, for already recognizing the utility of orthopaedic and cardiac telesurgery, electronic systems for preventing promises to improve care efficiency even iatrogenic injury [14], in domains further [8]. Although cost-effectiveness for ranging from drug dispensation, telemedicine has yet to be established [9], dosage errors, and interactions, to the associated shifts in resource allocation may prevention of idiosyncratic allergic still improve overall efficiency of healthcare reactions and dose-related toxicity. delivery in selected settings, such as rural Online medical information empowers areas [10] and public schools [11]. It has been patients to become more informed and proposed that a reimbursable-time or engaged in their treatment process, “billable hours” model, similar to that used and may encourage utilization of by the legal profession, might be used to preventative educational services. In encourage physicians and allied health care fact, 95% of patients in a professionals to incorporate electronic representative clinical study “strongly resources into busy clinical practices [12]. preferred” electronic education pre- Finally, implications for cost reduction may operatively over the conventional reach across domestic borders and physician-mediated consent process;

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 92 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

this was attributed in part to reduced patient physicians: disclosure statements levels of anxiety and intimidation [15]. In the about data sources and compensation, realm of prescription drugs, the World Wide explanations for blank or missing Web is increasingly being used by records, reports of database size and pharmaceutical companies to provide scope, and an indication of the marketing materials and prescription timeliness of each data field [16]. information directly to physicians and In the domain of public health, consumers. At the same time, independent informatics may play a key role in the organizations are releasing cost- evaluation of populations as well as effectiveness data and clinical practice the prevention and treatment of guidelines as part of publicly-accessible disease. For instance, under an therapeutics databases. Medical indices electronic system liked to established and journals are widely available online health authorities, the dissemination of though public systems sponsored by the reportable disease information may National Library of Medicine. Other types of become rapid, accurate, and automatic medical data are now accessible to the (privacy concerns notwithstanding). public as well, including the release of For instance, Dr. John Bartlett, chief of physician malpractice and disciplinary Division of Infectious Diseases at the records by state boards of certification, as Johns Hopkins School of Medicine, well as morbidity and mortality results for established an e-mail broadcast practicing individuals, albeit in limited cases system in response to the anthrax [16]. Electronic mail, bulletin boards, and attacks of October 2001, with an directed broadcast systems may be vital estimated 18 thousand subscribers to facets of future coordinated responses of the service one year later. care providers during times of medical Commercially, Oracle Corp. is emergencies. Enthusiasm of such marketing its Lightweight Epidemiology widespread dissemination of medical Advanced Detection and Emergency information must be tempered with caution, Response System for centralized however. With the flood of drug data outbreak monitoring and coordinated available online, the reports of “off-label” resource allocation. uses by patient group websites, and the Clinical measures studies of large increase in direct-to-consumer marketing, databases will allow for greater inefficient utilization patterns may quickly efficacy assessment across a wide emerge [17]. Even more significantly, population, help to identify dangerous judicious audits have revealed a wide range interactions or reactions to prescription in the accuracy and completeness of online pharmaceuticals post-FDA-approval, databases, presenting the potential for and aid public health planners in public confusion and misinformation [18;19]. identifying populations with the In response to these challenges, Stone, et greatest disease burden using al. suggest the following standards in objective and quantifiable metrics. particular for all websites which profile The European Effective Health Care

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 93 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Bulletins and systematic reviews of the The company has managed to secure international Cochrane Collaboration, all full and proprietary access to the available online, attempt to synthesize the health and family history of all Icelandic current state of medical care and compare citizens [24]. In less than two years, relative treatment efficacies in an attempt to the company has reportedly identified promote evidence-based, cost-aware putative genes for susceptibility to healthcare practices. In the U.S., the Federal complex conditions such as late-onset Agency for Healthcare Research and Quality Parkinson’s Disease, Alzheimer’s has sponsored studies correlating clinical Disease, Type II diabetes, and obesity practices and outcomes for several years [25;26]. The products of basic [20], although current limitations in dataset research, such as gene sequence and size and structure still are significant. homology, as well as related clinical Variable granularity, or specificity of and pathophysiological data, are also information fields, is a limiting characteristic correlated using open-access of current records, making cross-datatype initiatives such as Online Mendelian and cross-database comparisons difficult. Inheritance in Man. Implementation of methods gleaned from the disciplines of knowledge engineering, 4. Health Databases and Issues of complex systems, nonlinear analysis, Rights biostatistics, and predictive analytics will all be necessary in order to fully exploit a large 4.1 Assessments of Personal Liberty and accessible database of health In addition to the above measures and outcomes. Research teams considerations, convergence of the at IBM [21] and SAS [22] have proposed a Internet and medical practice has itself methodology grounded in these premises, occurred at the nexus of practical termed Unstructured Data Mining, that may implementation and the boundaries of be particularly well-suited to the task of civil liberties. Is privacy a moral sifting through arrays of disparate patient imperative? Regardless, there are datasets. In fact, many retail corporations implicit constitutional protections, as already use data mining techniques in sales outlined by the classical “penumbra” trends analysis and consumer profiling [23]. established within the U.S. Bill of Regardless of the power of sampling Rights, which protect reasonable methods, it is still a daunting task to extract expectations of personal privacy; information about poorly-characterized or comments Supreme Court Justice multifactorial disease syndromes with the William Brennan (1977): current predominance of relatively decentralized or disconnected independent “The central storage and easy accessibility of patient records. One controversial solution computerized data vastly increase the potential for abuse of that information, and I am not to this problem has been pursued by prepared to say that future development will not deCODE Genetics, a private entity demonstrate the necessity of some curb on such contracting with the government of Iceland. technology.” [27]

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 94 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

One unanswered and contentious issue cannot Table 1. Requirements for assessing the be ignored: who actually owns increasingly ethics of research on human subjects. commoditized patient data? In most local jurisdictions, it is actually the creator of the record, Social and scientific value of protocol not the patient, who has primacy over the use of 1 database, although individual privacy rights in fact 2 Scientific validity supercede authorship rights in selected instances Unbiased subject selection [28]. When databases span states and even 3 countries, which nations’ laws apply and in what 4 Clear risk-to-benefit proposition circumstances? When data becomes stripped 5 Independent review of protocol and reasoning of specific individual identifiers, dis-aggregated, completely de-identified, or compounded, at 6 Informed consent of participants what point do individuals whose data is part of 7 Respect for autonomy and welfare of subjects this new set abrogate their rights to the derivative work? Furthermore, in what circumstances Emanuel, et al. (1999) does the government justify the appropriation of personal health data for the public interest? One 4.2 Government and Corporations may view tension between public health and To what extent may a republic exercise individual autonomy as delineating the boundaries of personal liberty. The U.S. Supreme Court, powers of “eminent domain” over in Jacobson v. Massachusetts (1905), ruled that public health data? Collated and mandatory vaccination is justified to protect public mined datasets bear heightened welfare, notes that “The Constitution of the United utility in times of crisis such as a States...does not import an absolute right in each person to be, at all times and in all circumstances, looming threat of bioterror. In such an wholly freed from restraint. There are manifold environment, how is the appropriation restraints to which every person is necessarily of personal information justified? It subject for the common good.” These emerging may be useful to consider three issues, clearly beyond the scope of the federal Health Insurance Portability and Accountability concerns regarding decisions made Act of 1996 (HIPAA), will soon demand legislative by leadership bodies in times of crisis: attention and the establishment of common first, such decisions, by necessity, standards for privacy. In the case of deCODE are rapidly made; second, is the Genetics, for instance, individuals may opt-out of the private database if desired, although the opportunity and danger of over- process is cumbersome [1]. In some countries, generalization; third, discrimination such as the Republic of Singapore, a system of and judgment may defer to “herd unique medical identifiers is already in place mentality” and hysteria. The most nationwide. I would like to propose the application of the natural counterbalance to each of assessment of the ethical validity of the use of these tendencies is strong policy, personal data in research, using archetypical, formulated well in advance of a crisis, universal, and simple criteria outlined such that is both flexible and powerful, as those by Emanuel, Wendler, and Grady, summarized in Table 1 [29]. Adherence to models and granted legitimacy by support such as these should be given consideration from both the government and the as integral components of any comprehensive populace. medical data management infrastructure. In addition, significant pitfalls emerge from the research process.

Before research may be conducted,

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 95 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

to what extent may informed consent to audit and ensure the accuracy be a part of the process? Despite the of their personal data? Perhaps, relaxing of some draft provisions of HIPAA in a “clearinghouse” model similar pertaining to data access allowed to to that used by credit agencies, providers and researchers [30], HIPAA still consumers can be afforded legal incorporates the Security Final Rule as well protections to view their files and as privacy provisions, and as electronic contest inaccuracies. The provisions informed consent systems are under rapid of HIPAA allow for consumers to development [15], their use will soon be a request changes to their personal practical necessity. health records if they believe Finally, where do the rights of corporate that an error is extant, with the entities intersect with those of individuals responsible provider having a in a world of highly connected data- maximum of 90 days to review the flow? For instance, under present law, request. Given the complexity and the Learned Intermediary Rule shields possible subjective nature of some drug marketing companies from direct elements of the health history, the civil litigation, since information is often effectiveness of the clearinghouse funneled first through physicians. How approach is yet untested. will the increasing popularity of direct Also, in legal malpractice cases, marketing, facilitated by the Internet will lawyers be given access to and other electronic media, change this records during the evidence balance of power between individuals, discovery process? Cost/benefit corporations, and providers? Furthermore, analysis may also be conducted from which groups and individuals, specifically, the springboard of the precautionary should have access to personal health principle, as proposed by David information? Will access-licensure Kreibel; namely, that one must take boards be required to grant and preventative action in uncertain review privileges? These issues are times, that the proponents of an becoming increasing relevant with the activity bear the burden of proof, that rise of “computational medicine,” which correlates drug reactions and efficacy alternative actions must be explored, with specific patient populations. Using and that public participation is key data from patient records and clinical in the decision-making process [32]. trials, Compugen Corp. has contracted This model is particularly germane with HMOs to obtain access to millions of to both clinical research and public patient records for the purpose of such health research contexts. data mining [31]. In addressing issues of privacy protections, the nature of 4.3 Safeguards implementation of disclosure policies In the realm of individual electronic for large-scale databases is a key patient records, how will patients be able

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 96 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

issue. One consideration is the method of Table 2. Goals for a comprehensive electronic software and hardware development. As patient record andorder-entry system

sound security infrastructure is required in Primary objective: Archival of patient order to safeguard civil liberties, the first personal health data major task to be addressed is a complete 1 Histories and summary dictati assessment of the scope of the problem 2 Diagnostic imaging requisitions and reports (Table 2). What levels of protection are 3 Laboratory and pathology results necessary? Is version control and tracking 4 Treatments administered and problem list of records required? What degree of data 5 Follow-up reports archival and access logging is desired? Specific Endpoints: In many situations, rapid deployment 1 Facilitation of fault-tolerant, highly-available can begin by enabling secure, peer- datastreams 2 Electronic prescription and impatient reviewed technologies such as public ordering capability key cryptography, redundancy, distributed 3 Assured data integrity through hashing and systems, relational and regenerative checksums databases that have been previously 4 Physical security safeguards to access and deployed in other service industries. modification 5 Crytographically-secure delivery of datastreams

6 Access auditing

7 Integration with billing processes and insurance claims 8 Dynamic assessment of eligibility for clinical trial enrollment and provision of value-added services 9 Links to external references (drug formularies, patient education literature, best- practice guidelines, and literature reviews) 10 Record of patient consent and support for electronic signature capture 11 Support for telemedicine (health care worker present at point-of-service) and cybermedicine (without end-location

physician) providers 12 Incorporation of intelligent models to highlight gathering epidemics and nosocomial outbreaks

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 97 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

5. Complexity and Information Security This might be facilitated through For collections of individual records freely-viewable source code to be assembled in databases, which themselves inspected by the community at large. are linked in various ways, the topology This transparency will allow for the of the network formed at each level implementers to be confident in the attains particular importance. Yook, et al. integrity of the middleware code – have modeled the structure of Internet cf. the Unix community’s experience connections, and proposed that such a with the OpenBSD operating system, network may be classified as scale-free which emphasizes security through [33]; namely, a relatively small number open source development and of central nodes are responsible for a open audits. Through the use of disproportionate level of the connectivity continuous auditing processes [36], within the system [34]. The implications of and the payment of reward bounties identifying such a structure are important for for reported security exploits, both several reasons: first, they offer an insight the private and public sector may into the underlying communications load be able to cooperate in developing that various elements of the system must a secure and reliable data services bear. Second, the central nodes are those infrastructure for medical practice, which generally subserve critical functions education, and research. Finally, (i.e., house data which is of particular utility). as the criminal assault on personal The random failure of such a node may be data grows [37], the development a rare event, but a coordinated attack upon of hardware and software must be several nodes may be catastrophic for the paralleled by legal protections against system [35]. A given health-care network, cybercrime and electronic terrorism. much like the Internet, is a system with The potential for theft and abuse by connectivity directed by human parsing, legitimate providers will only rise as that relies heavily upon centralized data- perceived value of personal medical centers for specific information such as records increases. patient identification numbers, allergies, and prior history. This implies that, to ensure 6. Issues for Future Consideration robustness of a health care network, the Despite the aforementioned hazards, most important nodes should be identified several positive ethical ramifications of and the majority of available resources records and treatment computerization should be directed towards protecting these should be noted. The Institute of centers against failure. Medicine (IOM), in a highly-publicized Routine audits of software are key in report entitled “Unequal Medicine,” maintaining effectiveness and security [36]. documented racial disparities in As software is developed, linking existing the administration of American database structures into an interoperable mental health services, medication continuum, secure practices should be a dispensation, and surgical procedures. key element of design and implementation. One path to closing the divide, the

Present and Future Challenges in Medical Data Management: Economics, Ethics, and the Law 98 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

IOM recommends, is the careful correlation allowed the Web to flourish as an of patient and doctor racial and ethnic economic and academic entity, and demography in order to identify the roots perhaps this model can be reprised and possible solutions to the problem [38]. by the creation of a “health board,” Even this pathway is not without controversy, charged with the responsibility of however, as racial profiling and correlation establishing consistent guidelines may itself be a violation of individual human for technological interoperability rights. Furthermore, information reform and access across all medical data may be one possible path to tort reform, networks. as changes in data storage, diagnosis, Thus, the potential for a bright and treatment modalities may force a re- future for public health and the public thinking of liability assessment strategies welfare is indeed promising, but only in [39]. For instance, as doctors from multiple the context of pro-active engagement regions all collaborate to treat a patient, and by government entities, health-care as doctors, managed care organizations, providers, industry leaders, scientists, and pharmacists build closer relationships, and the citizenry at large. previous protections and delineations of accountability become blurred and new References models must be developed for quality [1] eHealth Traffic Critically Dependent control, restitution, and risk assessment on Search Engines and Portals. Harris in medical practice [20]. In this way, the Interactive Health Care News April 23, Internet revolution may perhaps provide a 2001, 1-3. basis for moving toward a more egalitarian, [2] Nicolas Terry. Legal pitfalls of patient-centered, “no-fault” model of medical cybermedicine. Lahey Clinical Medical practice. Finally, the establishment of a Ethics Newsletter. Winter ed., 2000. broader records-based system may open [3] Christine Jones and Terrie Wheeler. a door for cross-sector and even trans- The Role of Knowledge-Based national coordination and cooperation in Information. SEA Currents 1994 12(5). terms of deployment and maintenance [4] Karen Kaplan. E-Business: Meeting of records systems, while preventing an the Technology Challenge; Health care imbalance in favor of governmental or network gets big payoff from a simple corporate interests. Lessons gleaned solution. Los Angeles Times April 2, from the governance mechanism of the 2001, 1U. World Wide Web itself, namely the non- [5] Joseph B Treaster. Doctors Face governmental Internet Corp. for Assigned a Big Jump in Insurance. New York Names and Numbers, show that private Times March 22, 2002. officials, elected at large to represent a [6] David W Bates. Commentary: diverse community, have the capability to Quality, Costs, Privacy, and Electronic set strong standards, in concert with industry Medical Data. Journal of Law, groups. It is precisely this adoption of open Medicine, & Ethics 1997 25(2-3):111-12. and consensus-based standards that has

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A.P. Pentland, Chapter 10: Big Data and Health use of big data, we present several T.G. Reid, T. H. Heibeck/ Big Alex P. Pentland, Ph.D. recommendations, including: (1) Data and Health Massachusetts Institute of Technology, how to ensure data access; (2) how in “World Health Strategy”, R.G. Cambridge, MA, USA to allow for open data; (3) how to Bushko (Ed.) Todd G. Reid, Sc.D., MBA, MPH promote big data health science; eBook FHTI, 2016. Massachusetts General Hospital / MIT (4) how to encourage public- Connection Science, Boston/Cambridge, private partnerships; and (5) how to MA, USA accelerate big data health practices. Tracy H. Heibeck, Ph.D Author 1. Introduction Since the beginning of time most Abstract people have been isolated, without veryday devices such as cell phones information about or access to the now provide us with an enormous best health practices. But in just Estream of data about human life and the last decade this has changed behavior. Combined with existing health completely – through the spread of data the behavioral data obtainable from cell phone networks, the vast majority these devices may greatly enhance of humanity now has a two- way digital opportunities to predict long-term health connection that can send voice, text, conditions and identify non-traditional and most recently, images and digital intervention points, as well as to design sensor data. Healthcare is suddenly better diagnostics tools, prevent diseases, something that is potentially available and increase access to – and reduce the to everyone; all across the world costs of – healthcare. Significant application we are beginning to see healthcare areas include: chronic and infectious workers collecting health information diseases, mental health, environmental and delivering telemedicine health, nutrition, and social health. While consultations in even the most remote there is enormous promise, there are areas. also dangers to be avoided in terms of This new digital nervous system is data privacy and ownership issues. Both also driving a more subtle and regulation and technology must continue potentially even more profound to evolve in order to provide us with the change known popularly as `big data’. potential benefits while not exposing The proliferation of wireless devices citizens to the dangers of exploitative such as cell phones provides an companies or unreasonable government enormous stream of data about oversight. To this end, we discuss a human life and behavior. Linking these taxonomy framed in terms of data control, petabytes of raw information to health including: open data commons; personal records, demographic data and and proprietary data; and government genetic information offers novel data. To better support the emerging opportunities to uncover population medical and health science based on the health patterns, predict long-term

conditions and identify non-traditional they require detailed, specific intervention points. Improved disease discussion outside the scope of this prevention, better diagnostic tools as well paper. as increased access to – and reduced cost While use of big data has of – health care are achievable. We are enormous promise for improving now beginning to be able to see the health health systems there are also dangers conditions for all of humanity with that must be avoided. There is unprecedented clarity. scientific risk, because the unfamiliar, This enhanced view of human health correlational nature of big data raises and behavior will enable important the possibility of misinterpretation that advances in medical science. The use of can cause serious harm. big data in health is a new and exciting Consequently, we must devise new field, full of promising case examples, but procedures for developing health there are also practical problems to be systems that incorporate big data. worked out, such as data privacy and There is also risk of misuse, which ownership issues. There are also dangers comes from the danger of putting so to be avoided such as the risks of misuse much personal data in the hands of of personal data and new types of medical either companies or governments. error. This chapter aims to give a view into Therefore, we will discuss how new the future of big data in health and to map approaches to regulation and out concrete steps that will help ensure that technology have been developed we can realize its full potential. that can help protect personal privacy from exploitation and can mitigate the 2. Scope of the Discussion problem of government overreach as In this chapter, we will provide a framework well. to inform discussion about the role of big data, summarize existing best practices, 3. The Role of Big Data in Health highlight the remaining barriers, and The potential uses of big data extend develop policy recommendations to far beyond enabling more efficient overcome the barriers in the intersection of healthcare systems. So far, these uses big data, health, and medicine. We will have mostly remained theoretical focus our discussion outside of the possibilities due to a number of complex hospital systems of developed barriers including privacy and data nations because: (1) the transformative ownership issues. There are potential for big data seems greatest where emerging best practice examples, there is currently the least data; (2) the vast however, which demonstrate the majority of humans do not have access to potential of these largely untapped advanced hospital systems; and (3) many of health and behavioral data. the challenges of using big data within hospitals concern entrenched financial interests and legacy legal barriers. Hence,

3.1 Chronic Diseases have done. With reality mining The overwhelming majority of chronic innovation, that is, using big data to diseases in humans arise as a measure what individuals have consequence of a complex web of causes actually done, researchers can gain that act over years before the disease is important new insights. [2] manifested. The mission and challenge of Rapidly developing countries face epidemiologic research is to unravel these the challenge of replicating such causes as a prerequisite for prevention. research suitable for their context The Achilles’ heel of such research is to given obstacles to dissemination of accommodate the complexity of the data questionnaires such as limited mail and adequately ascertain information about and land-line telephone service, and causes. In this regard, the new access to Internet by their technologies that help collect, analyze, and populations. Big data and reality correlate large volumes of personal health mining techniques give scientists in data might offer entirely new opportunities. these countries the opportunity to Indeed, interactive prevention via such “leapfrog” over these obstacles, accessible technologies could be used to collect better and more information reach segments of the population that than before, and dramatically improve cannot access medical care otherwise. health data at the same time. Much information that we have now Behavioral data also offer about preventing chronic, non- intriguing possibilities in other areas of communicable diseases (NCDs) has come chronic disease. For example, from traditional longitudinal studies. For research suggests that some chronic instance, studies based in North America health-related conditions and and Europe have heavily influenced behaviors are “contagious” in the preventive health policy such as dietary sense that individual-level outcomes standards for schools and restaurants, laws are linked to other individuals with regulating smoking, and air quality whom one shares social connections. standards. [1] In some ways, these studies For example, both smoking behavior could be considered the progenitors of big and obesity have been shown to data in that they typically enroll thousands spread within social networks. of people and assess them periodically, Smoking and obesity likely serve as usually by questionnaire. These good models for other health related questionnaires can be web-based, mailed, behaviors such as diet, exercise, or in-person or telephone interview. For the general hygiene, sexual habits, and most intensive of such studies the so on. As such, reality mining might frequency of assessment is typically every yield specific points of leverage for 6 months to 2 years. The data from these effective health interventions. That is, research instruments, however, are limited if certain behaviors are indeed to supplying only data about what contagious, then targeting individuals individuals have said (or think) that they in key parts of the social network

could result in more powerful approaches demonstrated its effectiveness in to intervention and more effective ways to transmission of malaria [3] and food promote behavior modification. Of course, poisoning. [4] privacy issues are paramount here (see Reality mining tools could also Managing Big Data discussion). assist in the detection of outbreaks of such temporarily disabling disease. 3.2 Infectious Diseases For instance, acute illnesses such as As the world becomes increasingly influenza that cause sufferers to interconnected through the movement of reduce their physical activity and people and goods, the potential for global mobility patterns (even confining them pandemics of infectious disease rises as to bed) or change their well. In recent years, outbreaks of SARS communication behavior, are and other serious infectious diseases in identifiable in several types of reality widely separated but socially linked monitoring data streams. [5] At the communities highlight the need for population level, fluctuations in digital fundamental research on disease traces of these behaviors may transmission and effective prevention and indicate outbreaks of temporarily control strategies. In developed countries, disabling infectious diseases. At the health officials typically investigate cases of individual level, examination of data serious infectious disease (e.g., about an individual’s exposure tuberculosis, SARS, malaria, etc.) to identify summary as part of an emergency the source of infections and other cases of room or clinical intake process could disease and to prevent further transmission. indicate if the person ate or spent In any of these scenarios, investigations significant amounts of time near are difficult and time consuming, while known outbreak areas, information transmission continues unabated. that might not have been otherwise Moreover, people often forget all the captured through self-report. In the locations they have visited, even for recent future such tools could offer a periods. Similarly, they might not know formidable defense against many of the people to whom they were pandemics: a recent pilot study has exposed or might have exposed demonstrated the potential for real themselves. All of these difficulties time tracking of flu propagation on an underline the potential value of individual-to-individual using only systematically analyzing location and social behavioral data collected from smart behavioral data, both readily obtained from phones. [6] cell phones, for disease control. Logs of location tracking data from cases’ cell phones can be examined to identify places where cases might have acquired or transmitted infection, thereby facilitating the investigation. Recently this approach has

based on population averages rather than individual characteristics. They assess patients for the appropriateness of the medication levels only occasionally – and expensively. With such a data-poor system, it is not surprising that medication doses are frequently over- or underestimated and that Figure 1: Map of the MIT campus showing risk of unforeseen drug interactions contracting infectious disease at the current time, obtained from analysis of cell phone mobility patterns account for a sizable proportion of and short cell phone health surveys of selected hospitalizations, notably among the individuals. elderly. Going further, correlating a 3.3 Diagnosis, Treatment and Follow-up of continuous, rich source of behavioral Human Disease data to prescription medication use Big data obtained from the continuous for millions of people could make drug monitoring of motor activity, metabolism, therapies more effective and help and so on can be extremely effective medical professionals detect new drug in tailoring medications/treatments for interactions more quickly. [7] individuals. Once a course of treatment (behavioral, pharmaceutical, or otherwise) 3.4 Mental Health has been chosen, it is important for a Mental diseases rank among the top clinician to monitor the patient’s response health problems worldwide in their to treatment. The same types of big data cost to society. Major depression, used for diagnosis can also be relevant for for instance, is the leading cause monitoring a patient’s compliance, response of disability in established market and side-effects to treatment especially economies. Diagnoses of psychiatric when such data on the patient are available disorders are overwhelmingly based for a period before diagnosis and can serve on reporting by the patient, a teacher, as a baseline for comparison. Even when family member, or neighbor. Many these data streams are not relevant for symptoms of psychiatric disorders diagnosis, they can be useful in assessing concern patterns of physical side effects of treatment, such as reduced movement, activity and communication mobility, activity, and communicative – all things that can be measured by behavior. Because these data can be cell phone data. Accelerometers can collected in real-time, a clinician would be reveal fidgeting, pacing, and abrupt able to adjust treatment according to the or frenetic motions. Location tracking patient’s response, perhaps leading to more can reveal changes in places visited effective treatment and preventing more and routes taken as well as the costly office visits. overall extent of physical mobility. The Currently, doctors prescribe medications frequency and pattern of individuals’

communications with others and the content quality monitoring stations and manner or their speech can also reflect and/or inferred from vehicle traffic key signs of several psychiatric disorders. [2, patterns and locations of industrial 8] facilities), may offer just the kind of The ability to use inexpensive, pervasive exposure measurement needed. [10] computational platforms such as cell phones to monitor these sensitive indicators of 3.6 Nutrition psychological state offers the dramatic Nutrition epidemiology may also be possibility of early detection of disorders revolutionized by big data driven such as depression, attention deficit innovations. Long a major challenge hyperactivity disorder, bipolar disorder, in health research, dietary record agoraphobia, and others. [9] In addition, keeping is often riddled with bias because these data streams provide direct, from the inaccurate recall of what continuous and long-term assessment of people have eaten over the course patterns and behaviors, new avenues of of a week, month, or year. Because it treatment monitoring and assessment in is now possible to track dietary intake mental health can be developed. at almost every point of consumption, previous inaccuracies in recording can 3.5 Environmental Health be minimized markedly. For example, Epidemiologic investigations of the links GPS enabled cell phone applications between various health conditions and could track whether individuals individuals’ exposures to airborne pollutants frequented fast-food restaurants or (e.g., particulate matter, carbon monoxide, farmer’s markets, or even the produce nitric oxide) have relied on a variety of aisle versus the snack-food aisle in a exposure measurement methods. To date, community’s grocery store. Detailed most studies of this type have been based consumer purchase streams will on comparisons of aggregates of persons serve not only as enormous, data-rich (e.g., residents of particular neighborhoods sources for dietary record keeping, or cities, or students at specific schools) but they will also offer unprecedented with exposure measurements applying to opportunities to track and analyze all individuals in a given group. Air pollution important correlated behavioral levels, however, can vary dramatically over data associated with nutrition health short distances and time scales in urban and outcomes. In addition, food security other environments. Hence, environmental and availability can be improved to health experts have called for more precise ensure more steady and adequate and dynamic measures of time-activity supplies of nutrition on a population patterns in relation to exposures. Location level. tracking data generated by cell phones, 3.7 Social Health when coupled with measurements of Despite compelling evidence, most ambient air pollutions at numerous places efforts to encourage healthy behavior in a community (gathered from existing air and medical compliance continue to

be organized around conscious, individual decision making only, neglecting the social dimension almost entirely. Using big data to better understand social conditions, we will be able to achieve more in terms of behavioral modification, a major key to health advancements. For example, big data can be used to provide the social pressure needed to establish new, healthy behavior norms. Online `friend networks’ have successfully been used to promote higher physical activity levels and to increase prosocial behaviors such as voting and energy conservation. [11, 12] The Data for Development (D4D) initiative [13] highlighted in Figure 2 is another good example of using big data to address social health issues1. In this collaborative effort, ninety research organizations from around the world reported hundreds of results from their analyses of cell phone data. These data described the mobility and call patterns of the citizens of the entire African Figure 2: This example from the D4D initiative shows a country of Ivory Coast, a country struggling map derived from a method for mapping poverty from with poverty and the aftermath of a recent the diversity of cell phone usage. As people have more disposable income, their patterns of movement and civil war. Together with more traditional patterns of phone calls become increasingly diverse. sources of information, these data were Another example of using the D4D data for social health is the development of a method for mapping of ethnic used to provide ubiquitous, up-to-the-minute boundaries. This method relies on the fact that ethnic and mapping of poverty and ethnic boundaries language groups communicate far more within their own group than they communicate with others. Mapping social within the entire country of Ivory Coast, two boundaries is important because, while we know that significant social health issues. ethic violence often erupts along such boundaries, the government and aid agencies are usually uncertain about the geography of these social fault zones. 4. Managing Big Data Reality mining of big data for behavioral information is still in its infancy. Today, smartphones monitor physical activity, 1 The D4D data were donated by the mobile carrier Orange, and the social interactions, sleep patterns, and research initiative was organized with help from the University of Louvain (Belgium) and the MIT Human Dynamics Lab (United States), along with routine behavior. These new tools, with collaboration from Bouake University (Ivory Coast), the United Nation’s Global Pulse, the World Economic Forum, and the GSMA (which is the their view of life in all its complexity, may mobile carriers’ international trade association). The D4D program was led by Nicolas De Cordes (Orange), Vincent Blondel (Louvain), Alex well be the future of medical science Pentland (MIT), Robert Kirkpatrick (UN Global Pulse), and Bill Hoffman (World Economic Forum). and public health policy. There is risk in

deploying this sort of data driven health infrastructure that provides strict system, however, because of the danger of control and auditing of use; and putting so much personal data in the hands (3) the secret data of governments of either companies or governments. Both which typically have less direct public regulation and technology must continue to oversight and more stringent controls. evolve in order to provide more scientific, The issues with data commons will be real-time public policy without exposing addressed first, followed by personal citizens to the dangers of exploitative and proprietary data, and then companies or governments. This section government secret data. will outline the current best practices in this area. 4.1 Open Data Commons The first entry in the data taxonomy is the data commons. A key insight is that our data are worth more when shared because they can inform improvements in systems such as health, transportation, and government. Using a “digital data commons” can potentially give us Figure 3: This big data taxonomy is comprised of: (1) open data commons, including geolocated and time stamped unprecedented instrumentation of statistics about aggregate costs, health outcomes how our policies are performing so and behaviors (e.g., mobility, smoking, drinking, crime, we can know when to take action to accidents); (2) personal data, including digital breadcrumbs quickly and effectively address the (mobility, call, and purchasing patterns, etc), personal annotations about eating, subjective variables, and situation. standard health data (temperature, glucose, genomic, etc); We already have many data and (3) government data, including detailed healthcare commons available: maps, census system costs, individual performance ratings, fine-grain data, and financial indices. With the outcome data. Overlapping regions require trust networks for data sharing. advent of big data we can potentially develop many more types of data It is probably hopeless to provide a commons. These commons can detailed taxonomy of data types and uses be both ‘real time’ and far more because the technology is progressing detailed than previous examples so quickly. But it is possible to provide because they depend mostly on a broad taxonomy framed in terms of data that are already produced as control. The three main divisions within a side-effect of ongoing daily life the spectrum of data control are: (1) data (e.g., digital transaction records, cell commons, which are available to all, with at phone location fixes, road toll records, most minor limitations on use; (2) personal etc.). That is, they can be produced or proprietary data, typically controlled automatically by computers without by individuals or companies, for which human intervention. there needs to be legal and technology

One major concern with such a data computer algorithms and contract law commons is that they can endanger to specify and audit how personal personal privacy. Another secondary data may be used and shared is concern involves the tension between the goal of new privacy regulations commercial or personal interests: these in the E.U., the United States, and proprietary interests might tend to reduce elsewhere. the richness of such a commons, and diminish the ability of such a data commons 4.2 Personal and Proprietary Data to enable significant public goods. The second category in the data To explore the viability of a big data taxonomy is personal and proprietary commons, what is perhaps the world’s first data, typically controlled by individuals true ‘big data’ commons was created for or companies, for which there the Data for Development (D4D) initiative, needs to be legal and technology and included data describing the mobility infrastructure that provides strict and call patterns of the citizens of the entire control and auditing of use. The African country of Ivory Coast as well as current best practice is a system of more traditional data sources. [1] data sharing called trust networks. The work of the ninety research groups [14] Trust networks are a combination involved in D4D suggests that many of of a computer network that keeps the privacy fears associated with the track of user permissions for each release of data about human behavior piece of personal data, with a legal may be generally misunderstood. In this contract that specifies both what can data commons, the data were processed and cannot be done with the data and by advanced computer algorithms what happens if there is a violation (e.g., sophisticated sampling and use of of the permissions. This is the model aggregated indicators). Hence, it was of personal data management that is unlikely that any individual could be re- most frequently proposed within the identified. In fact, no path to re-identification World Economic Forum Personal Data was discovered, even by several of the Initiative. [15] research groups that studied this specific In such a system, all personal data question. have attached labels specifying what In addition, while the data were freely the data can, and cannot, be used for. available for any legitimate research that These labels are exactly matched by a group was interested in, the data were terms in a legal contract between all distributed under a legal contract that the participants stating penalties for specified that the data could only be used not obeying the permission labels and giving the right to audit the use of the for the purpose proposed and only by data. Having permissions, including the specific people making the proposal. the provenance of the data, allows A similar technology-legal framework is automatic auditing of data use and used in trust networks described in the allows individuals to change their next section. The use of both advanced permissions and withdraw data.

Today, there are long-standing versions of That is, the government must organize trust networks proven to be both secure and big data resources in a distributed robust. The best known example is the SWIFT manner, with each different type of data network, reliably handling trillions of dollars separated and dispersed among many per day for inter-bank money transfer. Its most locations, using many different types distinguishing feature is that it has never been of computer systems and encryption. hacked. Until recently such systems were only Similarly, human resources should be for the ‘big guys’. To give individuals a similarly organized into cells of access and safe method of managing personal data, permission that are localized both researchers have built open-source software spatially and by data type. Both computer systems such as openmhealth and openPDS (open Personal Data Store), and are now testing and human resources should always be these systems with a variety of industry and redundant and fragmented in order to government partners. [16, 17] avoid overly-powerful central actors. The logic behind this observation 4.3 Government Secret Data is that physically and logically The third category in the taxonomy is secret distributed databases which also have government data, typically including tax data, heterogeneous computer and encryption detailed census data, detailed expenditures, systems are hard to attack, both and social health factors. The advent of physically as well as through cyber attack. big data health systems may dramatically This is because any single exploit is likely expand the depth and breadth of these to gain access to only a limited part of the secret government data to include all types of whole database. Similarly, the resilience individual behavior data. of organizations with a heterogeneous A major risk of deploying data driven cell-like human and permissions structure policies and regulations comes from the danger is familiar from intelligence and terrorist of putting so much personal data in the hands organizations.2 of governments. But how can it happen that governments choose to limit the data they keep? The answer is that unlimited access to 2 This architecture can help prevent the use of data about citizens’ behavior is a great danger big data to trample individual freedoms. The key to the government as well as the citizenry. insight is that for these types of data systems, each type of data analysis operation has a Consider the NSA’s response to the recent characteristic pattern of communication between Snowden leaks in the United States: different databases and human operators. As a consequence, it is possible to monitor the “This failure originated from two practices that functioning of the data analysis process without we need to reverse,” Ashton B. Carter, the deputy access to, or endangerment of, the analysis secretary of defense, said recently. “There was an content. In short, one can use ‘metadata about big data’ in order to monitor the use of big data, enormous amount of information concentrated in and with some reasonable confidence ensure one place,” he said. “That’s a mistake.” And second, that only ‘normal’ analysis operations are being no individual should be given the kind of access Mr. conducted without reference to specific content. Snowden had, Mr. Carter said. Governments that structure their data resources in this manner can more easily monitor attacks and http://www.nytimes.com/2013/08/04/sunday-review misuse of all sorts.

5. Recommendations 3. Promote big data health science: A medical and health science based on The academic community needs the use of big data is emerging. This new to train more computational social scientists and develop big data science leverages the capacity to collect experimental methodologies such and analyze data with a breadth and depth as living laboratories and rich open that was previously inconceivable. How data repositories. In addition, the can we best support the development of availability of easy-to-use tools big data health systems? We have five key would greatly accelerate a big data recommendations: health science. Just as mass-market computer assisted design software revolutionized the engineering world 1. Ensure data access: Some of the thorniest decades ago, common analysis tools challenges posed by our new digital and data sharing protocols will lead capabilities revolve around data access to significant advances. We suggest and sharing. Robust models of collaboration development of a ‘best practice kit’ and data sharing, between government, that lowers the barrier to entry for industry and the academy need to be interested countries. developed; guarding both the privacy of consumers as well as corporations’ 4. Encourage public-private legitimate competitive interests are vital partnerships: Big data health here. Privacy and data ownership policies systems require some investment should be updated to ensure that data in data handling infrastructure, but are accessible by patients and their are not as intrinsically expensive healthcare providers, and that trust network as many civil systems. On the other technology is required in order to provide hand, they require a continuous safe data sharing. partnership between the healthcare system and private companies, 2. Allow for open data: Current data in private individuals, and healthcare healthcare, particularly those stemming professionals, since all of these are from pharmaceutical and medical R&D, required to obtain the necessary clinical settings, patient behavior, and data. Public-private partnerships payer activity are highly fragmented and can serve to underwrite costs and not generally accessible by the health accelerate deployment; financial researchers or even patients themselves. entities such as special-purpose The creation of broad, open data commons banks that underwrite the required that support research is critical. The capital investment at low interest ability to pool unrestricted government rates are likely to prove especially data and non-proprietary private data in useful in promoting a big data health an open data commons would promote ecosystem. the development of a ‘big data’ health

ecosystem. We suggest that there needs to

be an international Charter for Open Data

Sharing, which specifies best practice and

commits nations to sharing health data for

their mutual benefit.

5. Accelerate big data health practices: [7] N. Duan et al., Single-patient (n-of-1) Significant potential health solutions are Trials: A Pragmatic Clinical Decision likely to be those developed in partnership Methodology for Patient-centered with more inquisitive front-line physicians, Comparative Effectiveness Research. who best understand the problems to be solved, who are interested in applying Journal of Clinical Epidemiology 66(8 new approaches and piloting promising Suppl) (2013) S21-8. ideas, and who, most importantly, are [8] A. Pentland and T. Heibeck, committed to the iterative development of Honest signals. MIT Press, new solutions. After all, most technological Cambridge, MA, 2008. success arises through a rapid, iterative [9] www.cogitocorp.com process with motivated early adopters. The combination of pioneering physicians [10] http://www.wilsoncenter.org/sites/ and behavioral scientists with experimental default/files/participatory_sensing.pdf platforms such as living laboratories which [11] N. Aharony et al., SocialfMRI: support rapid innovation, is central to the Investigating and Shaping Social rapid development of successful big data Mechanisms in the Real World. health practices. Pervasive and Mobile Computing 7(6) (2011) 643-659. References [12] A. Mani et al., Inducing Peer [1] http://en.wikipedia.org/wiki/Nurses’_ Pressure to Promote Cooperation. Health_Study Scientific Reports [2] M. Little et al., Quantifying Short-term 3(1735) (2013). Dynamics of Parkinson’s Disease Using [13] http://www.d4d.orange.com/home Self-reported Symptom Data from an [14] Alex Pentland, Reality Mining of Internet Social Network, Journal of Medical Mobile Communications: Towards a Internet Research 15(1) (2013) e20. New Deal on Data. In: S. Dutta and [3] A. Wesolowski et al., Quantifying the I. Mia (eds.), The Global Information Impact of Human Mobility on Malaria. Technology Report 2008-2009: Science 338(6104) (12 October 2012) 267- Mobility in a Networked World. World 270. Economic Forum, Geneva, pp. 75-80. [4] A. Sadelik et al., nEmesis: Which See www.insead.edu/v1/gitr/wef/main/ Restaurants Should You Avoid Today? fullreport/files/Chap1/1.6.pdf AAAI (2013). See http://www.cs.rochester. [15] Personal Data: The Emergence edu/~sadilek/publications/Sadilek-Brennan- of a New Asset Class. World Kautz- Economic Forum, 2011. See http:// Silenzio_nEmesis_HCOMP-13.pdf www3.weforum.org/docs/WEF_ITTC_ [5] A. Madan et al., Sensing the ‘Health State’ PersonalDataNewAsset_Report_2011. of a Community. Pervasive Computing 11(4) pdf (2012) 36-45. [16] http://idcubed.org [6] W. Dong et al., Modeling Infection with [17] http://openmhealth.org Multi-agent Dynamics. In: Proceedings of Social Computing, Behavior-Cultural Modeling, and Prediction (SBP) (2012)172-179.

Alex P. Pentland, Chapter 11: Using Reality Mining to and community health. Reality mining David Lazer, Devon Brewer, Improve Public Health and Medicine can provide new opportunities with Tracy Heibeck, Alex Pentland, Ph.D. respect to diagnosis, patient and Using Reality Mining to Massachusetts Institute of Technology treatment monitoring, health services Improve David Lazer, Ph.D. planning, surveillance of disease Public Health and Medicine in Harvard University and risk factors, and public health “World Health Devon Brewer, Ph.D. investigation and disease control. Strategy” eBook, (Ed.) Renata Interdisciplinary Scientific Research Currently, the single most important G. Bushko, Tracy Heibeck, Ph.D. source of reality mining data is the FHTI, 2016. Futureofhealth. Author ubiquitous mobile phone. Every time org a person uses a mobile phone, a few From Strategy for the Future Abstract bits of information are left behind. of Health (Ed.) e live our lives in digital networks. The phone pings the nearest mobile- Renata G. Bushko, IOS We wake up in the morning, phone towers, revealing its location. Press 2009 Wcheck our e-mail, make a quick The mobile phone service provider phone call, commute to work, buy lunch. records the duration of the call and Many of these transactions leave digital the number dialed. breadcrumbs – tiny records of our daily In the near future, mobile phones experiences. Reality mining, which pulls and other technologies will collect together these crumbs using statistical even more information about analysis and machine learning methods, their users, recording everything offers an increasingly comprehensive from their physical activity to their picture of our lives, both individually conversational cadences. While and collectively, with the potential of such data pose a potential threat to transforming our understanding of individual privacy, they also offer great ourselves, our organizations, and our potential value both to individuals and society in a fashion that was barely communities. With the aid of data- conceivable just a few years ago. It is for mining algorithms, these data could this reason that reality mining was recently shed light on individual patterns of identified byTechnology Review as one behavior and even on the well-being of “10 emerging technologies that could of communities, creating new ways to change the world” [1]. improve public health and medicine. Many everyday devices provide the raw To illustrate, consider two database upon which reality mining builds; examples of how reality mining may sensors in mobile phones, cars, security benefit individual health care. By cameras, RFID (‘smart card’) readers, and taking advantage of special sensors others, all allow for the measurement in mobile phones, such as the of human physical and social activity. microphone or the accelerometers Computational models based on such built into newer devices such as data have the potential to dramatically Apple’s iPhone, important diagnostic transform the arenas of both individual data can be captured. Clinical pilot

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data demonstrate that it may be possible self-report data: a yearly census, to diagnose depression from the way public polls, focus groups, and a person talks – a depressed person the like. Reality mining offers a tends to speak more slowly, a change remarkable, second-by-second that speech analysis software on a phone picture of both individual and group might recognize more readily than friends interactions over extended periods or family do. Similarly, monitoring a phone’s of time, providing dynamic, structural motion sensors can also reveal small information and rich content. changes in gait, which could be an early indicator of ailments such as Parkinson’s 1.1 Assessment of individual health disease. The basic functionality of mobile Within the next few years reality mining phones consists of the digital signal will become more common, thanks in processing and transmission of the part to the proliferation and increasing human voice. Advanced mobile sophistication of mobile phones. Many phones also have accelerometers, so handheld devices now have the processing that they can measure the body power of low-end desktop computers, and movement of their users, and they can also collect more varied data, geolocation hardware (both due to components such as GPS chips that GPS and other methods), so that they track location. The Chief Technology Officer can report their users’ locations. As of EMC, a large digital storage company, a consequence, when users carry estimates that this sort of personal sensor around and use their mobile phones data will balloon from 10% of all stored they produce a rich characterization information to 90% within the next decade. of their behavior. While the promise of reality mining Reality mining of these behavior is great, the idea of collecting so much signals may be correlated to the personal information naturally raises many function of some major brain systems. questions about privacy. It is crucial that This statistical behavior analysis behavior-logging technology not be forced therefore provides capabilities that on anyone. But legal statutes are lagging can be thought of as a sort of low- behind data collection capabilities, making resolution brain scanning technology. it particularly important to begin discussing Figure 1 illustrates the relationship how the technology will and should be between brain state and observable used. Therefore, an additional focus of this behaviors for four types of behavior: chapter will be the development of a legal and ethical framework concerning the data • Arousal of the autonomic nervous used by reality mining techniques. system produces changes in activity levels. These changes can be measured by audio or 1. Capabilities of reality mining motion sensors, and have been To date, the vast majority of research on the successfully used to screen for human condition has relied on single-shot, depression [2,3,4]

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• Tight time-coupling between people’s speech or movement (called ‘influence’) These qualitative measurements of is an indication of attention, since such brain function have been shown to tight coupling cannot be achieved be powerful, predictive measures without attending to and modeling the of human behavior [10]. They play other person. This ‘influence’ measure an important role in human social has been successfully used for more interactions, serving as ‘honest than 30 years as a screen for language signals’ that provide social cues to development problems in pre-verbal dominance, empathy, attention, and infants [5]. trust, and may offer new methods of diagnosis, treatment monitoring, and • Unconscious mimicry between people population health assessments. (e.g., reciprocated head nods, posture changes, etc.) is mediated by cortical 1.2 Mapping social networks mirror neurons and is very highly One of the most important correlated with feelings of empathy and applications of reality mining may trust. Measurements of mimicry are thus be the automatic mapping of social considered to be reliable predictors networks [11]. In Figure 2(a), you see of trust and empathy [6], and mimicry has been manipulated to dramatically a smart phone that is programmed to improve compliance [7]. sense and report continuously on its user’s location, who else is nearby, the • Consistency or fluidity of movement user’s call and SMS patterns, and (with or speech production is a well-known phones that have accelerometers) measure of cognitive load: novel how the user is moving. One hundred physical activities or those ‘loaded’ of these phones were deployed to by other mental activity have greater entropy (randomness) than activities that students at MIT during the 2004-2005 are highly practiced and performed with academic year. a singular focus. This relationship has Careful analysis of these long been used for diagnosis in both data shows different patterns of psychiatry [8] and neurology [9]. behavior depending upon the social relationship between people. Figure 2(c) shows the pattern of proximity during one week, and it can be seen that self-reported reciprocal friends (both persons report the other as a friend), non-reciprocal friends (only one of a pair reports the other as a friend), and reciprocal non-friends Figure 1: Reality mining has shown that statistical (neither of a pair reports the other as analysis of behavior can be related to the function of a friend) exhibit very different patterns some major brain systems, providing capabilities that [12]. By using more sophisticated can be thought of as a sort of low-resolution brain statistical analysis, we can map each scanning technology. participant’s social network of friends

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and co-workers with an average accuracy 1.3 Beyond demographics to of 96% [13]. behavior patterns Reality mining’s capability for automatic Most government health services rely social network mapping is now being used on demographic data to guide service in a variety of research applications. As delivery. Demographic characteristics, an example, a current research project however, are a relatively poor underway at MIT is aimed at understanding predictor of individual behavior, health-related behaviors and infectious and it is behavior – not wealth, age, disease propagation. At this time, we have or place of residence – that is the above 80% participation of students in major determinant of many health a MIT dormitory that includes freshmen outcomes. Reality mining provides a and upperclassmen, and are beginning to way to characterize behavior, and thus compare the behavior and health changes provides a classification framework that freshmen normally experience that is more directly relevant to health with the changes in their various social outcomes [10]. networks. This experiment should help to

disentangle causal pathways about how Figure 2: Mapping social networks from mobile phone social networks influence obesity and other location/proximity data. 2(a) shows a ‘smart phone’ health-related behaviors, as well as provide programmed to sense other people using Bluetooth, 2(b) shows the pattern of proximity between people during one unprecedented detail for modeling the day, and 2(c) shows that different social relationships are spread of infectious disease. associated with different patterns of proximity.

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The pattern of movement between the places a person lives, eats, works, and hangs out are known as a behavior pattern. Reality mining research has shown that most people have only a small repertoire of these behavior patterns, and that this small set of behavior patterns accounts for the vast majority of an individual’s activity [14]. The fact that all mobile phones constantly measure their position (either through GPS Figure 3: Analysis of travel patterns allows discovery of largely independent subpopulations within a city. or by finding the nearest cell tower) means Movement patterns (a), measured from GPS mobile phones, allow (b) segmentation of the population into that we can use reality mining of mobile subpopulations with differing behavior patterns, and phone location data to directly characterize measurement of the ‘mixing’ between those groups [15]. an individual’s set of behavior patterns. We can also cluster together people with similar 2. The future potential of reality behavior patterns in order to discover the mining independent subgroups within a population. In the previous section, we discussed Figure 3(a) shows movement patterns how reality mining has the potential with popular ‘hang outs’ color coded by the to assess individual health, to map different subpopulations that populate these social networks automatically and to destinations, where the subpopulations discover subpopulations with different are defined by both their demographics behavior patterns. In this section, we and, more importantly, by their behaviors. will explore how these capabilities Figure 3(b) shows that the mixing between may facilitate research and public these different behavior subpopulations is health delivery in areas ranging from surprisingly small. encouraging healthy behaviors to Understanding the behavior patterns monitoring of medical treatments. of different subpopulations and the mixing between them is critical to the delivery of 2.1 Health behaviors public health services, because different Despite compelling evidence, subpopulations have different risk profiles most efforts to encourage healthy and different attitudes about health- behavior and medical compliance related choices. The use of reality mining continue to be focused on conscious to discover these behavior patterns can decision making, neglecting the potentially provide great improvements social dimension almost entirely. By in health education efforts and behavioral understanding how to leverage social interventions. networks, we may achieve more in terms of behavioral change. For example, research suggests that some chronic health-related conditions/behaviors are “contagious,”

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in the sense that individual-level outcomes for example, an intervention based are linked to other individuals with whom on targeting particular individuals one shares social connections. Both and changing their behaviors. In an smoking behavior [16] and obesity [17] seem attempt to create an avalanche of to spread within social networks. Smoking change, it would be good to know if and obesity likely serve as good models for a given intervention failed because other health related behaviors, such as diet, the targeting failed, or because the exercise, general hygiene, and so on. avalanche failed to materialize despite These findings, however, beg for an successful targeting. examination of the causal mechanism – an essential step if interventions are to be 2.2 Infectious disease designed to improve public health. For As the world becomes increasingly example, is the diffusion of these behaviors interconnected through the and conditions driven by the emergence of movement of people and goods, norms within the network – e.g., smoking is the potential for global pandemics cool; one should exercise frequently, etc.? of infectious disease rises as well. In Alternatively, is the diffusion driven directly recent years, outbreaks of SARS and by the social component of the relevant other serious infectious diseases in behaviors – e.g., smoking, eating, or widely separated but socially linked exercising with one’s friends? Or might the communities highlight the need for apparent spread of these behaviors reflect fundamental research on disease individuals seeking out others with similar transmission and effective prevention inclinations? The type of data needed and control strategies. to understand the causal mechanism is With GPS and related exactly the fine granularity data that reality technologies, it is increasingly easy mining can provide. to track the movements of people Further, once the causal mechanisms [18, 11]. Logs of location tracking are better understood, reality mining data from cell phones could prove might yield specific points of leverage for invaluable to public health officials effective interventions. For example, if when investigating cases of serious certain behaviors are indeed contagious, infectious disease (e.g., tuberculosis, this would suggest that targeting individuals SARS, anthrax, measles, Legionnaires’ in key parts of the network could prove disease, etc.) to help identify the useful (although privacy issues are relevant source of infections and prevent here; see privacy discussion). Taking this a further transmission. People often step further, one could imagine using reality forget all the locations they have mining to evaluate particular public health visited, even for recent periods, and interventions. Ideally, program evaluations similarly might not know many of the should test not only whether an intervention people to whom they were exposed was effective, but also the theory or might have exposed themselves, underlying the intervention. Consider, all of which underlines the potential

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value of systematically analyzing such affected in pathological states such records for disease control. as depression or mania. Thus, they have used audio features such as 2.3 Mental health fundamental frequency, amplitude Even though they are treatable, mental modulation, formant structure, and diseases rank among the top health power distribution to distinguish problems worldwide in terms of cost to between the speech of normal, society. Major depression, for example, depressed, and schizophrenic is the leading cause of disability in subjects [2,4]. Similarly, movement established market economies [19]. Reality velocity, range, and frequency mining technology might assist in the early have been shown to correlate with detection of psychiatric disorders such as depressed mood [8]. Today, common depression, attention deficit hyperactivity cell phones have the computational disorder (ADHD), bipolar disorder, and power needed to monitor these agoraphobia. sensitive indicators of psychological Many signs and symptoms of these state, offering the possibility of early types of psychiatric disorders explicitly or detection of mental problems. implicitly relate to an individual’s physical movement and activity patterns and communicative behavior, usually with reference to particular temporal periods or cycles. Data streams from reality mining allow direct, continuous, and long term assessment of these behavior patterns. Figure 4: (a) Voice analysis to extract activity, influence, Accelerometers in mobile phones mimicry, and consistency measures. (b) As estimates of depression level, there is a correlation of r=0.79 between might reveal fidgeting, pacing, abrupt or these telephone-based measures and the Hamilton frenetic motions, and other small physical Depression Index. movements. Location tracking functions 2.4 Treatment monitoring reveal individuals’ spatial and geographic Once a course of treatment (whether ranges, variation in locations visited, and behavioral, pharmaceutical, or the overall extent of physical mobility. otherwise) has been chosen, it is The frequency and pattern of individuals’ important for a clinician to monitor communications with others and the the patient’s response to treatment. content and manner of speech might also The same types of reality mining reflect key signs of several psychiatric data used for diagnosis would also disorders. be relevant for monitoring patient For a more specific example of the response to treatment, especially potential power of reality mining technology when such data on the patient in aiding diagnosis, consider the data are available for a period before presented in Figure 4. Researchers have diagnosis and can serve as a baseline long known that speech activity can be for comparison. Changes in mobility,

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activity, and communicative behavior standard, the result was high accurate could be collected in real-time, allowing identification of bradykinesia and clinicians to adjust treatment according to hypokinesia. In addition, the studies the patient’s response, perhaps leading to classified the two most important more effective treatment and preventing problems – predicting when the more costly medical visits. patient “feels off” or is about to Self-report data can also be collected to experience troublesome dyskinesia complement the unobtrusive, automatically- – perfectly [9]. This type of fine- generated and –collected reality mining grained information, key to monitoring data streams. In many cases, the outcomes patients’ treatment, is a strong of interest in medicine and public health endorsement of the value of reality (e.g., some kinds of symptoms) can only be mining techniques. measured through self-report. By gathering self-reported data in tandem with other 3. Reality mining and the new deal reality mining data streams, memory errors on data can be reduced and dynamic aspects of Reality mining of behavior data is health phenomena more fully revealed. just beginning. In the near future it As a more specific example, consider may be common for smart phones to the medication needs of Parkinson’s continuously monitor a person’s motor activity, social interactions, sleep patients. To function at their best, patterns, and other health indicators. Parkinson’s patients’ medications must The system’s software can use these be optimally adjusted to the diurnal data to build a personalized profile of variation of symptoms. For this to occur, the an individual’s physical performance managing clinician must have an accurate and nervous system activation picture of how each patient’s combined throughout the entire day. If these lack of normal movement (hypokinesia) rich data streams were combined and disruptive movements (dyskinesia) with self-reports and personal health fluctuates throughout the day. records, including medical tests and To achieve this, we combined movement taken and the medicines prescribed, data from wearable accelerometers with there is the possibility of dramatic standard statistical algorithms to classify the improvements in health care. movement states of Parkinson’s patients Creating such an information and provide a timeline of how those architecture, however, requires safeguards to maintain individual movements fluctuate. privacy. One approach to this problem Two pilot studies were performed, is to place control and ownership consisting of seven patients, with the of as much personal information as goal of assessing the ability to classify possible in the hands of the individual hypokinesia, dyskinesia, and bradykinesia user, a proposal that is central to (slow movement) based on accelerometer most proposals for creating personal data, clinical observation, and videotaping. medical records. Using the patient’s diary as the gold

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We suggest that a similar approach, a Social network mapping and the ‘new deal’ for privacy and data ownership, resulting subpopulation information be taken for data collected using reality inherently involves other people. mining: individuals own their own data. As a consequence, some of the The simplest approach to defining what it thorniest challenges posed by reality means to ‘own your own data’ is to go back mining’s ability to sense of the pulse to Old English Common Law for the three of humanity concern data access and basic tenets of ownership: the rights of sharing. There are enormous risks to possession, use, and disposal. both individuals and corporations in the sharing of data about individuals. 1. You have a right to possess your data. Robust models of collaboration and Companies should adopt the role of data sharing, between government, a Swiss bank account for your data, industry, and the academy need to be enabling you to check your data out developed; guarding both the privacy whenever you’d like. of consumers as well as corporations’ legitimate competitive interests are 2. You, the data owner, must have full vital here. control over the use of your data. If you’re Clearly, our notions of privacy and not happy with the way your data are ownership of data need to evolve being used, you can remove them. in order to adapt to these new challenges. 3. You have a right to dispose or distribute your data. If you want to destroy them 4. Summary or remove them and redeploy them Reality mining, although still in its elsewhere, it’s your decision. infancy, is poised to quickly become more common, due in large part to Social network mapping and the resulting the rapid proliferation and increasing subpopulation information inherently sophistication of mobile phones. involves other people. As a consequence, Many mobile phones and other some of the thorniest challenges posed technologies already collect a great by reality mining’s ability to sense of the deal of information about their users pulse of humanity concern data access – data such as physical activity and and sharing. There are enormous risks to conversational cadences – and this both individuals and corporations in the will only increase. Computational sharing of data about individuals. Robust models based on such data could models of collaboration and data sharing, dramatically transform many areas of between government, industry, and the human life. Here, we have focused academy need to be developed; guarding on improvements that could be both the privacy of consumers as well realized in individual and community as corporations’ legitimate competitive health. Reality mining can provide interests are vital here. new opportunities with respect to

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diagnosis, patient and treatment monitoring, 2005. Objective physiological and health services planning, surveillance of behavioral measure for tracking disease and risk factors, and public health depression. Technical Report 595, investigation and disease control, and MIT Media Lab. doubtless others, yet unexplored. http://hd.media.mit.edu In many respects, one of the most important applications of reality mining [4] France, D., et al. July, 2000. may be the automatic mapping of social Acoustical properties of speech as networks. Reality mining’s capability for indicators of depression and suicidal automatic social network mapping is risk. IEEE Trans. Biomedical Eng., 829- now being used in a variety of research 837. applications and has clear implications [5] Jaffee, J., Beebe, B., Feldstein, for work in infectious disease, health S., Crown, C., and Jasnow, M. 2001. behaviors, mental health, and treatment monitoring. While such data pose a Rhythms of dialogue in early infancy. potential threat to individual privacy, they Monographs of the Society for also offer great potential value both to Research in Child individuals and communities. Current legal Development, 66(2): 264. statutes are lagging far behind our data [6] Chartrand, T., and Bargh, J. collection capabilities, making it particularly 1999. The chameleon effect: The important to begin discussing how this perception-behavior link and social technology will and should be used. interaction. J. Personality and Social

Acknowledgements Psychology, 76(6): 893-910. This chapter is based on a February [7] Bailenson, J., and Yee, N. 2005. 2009 whitepaper commissioned by the Digital chameleons: Automatic Robert Wood Johnson Foundation. We assimilation of nonverbal gestures thank them for their generous support in immersive virtual environments. and encouragement of this work. The first Psychological Science, 16(10): 814-819. author can be contacted at: pentland@mit. [8] Teicher, M.H. 1995. Actigraphy edu, E15-387, The Media Lab, MIT. and motion analysis: New tools for psychiatry. Harvard Rev. Psychiatry, (3): References [1] Greene, Kate. April, 2008. Emerging 18-35. technologies 2008: Reality mining. Technology Review, 111 (2), 54-56. [2] Stoltzman, W. 2006. Toward a social signaling framework: Activity and emphasis in speech. Master’s thesis, MIT EECS. [3] Sung, A., Marci, C., and Pentland, A.

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[9] Klapper, D. 2003. Use of a wearable [18] Gonzalez, M., Hidalgo, C., ambulatory monitor in the classification of and Barabasi, A.L. June 5, 2008. movement states in Parkinson’s Disease. Understanding individual human Master’s thesis, Harvard-MIT Health mobility patterns. Nature, 453, 779- Sciences and Technology Program. 782. [10] Pentland, A., and Heibeck, T. 2008. [19] Rand Corporation, 2004. Honest signals: How they shape your http://www.rand.org/pubs/research_ world. MIT Press, Cambridge, MA. briefs/RB9055/index1.html [11] Eagle, N., and Pentland, A. 2006. Reality mining: Sensing complex social systems. Personal and Ubiquitous Computing, 10(4): 255-268. [12] Eagle, N., Lazer, D., and Pentland, A. 2007. Inferring friendship from proximity, unpublished manuscript. [13] Dong, W., and Pentland, A. 2007. Modeling influence between experts. Lecture Notes on AI: Special Volume on Human Computing, 4451: 170-189. [14] Pentland, A. 2007. Automatic mapping and modeling of human networks. Physica A: Statistical Mechanics and Its Applications, 378(1): 59-67. [15] Sense Networks, 2008. http://www.sensenetworks.com [16] Christakis, N., and Fowler, J. 2007. The spread of obesity in a large social network over 32 years. New England Journal of Medicine, 357: 370-379. [17] Christakis, N., and Fowler, J. 2008. The collective dynamics of smoking in a large social network. New England Journal of Medicine, 358: 2249-2258.

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Renata G. Chapter 12: 45+ Big Questions of the 5. What are novel strategies for Bushko, 45+ th Big Questions 20 FHTI Summit enhanced predictive modelling and at 20th Future Renata G. Bushko, [email protected] of Health deep learning in the biosciences? Founder, Future of Health Technology Technology Tom Chittenden Summit in Institute, Happier Longer Lives ® “World Health Strategy”, Renata and Chair, 2016 FHTI Summit 6. How will health care look like in G. Bushko (Ed.) @futureofhealth #FHTI 20 years? Renata Bushko, Xing Jijun, eBook FHTI 2016. www. Joseph Kvedar, Guergana Savova, FutureofHealth. th FHTI Summit resulted in the org 7. How can Big Data help you in work World Health Strategy eBook and life? Alex (Sandy) Pentland (Ed.) Renata G. Bushko www. 20 8. How to cure almost everything futureofhealth.org. Both chapters and video-lectures from the eBook provide in brain disorder with light? Newton an excellent roadmap to plan the future Howard of healthcare globally by answering Big 9. Can Chinese herb-based medicine Questions listed below 50+ Luminaries heal the immune system and cure Asking and Answering Most Pressing Questions of our Times: The best way to allergies? Xiu-Min Li progress with health investments to assure 10. Can we forecast changes in mood best outcomes for humanity. 2016 BIG and mental health, like we forecast a Questions selected by FHTI are: storm? Rosalind Picard

11. What is the healing story of Dr. 1. How can we honor and build upon Xiu-Min Li? Barbara Winston Marvin Minsky’s work? Aubrey de Grey, 12. How should we remember Marvin Joshua Feast, Glenn Fields, Renata Bushko, Minsky? Ray Kurzweil Mike McDonald 13. How can we chart the future for 2. What should the new world health digital health information systems? strategy be? What fundamental changes Gary Kreps and dramatic shifts do we need to prepare 14. What are seven secrets to staying for? Renata Bushko young? Aubrey de Grey 3. How do we treat patients like valued 15. What is the future of pain customers? Sanjay Sarma management? Darin Correll 4. Can terabytes of new data deepen our 16. What is the future of computation? knowledge of the state of health care in Stephen Wolfram the Commonwealth of Massachusetts? 17. Why Minsky's ideas are important Sylvia Hobbs for medicine? Henry Lieberman

18. How can we reduce opioid misuse 30. How can we build trustworthy, among chronic pain patients and what is secure and transparent health-apps? the role of risk assessment and innovative Urs-Vit Albrecht technology? Robert Jamison 31. How will health care look like in 19. Will healthcare be delivered by George 20 years? Renata Bushko, Guergana Jetson in the future? Nick van Terheyden Savova, Joseph Kvedar 20. What are new innovative offerings 32. What are the new possible ways to the consumer in the cancer treatment to fund basic bio-medical research? area? Lorraine J. Gudas Renata Bushko 21. Are exoskeletons a solution to physical 33. How can we accelerate formation disparity? Ernesto Rodríguez Leal and success of biotechnology 22. What would best catalyze 100% startups? Eric Elenko, Albert Di Rienzo, renewable energy distributed collectively Tanveer Patel, Adam Greenspan through intelligent grids globally? Michael 34. How can Big Data make a big McDonald difference in the end-of-life care?Dan 23. How can we harness healing power Hogan from plants? Jing-Ke Weng 35. Does your smartphone know 24. How should we communicate to the more about your mental health than public about health technology? Shelagh your doctor? Skyler Place Maloney 36. Is violin music healing? Yuan Mei 25. Is hospital a place? Robert Teague Xing 26. What is the future of international 37. What is the road from Artificial cooperation in health research, Intelligence to Intelligent Health? development and commercialization? Renata Bushko Renata Bushko 38. Can we repair a broken brain 27. Can art inspire? Wally Gilbert with movement therapy approach? 28. What is the best way to communicate Hermao Igo Krebs ideas through graphic design and media 39. How can Google Glass remotely arts?Christoper MacDonald, Jehan Said, integrate with microfluidic biosensors Lauren Callahan, Dianna Cox, Tania Saade, and actuators? Yu Shrike Zhang Marisa Campbell, Andrew R Emery, Charles 40. What’s next in the application of Searle nanotechnology-based molecular 29. What is the future of eHealth? Claudia delivery Systems? Guillermo Ulises Pagliari Ruiz Esparza

41. Can you imagine cities that feel, 49. What is the future of brain’s understand, and take care of your health? Is prevention of neural wellbeing? Agnis Stibe inflammation with Traditional Chinese 42. How Can 3-D printing help with Herbal Medicine possible? Renna epithelial wound healing? Louis Alonso- Bushko, Changda Liu, Beth Powell, Pastor Xiu-Min Li 43. Can Arctigenin reduce inflammation giving hope to treat igE related inflammatory diseases?Renna Bushko 44. What is the future of depression prediction based on self-report diary via smartphone applications? Yoshihiko Suhara 45. How can we reduce the economic burden of Type 2 Diabetes management through smartphone technology and Big Data? Todd Reid, Ian Pentland 46. How can network science be applied for an expanded understanding of large online network information structures and behaviors to modernize public health communication strategies for improved health outcomes? Brittany Seymour 47. How can we implement personalized positive psychology interventions in the form of interactive journaling? Sooyeon Jeong 48. How will fashion industry change healthcare? How will high-tech fashion and wearable technology market impact consumers' health? Will garment be a new health app development platform? Renata Bushko

Renata G. Chapter 13: Emerging technology areas Bushko / Technology that will have a profound impact on the Map in World entire economy including healthcare Health Strategy” eBook, www. sector. Order does not reflect importance. Futureofhealth. org (Ed.) Renata G. Bushko, I Human-Machine Interaction - Requesting Things from Machines FHTI, 2016. In Future of Health Hybrid Brain-Machine Interfaces (HBMI) – Thought to Computer Communication Technology, Natural Language Processing Ed. R. Bushko, IOS Press Automatic Voice Recognition 2002, Chapter 1: Defining Mobile, wireless, wearable, and textile computing Future of Health Technology – Computer Implants (connected to tagged smart environment) Biomechatronics - Renata G. Haptics Bushko II Machine Intelligence Processing Requests Data Mining Common Sense Reasoning Reasoning by Analogy Flexible Transistors (e.g. on plastic) Responding to Requests Organic Light Emitting Displays (data glasses, e-paper, smart windows) Speech Generation Affective Computing (emotional communication) Visualization of Data Automatic Summarization /Abstracting Triggering Action Decision Triggers Biomechatronic Interfaces (to cells and biomechanical devices) Electronic Skin (e.g. triggering payment transaction on the way out of supermarket with no cashiers) III Preservation of Individuality and Security Digital Rights Management Biometrics (Face, Voice, DNA, finger print, behavioral pattern recognition) Biometronics Ethics and Law IV Human-Machine Global Network Microphotonics (all optical Internet with super high bandwidth) High-temperature Superconductivity (inexpensive power quality devices SMES0)

Infinite High-density Data Storage Restructuring Code (Software Engineering) V Intelligent Machines Mobile Mechanical Machines Nanorobots (Microfluidics) Humanoids (Cyborgs) Machine Vision – Vision Genome Machine Learning Deep Learning VI Sources of Energy Body-heat Batteries Chemical Molecular Energy (e.g. ATP) Earth tides (Geothermal Energy) Solar Energy Superconductive Generators

1 Superconducting Magnetic Energy Storage

Renata G. Chapter 14: Unsolved Health Problems Bushko, 45+ Big Questions Healthons: Errorless Healthcare with Bionic at 20th Future Hugs […] of Health Technology in Future of Intelligent and Extelligent Summit in Environment, IOS Press 2005 “World Health Strategy”, Renata Renata G. Bushko G. Bushko (Ed.) Director, Future of Health Technology eBook FHTI 2016. www. Institute, [email protected] FutureofHealth. org y analogy to mathematics where there is always a list of unsolved Bproblems to guide the young generation of mathematicians, Future of Health Technology Institute conducted an “unsolved health problems” survey in 2003- 5. The results are listed in the table below. Solving these problems will get us closer to happier, longer lives for all.

Table 1. Unsolved Health Problems – Based on FHTI’s Unsolved Problems Survey 2003-5

Unsolved Problem What will we gain if we solve this What will we lose if we do not problem? solve this problem? Lack of clean water in much of Reduced (especially child) mortality Lives developing world. rates. Lack of drugs resulting from Cures for previously untreatable, Funding for genetic research human genome. fatal illnesses. Really effective interfaces with Efficiency Usability human users. Significant (in magnitude) Enormous increase in efficacy/ Status quo replacement of human productivity and better "results"/ professionals by machines. outcomes. Translation from the Laboratory We may see more of these We will waste a lot of our to the Bedside: many innovations projects make a difference in intellectual capital on projects that seem to never to get past the clinical treatment. don’t make it to the bedside. “proof of concept demo” phase.

Unsolved Problem What will we gain if we solve this What will we lose if we do not problem? solve this problem? Lack of tools to build causal If we are able to overcome the We will continue to build models that integrate all pieces of problems of how to build, interpret an increasingly fragmented medical and process information; and validate what will often be knowledge base and many information systems that can help massively underspecified models important discoveries will us to integrate all information into of physiological systems, then not get translated into useful causal models, test the models we will be able to accelerate the understanding. against available information, and process of discovery. help us do thought experiments to devise new hypothesis to test. Independent nanorobots with Stop disease before it develops. Lives. smart software controls. Anticipating human and system We will be better able to optimize Medical errors will continue to limit failures so that processes can be the care we can give with the our ability to give the best care devised to prevent these failures. clinical advances we have in hand. possible with the current clinical knowledge. Structured capture of clinical data Increased formal encoding of We will continue the present (history, physical examination, phenotype information to enable process of having this information progress notes, procedure research, clinical care, decision unavailable. Some could be reports, discharge summaries. support, etc. captured through natural language processing techniques, but structured data capture also encourages more discipline and thoroughness in recording, and provides more opportunity for timely decision support. Personal longitudinal integrated This will foster improved continuity We will continue the present health record. of care, access to relevant process of fragmented, information to care providers, incomplete, inefficient better decision making, decreased management of episodes of care errors (e.g., overlooking an allergy without ever having a complete or ordering of a medication picture of the health status of a conflicting with another), and patient. the ability to track a patient's care over time, issue reminders, recommendations for improved health, etc. Comprehensive structured This will provide the ability to Continued current state of limited population health data bases. do analyses of screening tests, comparability and size of datasets. genome-phenotype correlation, outcomes analyses, technology assessments, and clinical prediction/prognosis.

Unsolved Problem What will we gain if we solve this What will we lose if we do not problem? solve this problem? Application of cutting edge Decrease in incidence of Individual quality of life technologies for Primary chronic illness and money and economic stability in Prevention i.e. implanted spend for chronic illness, care health care costs as current calorie counter/blood sugar and improved quality of life. population ages with chronic monitor with beeper or such illnesses due to behavior for weight loss, nicotine or factors. drug aversion implants etc to give ongoing feedback and stimulus for behavior change. The simple low cost pedometer is a good example, but perhaps taken to a higher level or personalized monitoring. Cost benefit ratio analysis of Truly beneficial and cost Increasing personal and 3rd health technologies. effective health technology party costs for marginal efficacy applications. - "technology for technology sake". Inadequate distribution of Equity in world health. Continued Inequitable current technologies, based on distribution which may geography, income etc. eventually be the death of us all i.e. SARS AIDS etc. spreading world wide without available monitoring and prevention measure Lack of coordination. A specific example of positive If we do not attack the problem This problem crosses all coordination among medical of coordination, we risk applications of technology, systems includes the sharing additional sources of error, loss whether business, aerospace, of patient information among of our ability to track errors, or medical. In medicine, the pharmaceutical and patient and loss of time, not to mention cost of mistakes is already too records so that errors in increases in medical error and high. prescriptions, both in hospital possible law suits. and out of hospital are reduced, if not eliminated. But also that same mechanism of sharing, can provide a uniform source of information across many platforms, many software systems, so that validation and cross checking among the different systems may be simplified and when errors are detected, more easily tracked.

Unsolved Problem What will we gain if we solve this What will we lose if we do not problem? solve this problem? Lack of recognition that not Reduce patient load, empower Continuing on the path we are all medical problems can be patients, create first steps in on is no longer an option. solved with "more technology"... the cultural shift to one where Health insurance costs are sometimes, "LO TECH", is a patients begin to take an not going down. Not only are more cost effective and patient ACTIVE rather than PASSIVE Americans uninsured they are friendly. E.g., providing access role in their own health. also underinsured. to meditation classes can reduce the cost of medication for chronic medical conditions such as high blood pressure and pain management. Effective use of media such It will take time to help We will continue to see the as TV and the internet to consumers reach for self care deterioration of health status. raise awareness and engage in their medicine cabinets The cost of insurance, and the the average consumer into rather than pills, but eventually cost of Hi-tech healthcare need healthcare. Make being we can hope to see an to be offset by low tech, such healthy "trendy"; make it improvement in the overall as dietary habits, practice of "attractive". This requires health of human race reducing meditation, and so on. administrators to make this a the costs of chronic conditions line item in the budgets, and the incidence of health a non-technical issue, but problems. implementation is technical. Regenerative Medicine: ability Find cures for millions that Billions of dollars spent on to apply stem cells to address suffer and sometimes die unpromising therapy as well as regenerative medicine. prematurely from degenerative incalculable human misery. illnesses. Background noise in biological Ability to rapidly detect Millions of lives lost to agent detection system. pathogens to isolate infectious disease epidemics populations from further that may be able to be curbed exposure. with early detection. Growing new Telomeres from Potentially slow down the aging Immortality stem cells. process. 100% Electronic infrastructure Greater portability of data, Privacy lapses, consumer for medical records. greater collation of data for apprehension. research, longitudinal tracking of health information, and potential reduction in medical errors. Wide-spread mobile computing Instant access to reference Fragmentation of technological in medical care. and clinical information, greater application in well-funded evidence-based healthcare. vs. poorly-funded settings; physician resistance and lack of acceptance of new computing technology.

Unsolved Problem What will we gain if we solve this What will we lose if we do not problem? solve this problem? Personal understanding of Lower heath costs and better Lost market pressure for preventative health lifestyles. quality of life. improved health care costs with monies being extracted for drugs and procedures no care and health. Adequate pricing of health care Reduction of serious ethical 220,000 unnecessary problems in health care pricing. inpatients deaths and millions of outpatient deaths and disabilities. About $500 Billion in unnecessary healthcare costs. Inpatient medical error as the Eliminate of a substantial See Above third leading cause of death. portion of 220,000 Medication error is the largest unnecessary inpatient subcomponent and by itself deaths per year and millions is the fourth leading cause of of persons maimed or death. 60% of medication error incapacitated in some way. is caused by physician ordering Elimination of a portion and 30% is caused by nurse of about 1M unnecessary administration. outpatient deaths. Elimination of about half of patient visits and hospitalization by proper disease management. Outpatient medical error Human Lives See Above (even higher than inpatient error, perhaps by an order of magnitude) Disease management errors - Human Lives Slow progress the iceberg of which medical error is the visible tip. E.g., many unnecessary amputations on diabetics performed every year in the U.S., caused by improper follow-up. Bringing the bio-med Fast progress and better Lack of individualized hypothesis builders and penetration of innovations into biochemistry understanding the tech developers closer practice. and treatment. (educational challenge).

Unsolved Problem What will we gain if we solve this What will we lose if we do not problem? solve this problem? A reliable protein/proteomics Human Lives – Reduction in Wasted human effort. database for NORMAL human unnecessary anxiety about serum. (Surprisingly, from the “symptoms” that are part of many decades doctors have normal variation not a sign of looked for signs of disease disease. in the blood, the normal constituents--proteins-in blood are very poorly known, both qualitatively and quantitatively. Before we can exploit nanotech & high throughput methods, we really must get a handle on what the range of normal proteins is in peripheral blood). Expediting tech transfer from Reduction in suffering. We will fail to give people lab to clinic (administrative, longer healthy life spans and governmental challenge). reverse aging in order to reverse aging comprehensively enough to keep people alive and healthy for a few decades more than now, which will be enough to let us improve the therapies further and keep us alive indefinitely. Finding the genetic basis of We'll be able to control We will fail to give people the telomerase-independent telomerase-independent longer healthy life spans. telomere extension seen in cancers (including half of all See Above about 10% of human cancers. sarcomas, for example) by gene therapy in the same way that we will be able to control telomerase-dependent cancers by gene therapy against the telomerase genes. Making the 13 protein-coding We'll be able to ignore the We will fail to give people mitochondrial genes work accumulation of mitochondrial longer healthy life spans. when placed in the nucleus. mutations during aging, See Above. because they will be harmless -- the proteins that are made from the mitochondrial DNA will be made from nuclear copies of the genes so the mitochondria will still work.

Unsolved Problem What will we gain if we solve this What will we lose if we do not problem? solve this problem? Finding microbial enzymes to We'll be able to treat all major We will fail to give people break down the cholesterol diseases that are caused longer healthy life spans. analogues that cause by the accumulation of See Above. atherosclerosis and maybe garbage inside cells. That Alzheimer's disease. includes atherosclerosis, macular degeneration and probably most types of neurodegeneration. Lack of machines with common Well cared for population. Worldwide healthcare crisis sense that could take care of Increased health status of the due to lack of care givers. us population. Unnecessary suffering. Lack of comprehensive Faster progress towards Slow progress towards working easy to use framework errorless healthcare. errorless healthcare. for performance evaluation of adaptive complex systems. Maintaining long-term Increased speed of No good communication engagement between users acceptance of caring machines. between people and caring and health dialog systems machines. (caring machines), especially crucial for chronic disease management systems in which we need people to use the system regularly for the rest of their lives. Encoding of behavioral Exponential growth of the use Limited use of caring machines. medicine concepts and and utilization of the caring theories into shareable machines. computational ontologies, to support information sharing and re-use.

Conclusions Utilizing Intelligent Caring Creatures (ICCs) to achieve errorless healthcare requires departure from thinking that the only entity that can justify a medical action is an un-aided human being. Once we are ready to delegate management of our health to ICCs we need to make sure that they are able and willing to explain their multidimensional reasoning. Compiling a list of “unsolved problems” helps moving towards errorless healthcare. It would be useful to have awards system for solving currently unsolved healthcare problems to make healthcare errorless, invisible, infrastructure-free and continuous sooner.

Alice P. Pentland, Chapter 15: Inventing the Future – Tools think about caring for ourselves. Alex P. Pentland / Inventing the for Self Health It is very important to visualize how Future- Tools for Alice P. Pentland M.D. future health technology can affect us, Self-Health in “World Health Co-Director, Center for Future Health as the editor, Renata Bushko, and Strategy” eBook, and Professor and Chair, Department of contributors to this book have done. (Ed.) Renata.G. Bushko Dermatology, School of Medicine and For the full potential of new health FHTI, 2016. Dentistry, University of Rochester, NY, US technologies to be realized, we must Futureofhealth. org, From Alex P. Pentland Ph.D. collectively try to rationalize and Future of Health Academic Head, MIT Media Laboratory, discuss the best ways to capture the Technology (Ed.) Renata G. Cambridge, MA, US opportunities technology provides to Bushko, IOS serve our needs in health, in disease, Press 2002 hroughout the history of medicine, as individuals and as a community. This technology has produced radical task may prove difficult since our Tchanges in our understanding of individual needs can be in conflict with human disease, the therapies that we use to those of our communities, treat it, and how we provide care. A useful necessitating careful implementation of example of the potential for technology to public policy to balance them. transform our approach to health and Because of the complexity of the disease is the invention of the microscope. issues influencing these decisions, the Prior to its invention, we had little positive as well as negative effects of understanding of the existence of technical advances on the state of microorganisms or the cellular structure of medicine over the last century are the human body. However, once this tool therefore worth examining. We must became available, the groundwork was laid also consider and test different so that it was possible to propose the germ technology evaluation methodologies, theory of disease. We could also as well as methodologies estimating understand the cellular structure underlying technology impact as discussed in human anatomy, and so begin to understand chapters by Gary Kreps and Renata the fine processes of organ function. Bushko. These may help us to Medicine was revolutionized as a result. understand what goals we may want to Currently, we are in the midst of a new set and how we may achieve them in technology revolution, illustrated by the the next hundred years. many chapters included in this book. The Since 1900, the introduction of new effects produced by this newest wave of technology has had a profound impact technology have already begun to change on the field of medicine. An example medicine, and are likely to alter our health of this is the creation of the Pediatric care system in the next century as much as Intensive Care Unit. Who would it was transformed during the last one. The believe at the turn of the last century, impact is likely to reshape the processes that a child born at 26 weeks gestation and tools through which we interact with would have a chance at a normal health professionals, and ultimately how we healthy life? We see this with some

regularity today. Large machines, hospital and clinic-based model does ventilators, constant monitoring of heart rate, not provide. respiration, pulse, and temperature along However, it has not been possible with the ability to give tiny increments of fluid to provide the advanced medical care in proportion to a tiny infant’s size permit us that we have invented in a home to maintain these fragile beings. Now they setting. To treat prematurity, the baby can be supported until they are able to currently must live in an isolette, and prosper in the world outside of the womb perhaps also be on a ventilator for and live a long life. weeks on end. This equipment is very Similarly, we have also seen our expensive, and its proper use requires understanding of human cellular function a great deal of training. Because of permit us to design highly specific new the complex knowledge and expense drugs. Our understanding of intracellular required to take proper care of such mediators and cell receptors have allowed infants, it is currently necessary to the creation of new “designer” centralize where such care is pharmaceuticals. These chemicals can block provided. The highly specialized cellular regulatory pathways, stimulating physicians, nurses and other them to delicately tickle the balance of our caretakers needed to care for the blood flow, heart function or kidney infant must be available near the excretion and battle such killers as diabetes, equipment that contains their tiny and heart disease at their root. The result of patient. There must also be a library, so all of this success has been a wonderful and that these health professionals can dramatic increase in the length of the human take full advantage of the body of life span. People born in the United States knowledge needed to keep these can now count on an average life span into delicate infants alive. Centralization the late 70’s and the number of centenarians also allows the equipment to be is rising dramatically [1]. This is an increase regularly used, lessening its cost. A in average life expectancy of nearly 30 medical center environment also years! These benefits have come at a cost, supports the large complex of however. Many people recall great machines needed to perform the array satisfaction with the human aspects of health of tests that are necessary in order to care delivery in the middle decades of the monitor changes in the infant’s health century. For the most part, the doctor came status. So the technology that created to visit the sick at their bedside in their own the opportunity to keep the premature home. People were born at home and died infant (or the auto accident victim) alive at home. The cycle of human life was part has enlarged the complexity, expense of the cycle of family life in an integral and and centralization of health care. In community centered way. This integration the process, we find ourselves feeling of health care into the daily activities of the disconnected from our doctors, and family can have a strengthening effect on perhaps more importantly, our sick families and communities that the modern relatives. Health care is too expensive,

too tightly focused on care of disease and around monitoring of key parameters too separate from our daily lives. Ideally, the in those with chronic illnesses such as changes that are coming should work to emphysema, diabetes and congestive reverse this trend without diminishing the heart failure. The Physio Chair by benefits to our health we have already Commwell and Lifeshirt by Vivometrics achieved through technical innovation. are examples. These new tools are Until recently, there has been very little just beginning to be adopted as success in attempting to extend health care reimbursement strategies are created into the home environment, yet there clearly which make them profitable. is a huge demand for this. Americans In addition to extending the currently spend 27 billion dollars on health activities of health professionals into care outside of the health care the home, optimal health care in the establishment [2] because they find it so future will require the creation of new difficult to access, expensive, and painful. A tools that extend the capacity of the clear demand for better integration of the individual to assess and maintain their home into the health environment exists. No own health. The technology required only that, but a dramatic shift in the to implement this vision must be user composition of our population makes it friendly, intuitive, and have the user’s absolutely necessary to develop such trust. The technology will need to help distributed systems. an individual to maintain their normal In the year 1970, there were 25 health profile, allowing detailed caregivers for each disabled person [3]. information and measurements to be However, the success of our health care collected so that the earliest signs of system is such that the ratio of caregivers for disease can be detected. In contrast the at-home disabled is going to be 6:1in the to the current state of information - year 2030. How will those six people care measuring one’s values against those for that seventh disabled person? Certainly of entire populations, having we cannot have a centralized system of knowledge of one’s own individual visiting nurses that travel to their homes to variations should better enable take care of them because we will not have individuals to better determine when enough individuals left working in the they need to seek health care, before economy to support it. Thus, a more highly they actually feel ill. Armed with his or distributed system is not only something that her own personal information, the we desire but it is an absolutely necessary individual is also greatly empowered in change that must take place. Some efforts the doctor’s office. The visit can to alleviate the problem have been become a discussion between introduced with the advent of telemedicine individual and doctor, and more time as discussed in the chapter by Meg Wilson. can be spent discussing the Visiting nurses have recently begun to make implications of such changes and house calls via telemedicine connections. In providing personal support, rather than addition, a small industry is springing up trying to determine whether or not

changes have occurred. their skin is developing a pressure In the current system, a patient visits the sore. doctor at intervals, and health information/ data is collected through obtrusive or • The “Smart Bandage” to measure invasive means. For future health the bacteria or virus in an injury technology to be something that individuals and let the user know whether at home will use readily, the ongoing antibiotic treatment is needed and collection of personal information must which antibiotic to use. Such a occur in an unobtrusive and cost-effective device can be easily adapted to manner. monitoring food or water supplies, What sorts of devices could be created or identifying allergens in the to help an individual stay well? Collectively, environment. they can be thought of as a “personal medical advisor”, which could also be • The “Smart Bed” to monitor a adapted to function in remote areas of the person’s weight, temperature, world as a local clinic. Where the health care electrocardiogram, or even system is well developed, they can help electroencephalogram to identify keep the aging population functional longer, sleep disorders, early stages of guide parents more successfully through the depression, and generally act as difficulties of childrearing, and help those a central health data repository in with chronic diseases function at their best. the home. Some of the possibilities fulfilling this vision being explored currently are: • “Skin Surface Mapping” imaging • “Memory Assistance” glasses in which devices that collect images of the glass contains an extremely small an individual’s skin surface, then and lightweight computer monitor notes any change over time. This readable by the wearer, and cameras could allow very early detection which can interact with a tiny wearable of skin cancer such as melanoma, computer to help an elderly person greatly increasing survival. maintain their independence and social We will see many more such helpful circle. As an example, this device innovations over the next several could identify a person whose name decades, as we understand better has been forgotten or offer reminders when individuals can effectively act to regarding such tasks as taking help themselves, and when medication or paying bills. assistance from a health professional is needed. • Sensate Liner Garments such as shorts In this volume, there are or socks for people who have lost contributions from an array of experts sensation in their skin due to diabetes describing in detail how their or neurologic injury, to monitor skin particular expertise can reshape integrity and “warn” the wearer that aspects of the way we approach

health care in the future. To make effective technology may allow us to prevent changes, these technical advances must health problems in ways that were be integrated with new institutional previously impossible, as envisioned strategies for health care delivery that by Barry Robson. Inexpensive rapid address the needs of individuals for tests that determine an individual’s privacy, but still provide the benefit to susceptibility to disease or predict the communities of shared information likely side effects of medication may resources. Public policy discussions must spring from such nanoscale creations. bring balance to these sometimes Genetic information combined with contradictory needs and points of view. inexpensive sensors may allow a These discussions are already underway person to test themselves at home to with the new Health Insurance Portability ask questions such as “Do I have the and Accountability Act (HIPAA) legislation susceptibility gene for penicillin [4,5], but more work is needed. allergy?” or “what pollen is triggering The work presented here is therefore my runny nose today?” and help them offered in the spirit of advancing this make decisions about being exposed thoughtful debate. We hope that these to drugs before they become allergic, discussions will not only unlock the or selectively avoid triggers for allergy tremendous opportunities that new health in ways that were not possible without technology presents for treatment of acute these tools. In the case of seasonal illness and injury, but will also emphasize allergy, such tools could be used by the potential of the advances being made consumers without the need for a to remedy the problems caused by the last medical consultation – only wave of technical advancement and make knowledge and antihistamines preventive health care a reality. (already available over the counter) The general areas in which new are needed for the average sufferer. technology will be integrated to advance Much new information about the health care are information infrastructure, causes of drug allergy and the health technology interfaces, advances in markers of it must be collected before the understanding and treatment of such a test is possible, but with disease, and tools for understanding and microsensor arrays and knowledge of assisting behavior change. The area of the human genome, the ability is in disease understanding and treatment is our hands for the first time. huge, and the complexity has been greatly Similarly, such nanoscale sensors expanded by the recent complete can have a huge impact on traditional sequencing of the human genome [6,7]. hospital-based medicine, where they One promising aspect of having be used to improve the rapid sequenced the human genome will be the diagnostic tests available in clinical opportunity to understand the impact of laboratories to increase speed and one’s genetic makeup to prevent episodes sensitivity while reducing cost. of disease. Inexpensive nanoscale sensor Nanorobots as surgical assistants will

make possible selective surgery with Implementing and making interactive greatly reduced risk and higher success the currently available tools is already rates. These new approaches will have the a formidable task, and one that is same pervasive impact that microsurgery consuming large amounts of effort in has had over the past two decades. As health care systems and numerous nanotechnology is advanced, we can take corporations. Clear advantages in the the opportunity to change the large quality of health care and cost of machines we currently employ to make providing care are evident when the them radically smaller. Devices such as new infrastructure is successfully those envisioned by Robert Freitas utilizing implemented as shown in the chapter nanofabrication and constructed on a by Mary Jo Deering. molecular scale, can potentially be made Because of the complexity of cheaply enough that they can be more health information, and the many widely available. Ideally, such sensors needs that health information serves, could be cheap enough to be placed in the organizing the architecture to serve home, for self-assessment and health the needs of all likely users is an maintenance purposes. This change will active and fruitful area of research as make it so the afflicted would only need to discussed in the chapter by Gio travel to hospitals and clinics when Wiederhold. Communications catastrophic illness strikes, or the desire for between physicians, their patients the support and sympathy that can be and their insurers will all be subject to provided by interaction with a health systemization over the next few years. professional is needed. Such nanoscale We must be strong advocates for technology could also be used for creation patient ease of use, access and of implantable devices to supplement privacy protection as these inadequate organ function – for instance, it technologies unfold. could be utilized to assist in the creation of The ideal system will provide an artificial pancreas for those with access to doctors and medical diabetes. We have already seen the personnel when appropriate, and will earliest form of such a device with the also serve public health and research creation of the personal insulin pump[8]. As needs while privacy protection is the scale of the technology needed to adequately maintained. While support the acutely ill becomes smaller, systems providing health care are perhaps the hospital will seem a less strongly motivated to reduce costs by threatening place in which to be ill. moving information freely, this may not The information delivery requirements of be in the best interest of the patient. the existing centralized architecture will HIPAA rules now under discussion need to change radically as we are better address this set of issues, but clearly able to move and store information, as cannot deal with all eventualities. discussed by Blackford Middleton, Richard Giving patients better access to their Spivack and others included here. own record may help apply pressure

to health systems to create systems that about the quality of care that is being serve patients well. Some health systems provided in their doctor’s offices and are already exploring the role of the in their communities. This will actually patient’s personal medical record, and push doctors to provide better care assessing how it should be integrated with and improve everyone’s health. the records kept by hospital systems. Soon Better organization of the we will be able to use internet applications information infrastructure in medicine, for routine interactions with the doctor, and use of intelligent agents gives us nurse or pharmacist. the opportunity to consider a more Intelligent agent software and decision distributed health care system without support tools will be crucial to this process, losing the quality we currently have. as discussed here for use in health care by Those tasks that are less complicated Henry Lieberman and Robert Greenes. In and which people might perform a distributed system that is personalized, better if they felt they had ownership updates of new knowledge to individual of them should be put into the home. users will be crucial to keeping care The new technologies in testing and optimal, and new strategies are likely to be decision support will permit a needed regularly as the complexity of the redistribution of the kinds of care that information we require to keep us healthy occur in a clinic and in a doctor’s increases. Information will be pushed to us office. The doctor’s office will acquire (hopefully with our permission) about more of the functions of a laboratory therapies that may be helpful to us. More space where tests can be done important will be the direct delivery of quickly without having to send the warnings as side effects become known patient off to a central facility at a – such as the cardiac risk of taking Fen- hospital for testing. Hospitalizations Phen[9], or notification that flu has broken will really be reserved for those times out in your neighborhood. Intelligent when a person needs to have an agents will also be available to help us as intervention such as a surgery and we ask questions about our health, the big tools are absolutely required identifying information sources that are for health maintenance. Transfer most useful to our health. between hospitals will be guided by Intelligent agents will also be helpful in the type and availability of services guiding individuals choices about their needed by the individual, rather than medical care. People will be able to look standard policy, maximizing the ability to see whether or not the health care for patients to be treated nearer their system they are working with provides homes when they are hospitalized. quality services. Hospitals and physicians The LINCOS project (little will have a report card given regularly - intelligent communities) is an whether they cooperate with the process experiment in how this kind of by which such report cards are generated redistribution of care using low-cost or not! People will be able to know more high, tech interfaces impacts the

health of rural communities in the third interfaces hamper the adoption of world. These “digital town centers” built in technology, both by health care recycled shipping containers and powered consumers, providers and by generator with a satellite uplink if administrators. The new capabilities of needed, contain the basic equipment for natural language based interfaces will business access to the web, education and make it far more likely that future telemedicine. By bundling the health care systems will be easily used, and may needs of a community with its education help to address the problem of and business needs, LINCOS allows the technical literacy as well. Because creation of a relatively inexpensive high health is everyone’s problem, tech “town center” which can be placed in solutions for providing care must be very remote settings to give individuals and readily usable by EVERYONE who communities who have been cut off from needs care. Keyboards, monitors, the mainstream the access they need to wires and multistep instructions are an take action to improve their quality of life insurmountable barrier to many and health. Several containers have been people – even in the current placed in Costa Rica and in the Dominican environment communication Republic, and 60 more are planned. New problems regularly precipitate strategies for assessing community needs emergency room visits. prior to placement of the containers and The authors included here are new technologies for placement in these addressing the problem of the stand-alone city centers are underway [10]. interface with technology in a variety The information gained can provide a of ways. Natural language roadmap for how decision support, recognition, to avoid training needed sensors, telemedicine and health for current voice recognition information architecture need to be applications is a key goal for the constructed to optimize a distributed model future. Integrating this with affective of health care. computing as discussed by Rosalind Despite advances in the medical Picard, will make the interaction with infrastructure, sensors, disease new health technology be more understanding and treatments, a crucial intuitive, and thus more useable. In aspect for success of health technology in the more distant future, thought to the future will be the interface between the computer communication as technology and the person using it, as discussed by Kevin Warwick, may be explored in the chapters by Graziella the method of choice – particularly for Tonfoni and Jo Lernout.. Failed the handicapped, who have difficulty implementations of technology are with manipulating any interface. frequent, and are often due to problems in Preliminary work combining implants understanding the complexity of the with brain-wave operated controls problem - or lack of understanding of the has been promising [11]. users needs. Bulky, slow and non-intuitive

Clearly the future of health technology is [8] Savinetti-Rose B. Bolmer a bright one, with many opportunities to L. Understanding continuous enhance the quality of our lives. By working subcutaneous insulin infusion therapy. to personalize, distribute, and cheapen American Journal of Nursing. 97(3):42- state of the art disease care – perhaps we 8, 1997 may even succeed at emphasizing [9] Teramae CY. Connolly HM. Grogan prevention and health! Shouldn’t health M. Miller FA Jr. Diet drug-related care focus on health, after all? cardiac valve disease: the Mayo References Clinic echocardiographic laboratory [1] Older Americans 2000: Key Indicators experience. Mayo Clinic Proceedings. of Well-Being ed. by Federal Interagency 75(5):456-61, 2000 Forum On Aging Related [10] Manderson, L., and Aaby, P., Statistics. Report available on US “An epidemic in the field? Rapid Government Heath and Human Services assessment procedures and health website http://www.agingstats.gov research” Social Science & Medicine [2] Eisenberg, D.M., Davis, R.B., Ettner, S.L., 35:839-850,1992 Appel, S., Wilkey, S., Van Rompay. M., and [11] Barreto AB. Scargle SD. Adjouadi Kessler, R.C., M. A practical EMG-based human- “Trends in alternative medicine use in computer interface for users the United States, 1990-1997: Results of a with motor disabilities. Journal follow-up national of Rehabilitation Research & survey”, Journal of the American Medical Development. 37:53-63, 2000 Association 280:1569-1575, 1998. [3] Chronic Care In America: A 21st Century Challenge ed Ellen Freudenheim Robert Wood Johnson Foundation, 1996. http://www.rwjf.org

[4] Christiansen JR. Miller, Nash, Wiener, Hager & Carlsen, LLP, Health information technology and privacy: the legal perspective. MD Computing. 16(4):15-6, 1999 [5] Haugh R. Confronting HIPAA. Hospitals & Health Networks. 74(3):58-62, 64, 2000 [6] International Human Genome Consortium. The human genome. Nature. 409:860- 958,2001 [7] Venter, C. et al., The sequence of the human genome. Science. 291:1304- 1351,2001

S.S. Sarma / Chapter 16: How Do We Treat Patients First, providers and payers must How Do We Treat Patients Like Valued Customers? collaborate effectively to unify the like Valued Sanjay S. Sarma experience for patients. Providers Customers? in “World Health Co-Founder, Prosperata, LLC, Vienna VA, must share data from EMRs and other Strategy” eBook, USA relevant applications to inform payers (Ed.) Renata.G. Bushko of the health status of their members. FHTI, 2016. Abstract Payers must also share data on Futureofhealth. org he notion of treating patients like coverages levels, care approvals, and valued customers in healthcare expected reimbursements, bonuses Tinvolves and penalties. Second, EMR and other companies • A fundamental transformation of that store patient-level data must healthcare from episodic, reactive care to provide open APIs to facilitate data a highly advanced system that leverages sharing and collaboration. Appropriate genetic, psycho-behavioral, social, clinical incentive structures and regulations and environmental data and insights must be in place to make this happen. through advanced analysis, predictive Most importantly, patients must take algorithmic applications, and artificial charge by demanding access to the intelligence information and resources that will inspire them towards healthy behaviors • That, combined with the support of and wellness. health system and healthcare payer We are currently at a critical leadership, organizational and cultural convergence point of forces in transformations healthcare that is driven by rapid advancements in data sciences • Creates a new futuristic system that and technology, massive economic predicts and prevents disease while challenges to the system and a providing necessary care combination of individual and societal • By empowering patients with engaging forces. The time to make this vision a experiences that motivate and inspire reality is now, and the opportunity has dynamic collaboration across the never been greater. healthcare ecosystem 1. Introduction - What does it mean to • That dramatically improve individual and treat patients like valued customers? societal health outcomes affordably and To understand what this all means, first equitably. we must break this down into elements and understand: What is a patient? • The responsibility is shared equally Etymologically speaking, the word between patients and consumers, “patient” comes from the providers and health insurers, policy Latin verb patere “to suffer.” In today’s makers and technology vendors. system, this definition holds true. The

patient is merely a conduit for disease or constantly innovate. Financial advisors sickness, suffering as health care still now serve as a central hub that remains focused on transactions. Doctors, connect consumers to a variety of hospitals, and health systems are paid for insurance, loans, and legal products treating sickness and symptoms, not for that are based on the needs and treating patients as individuals or, for that preferences of the clients they serve. matter, as valued customers. Amazon is already famous for its Then what’s a customer? I thought about product recommendations, product this for a while and decided to look at a education, ordering at a single click variety of definitions. According to and many other features that Shakespeare’s Othello, a customer was in encourage people to use their website fact a prostitute. Shakespeare’s poetic and services. It has also taken license is quite obvious here! According to ownership of the entire delivery business dictionaries, a customer is an process with same-day delivery and individual who consumes a product or drones, displacing the Post Office and service and has choice over what he buys. UPS as the last step. Disney has This sounds reasonable, but what does it evolved its brand well beyond mean to be a valued customer? To individual customer interactions and understand what it means, let us refer to started to capture additional areas of what the great Mahatma Gandhi said many the customer journey — they’ve years ago: “A customer is the most important moved from cartoons to parks to visitor on our premises. He is not dependent hotels and beyond. on us. We are dependent on him. He is not an interruption of our work. He is the 3. What are the current state purpose of it. He is not an outsider of our dynamics? business. He is part of it. We are not doing So why can’t health care learn from him a favour by serving him. He is doing us these other industries? Why is a favour by giving us the opportunity to do healthcare always the last industry to so.” This became the source of my learn from these experiences? Why inspiration for where healthcare needs to haven’t the same great minds that go. have been able to solve the customer experience problem for other 2. What can we learn from other industries failed in health care or industries? simply avoided it altogether? The Many other industries have already figured answer is that healthcare is not a this out. The financial services, retail, and traditional market, it is unlike any other entertainment industries have made major industry. strides in ensuring that customer Today, healthcare is triangulated in experiences are personalized, and each has incentives. For the majority of a system that learns about their customers Americans, over 60%, healthcare is more and more which helps them to paid for by their employer and they

rarely feel the cost of healthcare. Those annually more than is spent in 32 costs are paid as premiums to health industrialized nations. It’s safe to say insurers. When a patient visits the doctor or that the current triangulation between hospital, the provider does not view the patients, providers, and payers puts patient as a customer. Their customer is in patients in a difficult position and is, fact the health insurer, who determines how frankly, undemocratic. much will be paid to the provider based on the claims they submit. Patients are viewed 4. What are the future trends and as a third party. Let’s assume the patient was how do they impact? paying for each test that a hospital Speaking of politics, the good news is conducted, such as EKGs, labs, and blood that the Affordable Care Act makes tests. Would the provider order the same reasonable attempts to address the tests as they do today? That is doubtful, as triangulation. The ACA, as we all know, consumers would be put in an extremely contains the controversial mandate for challenging position of making decisions consumers to purchase their own based on personal finances against plans and established the state-based healthcare quality and safety protocols. health insurance marketplace. It also Therefore, we rely on the bureaucracy of fostered the new model of payers to determine our coverage levels accountable care that provides and providers to make our healthcare financial incentives for hospitals and decisions. health systems to keep people Then who does view the patient as a healthier. In some of these new “value- customer? Since customers pay for health based” models, providers are care through premiums, shouldn’t health reimbursed on claims based on the insurers view them as their customers? positive health outcomes of patients. In While this may seem like common sense, other more integrated and involved health insurers today view employers and “accountable care” models, provider H.R. departments as their primary customers. systems are being paid a fixed amount According to Ingrid Lindberg, a noted of dollars per patient on a monthly healthcare customer experience expert, basis. They must keep the patient “Health insurance is the only business that healthy and out of the hospital and are requires its customers to get permission to at financial risk if they fail to do so. use services they’ve already paid for. If they These models are incenting patients to get approval for a costly procedure, service, experiment with their payers and or medication after going through the providers, which makes the customer mother-may-I process, customers then likely experience important. have to pay again for their share of the cost Providers also now have specific of this ‘approved’ care,” she adds. In some financial incentives tied to their ways patients are treated like children by HCAHPS scores. The HCAHPS parents who fly in their private jets, as health (Hospital Consumer Assessment of insurers now spend in excess of $1.7 trillion Healthcare Providers and Systems)

survey is the first national, standardized, 5. Why is the transition proving to be publicly reported survey of patients’ so difficult? perspectives of hospital care. HCAHPS, also While the incentives may be a starting known as the CAHPS Hospital Survey, is a point, the initial results on these new survey instrument and data collection models have been mixed. Many of the methodology for measuring patients’ major provider-payer organizations perceptions of their hospital experience. that were part of CMS’s initial Pioneer While many hospitals have collected ACO program either lost money due to information on patient satisfaction for their the financial incentives and/or dropped own internal use, until HCAHPS there was out of the program altogether for the no national standard for collecting and same reason. Why is this transition so publicly reporting information about patient difficult? There are two sides needed experience of care that allowed valid to make this possible: first patients comparisons to be made across hospitals must be empowered and engaged in locally, regionally and nationally. their own health, while at the same Moreover, in 2015 CMS eliminated financial time providers and payers must work bonuses for Medicare Advantage health collaboratively within their own plans that didn’t have star ratings of four or systems and develop modern, efficient five (on a five-point scale). Previously, any processes and IT systems to ensure health plan with a star rating of three or that patients are provided with a higher was would receive a bonus. The star positive experience. At the same time ratings now have a component entirely providers must remain focused on the around patient satisfaction, which many ultimate responsibility of providing safe health plans have failed to achieve. One and effective care. This is all much health plan calculated the loss from getting easier said than done, of course. no star ratings bonus at about $1.2 million. Today, over 25% of patients are CMS now calls it patient experience while considering switching or have already health plans favor “customer experience.” switched either their health plan. Regardless of the label, the point is clear: Patients are demanding the same level Hospitals and health plans now have of conveniences and customization incentives tied to the quality of their that they have been afforded in other customers’ experience, whether that industries. The Millennial generation is experience is a trip to the emergency room, a prime example of that. A recent study an inpatient hospital stay, or the enrollment by the consulting firm Accenture found in a health plan. In summary, healthcare that some segments of patients switch payers and providers are realizing that providers simply due to poor digital patients are customers, and healthcare experiences. services should be marketed and tailored to Moreover, to engage patients and their specific needs at each turn in their to create positive experiences health patient journey. systems must also show empathy and provide positive motivation to keep

patients healthy. This is in addition to the perspective. The key is focusing on numerous initiatives that need to take place how to use clarity to drive ongoing to ensure that clinical, operational and engagement. Patients are requesting financial processes are designed and clarity of communications. This can be optimized with a customer focus. in the form of clear and consolidated bills, clear discharge instructions, and 6. What do patients want? clarity with medical education. Think Patients are seeking more fee-for-value about how many times discharge features like concierge health, membership, instructions are only provided by a and a breadth of services—online, clinician during the encounter with no telehealth, mobile. They want to do as much documentation and follow up. Think as they can for themselves and their about how confusing it is to receive families, and they want to get care and bills for out of pocket expenses support when they need or want it. They are sometimes months after the fact, and looking for more engagement with their sometimes, after they have already providers, the health system, and others like gone into collections. themselves. In this model, health coaching, One of the most important shared decision making, personalized experiences for patients is health education, and support groups will convenience. Patients are demanding continue to grow. more ways to interact and Customers will come back when we communicate digitally with their make things easier, more personalized, and healthcare experience, whether that is convenient—not simply making the hassles through providing access to medical easier and faster, but eliminating the hassles records, digital appointment and maximizing the relationships. Retaining scheduling or prescription refills. patients not only improves today’s bottom Patients should be able to contact their line but prepares these patients for the providers to address any issue by way future, training them in new ways to interact of phone, email, text messages, online, so that when the new reimbursement applications, and the web. Think about models emerge, together we will be a family with a serious chronic efficient, connected, and engaged. To condition such as Cancer. Cancer identify the key values and principles that patients deal with numerous providers explain what the patient experience and and likely have primary and secondary engagement is all about, I propose a new forms of insurance coverage. Any model using the 5 C’s: Clarity, Convenience, inconvenience in a scheduling, Customization, Compassion, and Carrots. payment or approval process, for Let’s illustrate each of these in more depth. example, has the potential to take Patients are clearly demanding better away time and cause unnecessary clarity from their providers and payers. This stress to patients and families, and can can mean many different things from a take away precious time spent with clinical, operational, and financial loved ones who may not have much

time left to live. In a capitalist society driven different than an application to remind by so many conveniences, health care still an adult to pay a delinquent bill. remains mired in lack of access and Finally, patients need carrots that confusing prices. Convenience includes motivate them effectively. While most multiple ways to contact and schedule with patients know what they need to do, providers and insurance companies, the tendency to do the opposite is simplification and clear explanation of bills often very tempting. Positive and coverage levels, and having an overall reinforcement is a concept that health unified experience both within facilities and systems must employ to encourage outside of the care setting. healthy behaviors. This was the insight Customization is a broad term that means gathered by Adam Bosworth, co- treating patients based on their individual founder of Keas, an employee health situation. One way to analyze this is to look and wellness program that combines at behavioral, environmental and genetic social media and online games to factors. Some examples of this include create happier, healthier workforces. understanding the psycho-social factors that Keas participants get points, badges determine whether a patient is more likely to and achievements for completing tasks respond to reminders through text and supporting their coworkers in messaging or through phone-based health achieving their goals. Keas believes coaching, whether a patient is more likely to that to successfully change behavior, contract a particular illness due to where people need to be effectively they live or their environment, or whether a engaged around common, meaningful patient is likely to respond to a particular goals. It uses gaming mechanics, treatment based on his or her genetics. social interaction and small groups to These factors can be used to determine the motivate people to achieve their health right treatment or solution for each individual goals. patient. Health systems must also employ 7 What is patient empowerment, and compassion when dealing with patients, will it work? which will help create connections that then Motivation will lead to patient motivate patients to be more engaged in empowerment. What is patient their health. Today, 41% of US citizens empowerment? The idea rests on the believe the healthcare system is more assumption that those who participate concerned about money than people. in their own healthcare decision Showing compassion is not only about making are more likely to feel secure providing pleasant experiences during and are more likely to recover from clinical encounters, but also impacts how we illness. Shared decision making is design applications and health interventions especially important when it comes to outside the healthcare facilities. For deciding between a number of options example, an application for a pediatric for treatment, all which are clinically cancer patient must be thought out entirely appropriate. In these cases, it is

important consider patient values and centered approach and patient preferences. Today, patients often make empowerment. Mobile engagement is decisions without understanding all of their becoming one of the best options for various options. I myself have had multiple delivering care personalization, conditions which became chronic over time. convenience and motivation by I am sure that if I had been presented all of providing targeted, relevant the options I have learned about over the information through smartphones. App years upfront, I may have been able to usage has grown significantly over the reverse the impact of these conditions. past few years, and now more than half Research suggests that patient of health consumers desire to use their participation leads to better experiences smartphones more to interact with related to the quality of care received. healthcare providers. Mobile Patients who participate in their own care interventions have much farther reach show greater belief that they will recover, than individual providers can have. which in turn leads to better health They can reach many more people outcomes. Patients with diabetes, for beyond those seen in the clinic or example, show a greater capacity to hospital. And a health system that manage their condition and recover if they adopts these kinds of tools can process the guidelines from their care team improve their bandwidth and their effectively. Patients who receive clear ability to address these problems discharge instructions report higher patient beyond the capacity of their workforce. satisfaction and adherence to clinical A recent Accenture study highlighted guidelines, which reduces readmissions. the patients’ high demand for mobile: Previous research has demonstrated that providing patients with personal coronary • Today, 33 percent of U.S. risk information may assist patients in consumers are using mobile improving cholesterol levels. Additionally, health apps, compared with just 16 another study found that a cardiovascular percent in 2014. risk calculator led to increased patient participation and satisfaction with the • 66 percent of the largest 100 treatment decision process and outcome, US hospitals have mobile apps and reduced decisional regret. Patients for consumers. Less than 40 need decision aids so they can make percent of that subset have built informed choices. These should not replace proprietary apps. but supplement the counsel of healthcare providers. • At the same time, only 2 percent of patients use apps offered 8. How do we design health applications? by their hospital. Evidently, few Offering easy, secure access to health currently available healthcare information when and where it is needed provider apps meet consumers’ most is the key principle of the patient- expectations and needs.

• Roughly 7 percent of patients have easy for the target audience. switched healthcare providers due to a There are no unnecessary steps, poor experience with digital customer bulky splash screens, upfront service channels, such as mobile apps. registration, or annoying ads.

It’s no longer enough to build one Disruptor healthcare apps are application for the entire healthcare system. increasingly meeting consumer’s While the “big bang” approach may have unmet needs and closing that chasm. worked with EMR systems, with consumer The most downloaded and highly apps the right mantra is “start small and rated health applications today at act fast.” Various groups of patients Calorie Counter, iTriage, and WebMD require specific, targeted apps. Moreover, followed by others such as GoodRx, patients may want different apps for each ZocDoc, Healow, and Dosecast. encounter with a healthcare system, Personal health record (PHR) at each turn in their patient journey. It’s applications have evolved over about understanding all of your patients’ the years. The early attempts by mobile interactions - and delivering the large well-known companies such right information and tools for a smooth, as Google and Microsoft, for the rewarding patient experience. most part, were unsuccessful. The Key Characteristics of a Compelling Patient newer generation of applications App: holds more promise by combining • Personalized – The UI and functionality a few key features together in one are tailored to a specific audience: application and creating engaging seniors; children; busy executives; user experiences. moms; athletes; etc. Health Companion uses a social network model as a way to • Less is More –Applications should not encourage users to take better be too busy - stick with 2-3 key features control of their healthcare. Although and 2-3 secondary features. the site does allow users to share personal health information, all • Dynamic – New content can be added records are kept secured and not regularly by your in-house team, without shared without the patient’s express having to resubmit/re-download the permission. Health Companion also app. has tools for users who wish to track their medical expenses, insurance • Has a “Mobile Hook” – Performs a claims and record the statuses of helpful and frequently needed function each claim. Insurance information that makes the app indispensable can be automatically downloaded from the insurance provider or • Easy to Navigate – UI elements are manually entered into the Health optimized to make the user experience Companion database. Patients can

track their medical statistics through Health according to Healthcare Finance, Companion, such as body measurement, co-payments are growing at nearly cholesterol readings, blood pressure 10% annually, and premiums are levels, calorie values and blood glucose increasing by over 7% annually. Even results. The application also provides for those who do have insurance, appointment reminders and alerts for medical care is still not necessarily medications and immunizations. affordable. According to the Patients Know Best is a significant Washington Post and New York PHR because of the vast importance Times, approximately one in four who placed on putting patients in charge of has insurance still cannot afford their own healthcare. The company has medical care. High deductibles of recently added new features in order to $1,500 or more seem to be the better enhance user experience. The leading cause for the missed care. application provides the ability to have Medical tests, treatments and follow- online consultations for non-emergent up care were the most common types issues, secure control over medical records of care adults skipped. and the ability to share view access with The ACA is already forcing payers healthcare professionals, unlimited storage, to shape up by placing restrictions on appointment scheduling and reminders, the medical loss ratio (MLR), which a patient diary, and organization of now states that insurers must spend records based on body parts with medical 80% of the cost of their premium on education for each area. value adding services while Tonic for Health is another unique company minimizing administrative costs. There that uses patient engagement tools that are several ways insurers can add combine games and graphics to provide value to consumers to reduce the a unique experience for patients. For MLR. example, kids who are asked to submit Although there are many health self-reported data on their medical insurance products for consumers, condition, upon completing the survey use they must be customized based on a fun maze to submit the results. health and financial situations. For example, insurers can offer base 9. What do healthcare payers need to plans with a la carte add-ons, or offer do? perks or special benefits (free bottled Whether they realize it or not, health water, gym memberships) to low insurers have their work cut out for them. utilizers to encourage them to The mandate placed on consumers to continue coverage. Creative options purchase health insurance caused a may help insurers address the national debate that has not ended. spectrum of needs: providing optimal Consumers are starting to ask themselves benefits for those with large medical whether having health insurance is actually expenses while preserving the worth it. The numbers are staggering: portion of their customer base with a

low medical loss ratio (MLR). various referral options – providers Insurers also need the right tools in could more easily play a role in place to help consumers make the right creating a positive member decisions. Consumers must be able to both experience. determine the kind of coverage they need and find the right balance of affordability 10. What do providers need to do? between premiums and deductibles. If the challenges for payers seemed Already today, tools are being developed daunting the challenge for providers that can integrate health plan benefit is even greater. Consumers interact coverage level information with provider with their providers much more often charge masters to provide expected than they do with their payers, and charges to patients and consumer. these interactions take place both Estimators and calculators can leverage within and outside the provider predictive algorithms that warns consumers, facilities. Not only that but providers based on income or other factors, about (unlike payers) are actually their risk for being underinsured if they responsible for what matters most to select certain kinds of plans. In the future patients: the quality and safety of maybe they will predict healthcare costs healthcare. To the extent that quality and provide financial assistance by and safety are improved through predicting and planning for expected patient-centered initiatives, providers healthcare costs. have direct economic, legal and Even after consumers have selected moral incentives. However, this plans and enrolled, many still need involves engaging patients towards guidance on how to get the most out of safe and effective health activities. their benefits. It’s important for insurers to The promise of engagement with improve onboarding materials and other patients will only happen when member communications. If consumers providers first improve the experience have the information they need and want at that patients have with the system, the appropriate times to motivate them to whether that be through take action, consumer satisfaction will communications, customization, and/ increase which will lead to greater member or providing the same conveniences retention. of the digital age. You can see this in While providers don’t manage a patient’s the slow adoption of portals. Portals insurance, they do have an impact on the were launched for patients over the member experience, for example, in last 10 years, and most have low helping patients make decisions on follow- adoption. Why? Because the up care, such as diagnostic imaging and healthcare industry assumed they lab work. If insurers offered resources to could engage us just by providing providers and offices – like access to “look- information in a secure location. up” tools that enable them to provide Consumers have shown through detailed cost and benefits information on observation and research that

adoption can be fickle and elusive. harmful events. And as the process of First, providers need to understand their delivering standard care becomes individual customers and populations. more sophisticated, the care team Collection and standardization of systems can look for data coming back from with patient and population level data is the patient. Patient response data or fundamental to any customer-centric patient-generated data can tell the reform. While the hype today is around “big care team if education and data”, most healthcare organizations are instructions have been opened and still struggling with having all basic patient read. And more importantly, patients information in one place, including clinical, become contributors to their care, demographic, financial records, logs of all including treatment options, medical calls or emails made by the patient, etc. records, and short- and long-term Only when these areas are fixed should care plans. This allows the care team health systems attempt to develop more to tailor care to the unique needs of complex systems with genetic and individual patients and create environmental data for analysis. These personalized care plans that lead to advanced analytics systems over time will quality outcomes, improved know more about us than even we know, communication, and better and more and will be used to optimize our health and user-friendly work processes. wellness. Devices will use analytics to Care coordination allows the provide automated drug dosing and alerts organization of patient activities and to clinicians and care teams about the sharing of information to all of the expected or encountered clinical events. care team involved with a patient’s Having this information in one place will care. The care manager can send improve the experience for the individual patient education that answers interacting with the patients as well as give questions the patient may be confidence to patients that their provider reluctant to ask, gives greater understands them and their history. understanding of symptoms, and Analytics is at the core of the transformation explains options for treatment. The to a customer-centric healthcare system. entire care team has visibility into Providers must also do a variety of what was sent and opened by the things to improve customer experiences. patient. Shifting to a care team model They must standardize care and that includes more non-medical staff communications to patients, so that they interacting with patients means being don’t have to worry about the quality of able to reach patients in between care being provided. When standardized visits with education and care. It also care is used, quality increases, variation in means being able to identify and care plans decreases, and costs decrease. reach specific populations (e.g., Standardization of any process of care high-spending, low-utilization, high- through the use of protocols and checklists risk, and chronic care) with education, can be expected to achieve a reduction in treatment planning, benefit

management support, healthy behavior APIs, patients can then have their own reminders, and utilization reporting. To shift secure access to all of their health coordination tasks away from medical records and information in their own providers, teams needs to be composed of application, which will empower them medical and non-medical staff. Entire and allow them to make more multi-disciplinary teams can then share informed decisions. Patients will no expertise, knowledge, and skill to solve the longer have to access multiple patient complex problems of coordinating patient- portals to view their health information centered care. Effective care teams can and can instead use one single assist with follow ups, identifying and application. Information from patient overcoming barriers to engagement, devices in the home can be sent motivation, education, communication, back and forth between EMRs and targeting specific populations, providing other provider applications, and benefit management support, and helping patients can decide what data goes navigate providers. Care coordination to which provider. teams create a path within an organization’s Providers can leverage this workflow that moves some coordination dynamic data exchange to develop work away from physicians and still delivers more advanced analytics and to coordinated care at the right touchpoints to improve clinical decision making. With engage your patients. As a result of the APIs, providers can receive data such team’s efforts, information is exchanged, as patterns of adherence to clinical care gaps are closed, and good health protocols, dosages and other outcomes are delivered to patients. information to inform departments in hospitals that are working with What is the role of technology? specific patients. Providers can also There are numerous technologies that see a full longitudinal view of all are just now coming into healthcare that will patient healthcare encounters, such make the industry more customer-focused. as primary care visits that may not be These include customer relationship within an institution’s network. management systems, business process Researchers will benefit from having management systems, advanced analytics, access to large sets of clinical or artificial intelligence and robotics. While all claims data to conduct studies that of these are important, there is one key to could advance healthcare. Open APIs unlocking the power of data to both will also allow providers to evolve transform the patient experience and beyond EMR interfaces and create empower patients: application their own customized user programming interfaces (APIs). experiences that are simpler and APIs allow developers to access more intuitive than what is available information so they can build new today, while still leveraging the applications or businesses. When underlying platform. healthcare providers and payers adopt In the future, providers and

patients will share in decision making in broadly will we find the best care near real-time as devices will pass protocols at a reasonable cost for information back and forth into EMRs, which specific patients or groups of patients will be built with clinical alert rules to inform that can be assumed by the system. physicians of potential conditions that can Second, EMR and other be managed by both the patient and companies that store patient- clinician. Stanford Children’s is already level data must provide open experimenting with this concept by APIs to facilitate data sharing and leveraging APIs built for its EMR along with collaboration. Patients are currently Apple Health Kit. Oschner Health System hostage to closed applications currently has a pilot program to prevent that store important data that forms heart failure and hypertension that uses an the basis of their unique customer API to collect body weight and blood experience. Appropriate incentive pressure data from over 500 individuals’ structures and regulations must be in connected devices, which led to significant place to make this happen. reductions in hospitalizations and improved Finally, patients must take blood pressure control. charge by demanding access to the information and resources that What is the call to action? will inspire them towards healthy First, providers and payers must collaborate behaviors and wellness. This effectively to unify the experience for includes access to all of their health patients. The patient is currently confused record information, as well as other in the triangulation between those who are convenient applications such as multi- approving care and those who are channel communication with care providing care, which puts their health and teams and payers, digital appointment wellness at risk. The number of integrated scheduling, automated prescription payer-provider organizations is growing, refills, and health education and and there is much to emulate from models tracking tools. Patient and consumer such as Kaiser Permanente. However, for advocates must raise the voice of the most part payers have their own the customer to the forefront of both programs and applications to engage national and local healthcare policy members which are different from those and inform process and application that providers have. design with deep research both at To become customer-focused, providers the individual and population level. must share data from EMRs and other The transition from patient relevant applications to inform payers transactions towards a customer of the health status of their members. focus that fosters industry-wide Payers must also share data on coverages collaboration enduring relationships levels, care approvals, and expected is indeed all encompassing and reimbursements, bonuses and penalties. complex, as are all great challenges. Only when these collaboration succeed However, we are currently at a critical

convergence point of forces in healthcare June. 2015. Web. 6 March. 2016. that is driven by rapid advancements in 7. United States. Genesys data sciences and technology, massive Telecommunications and economic challenges to the system and Laboratories. Customer a combination of individual and societal Experience meets the forces. The time to make this vision a reality Healthcare Journey: How to win is now, and the opportunity has never been today’s healthcare customer. greater. When we look back twenty to USA. 2003. Web. 18 March. thirty years from today we will see that we 2016. have created a highly advanced health and 8. Orchard, Chris. Five Ways to wellness system that treats patients like Improve Customer Experiences valued customers and is truly an example with Health IT. ECPE. Harvard for the rest of the World. T.H. Chan. 2016. Web. 13 April. 2016. References 1. Darby, Kristin H. CIO. Cancer 9. United States. GSW. 13 Treatment of America. Technology Best Healthcare Customer Enables Patient Empowerment. Web. Experiences. LinkedIn. 20 5 April. 2016. January. 2014. Web. 13 April. 2. Schrimpf, Paul and Epperson, 2016. Josh. 4 Ways to Fix the Ailing Patient 10. United States. Oracle CX. Experience. PM 360. 17 November. Modern Customer Service for 2015. Web. 6 March. 2016. Healthcare. LinkedIn. 17 June. 2015. Web. 13 April. 2016. 11. Conn, Joseph. Consumers want an improved online 3. Aaker, David. Vice Chairman of healthcare experience. Modern Prophet. The Patient Experience Healthcare. 21 October. 2014. Study: 7 Learnings to Improve the Web. 27 April. 2016. Healthcare Experience. 10 March. 12. Burns, Joseph, ed. Chief 2016. Web. 25 March. 2016. Experience Officers Push 4. United States. Prophet and GE Patients to Forefront. Managed Healthcare Camden Group. The Care. November. 2015. Web. 18 Case for Investment. Web. 25 March. March. 2016. 2016. 13. Richardson, Adam. What 5. United States. Prophet and GE You Can and Should Be Doing Healthcare Camden Group. Getting with Your Customer Journeys. Started. Web. 25 March. 2016. Harvard Business Review. 25 6. United States. Health Care Team. March. 2016. Web. 31 March. Media Logic. Future of Health Care 2016. Isn’t Just Gadgets and Gizmos. 12 14. Huckman, Robert and

Uppaluru, Maya. The Untapped April. 2016. Potential of Health Care APIs. Harvard Business Review. 23 December. 2015. Web. 31 March. 2016. 15. United States. Altarum Institute Center. Physicians Underestimate Consumer Likelihood to Switch Doctors. Web. 14 April. 2016. . 16. United States. Healthwise. Four Game-Changing Strategies for Transforming the Patient Experience. 2015. Web. 9 April. 2016. . 17. United States. MobileSmith. Patient-Centered Care, One App At a Time. 2016. Web. 10 April. 2016. 18. United States. Zirmed. Patient Estimation. 2016. Web. 21 March. 2016. 19. United States. Online Journal of Public Health Informatics. Mobile medical and health apps: state of the art, concerns, regulatory control and certification. N. pag. Web. 10 April. 2016. 20. Jayanthi, Akanksha. Patient- controlled data: The key to interoperability?. 17 March. 2016. Web. 2 April. 2016. 21. United States. Elsevier Clinical Solutions. The Business Case for Patient and Consumer Engagement. Elsevier, 1 January. 2016. Web. 22 March. 2016. 22. Mycek, Chris. 4 Steps to Achieve Patient Engagement With Technology. 16 March. 2016. Web. 2

Chapter 17: How should we more efficient delivery of services for Communicate to the Public about Health patients and clinicians. Technology? As of December 2015, Infoway has Author 1: Shelagh Maloney received $2.1B in funding from the Canada Health Infoway, Toronto, Canada federal government. This funding, along with matching investments Abstract from provinces and territories has o guide its public communication essentially been used to usher in two efforts, Canada Health Infoway waves of digital health transformation T(Infoway) developed a patient/ across Canada. The first wave citizen engagement framework. The focused on building the foundational framework identifies four components infrastructure for digital health. The of engagement: listen to the needs and second wave focused on putting perspectives of Canadians, amplify the digital tools in the hands of health voice of patients and patient advocates, care providers. And now, with a new invest in initiatives that directly address commitment of $50 million over two Canadians’ priorities, and influence others years from the federal government, to support the effective use of consumer Infoway will focus on a third wave. This health. Infoway’s Annual Tracking Survey, the wave will put digital health tools in the ImagineNation Challenge Series, the Better hands of patients and empower them Health Together public education campaign to be more active members of their and Digital Health Week were used as care teams. examples of various components of the To ensure that investments in framework. This paper also describes some digital consumer health solutions and of the challenges that are associated with other activities related to improving communicating with the public about health the patient experience are producing technology. tangible benefits for Canadians, Infoway developed a patient/citizen 1. Introduction engagement framework that guides Canada Health Infoway (Infoway) was and informs activities. This framework established in 2001 as an independent, not- includes public outreach and for-profit organization funded by the federal engagement. government to drive the digital health agenda in Canada. Infoway helps to improve the 2. Setting the stage for consumer health of Canadians by working with partners health investment in Canada to accelerate the development, adoption When Infoway was established in and effective use of digital health innovations 2001, the Canadian health care system across the country. Through its investments, was largely run on paper. There was Infoway has three primary objectives: to very little digitization and health care improve access to care, to improve the quality costs were escalating and expected and safety of the care delivered and to drive to continue to increase due in part to

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greater demands on the system by an aging innovation in Canada focused on population and higher medication costs. It improving clinicians’ access to digital was against this backdrop that Canada’s health solutions. This effort was First Ministers created Infoway to provide accelerated by a $340 million dollar national leadership and to develop a pan- investment in EMR systems by Infoway Canadian approach to modernizing the starting in 2011. An EMR is an office- health care system. based system that enables a health In addition to establishing an electronic care professional, such as a family health record (EHR) Blueprint as a doctor, to record the information common architecture and establishing gathered during a patient’s visit. This pan-Canadian standards to ensure might include things such as weight, interoperability between systems, Infoway blood pressure and symptoms, which and its jurisdictional partners began would have previously been hand- their digital health journey by focusing written and stored in a file folder in a on building six core systems to collect doctor’s office. information electronically: client and Investments in EMRs were provider demographics, diagnostic images complemented by a clinical in hospitals, profiles of dispensed drugs, engagement strategy that focused laboratory test results and clinical reports or on establishing relationships with immunizations. This information constitutes and providing resources to national the essence of an EHR – the secure and professional associations (e.g., the lifetime record of a person’s health and Canadian Medical Association, the health care history – that’s available to Canadians Nurses Association and the authorized health care providers and to the Canadian Pharmacists Association) so individual. they can advocate for the adoption Today, most of the work on the of digital health technology; working infrastructure is complete. For example, the with the associations of schools of pan-Canadian average EHR availability is medicine, nursing and pharmacy to 91 per cent as of March 31, 20151. In terms add digital health and technology of benefits, investments by Infoway and the to the curricula to equip young jurisdictions in electronic medical records professionals with the tools they need (EMRs), diagnostic imaging, drug information to work in an e-enabled environment; systems and telehealth have produced an and establishing clinical peer networks estimated $13 billion in access, quality and to provide clinician-to-clinician productivity benefits for Canadians and the mentoring for those adopting the health care system since 20072. And, in technology. September of 2014, Canada’s Ministers of Canadian EMR adoption rates are Health described EHRs as “one of the most a testament to the success of these transformational innovations in health care in investments and initiatives. According a generation”3. to the 2015 Commonwealth Fund The second wave of digital health Survey, 73 per cent of family physicians

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and nurse practitioners in Canada were invest and influence. There are one using an EMR4, triple the number from 2007. or more activities associated with each Similarly, the 2014 National Physician Survey of these components, which will be found that 76 per cent of family physicians described in detail below and with reported increases in quality of care since examples as appropriate. implementing an EMR5, up from 63 per cent in 2013. Infoway expects the use of EMR Patient/Citizen Engagement Approach systems in Canada to continue to grow. With the infrastructure largely in place, and significant uptake in EMR use by clinicians, the stage was set for the next wave; providing Canadians with online access to their information and with digital tools to enhance their roles as informed and engaged members of their health care team.

3. Canada Health Infoway’s patient/citizen engagement framework Engaging with the public, however, is not as straightforward as it may sound. Its complexity is immediately inherent as one tries to define “the public” and/or view Canadians as a single, homogenous group with a common set of attributes that summarize their collective attitudes, Figure 1. Canada Health Infoway Patient/ perceptions and needs. In 2013 Infoway Citizen Engagement Framework. developed a patient/citizen engagement framework to guide and inform outreach 3.1. Patient engagement: listen efforts and investments, as demonstrated in First and foremost, listening to Figure 1. The framework is intended to be the needs and perspectives of sensitive to the multitude and complexity of Canadians is imperative to ensuring patients’/citizens’ needs. It should be noted that outreach activities derived from that the use of the term patient/citizen in this these efforts are relevant and helpful case is intended to convey all Canadians to those for whom they are intended. regardless of their health status and include Infoway engages with Canadians all those who engage with the health directly through its ImagineNation system. Challenge series. The Challenges The patient/citizen engagement seek to inspire, provoke, and promote framework has four components that innovation in health and health care describe the ways in which Infoway interacts to improve the quality of care and with Canadians. They are: listen, amplify, the patient experience for Canadians

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by leveraging widely distributed Infoway engages Canadians knowledge, skills, and resources to directly through surveys and accelerate value from emerging digital focus groups. Since 2010, Infoway health solutions. Desired outcomes are has been conducting public identified up front (e.g. growth in the opinion research to measure use of e-visits or improvement in quality Canadians’ attitudes, awareness of care through clinical information and support for digital health, exchange), and individuals or teams EHRs and consumer health tools. register to participate via a website. The surveys are conducted using They then track their outcomes, share an online panel of approximately their experiences, and receive support 1,500 Canadians aged 18 years through a community of innovators. and older. Survey results are Teams that are most successful in segmented by the following delivering on the desired outcomes subgroups: general population, receive recognition, funding, and other opinion leaders, seniors (55 awards. years+), female caregivers (40 The first Challenge, launched in years+), those living with chronic 2011, reached out to Canadians and conditions and high system users. asked them to submit their best ideas Figure 2 provides more detail for improving health and health care about the definition of these through innovative digital health audience segments. From 2010 solutions. Thousands of Canadians to 2013, the survey included were inspired to send in their ideas questions about attitudes and and/or vote on their favourite idea. perceptions about EHRs only, The ideas submitted were useful in as this was Infoway’s early understanding what Canadians desired focus. In 2013 the survey was from their health system and how they expanded to include questions perceived the role of technology in about electronic health and then allowing positive change to happen. digital health. These terms are Since 2011, there have been ten often used interchangeably, but ImagineNation Challenges involving Infoway’s preferred term is digital 435 team or individual submissions, health. This refers to the use of 211 volunteer judges, over a dozen information technology/electronic supporting organizations, and $2.3 communication tools, services million in awards. The ImagineNation and processes to deliver health Challenge series is now a core care services or to facilitate better component of Infoway’s innovation health. program.

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Canada Health Infoway Annual Tracking Survey Key is having a positive impact on the Audiences Canadian health care system. A strong majority of Canadians agree or Key Definition strongly agree that digital health helps Audiences health care providers by ensuring General Population Representative sample access to a comprehensive picture of Canadian adults 18+ based on age, gender of patients’ health histories (86%), and region. helping coordinate care between Opinion Leaders Occupation = multiple care providers (85%), Executive/Managerial helping provide more effective care or Professional and (76%), and increasing the accuracy income of $80K+; above average of health records (78%). In addition, activism (e.g., writing almost all Canadians (95%) support a on blogs/letters to requirement for physicians to keep media, volunteerism, an electronic record of their patients’ talk about political and social issues) and health information. It is important and above average early informative to track these awareness adopter. levels over time and to understand Seniors Representative sample how Canadians’ thinking has evolved. of Canadians aged 55+ For example, understanding what based on gender and region. they perceive as the benefits and Female Caregivers Women aged 40+ who what they see as concerns (54% have an adult family worry that personal health information member, relative or might be used for other purposes in close friend 50 years the future and 80% are confident that of age or older they are personally helping safeguards are in place to protect deal with their health medical records from being seen by care issues. people who aren’t permitted to see Chronic Condition Those suffering from a them), helps inform the messages we chronic disease, illness deliver to them. or condition. It is also informative to track these High System Users Those who have used the health care system responses over time to judge whether 20 times or more in the awareness levels have changed past six months. and whether messages have been effective. For example, 75 per cent Figure 2: Definition of Key Audiences: Canada of Canadians had heard of digital Health Infoway Annual Tracking Survey health according to the 2016 survey. The 2016 Annual Tracking Survey6 That number has increased from 27 (March 2016) showed that the majority per cent in 20157 and 21 per cent of Canadians (75%) have heard of digital in 20148. This metric is an important health and believe (74%) that digital health indicator of whether Infoway’s efforts

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to communicate and inform the public messages that we heard and to about digital health have been successful. give Canadians a forum in which When asked which digital services to engage. While Infoway as an they would most likely use, the results organization focuses on the needs of are consistent across the country and all Canadians, because of the limited over time. Since 2010, Canadians have budget allocated to this campaign, consistently reported that the patient it was important to look at audience online services most useful to them are the segmentation to ensure success. following: We needed to examine population subsets and their behaviour to • e-Booking, allowing patients to books understand their motivation and appointments and receive reminders calls to action. Most particularly, we online and at their convenience needed to identify the audiences that would be most receptive to • e-Visits with doctors or other clinicians, messages around digital health. including secure messaging and video With this in mind, we identified the visits “health actionist” as the bull’s-eye target for the campaign. Health • e-Renewals so patients can request actionists are catalysts who have prescription renewals online the power to motivate others to take action related to health issues. By • e-Views, which enable online access ensuring that campaign messaging to health records (e.g., laboratory test was tailored toward health actionists, results, children’s immunizations and we increased the likelihood of other components with high value) driving desired actions such as social . sharing and peer-to-peer discussions This information has shaped Infoway’s about digital health. current Consumer Health Investment Health actionists tend to be Strategy “health educated” and actively take care of their health. They are more 3.2 Patient engagement: amplify likely to motivate others to take a The second component of the patient health action, likely to live in an urban engagement strategy is to amplify the area, are on the internet frequently, voice of patients and patient advocates. and are more likely to be a caregiver Providing a forum for discussion, education to someone with a chronic disease and sharing is an important component of (26%). This category includes men, communicating with the public. but skews to women, likely married After listening to Canadians and with children, and averages 40 years engaging them through surveys and of age. focus groups, Infoway launched a public Infoway launched Better Health education campaign to amplify the Together, a public education

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campaign, in September 2013. The • Not being able to communicate campaign was designed to create health information in the event of awareness of, and support for digital health an emergency; among Canadians. Our research had revealed that, while Canadians were aware • Sitting in a waiting room of the benefits of digital health to care surrounded by sick people when providers, they were not generally aware all you need is a prescription of the benefits of digital health that would renewal. accrue to them personally. For this reason the main focus of the campaign was to These ads were posted on the share stories of “real” Canadians who were betterhealthtogether.ca website, positively impacted by digital health. created especially for the campaign. Year one of the campaign featured The website enabled in-depth Sarah and her seven year-old diabetic education for Canadians about digital son, Marcus. In a TV and online ad, Sarah health. Again, knowing that health described how she used digital health actionists spend significant time tools to help manage Marcus’s health and online, it was important to ensure that interact with his care team. The campaign there was an online resource that also featured a number of other Canadian provided information about digital storytellers who shared their positive health in Canada. The website experiences. featured videos of the storytellers A different advertising approach sharing their experiences, as well was used in years two and three of the as background information about campaign. Instead of an ad featuring one digital health implementation across storyteller, we used ads that mimicked Canada. The campaign website situations but did not feature people. This encouraged Canadians to post their allowed viewers to put themselves in those stories, comment on what they saw same situations. Because of the cost and/or ask questions. efficiencies realized by not using people, In addition to soliciting the budget allowed for the creation of engagement through the campaign seven ads featuring real life situations website, the campaign messages that Canadians have experienced or can were amplified via a number of social experience through digital health. These media and other channels. Special included: attention was paid to ensure that amplification efforts were aimed at • Missing a doctor’s call to hear lab channels that were frequented by results; health actionists to ensure maximum reach. For example, in year three • Calling a medical clinic to arrange an of the campaign, Infoway hosted a appointment and getting voice mail; tweet chat on a blog host platform aimed at young mothers. This chat

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attracted more than 140 participants of Canada, COACH: Canada’s Health and generated more than 25 million Informatics Association) all supported impressions in one hour. This example the campaign and were instrumental highlights the importance of knowing who in accelerating our amplification your audience is and taking your message efforts. to them (versus expecting/waiting for them to come to you). 3.3 Patient engagement: invest Another important component of the The third component of the patient campaign and one that was especially engagement framework is invest. As effective in amplifying the message was stated in the introduction, Infoway strategic partnerships and relationships. achieves its mandate by investing in Infoway had support federally, through projects and initiatives that advance Health Canada, as well as campaign the digital health agenda in Canada. endorsement from all provincial and In 2010, Infoway established a territorial governments. These partnerships Consumer Health Strategy to guide increased the credibility of the campaign investment in this domain. Figure 3 and added weight to the message. illustrates the program model. In addition to these partners, Better Investments related to Getting Health Together was supported by more Patients Online refer to the services than 25 national health care associations. that were identified through the For example, we knew it was important listen initiatives (i.e., e-booking, to have professional associations like e-visits, e-renewal (prescriptions) the Canadian Medical Association, the and e-viewing of one’s own health Canadian Nurses Association and the information). Similarly, investments Canadian Pharmacists Association support in Keeping Patients at Home the campaign because some Canadians refer to telehomecare initiatives. told us that they cared about what their Telehomecare is defined as the clinicians thought about digital health electronic transmission of patient and would ask them before they made data (e.g., symptoms, vital signs) up their own minds about it. Similarly, from a patient’s home to a health the professional associations shared care provider for monitoring and the campaign information with their support over a specified time memberships; this resulted in clinicians period. The evidence is clear being more informed and better able to that the benefits associated with respond to their patients’ questions. Patient monitoring a patient’s condition advocacy groups (e.g., Patients Canada, remotely (e.g., fewer emergency Patients for Patient Safety), disease-specific room visits and hospital stays) far groups (e.g., Heart and Stroke Foundation, outweigh the costs associated with Canadian Diabetes Association, Canadian establishing and maintaining the Cancer Society) and industry associations service. The Consumer Health (e.g., Information Technology Association Strategy also enables investments

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in new and emerging innovations that (known in some parts of Canada hold some promise as cost-effective and internationally as remote patient means to improve the patient experience monitoring or RPM) in 2014. Infoway (Innovation & Learning). Finally, Building a commissioned an extensive review Strong Foundation for Consumer Health of the literature, reviewed ongoing enables investments that will accelerate or completed projects from across our learning, lead to greater understanding the country and received advice and of the consumer digital health landscape opinions from a multi-disciplinary panel in Canada, increase engagement activities of experts. The result of this work, titled and stimulate thought leadership. Connecting Patients with Providers: A Pan-Canadian Study on Remote Patient Consumer Health Program Model Monitoring, has been used to advance telehomecare thinking in Canada by identifying areas where there is sufficient evidence to suggest that telehomecare is an effective and cost- Figure 3. Canada Health Infoway Consumer Health efficient alternative to conventional Program Model treatment (e.g., high risk pregnancy, dementia). 3.4 Patient engagement: influence Similarly, in March 2014, Infoway The fourth and final component of the published a white paper called patient engagement framework is influence. Exploring the Value, Benefits and Influencing others to support effective use Common Concerns of e-Booking to of consumer health is paramount to long inform and influence take-up of this term success. Infoway looks to influence the technology across the country. consumer health agenda through a variety of Infoway also makes a concerted means, including: research and evaluation, effort to influence and inform policy knowledge translation, empowering patients, decisions by communicating directly informing policy decisions, and supporting with policy makers and/or to the public change management. to encourage them to raise issues with For example, every project in which their local Members of Parliament. For Infoway invests must include a rigorous example, in 2014 and 2015, Infoway benefits evaluation plan that will enable an led a campaign to celebrate Digital objective assessment of how well project Health Week during the second week goals and performance targets were met. of November. Originally launched as Information from each benefits evaluation a media hook to promote the Better report, in turn, contributes to a growing body Health Together campaign, Digital of knowledge and influences the direction Health Week has grown into an of future investments. An excellent example important event for the digital health of influence in this context is work that was community in Canada. Many of the conducted in the telehomecare domain national associations and governments

How should we Communicate to the Public about Health Technology? 169 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

plan announcements and/or activities (e.g., Infoway’s Better Health Together public webinars, tweet chats, patient forums) to education campaign. Feedback to coincide with Digital Health Week. Public the betterhealthtogether.ca website relations activities and earned media events suggested that Canadians who did also figure prominently during this week and not have access to these services and they are often targeted to government and had not heard of them being available, health care leaders who can influence policy were less likely to believe the discussions and decisions. We are planning message or expect that these services another Digital Health Week in November were available today. Canadians who 2016. had experienced these services for themselves or who had a friend or 5. Challenges family member who had benefited Communicating with the public about from one of the services, were more health technology is complicated for a supportive of the message and more number of reasons. As previously stated, likely to discuss it with others. the “public” is not a homogenous group. Finally, when communicating with Canadians are a very heterogeneous the public about health technology, group with different experiences, attitudes, one must be aware of key influencers perceptions and biases that influence what who may impact how the public and how they interpret communication will react to certain messages. For about health technology. Infoway’s public example, focus groups conducted opinion research demonstrates that people’s to inform the Better Health Together experiences with the health care system, campaign suggested that some familiarity with technology, age and socio- Canadians were heavily influenced by economic status influence their perceptions their care providers, so it was important about health technology. to develop a campaign that was A second factor that impacts how we supported by physicians and nurses. communicate with the public about health Similarly, provincial and territorial technology, or more specifically, how these governments, who are responsible communications will be received, is the for implementing consumer health extent to which digital health tools are services amid a number of competing available to them. For example, there is priorities, were very aware of the need significant variability across Canada with to manage the public’s expectations. respect to the digital health services that are Would the viewing of ads create available. Citizens in British Columbia, for undue pressure on governments and/ example, can access their lab results online. or health providers to accelerate the In 2015, this service became available on adoption of new technology? Or would a limited basis in Ontario, and is largely the ads create more awareness of the not available in any other jurisdiction. progress that has been achieved to This fact had an impact on the response date? to the message communicated through

How should we Communicate to the Public about Health Technology? 170 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

6. Conclusions [3] Alberta Public Affairs Bureau, As it has in many countries, the digital news release via Canada health agenda in Canada has evolved Newswire, September 30, 2014, over the years. Early initiatives were focused on digitizing, connecting and [4]Canadian Institute for Health sharing information between clinicians Information. (2015b). How Canada and building the infrastructure to support Compares: Results from The these efforts. The focus more recently Commonwealth Fund 2015 has been to provide Canadians with International Health Policy Survey access to their health information and of Primary Care Physicians. online services that will allow them to be more informed, empowered and [5]Canada Health Infoway (2015). proactive members of their health Advanced use of digital health care teams. In Canada, this third wave functionalities in Canadian primary of digital health innovation includes care settings: Results from the 2014 a significant public communication National Physician Survey effort. Communicating with the public [PowerPoint Webinar Presentation] about health technology, however, is challenging. [6]Neilson Consumer Insights The purpose of this paper was to (2016) Annual Tracking Survey, describe each of the four components March 2016 [PowerPoint slides, of Infoway’s patient/citizen engagement unpublished] framework using examples of various initiatives like the ImagineNation [7] Ipsos-Reid (2015) Annual Challenge Series, the Better Health Tracking Survey, March 2015 Together public education campaign [PowerPoint slides, unpublished] and Digital Health Week and to describe the challenges inherent in [8] Harris/Decima (2014) Annual communicating with the public about Tracking Survey, March 2014 health technology. [PowerPoint slides, unpublished]

References [1] Canada Health Infoway Annual Report 2014-2015

[2] Ibid.

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G. L. Kreps Chapter 18: Evaluating New Health Technology / Evaluating New Health Information Technologies: Expanding New health information technologies Information the Frontiers of Health Care Delivery (such as specialized websites, Technologies: Expanding the and Health Promotion innovative new communication Frontiers of Gary L. Kreps, Ph.D. devices, and powerful health data Health Care Delivery Chief, Health Communication and analysis tools) are being developed and Health Informatics Research Branch, National and introduced at a rapid rate into Promotion in “World Health Cancer Institute Behavioral Research the modern health system to facilitate Strategy” eBook, Program, Division of Cancer Control and improved health care delivery, health (Ed.) Renata.G. Bushko FHTI, Population Sciences education, and health promotion [1; 2016. 2]. While these new technologies Futureofhealth. org, From Abstract are likely to revolutionize the modern Future of Health he modern health care system is health system, it is imperative to Technology (Ed.) Renata G. being irrevocably changed by the carefully examine and assess the Bushko, IOS development and introduction of effectiveness of these technological Press 2002 T new health information technologies (such tools to determine which products as health information systems, decision- are most useful to apply in different support tools, specialized web-sites, and contexts, as well as to learn how innovative communication devices). While to best utilize these products and many of these new technologies hold the processes. Without good evaluative promise of revolutionizing the modern information about new technologies, health system and facilitating improvements we are unlikely to reap the greatest in health care delivery, health education, and benefits from these powerful new tools health promotion, it is imperative to carefully [3; 4]. examine and assess the effectiveness of Evaluation research is an these technological tools to determine essential process in developing and which products are most useful to apply in implementing health information specific contexts, as well as to learn how to technologies [2; 5]. Failure to best utilize these products and processes. engage in careful and concerted Without good evaluative information about evaluation research is pure hubris new technologies, we are unlikely to reap (a fatal miscalculation) that is likely the greatest benefits from these powerful to doom the success of new health new tools. This chapter examines the information technologies. It is unlikely demand for evaluating health information that new technical products will work technologies and suggests several well for users without the use of strategies for conducting rigorous and relevant evaluation data. Effective relevant evaluation research. development and institutionalization of new technological products involves a series of product adaptations. Good evaluation data provides needed 1. Evaluation Research and Health direction for product refinement.

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Every new health technology should needs. In fact, the more radical the have both formative and summative technical innovation is, the more evaluation strategies built right in to the difficult it will often be to integrate development process from the very within the health care system. The beginning [6]. (Formative and summative technical interventions that typically evaluation will be discussed in more work best within the health care depth later in this chapter). Evaluation system are developed incrementally data provides technology developers through a process of reinvention, with a broad range of critically important reinventing current processes and information about: products to better meet health care/ • level of demand for new health promotion needs. information technologies, Prior to the development of new health information technologies, • environmental constraints and comprehensive reviews of relevant specifications for the implementation of literature should be conducted to new products, identify key findings from literature in the scientific and professional fields • specific design flaws and limitations of most closely related to the new products, technological product. It is foolish to reinvent the wheel, when good • assessments of the relative efficiency information about product demand and effectiveness of new products, and practices is already available. Key established research and • the appropriate fit of these products for practice findings should guide specific audiences and contexts, and product development and implementation. • strategies for adapting new health information technologies to fit the 3. Formative and Summative idiosyncratic demands of different users Evaluation Research and unique social situations. Formative evaluation is an essential process in the development and 2. Research and Reinvention; What Do refinement of new health information We Already Know? technologies. Formative research is Technological innovation is a process of used to test the adequacy of invention and reinvention, however it technological interventions, providing appears that reinvention is the process that relevant data for improving the is most often utilized in health technology technologies. By examining key development and implementation [7]. It is components of new technologies, the usually unnecessary to develop radically ways the technologies are used, and new products or processes to effectively identifying constraints to system address current health care/promotion performance, formative research data

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can provide clear directions for the development of improvements to these 4. Audience Analysis Research: technologies. Targeting the New Health Summative evaluation research is used Technology to measure overall new technology impact Successful technological innovations and outcomes. Summative research is depend on data gathered through used to document the positive and audience analysis research to design negative influences and impacts of new programs to fit audience needs. health technologies. These data provide Needs analyses are initial applications important measures of the utility of health of audience analysis evaluation information technologies for health care research that gather data from and promotion. Summative data should potential product users to establish examine the costs and benefits of the levels of audience demand and technology and help health care systems opportunities for new health determine the effectiveness and long-term information technology products and utility of employing specific technological processes [6]. Are there significant products and processes. performance gaps (differences Formative and summative evaluation between the intended and actual research should not be viewed as separate outcomes) in current health system and unrelated research processes. Rather, products and processes that formative and summative evaluation can be necessitate technological innovation viewed as different ends of an evaluation and intervention? It is essential to research continuum. Formative research begin the process of health looks at the small pieces of the technology, technology innovation and product providing a microscopic analysis of the development by examining the individual components of the product or perceptions of potential users process. Conversely, summative evaluation (audience members) about current looks at the big picture, providing a technologies in the health care macroscopic global evaluation of the way system, identifying limitations to these these different components work together products, and developing strategies to accomplish relevant health care/ for extension and innovation to promotion goals. Formative and summative increase the effectiveness of research should work together in the products that are not delivering evaluation of new health information satisfactory service. Careful technologies. Ideally, formative data evaluation of current products and informs summative research, providing processes in health care/promotion is pieces of the data needed to evaluate essential for guiding technological overall system impact and outcomes. reinvention. Results from formative evaluation should be All technological interventions mined and combined in compiling should be based upon clear summative evaluations. evidence of what works. There is a

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wealth of important data often lying The best technological interventions dormant in every health care/promotion are based upon strong evidence. setting that indicates what has and what Evaluation data should provide has not worked in the past to achieve evidence about what has and has not health care/promotion goals. Needs worked in the past within the health analysis data should reveal whether there care/promotion system. It should is sufficient demand for new technological help demonstrate the need for products and processes for achieving change and intervention within the health care/promotion goals to initiate system. It should help identify the development of new health technologies. kinds of technologies that best fit the Furthermore, audience analysis research needs of users and the demands of will help identify many important user the social context for interventions. It expectations and predispositions that will should demonstrate the utility of undoubtedly influence product acceptance proposed interventions, identify the and utilization [8]. most promising implementation It is also important to get to know the strategies, and test the effectiveness orientations, attitudes, beliefs, and of new health information expectations of audiences for new health technologies in action. information technologies so user interfaces There are rich natural data can be designed to meet consumer sources that should be identified communication orientations [8; 9]. The during audience analysis research more revealing data health information efforts that can help provide evidence technology developers have gathered for directing technological about the intended audiences for their intervention and provide data about products, the better they can target the relative success of new development of products to fit user technological interventions. For characteristics and skills [10]. Usability example, the evaluation researcher testing will help technology developers to can identify “natural” (normally assess the extent to which they have collected) records of key events (such targeted technologies to match the as product performance, employee technical skills and needs of users [11]. (The attendance, quality control, error importance of usability testing as a rates, usage levels, and sales records) particularly rich evaluation research that can provide the researcher with strategy for determining the extent to which interesting trend data to track system health information technology programs performance before and after the match individual user skills and abilities will implementation of new health be discussed in more depth later in this information technologies [6; 12]. chapter.) Natural data collected before new technology implementation can help 5. Evidence Based Technological provide a clear baseline measure Intervention Efforts from which to track system changes

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that, at least in part, can be tied to the conduct usability tests of new health influences of the new health information technologies. Usability tests are technologies. (Care must be taken to hands-on evaluations of users’ recognize multiple influences on system perceptions about and abilities to performance due to uncontrolled events operate new health information and extraneous variance, and not to technologies [11]. Usability tests overstate (or understate) the influences of assess technology users’ evaluations new technologies. Control measures in of their experience with products, similar contexts that have not implemented including the ease, comfort, efficiency, the new technologies can provide speed, and effectiveness of use, as important points of comparison for clarifying well as track these users’ actual the impact of new technologies.) abilities to navigate the technological It is a good idea for health information products and achieve health care/ technology evaluation researchers to promotion goals [6]. Can users implement user response mechanisms accomplish the goals the new that are built right into the new technology was designed to help technological products [13]. These them accomplish? How readily can a response mechanisms can be both passive new user learn how to use this (provide invisible data collected system? Are there ways to improve automatically by tracking and recording the usability of this system? Usabilty characteristics of technology use) and data will help answer these questions active (requesting feedback, comments, and suggest strategies for refining and suggestions from users). Passive health information technologies. usage data is relatively easy to collect, but can often be misleading if analyzed in 6. Methodological Issues and isolation of other data. For example, high Constraints in Conducting time of use data may seem to indicate a Evaluation Research successful new technology, but it might just A major limitation in the way that as easily indicate that the technology is evaluation research is often time-consuming and cumbersome to use. conducted is the over-use of single Active response data can suffer from point of data collection evaluation validity issues concerning self-report data studies, based on the false (discussed in more depth later in this assumption that one cross-sectional chapter). Passive user response and active data set will suffice in evaluating new user response data should be analyzed health information technologies. One together to clarify user reactions and ideas point in time cross-sectional data will about the new technologies. not provide the depth of information needed for most evaluations. It is Prior to implementation of new important to see how new technologies, as well as after technologies technologies are accepted and have been implemented, it is important to utilized over time. There are peaks

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and valleys in technology use. Users have validity) [6]. Due to these threats to to learn about new technology products, validity, caution must be taken in get used to them, learn how to use them, interpreting survey data in evaluation experiment with them, and figure out how studies. to adapt the technologies to different Evaluation researchers often focus applications and situational demands. This on tangential variables (variables that learning process takes time. Gathering are not directly relevant to research cross-sectional data (one point in time) is goals), especially with the use of likely to miss the key moments in standardized survey instruments. evolutionary trends of technology These standardized scales can be implementation and usage, missing both attractive to use due to their potential strengths and weaknesses of the established reliability, availability, and technology. ease of use (the law of the hammer) A common problem experienced in [6]. The variables measured in many evaluation efforts is over-reliance on the of these standardized scales (such as use of self-report data. Self-report data is health beliefs, personality attributes, information requested from respondents and attitudes) are not always relevant through the use of survey research tools to the technological products and (typically with questionnaires and processes being evaluated. These interviews). In many cases self-report data tangential variables inevitably provide has become the default measurement weak and equivocal evaluation data. approach used in evaluation studies. While Technological evaluation research surveys often provide interesting depends on the measurement of information, there are serious questions important variables that provide data about the veracity of survey responses of direct relevance to the goals set for leading to threats to the validity of survey the products and processes under data, especially in organizational contexts examination. where socio-political pressures can Another problem that often limits influence responses. It is all too common the effectiveness of evaluation for respondents to praise new technologies research efforts conducted for new because they fear organizational reprisals health information technologies is from management for providing negative over-reliance on shallow data, such information (the mum effect threat to as the number of web hits. Such data validity) [7]. Respondents also often try to are very equivocal and difficult to provide the “right” answers to surveys to interpret due to limited information. please researchers and management (the Conclusions made based on such Hawthorne effect threat to validity) [6]. data are often unwarranted. For Sometimes survey respondents just give example, does increases in the the same, most expedient answers to number of hits (log-ons) to a new survey questions to get through with the web-based health information survey quickly (the response-set threat to dissemination program indicate the

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program has been successful at achieving health promotion goals? Not necessarily. 8. Methodological Additional information is needed. Who is Recommendations for Conducting accessing the website? What is their Evaluation Research experience with navigating and using the The following suggestions are website? What kinds of information are designed to help researchers users getting from the site? How are these increase the effectiveness of their individuals using information from the site? efforts to evaluate new health What impact has the information they have information technologies: accessed had on their health behaviors • Longitudinal Evaluation Research and health conditions? Effective evaluation Designs. It is important to research of health information technologies develop longitudinal evaluation must answer these key questions. research designs that gather data at multiple points in time 7. Data Reduction and Information to capture the evolution of Overload technological implementation and The way that evaluation research results use. In fact, it is a good idea to are presented is fundamental to making the build in strategies for continuing findings from the research useful. measures of both passive and Consumers of evaluation research need to active evaluation data over the understand the strengths, weaknesses, and life of the health information overall influences of new health information technology, beginning from before technologies. All too often, evaluation data implementation to establish clear are presented in ways that do not baseline data. communicate well to different audiences, increasing information overload in health • Multi-methodological Research care systems, rather than increasing Designs. Multimethodological understanding. Statistical presentations of research designs combine evaluation research results are often different methods to offset the complex and confusing for many weaknesses of each method with audiences. To get the most out of the strengths of other methods [6]. It is a particularly good idea evaluation research, researchers have to to augment the use of self-report translate findings in clear and compelling survey research with other ways. Strategic use of tables, charts, and measures to help establish the examples can help technology managers validity of survey results. Multiple and users interpret and apply evaluation measures can provide important research findings [6]. Researchers must complementary perspectives clearly identify the implications, for analyzing health information technologies. applications, and limitations of evaluation • Combining Quantitative research. and Qualitative Data. While

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quantitative data can be powerfully health outcome variables, analyzed statistically, quantitative data evaluation researchers can often fails to provide great depth of assess the impact of new health explanation. Alternatively, qualitative information technologies on data (gathered from unstructured important health consequences, interviews, focus groups, observations, such as users’ knowledge, etc.) can usually provide great depth attitudes, behaviors, and health of information and can be profitably states [14]. Measurement of combined with more traditional important health outcomes is quantitative research methods in especially important in summative evaluation efforts [6]. Triangulation of evaluation to identify the quantitative and qualitative measures contributions of the technological can afford the evaluation researcher programs and processes. both precision and depth of analysis. • Translating Data into Practice. A • Unobtrusive Evaluation Measures. significant advanced step in the Wherever possible, evaluation evaluation research process is researchers should design non-reactive interpreting data and applying data gathering strategies into evaluation them to action strategies for efforts, such as measures that do not increasing the effectiveness of depend upon respondents self reports health information technologies. (unobtrusive measures) to increase It is not enough to just describe the validity of evaluation research [12]. evaluation data; data must be By observing naturally occurring data, leveraged into real activities for such as examination of archival records achieving important health care/ and the natural build-up (accretion) or promotion goals [9]. Too often wearing away (erosion) of observable rich evaluation research data elements in social contexts, researchers are merely reported and not can often reach strong conclusions applied to the development of about social behavior that are not interventions for refining and influenced by social and political improving health information constraints. Unobtrusive data can also technologies. Translating data into be used to check the validity of self- practice is an essential culminating report data, increasing confidence step in evaluation research. in conclusions reached from survey research [6].

Using Evaluation Data to • Communication and Health Outcomes Demonstrate Progress. Evaluation Variables. By measuring relevant research should provide clear

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information about the contributions of White Plains, NY, 1990. new technologies to the accomplishment [8] E.W. Maibach, G.L. Kreps, & E.W. of important health care/promotion Bonaguro. Developing strategic communication campaigns for HIV/AIDS goals and outcomes [15]. By tracking prevention. In S. Ratzan (Ed.), AIDS: progress, evaluation researchers can Effective health communication for identify the achievements and shortfalls the 90s (pp. 15-35). Taylor and Francis, of new technologies, helping to direct the Washington, D.C., 1993. development of future health technologies [9] I. Rootman, & L. Hershfield. Health communication research: Broadening for enhancing health care and health the scope. Health Communication, 6: 1, promotion [16]. (1994), 69-72. [10] T. Albrecht, & C. Bryant. Advances References in segmentation modeling for [1] AHCPR (Agency for Health Care Policy and health communication and social Research). Consumer health informatics and marketing campaigns. Journal of patient decision making. Final report. US Health Communication: International Department of Health and Human Services, Perspectives, 1: 1, (1996), pp. 65-80. Agency for Health Care Policy and Research. [11] J. Neilsen.. Designing web usability. AHCPR publication 98-N001, Rockville, MD, New Riders, Indianapolis, IN, 2000. 1997. [12] E. Webb, D.T. Cambpell, R.D. [2] T.R. Eng, & D.H. Gustafson. (Eds.). Wired Schwartz, & L. Sechrist. Unobtrusive for health and well-being: The Emergence measures: Non-reactive research in of interactive health communication. Office the social sciences. Rand McNally , of Disease Prevention and Health Promotion, Skokie, IL, 1973. US Department of Health and Human [13] V.S. Freimuth, J.A. Stein, & T.J. Services, Washington, DC, 1999. Kean,. Searching for health information: [3] T.R. Eng, A. Maxfield, K. Patrick, M.J. The Cancer Information Service model. Deering, S. Ratzan, & D.H. Gustafson. Access University of Pennsylvania Press, to health information and support: A public Philadelphia, PA, 1989. highway or a private road? Journal of the [14] G.L. Kreps, & D. O’Hair, (Eds.). American Medical Association, 280 (1998), Communication and health outcomes. pp. 1371-1375. Hampton Press, Cresskill, NJ, 1995. [4] F.A. Sonnenberg. Health information [15] G.L. Kreps, L.R. Frey, & D. O’Hair. on the Internet: Opportunities and pitfalls. Applied communication research: Archives of Internal Medicine, 157 (1997), 151- Scholarship that can make a difference. 152. Journal of Applied Communication [5] M. Chamberlain. Health communication: Research, 19: 1, 1991, pp. 71-87. Making the most of new media technologies. [16] G.L. Kreps, S.M. Hubbard, & V.T. Journal of Health Communication: DeVita, The role of the Physician Data International Perspectives, 1: 1 (1996), 43-50. Query on-line cancer system in health [6] L.R. Frey, C.H. Botan, & G.L. Kreps. information dissemination. In B.D. Investigating communication: An introduction Ruben (Ed.), Information and Behavior 2 to research methods (2nd ed.). Allyn & (pp. 362-374). Transaction Press, New Bacon, Boston, MA, 2000. Brunswick, NJ, 1988.

[7] G.L. Kreps. Organizational communication: Theory and practice (2nd ed.). Longman,

Evaluating New Health Information Technologies: Expanding the Frontiers of Health Care Delivery and Health Promotion 180 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

John Moore, Chapter 19: Flexibility and Constraints in relevant categories. For example, if a Henry Lieberman / Patient Interviews patient describes his or her pain like, Flexibility and John Moore M.D. “someone sticking in a knife and then Constraints in Patient Henry Lieberman Ph.D. turning it”, the system could categorize Interviews in MIT Media Laboratory, Cambridge, MA, USA it as sharp, intense, and localized. World Health Strategy” eBook, (Ed.) Renata G. Abstract 1. Introduction Bushko, FHTI, 2016. www. ncreasing understanding of how to Jane is a 63 year old woman who Futureofhealth. categorize patient symptoms for efficient is having trouble with her vision. org From Strategy for the diagnosis has led to structured patient She describes her chief complaint Future of HealthI interviews and diagnostic flowcharts that to the doctor’s receptionist over the (Ed.) Renata G. Bushko, IOS can provide diagnostic accuracy and save phone as, “I see floating things in my Press 2009 valuable physician time. But the rigidity vision that aren’t really there”. Before of predefined questions and controlled seeing the doctor, she is given a new vocabulary for answers can leave patients computerized medical questionnaire to feeling over-constrained, like the doctor fill out. It takes a standardized new- (or computer system) is not really listening patient medical history, complete with to them. In addition, not hearing the disease and hospitalization history. patient’s own words can lead to the Since her complaint is visual, she is physician overlooking subtle details that given a vision-specific questionnaire. are diagnostically relevant. How can we Among the questions, it asks, “Do you reconcile the need for patients to express see flashes of light in your vision?” themselves with the doctor’s need to She answers, “No”. understand the patient’s experience in When Dr. James sees Jane, medically appropriate terms? he looks over the summary of We present I’m Listening, a system for her answers. In a case like this, automatically conducting patient pre-visit he suspects posterior vitreous interviews. It does not replace a human detachment (the vitreous jelly in the doctor, but can be used before an office visit back of the eye condenses over to elicit complaint details. This information time and separates from the retina can be used to triage care and prepare causing opacities commonly known as patients for visits with educational materials “floaters”). Since she answered “No” and appropriate tests, making better use to the direct question about flashes of of both doctor and patient time. It uses light, his suspicion of a complication an on-screen avatar and natural language such as a retinal tear or detachment is processing to (partially) understand the low. He asks a series of questions and patient’s response. Key is a Commonsense examines her. In his exam, he sees reasoning system that lets patients clear evidence of posterior vitreous express themselves in unconstrained detachment. His exam is cursory since natural language, even using metaphor, he sees this all of the time without and that maps the language to medically complications. Just at the end of his

exam, however, he sees a small retinal Commonsense reasoning system that tear. He is relieved that he did not miss this has a broad understanding of topics important finding, but he is confused. He of everyday life. The latter is essential decides to revisit the topic with Jane. “Are because it provides the ability for you SURE that you’re not seeing flashes the patient to express themselves in of light in your vision?”. “Yes, I’m sure.” she metaphorical language (“like Fourth of says, “Um... well... I am seeing something, July fireworks”) that can be mapped, they’re not flashes, but they’re more like either by a system or by a doctor, to squiggly little lines, kind of like those you medically relevant vocabulary and see at Fourth of July fireworks, and they categories. come and go.” For example, a patient can type, Dr. James realizes that her answer “I have been having stabbing pain in should have been a “Yes”. But she wasn’t my right foot for five days that gets lying or mistaken, it’s just a matter of how worse when I walk.” The system will the questions and answers are interpreted. identify the medical problem as “pain”, Patients sometimes don’t understand the location as “right foot”, duration as “five days”, and aggravating factor as vocabulary of medical questionnaires, “when I walk”. In addition, it is able and when they are forced to choose an to reason that “stabbing” pain should answer, the most appropriate choice is not likely be categorized as “sharp” since always clear. Questionnaires put words into a knife can be used for stabbing and people’s mouths. Human experience is a knives are sharp. The system then complicated thing; we don’t have enough takes a conversational approach words in our language to capture all the to the confirmation of each of the subtleties of how people experience their attributes that were determined. The bodies. advantage of this technique is that it Our goal is to improve the use of not only obtains crucial information online medical questionnaires, diagnostic for the physician in a patient-friendly flowcharts, and automated medical history manner, but it also becomes a learning and diagnostic systems. We want to provide tool for the patient. It is essentially a more flexibility in the way computers dress rehearsal for the patient before visiting the office. Patients can learn interpret what patients say and how the what kinds of questions to expect computer responds to them. We aim to every time that they have a complaint reconcile the desire of people to express so that they can express themselves themselves in their own terms with the more clearly and have their problems need to categorize responses and follow addressed more appropriately. predefined diagnostic procedures (and know when to depart from them). 2. Background 2.1 Physicians as Interviewers Our key tools are a mixed-initiative Traditionally, physicians consider natural language understanding system themselves to be excellent patient that can interpret patient responses and a interviewers. There is significant

research, however, suggesting that this is computer systems because they do not true today. They are generally not good not feel rushed and do not feel like listeners. During a standard encounter, they are being judged. studies have shown that physicians interrupt Although it is true that computer- patients in less than 24 seconds.1,2 In based questioning systems are well addition, they are not good at explaining received by patients and that they medical findings in that they often use outperform physicians in eliciting terminology that is not well understood thorough histories, their adoption is by patients.3 Finally, they are not good at currently very poor. Statistics are not being thorough and performing exhaustive available, but with only 13% of doctors questioning. A study of primary care in this country using electronic medical physicians shows that they asked only 59% records and only 4% of them using of essential history items.4 In addition, it has more advanced systems14, it is clear also been shown that up to 54% of patient that well less than 1% of them are problems are not elicited by physicians.5 It using computer-based questionnaires. should be clarified that much of the fault In addition, even though patient here lies on the constraints that have been responses to individual encounters placed on physicians and not on their skills. have been positive, little research They have limited time for visits and are has been done on optimizing user expected to pick up problems that are not experience by using more complex associated with the main reason for a visit. interaction techniques so that long- This suggests that we need to design good term interactions can be sustained. assistive technologies for physicians, and there is good evidence that data collection 2.3 Major Flaws in Current Medical is an area where physicians can use help. Questioning Systems • Systems are not Completely 2.2 Computer-Based Medical Automated Current systems, Questionnaires such as the one outlined in the A great deal of research has been done, introduction, require a human starting in the 1960s, to prove the benefit of to briefly interview the patient in computer-administered medical interviews and questionnaires.6,7 Bachman8 provides order to choose the appropriate an excellent review of the literature. As questionnaire for the patient’s opposed to physicians, computer systems chief complaint. There are a are very good at patiently listening, using number of significant problems patient-appropriate language, and being with this paradigm. First of all, thorough. In fact, it has been shown in it involves the communication numerous studies that patients report of sensitive health information sensitive health information more reliably to someone other than the to computers. These studies have included physician. Despite new laws alcohol use9, drug use10, sexual activity11, for health privacy such as the 12 13 suicide attempts , and domestic violence Health Information Portability among others. Patients have also reported and Accountability Act (HIPAA)15, that they appreciate interacting with there is still significant risk for

breach of confidentiality. Secondly, inventory higher for their relationship it typically requires that the patient with the relational agent, suggesting come into the office to speak to a staff that they had a better working member and complete the survey. This relationship with this empathetic defeats the purpose of automated agent.16 medical questioning in that the potential There are many people in the for efficient triaging and staging of field of human computer interaction diagnostic laboratory tests before who argue for interfaces that are the visit is removed. In addition, the maximally efficient over those that opportunity for the patient to complete are chatty and friendly. It is certainly lengthy interviews from the comfort of true that in many scenarios, users home is lost. appreciate an interface that is quick and minimal, but it is hypothesized • Focus on Efficiency Leads to that this type of interface will not be Unfriendly Experience sustainable in the area of automated medical questioning. Since Current systems are designed for maximum medical questioning is inherently efficiency with text-based interfaces with a conversational situation, there is rigidly structured question sequences. likely significant benefit that will be Patients may find them novel and obtained from enabling the interface interesting on the first encounter, but long- with human-like conversational term studies have not been conducted to techniques. determine patient satisfaction. Discussions • Rigid Categorization and with providers using such systems, Controlled Vocabulary Limit however, suggest that patients find these Patient Expression systems tedious and impersonal on Current systems rely solely on multiple encounters. forced-choice responses and do Tim Bickmore is an alumnus of the not capture the richness of patient Media Lab who is now the lead of the input. This can be dangerous Relational Agents Group at Northeastern because important details can be University. In his doctoral thesis, he lost as portrayed in the patient designed a relational anthropomorphic scenario. In addition, it can be agent that used empathetic remarks and frustrating for patients because affective facial and body gestures that were they feel that they are not being appropriate to the state of the relationship listened to appropriately. The in the context of exercise behavior system always forces a choice modification. He found that subjects chose that typically does not match to continue interacting with relational agent exactly what the patient want to over a non-relational anthropomorphic express. agent. In addition, they rated the bond component of the therapeutic alliance • Value of the Interaction is not

Proven to the Patient at Northeastern University. They are Patients spend a great deal of time capable of changing her proximity answering questions offered by current and facial expression in order to systems, but the benefits from spending match the emotional content of their this time are not clearly demonstrated speech. to them. If patients do not feel that the time that they spend interacting with 3.2 Mixed-Initiative Natural a technology is fruitful for them, it is Language Understanding System likely that they will resent it. In addition, Physicians are typically trained to take they will likely resent the physician for an approach with patients starting making them speak to a computer and with open-ended questions and then limiting face-to-face time. drilling-down with more constrained questions. I’m Listening takes this 3. I’m Listening same mixed-initiative approach to I’m Listening is a system for automatically eliciting patient chief complaints. The conducting patient pre-visit interviews. chief complaint is the term used to It aims to take a dramatically different describe the patient’s main reason approach than current computer-based for a visit to the physician. The agent medical questionnaires in order improve starts with the open-ended question. patient experience and the usefulness “What is the main reason for this of the data obtained. The goal is for the visit? By that I mean, what is the one system to parallel the conversational problem that is bothering you the approach of a physician as closely as most?” The patient is able to enter possible. Physicians are trained to a complaint that is one sentence develop rapport in their interviews with or shorter. The system then uses patients while at the same time collecting a context-specific natural language categorized information that is crucial in understanding algorithm to process diagnosis and treatment planning. They the complaint. The algorithm uses are able to make the patient feel attended tagging, chunking, and parsing to even though they must drive the majority rules specific for chief complaints of the interview in order to get the required and is capable of identifying the information. core medical complaint as well as onset, duration, frequency, location, radiation, intensity, character, and 3.1 On-Screen Avatar aggravating and alleviating factors. I’m Listening currently communicates with For example, a patient can type, “I the patient through an on-screen avatar have been having pain in my right using computer-generated speech through foot for five days that gets worse a text-to-speech engine. The avatars, when I walk.” The system will identify Laura and Karen, were designed by Tim the medical problem as “pain”, Bickmore of the Relational Agents Group location as “right foot”, duration as

“five days”, and aggravating factor as “when eliciting patient complaints. First of I walk”. The system is robust in that the all, it allows for the collection of not patient could have also typed, “My right only the patient’s free text complaint, foot has been hurting for five days when I but also the categorized attributes walk” or “For five days, there has been pain of the complaint, which are useful for in my right foot when I walk” or even non- the physician. In addition, it performs grammatical sentences such as “right foot this whole process in an automated pain five days when I walk.” fashion, so that it can be carried out Of course the natural language in the comfort of the patient’s home processing algorithms will make mistakes. without requiring sensitive patient To address this problem, the system takes information to be communicated a conversational approach to confirming to any third party. It also gives the each of the conclusions that it makes. It patient a feeling of being listed to, starts with the most crucial conclusion, so that, when the system progresses which is the core medical problem coupled to more forced-choice questions, with the location if appropriate, and these are more acceptable to the progresses to other groups of conclusions. patient. Finally, it becomes a learning The agent will ask, “It sounds like your tool for the patient. The system problem is right foot pain, is that correct?” always asks the patient: “When did If any component of the conclusion is the problem start?”, “How long has it wrong, the system will elicit from the patient lasted?”, “Is there anything that makes which component so that only that one it worse?”, “Is there anything that is addressed. It might initially appear to makes it better?”, etc. Eventually the some that such an approach is inefficient patient will start to add these details and could be tedious. In fact, however, this to the complaint so that the system type of conversation is very similar to the will not have to ask. The patient way that a physician conducts an interview. starts to understand the attributes Confirmations not only assure that details of complaints that are important in were heard correctly, but they also serve communication with the physician. the purpose of making the patient feel as Instead of saying, “Aunt Sally thinks if the physician (or computer) is actually that I have pneumonia,” they will listening. If a conclusion is wrong, the start saying, “I have been having system apologizes for the error and elicits difficulty breathing for five days that is the detail in a more constrained frame. It associated with a productive cough is hypothesized that this apology will help and mild fever.” to minimize the user’s perception of error rate since there is some evidence that 3.3 Commonsense Reasoning affective support and apology are valuable System in minimizing user frustration.17 New techniques have been There are a number of advantages of developed to allow open-ended using this natural language approach to responses from patients to be

mapped to system-established choices. complex. Rather than making the The goal is to let patients express patient choose from a list the word themselves and to capture the richness that best characterizes his or her of patient input but, at the same time, pain, the system gives the patient the to allow the decision tree to proceed opportunity to free-text a description appropriately. The approach being used of the pain. The system then stems borrows techniques from a new trend in each of the words in the input and artificial intelligence called Commonsense progresses through a series of computing. four main algorithms to attempt to The Open Mind Common Sense (OMCS) categorize the input. project is a distributed solution for the • Our Commonsense reasoning collection of common sense knowledge.18 system for mapping open- It enables the general public to enter ended patient input to system- common sense information through a web established choices uses both interface with 18 different semi-structured ConceptNet and AnalogySpace. frames such as “______is a kind of The preliminary implementation ______” or “______is used for allows patients to express ______”. In this way, knowledge is complaints involving pain. Pain entered using natural language, but in was chosen because it is the a manner that is more reliably machine- reason for over 70 million medical interpretable. ConceptNet is then a visits per year and because the semantic network representation of the language used to describe pain knowledge in OMCS that can be used complains is some of the most to explore concepts using advanced complex. Rather than making techniques including spreading activation.19, the patient choose from a list the 20 It also allows the translation of the word that best characterizes his machine-interpretable information back into or her pain, the system gives the natural language. Finally, AnalogySpace patient the opportunity to free- uses principal component analysis to text a description of the pain. allow users to infer new common-sense The system then stems each knowledge and to compare concepts.21 of the words in the input and Our Commonsense reasoning system progresses through a series of for mapping open-ended patient input four main algorithms to attempt to to system-established choices uses both categorize the input. ConceptNet and AnalogySpace. The preliminary implementation allows patients to express complaints involving pain. Pain was chosen because it is the reason for over 70 million medical visits per year and because the language used to describe pain complains is some of the most

• Otherwise AnalogySpace is used to evaluate the possibility that the stemmed input has a “HasProperty” relationship with each of the predefined pain categories. The scores from each evaluation are compared to determine the relationship that is most likely. The patient is prompted for Figure 1: Patient’s pain description matches a pre- confirmation. For example, if the defined category. patient inputs that his or her pain is like a “chainsaw”, there might not • Otherwise it is determined if the be a direct relationship between stemmed input is already a node in chainsaw and any of the categories ConceptNet, indicating that there is of pain. ConceptNet does know information concerning it in the OMCS that a “chainsaw” is used to cut database. If so, then it is determined if and that a knife is used to cut and any of the predefined pain categories that a knife if sharp. AnalogySpace is a property of that node with the therefore rates the possibility “HasProperty” relationship. The that a chainsaw is sharp with a patient is prompted for confirmation. relatively high score. Again, the For example, if the input is “a knife”, results a conveyed to the user ConceptNet knows that “a knife” is through natural language with the “sharp.” The system presents the suggestion that the system thinks association in natural language as that the relationship is possible, but shown below. that its confidence is lower.

Figure 2: Patient’s pain description has a Figure 3: Patient’s pain description does not have a direct relationship with one of the pre- direct relationship with one of the pre-defined defined categories, but there is an indirect categories. Confirmation is required to relationship. The confirmation language determine if the relationship is valid. reflects the uncertainty of the inference.

• If the second and third algorithms 4. Related Work fail, then the patient is prompted to As discussed in the background choose directly from one or two of section, there has been a significant the predefined pain categories. If amount of work done in the area the patient thinks that the chosen of computer-based medical categories describe the initial input well, questioning. This work has foc then those categories are added as structured, forced-choice, non- “HasProperty” relations to the input in conversational decision trees as the OMCS database. opposed to our work that aims to allow conversational structure with Although this Commonsense reasoning more open-ended patient prompts system has been initially developed to while still capturing structured data deal with pain complaints, it can now be that satisfies the goals of a decision generalized to deal with any free-text tree. Outside of the field of medicine, patient input that needs to be mapped to there are many examples of natural pre-defined categories. The advantage language based conversational of this approach is that, as more patients systems. These systems typically use interact with the system, the system statistical inference to drive program becomes more intelligent. Once one flow in cases where input is open patient confirms a relationship that did not ended. The drawbacks of statistical previously exist, the system will be able techniques are that the reasoning to relay the possibility of that relationship behind an inference cannot be to the next patient with a similar input. In determined and that there is no addition, the more patients who match opportunity for reasoning outside of a given input with a given category, the previously encountered examples. higher the confidence the system will Our approach of mapping open have in that relationship and this can be ended responses to categorical expressed in the language that it uses. outputs using Commonsense Quickly the system will not need to use inference is novel in this respect general information to make associations, because the semantic relationships but will be able to use context-specific between concepts can be used to associations that are created from the many construct meaningful conversational users interacting with it. moves and new responses can Just as with the natural language potentially be mapped to appropriate understanding system, not only does the outputs through the use of other physician receive the categorized version semantic relationships that are known of the patient input, but also the patient’s in the Open Mind Commonsense own words describing each aspect of a Database. problem. In this way, the system is flexible yet provides a constrained output.

5. Conclusion patients to take a more active role Doctors are beginning to benefit from in their care such that they become the assistance of computers, but they are equal partners with their medical going to need even more help in the future providers. One project that is being to keep up with a tremendous influx of developed in parallel is a multimodal data and increasing need from patients. (speech and touch) workstation This does not mean, however, that we for doctor-patient shared decision need to force patients to interact with making. A goal is to integrate the unfriendly and inflexible robots in order agent from I’m Listening into this to get the structured data that is needed. interface so that there can be three I’m Listening is a system for automatically way conversations between the conducting patient pre-visit interviews doctor, patient, and technology. This that presents a number of important will likely have profound effects on advances including a mixed-initiative the psychological relationships that natural language understanding system patients will have with the agent and and a commonsense reasoning system. their evaluations of the value of such These advances are key components that a system. Another project being will allow for conversational systems that developed by Ian Eslick of the New can mimic important aspects of doctor- Media Medicine group is a collective patient communication so as to make the intelligence system for disease interaction friendly and flexible for patients communities. The agent-based while at the same time collecting structured conversation techniques will also be and categorized that is usable by the adapted to allow for more patient- computer and useful to the physician. friendly data input in this system. It will be a recurring theme of the 6. Future Work group’s work to design technologies Immediate work on this project involves that not only improve the health of generalizing the Commonsense reasoning patients but also engage them and system so that it can deal with a broad make them feel better about their range of medical complaints. In addition, healthcare experience. testing the system on a large number of patient complaints will be crucial in Acknowledgements determining its initial performance and its We would like to thank Zuzana learning abilities. Trnovcova for her hard work in the ance and its learning abilities. development of the mixed-initiative The work highlighted here is part of a natural language understanding larger effort by the New Media Medicine system. We would also like to thank group at the MIT Media Laboratory to Ryan Young for his contribution to the enable radical new collaborations between initial prototype of I’m Listening and doctors, patients, and communities. The Ken Arnold for his assistance with goal is to develop technologies that allow ConceptNet and AnalogySpace.

References 14. DesRoches CM, et al. Electronic 1. Marvel MK, et al. Soliciting the patient’s health records in ambulatory care--a agenda: have we improved? JAMA. 1999; national survey of physicians. N Engl J 281: 283-287. Med. 2008 Jul 3; 359(1): 50-60. 2. Rhoades DR, et al. Speaking and 15. Department of Health and Human interruptions during primary care office visits. Services. “Standards for Privacy Fam Med. 2001; 33: 528-532. of Individually Identifiable Health 3. DiMatteo MR. The Psychology of Health, Information.” Federal Register. 2002: Illness, and Medical Care: An Individual 67: 53181-53273. Perspective. Pacific Grove, Calif: Brooks/Cole; 16. Bickmore T, Gruber A, Picard R. 1991. Establishing the Computer-Patient 4. Ramsey PG, et al. History-taking and Working Alliance in Automated Health preventive medicine skills among primary Behavior Change Interventions. Patient care physicians: an assessment using Education and Counseling. 2005; 59(1): standardized patients. Am J Med. 1998; 104: 21-30. 152-158. 17. Klein J, Moon Y, Picard RW. 5. Stewart MA et al. The doctor/patient This Computer Responds to User relationship and its effect upon outcome. J R Frustration. Conference on Human Coll Gen Pract. 1979; 29: 77-81. Factors in Computing Systems, CHI ’99 6. Slack WV, Van Cura LJ. Patient reaction extended abstracts on Human factors to computerbased medical interviewing. in computing systems. 1999: 242-243. Comput Biomed Res. 1968; 1: 527-31. 18. Singh P, Lin T, Mueller ET, Lim 7. Mayne JG, Weksel W, Sholtz PN. Toward G, Perkins T, Zhu WL. Open Mind automating the medical history. Mayo Clin Common Sense: Knowledge Proc. 1968; 43: 1-25. acquisition from the general public. 8. Bachman JW. The Patient-Computer Proceedings of the First International Interview: A Neglected Tool That Can Aid the Conference on Ontologies, Databases, Clinician. Mayo Clin Proc. 2003; 78: 67-78. and Applications of Semantics for Large 9. Lucas RW, et al. Psychiatrists and a Scale Information Systems. Irvine, CA. computer as interrogators of patients with 2002. alcohol-related illnesses: a comparison. Br J 19. Lieberman H, Liu H, Singh P, Barry Psychiatry. 1977; 131: 160-167. B. Beating some common sense into 10. Paperny DM, et al. Computer-assisted interactive applications. AI Magazine detection and intervention in adolescent 2004. high-risk health behaviors. J Pediatr. 1990; 116: 20. Havasi C, Speer R, Alonso, J. 456-462. ConceptNet 3: a Flexible, Multilingual 11. Millstein SG, Irwin CE Jr. Acceptability Semantic Network for Common of computer acquired sexual histories in Sense Knowledge. Proceedings of adolescent girls. J Pediatr. 1983; 103: 815-819. Recent Advances in Natural Languge 12. Greist JH, et al. A computer interview for Processing. 2007. suicide-risk prediction. Am J Psychiatry. 1973; 21. Speer R, Havasi C, Lieberman 130: 1327-1332. H. AnalogySpace: Reducing the 13. Lapham SC, Kring MK, Skipper B. Prenatal Dimensionality of Common Sense behavioral risk screening by computer in Knowledge. Proceedings of AAAI. July a health maintenance organization-based 2008. prenatal care clinic. Am J Obstet Gynecol. 1991; 165: 506-514.

Christopher Chapter 20: The Value of Impermanence comfort. Good UX design remembers Previte, The Value of in Design that “users” are, in fact, humans. Impermanence Christopher Previte Despite this, the marriage of UI in Design, Chapter 20 New England Institute of Art, Brookline, MA, US and UX design, and the products in “World Health Mount Ida College, Newton, MA, US and spaces they help to create, often Strategy” eBook, (Ed.) Renata G. overlook many aspects of the human Bushko, FHTI, Abstract experience. Here we specifically want 2016. www. Futureofhealth. any spaces on the web (social to speak about the balance between org media, photo sharing, genealogy documentation and impermanence. Msites, etc.) ask us to document What is permanent versus what is so much of our lives. There is an implied ephemeral. Much interactive design permanence to these collections and for the web focusses heavily on the they are used as currency in making and former with little to no attention paid to maintaining social relationships. This need to the latter. document and save everything is only half the story however. Here we will discuss the value of impermanence and ways we can 2. Documentation incorporate it into our design practice. noun 1. the process of classifying and 1. Introduction annotating texts, photographs, Artists, designers and programmers focused etc.1 on interactive design are alternately referred to as User Interface (UI) and User 2. the photos taken during a night Experience (UX) Designers. These terms of sin that “document” all of the are relatively new and can include those less that glamorous moments. who work in graphic and web design, These may include random drunk programming, visual design, and mobile dancing, any shirt malfunctions, design and development. dress mishaps; ending with bare UI design addresses how users interact ass being visible to the public with machines, computers, and software. eye.2 It addresses all points of input and output, both physical and virtual. These can include 2.1 By the Numbers keyboards, buttons, menus, screens, and Facebook windows. The goal of UI design is to make • As of 2013, there were over 250 this interaction easy, efficient, and enjoyable. billion photos on Facebook3 UX design addresses the quality of those interactions governed by the UI. • That’s an average of 217 photos UX concerns are more intangible and speak per user to concepts such as atmosphere, personality, familiarity, and Facebook users upload a total of 350 million new photos each day

Flickr • A 2012 study showed that 73% • As of 2013, there were about 3.57 billion of respondents would feel photos on Flickr4 “panicked” and 14% “desperate” if some catastrophic event caused • Users upload an average of 586 million them to lose access to their per year, or 1.6 million per day mobile devices and online life.9

Ancestry, MyFamily, Genealogy.com 2.4 This Need to Document and • Users and employees added about 1.2 Reliance on Connectivity Creates an billion documents to their database last Imbalance in the Human Experience year5 • Online culture and mobile connectivity will continue to grow, • 2.7 million users generate an average but it must also evolve. of 75 million searches per day • Alternative means of interaction Twitter that speak to the entire human • Every second, on average, around experience can influence user 6,000 tweets are tweeted (over experience. 350,000 per minute, 500 million per day and around 200 billion tweets per 3. Impermanence year)6 noun

2.2 Driven by Smartphone Adoption 1)The state of not being permanent.10 • 64% of all US mobile phones are smart phones7 2)The term expresses the Buddhist notion that all of conditioned • 80% of new mobile phone purchases existence, without exception, is in a are smart phones constant state of flux.11

2.3 Opportunities for Content Creation 3.1 The Buddhist Notion12 and Design; Opportunities for User Early Buddhism dealt with the Anxiety problem of impermanence in a • In 2014, Zhiling Tu, Yufei Yuan and very rationale manner. This concept Norm Archer (of McMaster University is known as anicca in Buddhism, in Hamilton, Ontario), writing in the according to which, impermanence “International Journal of Mobile is an undeniable and inescapable Communications” explained that: Smart fact of human existence. The early phones and other portable digital Buddhists did not believe in the devices have led to more and more existence of a permanent and fixed people “carrying with them” valuable reality. According to them what was data assets wherever they go.8 apparent and verifiable about our

existence was the continuous change it freedom and shatters the concept undergoes. of predestination. Take for example the life of an individual. It is a fallacy to believe that a person would • Impermanence denies the control remain the same person during his entire of gods. life time. He changes every moment. He actually lives and dies but for a moment, or 3.3 Impermanence in Action Oral lives and dies moment by moment, as each Tradition moment leads to the next. A person is what The “oral tradition” refers to “the lore he is in the context of the time in which he of cultures. It is transmitted by word of exists. It is an illusion to believe that the mouth and consists, as does written person you have seen just now is the same literature, of both prose and verse as the person you are just now seeing or narratives, poems and songs, myths, the person whom you are seeing now will dramas, rituals, proverbs, riddles, and be the same as the person you will see the like. Nearly all known peoples, after a few moments. now or in the past, have produced Even from a scientific point of view this it.”14 is true. We know cell divisions take place in Person Perception15 each living being continuously. Old cells in • Refers to the different mental our bodies die and yield place continuously processes that we use to form to the new ones that are forming. Like impressions of other people. the waves in a sea, every moment, many thoughts arise and die in each individual . • Can be a very subjective process Psychologically and physically he is never that can be impacted by a number the same all the time. Technically speaking, of variables. no individual is ever composed of the same amount of energy. Mental stuff and • We often form impressions of cellular material all the time. He is subject others very quickly with only to change and the change is a continuous minimal information. movement. Impermanence and change are thus the • We frequently base our undeniable truths of our existence. What is impressions on the roles and real is the existing moment, the present that social norms we expect from is a product of the past, or a result of the others. previous causes and actions.

3.2 The Value of Impermanence13 • Impermanence brings us hope.

• Impermanence embodies the spirit of

The Rest of the Story16 4.1 Leaving a Place for the Viewer/ Understanding the value of personal User perception as it relates to the events in our • It has been said that no work of lives. art is complete until someone The Importance of Imagination experiences it.22 • Imagination is the ability to form new images and sensations in the mind that • Classic art often left room for the are not perceived through senses such viewer.23 as sight, hearing, or other senses. • What the mind can imagine, is • Imagination helps make knowledge often better than what you can applicable in solving problems and is show.24 fundamental to integrating experience and the learning process. • Respect your audience’s intelligence.25 • A basic training for imagination is listening to storytelling.17 4.2 An Example of Balance SnapChat 26 • The Swiss developmental psychologist • Building Snapchat has taught and philosopher, Jean Piaget18 posited us a lot about what makes that perceptions depend on the world conversation special. view of a person. • An application for sharing • The world view is the result of arranging disappearing pictures. perceptions into existing imagery by imagination. • The notion of deletion by default.

• Piaget cites the example of a child • Keep what you want, and we’ll get saying that the moon is following her rid of everything else! when she walks around the village at night. • Snapchat was missing an • Imagination is needed to make sense of important part of conversation: perceptions.19 presence.

4. Balance • There’s nothing like knowing you noun have the full attention of your 1. A condition in which different friend while you’re chatting. elements are equal or in the correct proportions.20 • When you leave the chat screen, 2. The ability to remain on ones feet.21 messages viewed by both you and your friend will be cleared

Impressions many things are temporary. What’s • Through conversation and observation more, our undocumented memories we create impressions of one another. of these moments are allowed to evolve and carry different meanings • Impressions however, are impermanent throughout our life. In a very specific and with the addition of more data over way, germane only to us, they time, evolve. become part of who we are through time. • Some impressions disappear entirely. References • A tool based on the impermanence of [1] New Oxford American Dictionary impressions could be useful in many [2] The Urban Dictionary situations utilizing a variety of ever- [3] “A Focus on Efficiency. A whitepaper changing data. from Facebook et. al.”, 09/16/2013 (https://fbcdn-dragon-a.akamaihd.net/ 5. Conclusions hphotos-ak- Human centered design should strive to prn1/851575_520797877991079_39325 create a sense of comfort and build trust 5490_n.pdf) amongst users. When documentation exists [4] https://www.flickr.com/photos/ with no thought of impermanence, users franckmichel/6855169886/ are denied a certain amount of control [5] http://www.baselinemag.com/ and the naturalness of human interaction. analytics-big-data/managing-securing- Human interaction, away from our digital data-for-the-worlds-families.html life, allows us to live in the moment, be [6] http://www.internetlivestats.com/ conversational, and understand that twitter-statistics/ many things are temporary. What’s more, [7] http://www.nielsen.com/us/en/ our undocumented memories of these insights/news/2013/smartphone-switch- moments are allowed to evolve and carry -three-fourths-of-recent-acquirers- different meanings throughout our life. In a chose-smart.html very specific way, germane only to us, they [8] http://www.inderscience.com/dev/ become part of who we are through time. search/index.php?action=basic 5. Conclusions [9] https://www.lookout.com/static/ee_ Human centered design should strive to images/lookout-mobile-mindset-2012. create a sense of comfort and build trust pdf amongst users. When documentation exists [10] New Oxford American Dictionary with no thought of impermanence, users [11] The Urban Dictionary are denied a certain amount of control [12] http://www.hinduwebsite.com and the naturalness of human interaction. [13] http://www.ibps.org/english/master/ Human interaction, away from our digital Impermanence.html life, allows us to live in the moment, be [14] http://www.britannica.com/ conversational, and understand that EBchecked/topic/212142/folk-literature

[15] http://psychology.about.com/od/ 8 http://www.inderscience.com/dev/ socialpsychology/a/person-perception.htm search/index.php?action=basic [16] http://en.wikipedia.org/wiki/The_Rest_of_ 9 https://www.lookout.com/static/ee_ the_Story images/lookout-mobile-mindset-2012. [17] http://en.wikipedia.org/wiki/Imagination pdf [18] http://en.wikipedia.org/wiki/Jean_Piaget 10 New Oxford American Dictionary [19] Piaget, J. (1967). The child’s conception of 11 The Urban Dictionary the world. (J. & A. Tomlinson, Trans.). London: 12 http://www.hinduwebsite.com Routledge & Kegan Paul. BF721 .P5 1967X 13 http://www.ibps.org/english/master/ [20] New Oxford American Dictionary Impermanence.html [21] The Urban Dictionary 14 http://www.britannica.com/EBchecked/ [22] http://plato.stanford.edu/entries/dewey- topic/212142/folk-literature aesthetics/ 15 http://psychology.about.com/od/ [23] http://upload.wikimedia.org/wikipedia/ socialpsychology/a/person-perception. commons/c/c0/Supper_at_Emmaus- htm Caravaggio_(1601).jpg 16 http://en.wikipedia.org/wiki/The_Rest_ [24] http://www.youtube.com/ of_the_Story watch?v=9zUaNKBQ04c 17 http://en.wikipedia.org/wiki/ [25] http://www.brainyquote.com/quotes/ Imagination quotes/s/spikelee590059.html 18 http://en.wikipedia.org/wiki/Jean_ [26] http://blog.snapchat.com/ Piaget post/84407744185/putting-the-chat-into- 19 Piaget, J. (1967). The child’s snapchat conception of the world. (J. & A. 1 New Oxford American Dictionary Tomlinson, Trans.). London: Routledge & 2 The Urban Dictionary Kegan Paul. BF721 .P5 1967X 3 “A Focus on Efficiency. A whitepaper from 20 New Oxford American Dictionary Facebook et. al.”, 09/16/2013 (https://fbcdn- 21 The Urban Dictionary dragon- 22 http://plato.stanford.edu/entries/ a.akamaihd.net/hphotos-ak-prn1/851575_520 dewey-aesthetics/ 797877991079_393255490_n.pdf) 23 http://upload.wikimedia.org/wikipedia/ 4 https://www.flickr.com/photos/ commons/c/c0/Supper_at_Emmaus- franckmichel/6855169886/ Caravaggio_(1601).jpg 5 http://www.baselinemag.com/analytics-big- 24 http://www.youtube.com/ data/managing-securing-data-for-the-worlds- watch?v=9zUaNKBQ04c families.html 25 http://www.brainyquote.com/quotes/ 6 http://www.internetlivestats.com/twitter- quotes/s/spikelee590059.html statistics/ 26 http://blog.snapchat.com/ 7 http://www.nielsen.com/us/en/insights/ post/84407744185/putting-the-chat-into- news/2013/smartphone-switch--three-fourths- snapchat of-recent-acquirers-chose-smart.html

Xiu-Min Li / Chapter 22: Can Chinese Herb-based no definitive treatment. For many Chapter 22: Can Chinese Herb- Medicines Heal the Immune System and years, the rise of allergic disease based Medicines Cure Allergies? has been widely attributed to the Heal the Immune System and Xiu-Min Li, MD “hygiene hypothesis” which contends Cure Allergies? Professor, Professor of Pediatrics, Jaffe that hygiene and other byproducts of in “World Health Strategy” eBook, Food Allergy Institute, modern life have deprived our immune (Ed.) Renata Icahn School of Medicine at Mount Sinai, systems of their natural enemies such G. Bushko, FHTI, 2016. New York City as parasites and microbes, and have Futureofhealth. turned on normally harmless proteins org Abstract in food. But a more varied set of his chapter explores the science explanations has emerged. and practice of adapting traditional One researcher traces the TChinese medicine (TCM) to treat the beginnings of epidemic levels of modern epidemic of allergic diseases such sinus allergies and asthma to the as eczema, asthma, and food allergies creation of afternoon children’s and correct imbalances in the immune television programming, which shifted system. These diseases have burgeoned afterschool activity indoors. i More with the changes associated with Western recently, depletion of the protective models of economic development, microbiome through overuse of diet, and treating disease. They have antibiotics and Caesarian section resisted pharmaceutical cures. The TCM has come under scrutiny.ii So have formulary has a long track record of changes in gene expression—not the treating conditions in the skin, airways, and DNA itself but switching the genes digestion. In our research and my practice, on and off—which can be induced we use derivatives of the classical formulas by environmental factors and stress. to treat all the organ systems involved in These epigenetic changes can be a disease rather than single systems and passed to offspring and may account symptoms. Contemporary science gives for the accumulation of allergic us the ability to refine the medicines to tendencies from one generation to increase potency, and make them more the next. While the specific etiology compatible with patient behavior. We chose of individual cases of allergic disease this path because patients are suffering, and is difficult to pin down, what we do depriving children of their childhoods. know is there is an imbalance of innate immunity, which is governed by one 1. Introduction set of T helper cells, known as Th1 and Allergic diseases are a significant health acquired immunity, Th2. The medical problem in “Westernized” countries. They challenge is to reset that balance. are a tremendous burden on quality of life The term “atopic march” describes for both patients and their families, and the progression of allergic disease health care expenditures for the society from early infancy, in the form of as a whole. Food allergy in particular has eczema, through sinus allergies

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and asthma, to food allergies. These are investigational new drug if this is diseases of the tissue that faces the external shown to be infeasible. Instead, the environment where the immune system FDA will rely on other tests, including is potent—the skin, the airways, and the chromatographic fingerprints, chemical digestive tract. assays of characteristic markers, and The accustomed medical approach is to biological assays, to ensure the quality, control the response through medication potency, and consistency. and curtailing exposure. Certainly these In this changing landscape, we are valid and important. But medications began to explore the possibility of have problems of their own. For example, applying the lessons of thousands corticosteroids, which are used in various of years of Chinese medicine to a formulations to control inflamed skin, modern global epidemic. sinuses, lungs and the esophagus depress We have been pursuing this innate immunity, can damage tissue, and research on two tracks. One is can produce both depression and anxiety. the protocol for pharmaceutical Limiting exposure particularly to food development in full accord with our allergens is difficult because sensitization regulators. We have two certified happens early, usually to the most common investigational drugs, one for food foods in the customary diet, such as allergies and one for asthma. peanuts, milk, and eggs, which are often I also use medicines in current eaten alone or are additives to prepared treatment for a range of co-morbid foods. allergic diseases in weekend private Traditional Chinese medicine has been practice, mostly with children, where used effectively to treat diseases of the we not only see very encouraging gut, airways, and skin for thousands of results and gain insights that can years. Western science allows us to study be used to refine and adjust the the underlying mechanisms of disease and medicines. These patients and their treatment. TCM practitioners know that their parents feel poorly served by standard medicines work, but the science allows us of care from their allopathic physicians. to understand how and why they work, and We also conduct “practice-based how to make them more effective. research” on a smaller scale and at less cost than full clinical trials. 2. Dual Approach to Research and Clinical It is important to recognize Efficacy that these drugs work with one After years of discussion, in 2000, the another. While we have registered FDA recognized the importance of the investigational drugs for food allergies movement towards alternative medicine by and asthma, in practice the different issuing the Guidance for Industry Botanical medicines are administered in Drug Products, which states that active combination to treat the co-morbid constituents in a botanical drug might not conditions. They also are delivered in need to be identified when studying an different forms, some by mouth and

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others via the skin, to enhance absorption. Eczematous skin is vulnerable to these residues, which can penetrate in 3. Eczema sufficient quantities to start an immune Eczema, which is often used synonymously response. with the term atopic dermatitis, has gained Starting with medicines to treat new prominence in discussions of allergic open wounds and burns suffered in disease. It has long been considered the combat dating from the bellicose Tang first sign of allergic tendencies in small Dynasty (618-906), we developed a children, but we are only beginning to protocol of an internal remedy and two understand how central a role it plays in the external remedies to treat the skin. We atopic march. Healthy skin is a barrier to have used these to treat dozens of infection and irritants. An imperfect barrier, patients, and studied 14 of them inflamed and dry, allows these things to retrospectively who began with penetrate. This imperfect barrier has been recalcitrant eczema. They were aged attributed to a filaggrin mutation. The six months to 52 years with various peanut-allergy epidemic has led to a new co-morbid asthma, environmental prominent line of research that attributes allergies, and food allergies. Half had sensitization to peanuts not to ingestion but been treated intermittently with oral to infant exposure to peanut protein in the corticosteroids before starting TCM, home. As discussed above, the first line of including five who had taken oral pharmaceutical defense is to reduce steroids in the previous three months. inflammation, but while the immediate Three had taken immune suppressants inflammation may be reduced, persistent usually used by organ transplant use of topical steroids can weaken the skin patients to combat rejections. All further and in infants especially weaken patients reported topical steroids innate immunity to infection. Another on-and-off, including half in the three necessary treatment is the application of months prior to presentation. Median emollients, but these may contain potentially quality of life as measured by the allergenic ingredients that may sensitize SCORAD Index (0-103), was 89. iii patients. While not life threatening, as The internal remedy is Erka measured by various quality of life scales, Shizheng Herbal Tea, in practice eczema is even worse day-to-day than other called Shi Zhen tea, an extract of nine asthma or serious food allergies. herbs. The external ones are a bath The peanut allergy epidemic, which has additive containing eight individually attracted so much attention to allergic extracted herbs, an herbal cream disease, has led to a possible role of the containing two herbs, and a paste skin as the starting point for allergic made from herbs used in our food sensitization. British researchers have found allergy herbal formula. that peanut residue is stubborn and Three months after therapy began, biologically active in homes where lots of oral steroid use fell 25%. Topical peanut products are consumed. steroid use went down 21% after three

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months. The reduction in both oral and powerful systemic steroids, have some topical steroid use after 3 months was 29%. serious side effects. Moreover, there Antihistamines, which all patients used, are other conditions that have asthma- including 11 out of 14 at the onset of TCM, like symptoms that don’t respond to was reduced 32% after three months. steroids although they are treated with Eleven of 14 patients experienced at least them. There is no broad-based a 50% improvement in quality of life during treatment for all asthmatic phenotypes. the first 1-3 months of therapy. At the end of We faced hurdles in creating a TCM the study period, 12 of 14 patients reported anti-asthma drug. Many TCM drugs sustained improvement in quality of life with have relied on Ma Huang, or ephedra, 10 of 14 reporting >80% improvement. which is frowned on by Western Going forward, we are creating a practice regulators because it can be used to network of physicians to treat patients for make methamphetamine. We used a recalcitrant eczema. Using these medicines 14-herb combination to create an requires no special training in TCM. In this investigational drug we called MSSM- way, we hope to not only relieve current 002 which showed promise but suffering, but also to slow the progress of because it had so many ingredients the rest of the atopic march. Q we studied the components and arrived at a three-herb version we call 4. Asthma ASHMI (anti-asthma herbal medical According to the World Allergy Organization intervention). This combination of 2011 White Book, some 300 million people Ling-Zhi (Ganoderma lucidum), Ku- suffer from asthma worldwide, contributing Shen (Radix Sophora flavescentis), and to the deaths of 250,000 people annually. In Gan-Cao (Radix Glycyrrhiza uralensis), the United States, 9.3% of children and 8% suppressed airway hyper- of adults have asthma. Economic costs to responsiveness and the collection of the United States approach $60 billion each certain white blood cells in the airways, year in treatment, 10.5 million missed days of called eosinophils, which are drawn to school, and 14.2 million missed days of work. inflammation, as effectively as the About nine people die from asthma every original. This research has been going day, well over 3,000 each year. Poorly on for 10 years as part of an NIH controlled asthma can have very serious protocol.iv consequences for food allergy patients with We have now done a series of no previous history of respiratory reactions. clinical studies in China in cooperation There is also the danger of “airway with my former fellows. We have seen remodeling” causing airway smooth muscles that the drug is safe and as effective at (ASMs) to lose their elasticity, among other suppressing asthmatic inflammation as problems. systemic steroids but with no Inhaled corticosteroids (ICS) have been cytotoxicity and suppression of innate the dominant treatment for controlling immunity. Moreover, in murine models asthmatic inflammation, and they, like we have seen evidence that it can

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help control neutrophilic asthma, which is proteins in peanut resemble proteins dominated by another white blood cell—the in helminths. One feature of this neutrophil—and doesn’t respond to inhaled approach is that it addresses food steroids. allergies as a digestive problem as ASHMI inhibits the production of several well as an immune problem. inflammatory cytokines all at once. Standard I chose a nine-herb formula Wu Mei pharmacological research focuses on these Wan (WMW). It was classically one at a time, in the form of monoclonal prescribed “for colic, vomiting, chronic antibodies. diarrhea or dysentery, and collapse Finally, whereas steroids suppress innate (also translated as syncope) caused by immunity while controlling inflammation, they parasitic worms.” We added two more also are associated with mood disorders, ingredients particularly effective at resulting in higher rates of anxiety and immobilizing worms. This formula, depression for asthmatics in treatment than which we called Food Allergy Herbal among their peer groups. This is considered Formula-1 effectively cured especially problematic for children and anaphylactic peanut allergy in a murine teenagers. These effects can be measured model. Before we could adapt it to in the peripheral blood. ASHMI doesn’t human use, we had to remove two produce these effects. alkaloids and came up with Food Allergy Herbal Formula-2, which also 5. Food Allergies cured peanut allergy in mice.v Food allergies seem to have come from We have now been through two nowhere, although they have really always human trials—Phase 1 for safety, which been with us, as literature from Greek and we passed with no serious adverse Chinese medicine tells us. They have grown events or toxicity. The Phase 2 had an as a public health issue over the past two equivocal result, although there were decades, with most cases in commodity encouraging signs in the peripheral foods—milk, eggs, peanuts, tree nuts, wheat, blood. The study was too brief—six and soy—which are not only common but months compared to the equivalent of are often incorporated in processed foods. two years for the mouse studies. And Symptoms range from uncomfortable itching the dosing was too arduous. Subjects of oral allergies, which are like pollen aged 12-48 years were expected to allergies, to alarming pruritis and hives, to take 10 pills at each of three meals a vomiting, to catastrophic and occasionally day—30 in all. At least 44% of them fatal anaphylaxis, in which two or more were non-compliant.vi organ systems react. This gives urgency to our efforts to I began studying the potential for treating apply Western chemistry to the herbal food allergies with TCM when I noticed a medicines. Using butanol, we have connection between the symptoms of food reduced the therapeutic dose by 80%, and the symptoms of infection by intestinal which the NIH has approved for parasites. This made sense because the another trial of 26-months duration. We

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have also experimented with another A pediatric nephrologist at Mount solvent that appears to be even more Sinai has been exploring the use of a efficient at separating the active ingredients. Chinese herb she found in our data As with our eczema and asthma base to try to mitigate rejection of medicines, we use supplement versions of transplanted kidneys in her patients, the food allergy herbal formulas in practice, who currently must rely on powerful with very good results, including immune suppressants, and her work documented, published cases of patients has been published in a major journalviii with frequent severe food anaphylaxis We have a unique resource—the experiencing no additional exacerbations. combination of a busy practice and a We also use our medications adjunctively world-class lab team. We are using this with the desensitizing techniques oral combination in practice-based immunotherapy (OIT) and sublingual research operating under IRB rules to immunotherapy (SLIT), which involve learn as we go. We have a bio-marker ingestion of increasing amounts of the study to determine whether our allergen, often provoking adverse effects, patients are achieving tolerance to particularly gastric distress. We are also their allergens using individualized working with researchers to explore various treatments. The initial phase was combinations because allergies are funded by parents of patients, who are heterogeneous diseases for which no single also paying for treatment. therapy will ever be sufficient. 7. Altering the heritability of allergies 6. Other Research Food allergy parents particularly My colleague Dr. Scott Sicherer has said that wonder what they did wrong, why their where Western science tends to focus on children were born allergic. In addition the effects of one molecule on another to trying to halt the atopic march, we molecule, TCM allows us to study multiple are working to create an oral vaccine molecules on multiple other molecules. That that would protect children from is the basis for use of our food allergy herbal inheriting allergic tendencies, starting formula with Crohn’s disease, for which the with peanut. It will employ as an current standard of care involves regular adjuvant non-toxic cholera toxin B infusion of an expensive monoclonal (CTB), which has been used safely by antibody. We observed that in addition to pregnant women and infants for 30 inhibiting allergic antibodies, our food years in an oral cholera vaccine, allergy formula inhibited production of tumor delivered by a probiotic bacillus necrosis factor alpha (TNF-α). High levels of subtilis (BS) spore with the allergen and TNF-α are also associated with Crohn’s adjuvant bound to the surface. It also disease. Two studies have shown that induces antigen-specific clinical FAHF-2 two is very promising for modulating tolerance in autoimmune disorders the inflammatory cytokines associated with when co-administered with antigen by Crohn’s.vii induction of IL-10 and Tregs.

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This study doesn’t strictly fall under the umbrella of TCM. However, our exploration References of the immune system in studying the i Thomas A.E. Platts-Mills, MD, PhD, actions of herbal medicines gives us hope FRS “The allergy epidemics: 1870- that this approach will work. 2010” Journal of Allergy and Clinical We also are trying to understand what it Immunology July 2015Volume 136, is about food processing and preparation Issue 1, Pages 3–13 that elicits a violent immune response through the study of advance glycation end ii Susan L. Prescott, MD, PhD “Early-life products. environmental determinants of allergic Much of this research is being done diseases and the wider pandemic through collaboration with other scientists of inflammatory noncommunicable around the world. diseases” Journal of Allergy and Clinical Immunology January 2013 Discussion Volume 131, Issue 1, Pages 23–30 Australian allergist Dr. Susan Prescott has expressed optimism that the allergy epidemic, which has overtaken us in a matter of decades, it might be reversed over a similar period. “In theory, the very fact that modern diseases have increased means they must be modifiable. The same factors iii J. Wisniewski, A. Nowak-Wegrzyn, E. that are promoting the disease could also Steenburgh-Thanik, H. Sampson, X. Li be actively harnessed to reduce the risk of Efficacy and Safety of Traditional disease.” Chinese Medicine for Treatment of However, while excellent work is being Atopic Dermatitis (AD) conducted, much of it is being done on the Journal of Allergy & Clinical same timetables and piecemeal fashion that Immunology February 2009 Volume have left us with no more ability to cure 123, Issue 2, Supplement, Page S37 allergies than we had a century ago, and at high cost. While it would be very difficult to iv Xiu-Min Li, MD; Chih-Kang Huang, unwind all the environmental, dietary, MS; Teng-Fei Zhang, PhD; Ariel A. medical, and behavioral changes that have Teper, MD; Kamal Srivastava, BS; Brian contributed to the epidemic, greater H. Schofield, JD; Hugh A. Sampson, understanding of the physiology is giving us MD, “The Chinese herbal medicine clues to how to roll back the effects. formula MSSM-002 suppresses Traditional Chinese medicine, which has so allergic airway hyperreactivity and many centuries of treating complex, multi- modulatesTH1/ TH2 responses in organ, infectious and inflammatory disease, a murine model of allergic asthma, gives a platform to build on. ” Journal of Allergy and Clinical Immunology 2000; 106(4): 660 –668.

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v Kamal D. Srivastava, MPhil, Jacob D. Kattan, BS, Zhong Mei Zou, PhD, Jing Hua Li, MD, Libang Zhang, MD,b Sylvan Wallenstein, PhD, Joseph Goldfarb, PhD, Hugh A. Sampson, MD, and Xiu-Min Li, MD “The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy” Journal of Allergy and Clinical Immunology January 2005 171-178

vi Jaime Ross, RN Suzanne K. Carlisle, RN, BSN, CCRP Maripaz Vazquez, RN, BSN, CDE Stacie M. Jones, MD, Dr. Jacqueline Pongracic, MD, FAAAAI, Dr. Julie Wang, MD, FAAAAI “Food Allergy Herbal Formula-2 (FAHF-2) – Adherence To Treatment” Journal of Allergy and Clinical Immunology February 2014 Volume 133, Issue 2, Supplement, Page AB66

vii Clare Ceballos, PNP; Ruijun Bao, MD; David Dunkin, MD; Ying Song, MD; Xiu-Min Li, MD; Keith Benkov, MD, “Complementary and alternative medicine use at a single pediatric inflammatory bowel disease center” Gastroenterology Nursing 2014; 37(4): 265

viii J. Reid-Adam; N. Yang; Y. Song; P. Cravedi; X-M. Li; P. Heeger. “Immunosuppressive Effects of the Traditional Chinese Herb Qu Mai on Human Alloreactive T Cells” American Journal of Transplantation Volume 13, Issue 5, pages 1159–1167, May 2013

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Renna Bushko, Chapter 23: Future of Brain’s Health: of microglial cells and their importance Changda Liu, Beth Powell, Xiu- Prevention of Neural Inflammation with in immune function as well as natural Min Li/ Future of Traditional Chinese Herbal Medicine products derived from Traditional Brain’s Health: Prevention Renna Bushko Chinese medicinal herbs that inhibit of Neural Research Intern, Department of Pediatrics, microglial activation will be discussed. Inflammation with Traditional Icahn School of Medicine at Mount Sinai Development of new drugs from well Chinese Herbal & Neuroscience Program, Smith College, known herbal remedies show promise Medicine in “World Health Northampton MA, USA [email protected] in alternative drug discoveries and Strategy” eBook Changda Liu, Ph.D. measures to prevent excessive neural FHTI 2016 www. Futureofhealth. Research Scientist, Department of inflammation and degeneration. org Pediatrics, Icahn School of Medicine at Mount Sinai, Keywords: Microglia, Microglial New York, NY, USA activation, Traditional Chinese Beth Powell, Ph.D. Medicine, neurodegeneration, Senior Lecturer neuro-inflammation, herbal remedies, Neuroscience Program, Smith College, Parkinson’s, Alzheimer’s Northampton, MA, USA Xiu-Min Li, M.D. 1. Introduction Professor of Pediatrics, Department of Inflammation in the central nervous Pediatrics & Jaffe Food Allergy Institute, system (CNS) is known to cause Icahn School of Medicine at Mount Sinai, neurodegenerative disorders and New York, NY, USA diseases. Inflammation in the body arises when white blood cells are Abstract generated in the presence of a nflammation in the central nervous system foreign pathogen to combat infection is commonly responsible for many serious and maintain homeostatic integrity. Ineurological diseases and inflammatory Additionally, inflammation can arise responses in microglial cells specifically from autoimmune disorders such as can result in harmful neurotoxic effects. arthritis or more serious neurological Although activation of microglial cells diseases such as Alzheimer’s and is neuroprotective to a certain degree, Parkinson’s as well as many more [1]. excessive activation of microglia can result The function of inflammation is to in neurodegeneration and can create enclose injury and to ultimately restore disorders such as Parkinson’s, Alzheimer’s, tissue but it can be harmful since many or amyotrophic lateral sclerosis (ALS). chemical inflammatory mediators Pharmacological strategies are being can also produce hypersensitivity explored to inhibit microglial activation reactions leading to progressive and any harmful associated inflammation organ damage. Based on research predominantly through natural remedies so far it is evident that microglia, the derived from Traditional Chinese Herbal immune cells of the CNS, are involved Medicine. In this review, the characteristics in neurodegeneration caused by

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excessive inflammation [2]. The central solely in the peripheral nervous nervous system, which consists of the system [4]. Unlike neurons which are brain and the spinal cord, is especially mostly responsible for transmitting susceptible to inflammation and oxidative chemical and electrical impulses for stress1, ensuing irreversible neuronal and information processing, microglial cells glial damage [1]. Microglial activation and act predominantly as phagocytes to chronic inflammation creates greater risk of remove excess debris from the brain elevated levels of neurotoxic molecules and left by dead or dying neurons [4] pro-inflammatory cytokines that can further Additionally, microglia are essential for contribute to neurodegeneration [2]. maintaining the stability of neurons, Although damage to the CNS cannot be add a protective barrier fully reversed, it can be decelerated with the for neurons against foreign objects use of neuroprotective compounds derived or physical distress, and myelinate3 from anti-inflammatory herbal agents. These neuronal axons to speed up electrical herbal anti-inflammatory agents developed impulse transmissions. Microglia are from Traditional Chinese Medicine (TCM) always active and continuously survey remedies, play role in reducing inflammation their local microenvironment [5]. and neurological impairment from oxidative Over the last decade, microglial stress and neurotoxin secretions. TCM cells have been studied more has used compounds from herbs such thoroughly because most neurological as Glycyrrhiza uralensis and Ganoderma disorders have been attributed to lucidum to cease neurotoxin secretions and microglial activation and dysregulation to combat inflammation by downregulation [6]. Interestingly, microglia may not of neuroinflammatory responses [2]. only be involved in neurological By using such compounds, comorbid disorder development, but they also disorders such as depression and anxiety potentially contribute to inflammatory associated with CNS cell inflammation could and adaptive immune responses in also be moderated [3]. Here we review non-specific CNS regions [6]. Microglial recent literature on Traditional Chinese cells undoubtedly have innate immune herbal inhibitors of microglia-mediated functions and play a large role in neurotoxicity. nervous system immunopathology. The

2. Microglial Cells and Microglial Immunopathology A variety of specialized cells compose 1 An inability for the body to produce the nervous system including neurons, antioxidants at an equal or faster rate in which ependymal cells, and microglial cells2. Of free radicals are being created. Free radicals the three types of microglial cells, astrocytes are uncharged molecules that accelerate aging. are the most numerous glia in the brain and coexist with oligodendroglial cells in 2 Types of microglial cells include astrocytes, the CNS whereas Schwann cells reside oligodendroglial cells and Schwann cells. (Bear et. al 46)

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CNS has ultimately evolved4 to protect itself of inflammatory reactions based on from immune-mediated inflammation that these neurochemical ratios [6]. can damage its delicate and vital functions Microglia and Cytokines [6]. As aforementioned, microglial cells There are a variety of immune secrete cytokines and neurotrophic responses and protective measures in factors when exposed to physiological the brain in order to defend it, such as the or stressful stimuli. Cytokines are blood brain barrier that prevents blood- proteins secreted by non- inflammatory borne substances from entering cerebral leukocytes and non-leukocyte cells extracellular fluid [4]. Additionally, Microglial that are responsible for acting as cells serve considerable homeostatic and intercellular mediators. These non- reparative functions as well because of their antibodies differ from other hormones ability to respond quickly to physiological because they are produced by varying and stressful stimuli while also secreting tissue cell types rather than from lymph cytokines and neurotrophic factors5. nodes or other specific glands making Microglia quickly alter their phenotype in them autocrine and paracrine proteins response to a nervous system homeostatic rather than endocrine proteins (nih. disturbance and become activated gov). when their cell surface antigens change Microglia are able to recognize morphology or expression [5]. Lastly, cytokine production intracerebrally microglia can become phagocytic when during CNS inflammation [6]. On the neurons are damaged or dead and need to surface of microglia, certain receptors be removed from the CNS as not to cause are able to distinguish between pro toxicity [6]. and anti-inflammatory cytokines and Although microglia already appear the balance between these two to have a plethora of functions, they are types result in microglia inducing the also responsible for host-defense. When appropriate immune function [6]. the CNS becomes infected, inflammatory One particular Cytokine tested stimuli and interaction with blood- derived cells activates microglial cells to induce 3 Myelin is a membranous wrapping, or sheath, inflammation, cytotoxicity and initiate around axon provided by oligodendroglia in T-cell action through antigen exhibition, the central nervous system and Shwann cells ultimately supporting the theory of microglial within the peripheral nervous system (Bear et al. 806) importance in CNS immune surveillance [6]. Microglia do not, however, function alone 4 CNS evolution is both anatomical and to protect the CNS, but rather, communicate physiological (Aloisi 165) extensively with neurons to achieve both 5 e.g. Neurotrophic tumor necrosis factor their quiescent and reactive states [6]. (TNF-α) Unlike in other bodily immune responses, microglia are tightly monitored by chemical 6 CNS signaling molecules include ATP, responses 6 and react in different degrees neuropeptides, and neurotransmitters (Aloisi 2001

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for is tumor necrosis factor (TNF-α). and in both infection and autoimmune TNF-α is a pro-inflammatory cytokine that disorders of the CNS, macrophages, when released, activates macrophages microglia and astrocytes have (astrocytes) to promote glial phagocytosis produced these cytokines to generate in the CNS. Additionally, with TNF-α release CNS-specific inflammation [6]. Taking into the CNS, the production of additional a closer look within this particular pro- and anti- inflammatory cytokines has inflammatory cascade, we can easily been observed [6] learn what herbal treatments we can TNF-α and Inflammation utilize to stop it. TNF-α is produced when TH1 cells, microglia and macrophages become 3. Traditional Chinese Medicine and activated. With its release, TNF-α attaches Inflammation itself to two similar receptors TNFRI and Traditional Chinese Medicine is a TNF-RII [6]. Additionally, TNF-α activates a practice that originated in Ancient variety of transcription factors such as China and evolved over thousands (nuclear factor kappa B) NF-κB to induce of years, transforming it into what we transcription of immune genes [6]. NF- consider herbal medicine today. In κB transcribes TNF-α while also allowing recent years, the re-emergence of TNF-α to activate it [3]. NF-κB is usually these remedies have been researched harvested in the cytoplasm of inactivated extensively and authenticated by cells but must be transmitted to the nucleus their long-term use over centuries as to have any effect [3]. This activation and compared to newer supplements [2]. cascade suggests that TNF-α and NF-κB Because of their already trustworthy act together during immune inflammatory ethnopharmacologial properties, responses as seen predominantly when these traditional herbs have been observing numerous microglia and CNS revisited in research and have been macrophages [6]. confirmed to contain neuroprotective TNF-α production in the CNS is ultimately and neurotrophic capacities useful harmful because it has depressive effects. in preventing neurodegeneratory Asthma sufferers, for instance, exhibit high and neuroinflammatory diseases incidence of anxiety and depression due to [2]. Furthermore, during the last increased levels of TNF-α in the peripheral two decades, it was observed that and central nervous systems [3]. TNF-α various botanicals have exhibited promotes neuroinflammatory cascades anti-inflammatory and antioxidant and is toxic to oligodendroglia, causing functions to potentially protect the them to demyelinate and eventually die brain from inflammatory impairment [2]. [3]. The suppression of TNF-α prevents These herbal extracts can generate excess inflammation and the occurrence neuroprotective effects with varying of associated anxiety and depression [3]. mechanisms but those specifically Ultimately, Cytokines are essential regulators targeted to block microglial activation of innate and adaptive immune responses may be most effective at improving

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neurodegeneration and neuroinflammation liquiritin, liquiritigenin, rhamnoliquiritin, caused by microglial activation. In the neoliquiritin as well as several more [7]. sections to follow, emphasis will be For instance, the flavonoid ILG placed on traditional herbal products with (isoliquiritigenin) demonstrated anti- discussion on their active constituents inflammatory and neuroprotective specifically in reducing inflammation and effects. An isomer of ILG, LG inhibiting microglial activation. (liquiritigenin) showed anti-depressive properties in murine models and 3.1 Chinese Licorice - Glycyrrhiza inhibited neurotoxicity created by Aβ uralensis and Glycyrrhiza glabra (amyloid-beta) peptides [8]. Chinese Licorice, referred to as Gancao Glycyrrhiza glabra in China, is a flowering plant native to Also a species of licorice, the Mediterranean, central and southern Russia flavonoids extracted from Glycyrrhiza and Asia Minor, used often in herbal Chinese glabra have also demonstrated medicine for its remarkable uses [7]. Utilized attenuation of cerebral injuries in alongside 50 other fundamental herbs used stroke animal models [9]. Just like in TCM, Glycyrrhiza uralensis has been many other neurodegenerative traditionally used in the respiratory system disorders, stroke can cause and the gastrointestinal tract to reduce inflammation and neurotoxicity since inflammation [8]. The family of licorice has blood is inherently toxic to the brain been used medically since 500 BC and has tissue. Very similar to Gycyrrhiza been nicknamed “The grandfather of herbs” uralensis, the flavonoid glabridin in for its extensive medicinal history [7]. Several Glycyrrhiza glabra can enhance the studies also suggest that Glycyrrhiza can be survival of neurons and prevent their useful in treating Alzheimer’s disease, a very apoptosis [9]. Glabridin specifically, prevalent neurodegenerative disorder [8]. is an isoflavan and the major active Within Glycyrrhiza, the triterpene saponin GA flavonoid in Glycyrrhiza glabra. and the aglycone GRA, have demonstrated Isoflavans are placed in a subclass neuroprotective and anti-inflammatory of the flavonoid compounds and characteristics capable of reducing such have a unique structure in which inflammation commonly found culprit in an A, C and B ring are connected patients with Alzheimer’s [8]. The licorice respectively through a Carbon 3 [9]. root itself has an abundance of triterpenoid The hydroxyl group on the B-ring has saponins (4-20%) known best as glycyrrhizin the most anti-oxidative properties as well as potassium and calcium ions and is the most useful factor in bio- forming glycyrrhizic acid [7]. Furthermore, actively combating bodily inflammation glycyrhhiza uralenisis contains a series of [9]. In a murine model, Glycyrrhiza potent flavonoids capable of interacting with glabra flavonoids and isoflavans biomolecules via hydroxyl groups, modifying demonstrated reduction in brain proteins to generate neuroprotective effects malyonyldialdehyde (MDA) while [8]. Some of these potent flavonoids include elevating two internal antioxidants in

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the brain; superoxide dismutase(SOD) and potent anti-inflammatory characteristics reduced gluthathione (GSH). Also, glabridin also can protect against prevalent isoflavan significantly inhibited cytotoxicity neurodegenerative disorders such as and apoptosis in cortical neurons insinuating Alzheimer’s and Parkinson’s [10]. the neuroprotective effects ofGlycyrrhiza Although lifespan is increasing glabra and its resourcefulness in traditional dramatically, with increased and contemporary medicine [9]. lifespan comes greater possibility of developing neurodegenerative Glabridin diseases. It is estimated that nearly eighty million individuals will suffer from dementia by 2040 where Alzheimer’s accounts for about sixty percent of the cases [10]. Like with Glycyrhhiza uralensis, Ganoderma lucidum has the ability to moderate Aβ hypersensitivity [10]. Furthermore, mushrooms such as G. lucidum have been shown to promote axon growth during brain development in the striatal region. This is possible because Ganoderma lucidum like many fungi contains palmitic, oleic, and linoleic fatty acids that have the ability to generate and promote axonal growth [10]. Unlike newer medications, studies on cell lines suggest taking high doses of fungal and herbal supplements has no adverse effects [10]. By taking extracts of Ganoderma 3.2 Reishi Mushroom (Ganoderma lucidum, neurodegenerative diseases lucidum) could be prevented earlier rather than Throughout history, mushrooms have been attempting to cure them in later stages used greatly within culinary practice, but of development [10]. In Ganoderma also have been utilized specifically for the lucidum alone, over 140 different treatment of diseases [10]. In addition to triterpenes have been discovered, all plants, fungi have been studied for their of which can inhibit the production of anti-inflammatory and neuroprotective free radical and act as anti-oxidative compounds. The Reishi Mushroom, agents7 [10]. commonly known for its anti-cancer With dietary supplement usage G. properties is particularly well known in lucidum has demonstrated its ability Traditional Chinese Medicine. Further in vitro to delay Alzheimer’s onset - a very evidence suggests, that this mushroom’s

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big step in the field of preventive medicine Testing Neuroprotective effects of [10]. In addition to delaying Alzheimer’s, Ganoderma Lucidum Ganoderma lucidum has been studied in Using a variety of lab techniques murine Parkinson’s models as well. Previous to test the neuroprotective effects studies on rats fed with G. lucidum oil have of Ganoderma lucidum gives us shown that they had fewer characteristic confidence in its effectiveness. To test symptoms. Those rats who were fed G. the effects of G. lucidum, dopaminergic lucidum also downregulated the neurotoxin neuronal cell line MES23.5 and 1- methyl-4 phenyl-1,2,3,6-tetrahydropyridine( LPS-activated microglia were used MPTP), a neurotoxin highly responsible after being treated with 1-methyl-4- for the originating Parkinson’s [10]. A lack phenylpyridinium (MPP+)[10]. MPP+ of dopamine in both the substantia nigra being a metabolite of neurotoxin and striatum is what results in Parkinson’s MPTP would have the same effects as symptoms so by reducing neurotoxin using MPTP directly. After treatment, MPTA levels with G. lucidum, dopamine G. lucidum extracts inhibited microglia levels could be partially restored [10]. With from producing inflammatory and Ganoderma treatments, these dopamine cytotoxic cytokines such as TNF-α and levels in mice increased in these two brain Aβ [10]. This inhibition of microglial cells areas and involuntary movement was producing cytokines makes G. lucidum considerably reduced [10]. a potentially useful agent in reducing Testing Neuroprotective effects of inflammation and thus neurodegerative Ganoderma Lucidum disorders like Parkinson’s as well [10]. Using a variety of lab techniques to test the neuroprotective effects of 3.3 Anti- inflammatory effects of Ganoderma lucidum gives us confidence Sophora flavescensand Sophora in its effectiveness. To test the effects of japonica G. lucidum, dopaminergic neuronal cell line Sophora flavescens is a flowering plant MES23.5 and LPS-activated microglia were of the Leguminoseae (bean) family used after being treated with 1-methyl-4- and is widely distributed in Asia and phenylpyridinium (MPP+)[10]. MPP+ being a Oceania. From the fifty-two species in metabolite of neurotoxin MPTP would have this family, fifteen of them have been the same effects as using MPTP directly. used extensively within TCM. Although After treatment, G. lucidum extracts inhibited S. flavescens has anti-inflammatory microglia from producing inflammatory and effects on other portions of the body, cytotoxic cytokines such as TNF-α and purer compounds allow for anti- Aβ [10]. This inhibition of microglial cells inflammatory function in the central producing cytokines makes G. lucidum nervous system as well [11]. From S. a potentially useful agent in reducing flavescens, pure compounds including inflammation and thus neurodegerative matrine, kurarione, and oxymatrine disorders like Parkinson’s as well [10]. and Sophoraflavanone G. have been extracted [11].

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Oxymatrine is one pure compound inflammation in various brain disorders that has been studied in depth. This [12]. compound derived from Sophora japonica, a subspecies of Sophora flavescens 3.4 Berberine possesses anti-inflammatory characteristics Berberine, an alkaloid extracted from [12]. Oxymatrine(OMT), is a monosomic plants like Berberis aquifolium, Berberis alkaloid derived from Sophora japonica aristata, Hydrastis Canadensis, Coptis and has a unique tetracyclic quinolizine chinensis, Xanthorhiza simplicissima as structure [12]. Possessing anti-inflammatory, well as several others has also been immune regulatory, antivirus, anticancer, extensively researched for its anti- anti-apoptosis and anti-fibrous activity, inflammatory properties. First known oxymatrine can be used to treat a plethora for its use in TCM, berberine has of illnesses including neurological ones [12]. been used to treat a host of diseases In one particular study conducted by including bacterial, fungal and viral Nanjing Medical University researchers infections. Because of berberine’s investigated the effects of oxymatrine ability to reduce inflammation in the on nuclear factor kappa B (NF-κB) and central nervous system, it also acts mitogen- activated protein kinase (MAPK) in inherently as an anti-depressant and Lipopolysaccharide activated BV2 microglial can also act as a neuroprotector cells [12]. In the investigation, Nitric Oxine against neural disorders. In mice that (NO), prostaglandin E2 (PGE2), tumor have experienced traumatic brain necrosis factor (TNF-α), interleukin-1beta (IL- injury (leading to neurodegeneartion), 1β) and interleukin- 6 (IL-6) were derived from berberine has shown promise in the supernatants of BV-2 cell cultures. In the reducing the severity of associated study, oxymatrine inhibited the production of negative symptoms [2]. Mice who NO,PGE2, TNF-α, IL-1β, and IL-6 while also received a controlled cortical impact diminished levels of inducible nitric oxide injury and had been treated with synthase (iNOS) and cycloozygenase-2 berberine 10 minutes after injury (COX-2), cytosolic inhibitor of kappa B-alpha showed that berberine significantly (I-κΒα)and phosphate I-κΒα in the MAPK diminished functional deficits and molecule kinases [12]. Furthermore, the brain damage even up to 28 days nuclear levels of phosphate fifty-six (p65), post-injury [2]. Additionally, berberine the extracellular signal- regulated kinase reduced neuronal death, apoptosis, (ERK), phosphate thirty-eight (p38) and c-Jun BBB permeability, and brain edema a N- terminal kinase (JNK) pathways were day after injury [2]. While reducing any blocked by oxymatrine [12]. After treatments of these undesired symptoms of TBI, with varying doses of S. japonica to this a significant reduction of leukocyte cell lines and released aforementioned infiltration, microglial activation and cytokines, it was evident that oxymatrine inflammatory mediator expression attenuated inflammatory responses in was observed [2]. Berberine treatment microglia. Thus it is capable of reducing did not have any effect on the ERK

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pathway, however it did reduced NF-κΒ ability to suppress the NF-κB and MAP signaling [2]. Additionally, after administering kinase neuroinflammatory cascades berberine in vivo to mice, it was observed [2]. Furthermore, ginsenosides Rh2, that berberine reduced TBI brain damage Rh3 and compound K extracted from by limiting glial inflammatory mediator P. ginseng inhibited LPS-induced production as well [2]. Furthermore, nitric oxide synthase (iNOS) and berberine was able to reduce the infiltration cytokine activation, demonstrating of neutrophils and slow IL-1β NO production their potential benefit in combating in glia and BV-2 cells [2]. Because of this neurodegenerative disorders [2]. P. research, the notion that berberine can ginseng not only inhibits LPS in (iNOS) inhibit glia-mediated inflammatory responses ,but also inhibited the tumor necrosis following brain injury is very likely and factor (TNF-α) and pro-inflammatory can be a primary herbal treatment for cytokines produced by inflamed inflammation resulting from central nervous macrophages and specifically in BV-2 injury [2]. microglial cells [2]. Ginsenosides and inflammation 3.5 Ginseng prevention Ginseng is a plant from the Araliacea family The Rg3 ginsenoside was a promising and it is found in a lot of locations in the compound in treating inflammatory world. Ginseng, or Panax ginseng, has an responses. The single compound interesting name that means “all healing” [2]. Rg3 inhibited phorbol ester-induced In modern society, Ginseng has become a cyclooxygenase-2 (COX-2) as well as very popular commodity not only in Chinese NF-κB generation [2]. Rg3 attenuated medicine, but in Western culture as well neuroinflammation in primary, murine because of its easy preparation such as in dopaminergic neurons and glia [2]. tea [2]. Although there are two known types Additionally, the polysaccharide ginsan of ginseng, white and red, TCM believes the extracted from P.ginseng, inhibited red ginseng is more potent and effective in p38 MAP kinase pathways and NF- treatments, however now it is believed both κB during in vitro studies while also white and red are equally as effective [2]. inhibiting pro-inflammatory cytokinesin P. ginseng is truly an “all healing” plant vivo [2]. A fermented extract of ginseng because it has the ability to inhibit DNA named BST204 inhibited iNOS damage, induce cancer cell apoptosis, and expression and NO production in LPS even inhibit cell proliferation [2]. Furthermore, RAW macrophages as well. Because the chemotherapeutic effects of ginseng these ginsenosides demonstrated their are also very strong and the consumption ability to reduce NO formation, PGE2 of ginseng significantly decreased several synthesis and interfere with iNOS and types of cancers in the pharynx, stomach, COX-2 expression, it is possible that liver, pancreas and colon in a variety of they can be useful in treating many studies [2]. Ginseng extract, like that of neurodegenerative disorders such as berberine and S. flavescens all have the Parkinson’s and Alzheimer’s [2].

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Ginsenosides and inflammation prevention [2]. Because green tea compounds The Rg3 ginsenoside was a promising can also cross the blood-brain compound in treating inflammatory barrier, it makes it a great compound responses. The single compound in antioxidant activity, inflammation Rg3 inhibited phorbol ester-induced reduction, and mediation of cell cyclooxygenase-2 (COX-2) as well as apoptosis [2]. Although there are NF-κB generation [2]. Rg3 attenuated many anti-oxidant compounds such as neuroinflammation in primary, murine vitamins E and D, EGCG is more potent dopaminergic neurons and glia [2]. and more effective in reducing free Additionally, the polysaccharide ginsan radical levels [2]. Furthermore, EGCG extracted from P.ginseng, inhibited p38 MAP inhibited NF-κB activities and was a kinase pathways and NF-κB during in vitro neuroprotective agent in autoimmune studies while also inhibiting pro-inflammatory disorders such as encephalomyelitis cytokines in vivo [2]. A fermented extract [2]. Like berberine, green tea also can of ginseng named BST204 inhibited iNOS protect against neuronal injury induced expression and NO production in LPS by N-methyl-D aspartate (TRAIL), RAW macrophages as well. Because these inhibited LPS-induced microglial ginsenosides demonstrated their ability to activation and protected against reduce NO formation, PGE2 synthesis and neuronal injury of dopaminergic interfere with iNOS and COX-2 expression, it neurons [2]. Lastly, EGCG inhibited LPS is possible that they can be useful in treating activated microglia secretions of both many neurodegenerative disorders such as NO and of TNF-α by down-regulating Parkinson’s and Alzheimer’s [2]. iNOS and TNF-α gene expression while significantly protecting against 3.6 Cammelia Sinensis microglial activation-induced injury Green tea is a very popular drink around both in mice and humans [2]. Based the world now, however not many people on this evidence, green tea and know from which plant it is produced. EGCG extract specifically, could Green tea, produced by the leaves of be very effective in treating and Camellia sinensis, is one of the oldest preventing neuroinflammation and beverages in the world while also having a neurodegeneration [2]. variety of benefits helping with for example cardiovascular disorders, obesity, cancer 10. Conclusions and it also slows the aging process [2]. Although Western medicine is used From observing the effect of green prevalently in modern medicine, a tea in humans and in laboratory research, new era of using traditional medicine it was determined that polyphenol to find cures has been on the rise. By epigallocatechin-3 galate (EGCG) is the using the time-testedtechniques of most therapeutic component [2]. EGCG can Traditional Chinese Medicine to cure inhibit the production of many inflammatory and prevent illnesses, scientists have cytokines such as TNF-α, IL-6, and IL-1β discovered a great deal about herbal

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remedies and their potential in curing and Parkinson’s and Alzheimer’s and preventing illnesses equally if not more using herbal remedies could prevent effectively than modern techniques. A few and slow down epidemics of these herbs, mushrooms and plants have been disorders. By observing herbal studied in depth and their therapeutic effects remedies and studying them further, along with their safety, affordability, and new neuroprotective agents could be availability have made them very desirable. discovered and the complex pathology Recently, these studied remedies have of neurodegenerative disorders could demonstrated that regular consumption be uncovered. can prevent or diminish the development of neurological diseases caused by excessive Acknowledgements microglial activation and inflammation. The author would like to thank the Excessive microglial activation can induce dedicated scientists from Pediatrics neuroinflammation capable of causing Department, Icahn School of Medicine neurodegenerative diseases such as at Mount Sinai who made this review Parkinson’s and Alzheimer’s and using possible; especially Professor Xiu- herbal remedies could prevent and slow Min Li & Dr. Chandga Liu. Thanks to down epidemics of these disorders. By Professor Beth Powell of Smith College observing herbal remedies and studying Neuroscience Program for guidance them further, new neuroprotective agents and encouragement. could be discovered and the complex pathology of neurodegenerative disorders References could be uncovered. techniques of [1]Jeong, Gil-Saeng, Dong-Sung Lee, Traditional Chinese Medicine to cure and Dong-Chun Kim, Yurngdong Jahng, prevent illnesses, scientists have discovered Jong-Keun Son, Seung-Ho Lee, and a great deal about herbal remedies and Youn-Chul Kim. "Neuroprotective their potential in curing and preventing and Anti-inflammatory Effects of illnesses equally if not more effectively Mollugin via Up-regulation of Heme than modern techniques. A few herbs, Oxygenase-1 in Mouse Hippocampal mushrooms and plants have been studied and Microglial Cells." European Journal in depth and their therapeutic effects of Pharmacology 654.3 (2011): 226-34. along with their safety, affordability, and PubMed. Web. 20 June 2015. availability have made them very desirable. [2] Choi, Dong Kug, Sushruta Koppula, Recently, these studied remedies have and Kyoungho Suk. "Inhibitors of demonstrated that regular consumption Microglial Neurotoxicity: Focus on can prevent or diminish the development of Natural Products." Molecules 16.12 neurological diseases caused by excessive (2011): 1021-043. PubMed. Web. 30 microglial activation and inflammation. June 2015. Excessive microglial activation can induce neuroinflammation capable of causing neurodegenerative diseases such as

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[3] Patil, Sangita P., Changda Liu, Joseph [10] Phan, Chia-Wei, Pamela David, Alban, Nan Yang, and Xiu-Min Li. "Glycyrrhiza Murali Naidu, Kah-Hui Wong, and Uralensis Flavonoids Inhibit Brain Microglial Vikineswary Sabaratnam. "Therapeutic Cell TNF-α Secretion, P-IκB Expression, and Potential of Culinary-medicinal Increase Brain-derived Neurotropic Factor Mushrooms for the Management (BDNF) Secretion." Journal of Traditional of Neurodegenerative Diseases: Chinese Medical Sciences 1.1 (2014): 28-37. Diversity, Metabolite, and Mechanism." PubMed. Web. 20 June 2015. Critical Reviews in Biotechnology [4] Bear, Mark F., Barry W. Connors, and (2014): 1-14. PubMed. Web. 1 July 2015. Michael A. Paradiso. Neuroscience: [11] Wu, D.-C., P. Teismann, K. Tieu, Exploring the Brain. Philadelphia, PA: M. Vila, V. Jackson-Lewis, H. Lippincott Williams & Wilkins, 2007. Print. Ischiropoulos, and S. Przedborski. [5] Ransohoff, Richard M., and V. Hugh "NADPH Oxidase Mediates Oxidative Perry. "Microglial Physiology: Unique Stimuli, Stress in the 1-methyl-4-phenyl- Specialized Responses." Annual Review of 1,2,3,6-tetrahydropyridine Model of Immunology Annu. Rev. Immunol. 27.1 (2009): Parkinson's Disease." Proceedings of 119-45. PubMed. Web. 9 July 2015. the National Academy of Sciences [6] Aloisi, Francesca. "Immune Function of 100.10 (2003): 6145-150. PubMed. Web. Microglia." Glia 36.2 (2001): 165-79.PubMed. 1 July 2015. Web. 11 July 2015. [12] Dong, Xiao-Qiao, Wen-Hua Yu, [7] Asl, Marjan Nassiri, and Hossein Yue-Yu Hu, Zu-Yong Zhang, and Man Hosseinzadeh. "Review of Pharmacological Huang. "Oxymatrine Reduces Neuronal Effects OfGlycyrrhiza Sp. and Its Bioactive Cell Apoptosis by Inhibiting Toll-like Compounds." Phytother. Res. Phytotherapy Receptor 4/nuclear Factor Kappa-B- Research 22.6 (2008): 709-24. Web. dependent Inflammatory Responses in [8] Link, Pille, Bernhard Wetterauer, Yujie Fu, Traumatic Rat Brain Injury." Inflamm. Res. and Michael Wink. "Extracts of Glycyrrhiza Inflammation Research 60.6 (2010): Uralensis and Isoliquiritigenin Counteract 533-39. PubMed. Web. 11 July 2015. Amyloid-Î² Toxicity in Caenorhabditis Elegans." Planta Med Planta Medica 81.05 (2015): 357-62. PubMed. Web. 12 July 2015. [9] Yu, Xue-Qing, Charlie Changli Xue, Zhi- Wei Zhou, Chun-Guang Li, Yao-Min Du, Jun Liang, and Shu-Feng Zhou. "In Vitro and in Vivo Neuroprotective Effect and Mechanisms of Glabridin, a Major Active Isoflavan from Glycyrrhiza Glabra (licorice)." Life Sciences 82.1-2 (2008): 68-78. PubMed. Web. 8 July 2015.

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Jason Kahn, Chapter 24: RAGE Control: Regulate how explosive disorders affect people Peter Ducharme, Brian Travers, and Gain Emotional Control is through the exploration of the case Joseph Jason Kahn M.S., Peter Ducharme MSW, studies of John and Emily. To this Gonzalez- Heydrich / RAGE LCSW, Brian Travers B.A., end, we outline two case studies, and Control: and Joseph Gonzalez-Heydrich M.D. intertwine the need for RAGE Control Regulate and Gain Emotional Children’s Hospital & Harvard Medical within the difficulties faced by Emily, Control in World School, Boston, USA John, and many like them. Health Strategy” eBook, www. John, a 13 year old enrolled at an Futureofhealth. Abstract inner city middle school, seems at org (Ed.) Renata G. Bushko, FHTI, dvances in neurobiology and first blush to be much like his peers. 2016. Original computer science make possible During a silent reading exercise, Chapter From: Strategy for the interventions designed to strengthen he was talking with his peers. His Future of Health A basic processes behind emotional control. teacher gave him a gentle reminder (Ed.) Renata G. Bushko, IOS We present one such computer-based in an exchange that would typically Press 2009 intervention, RAGE Control (Regulate And be completely unremarkable. But Gain Emotional Control). This extends the for John, these where the first steps usual paradigm of biofeedback by requiring toward a psychiatric explosive episode, relaxation in the midst of engaging executive where John, and others like him, are processes in a quick reaction task. RAGE unable to hold their emotions in check. Control teaches children to simultaneously These situations rapidly deteriorate, focus, react, inhibit impulses, and keep creating an emotionally tense and their heart rate down in the context of a potentially physically dangerous traditional space battle game. The program scenario. We want to examine is grounded in the theory of Cognitive whether there are certain steps that Behavioral Therapy and is currently in can be taken to help children like John clinical use by psychotherapists at Children’s regain control before the situation Hospital in Boston. It aims to reduce the gets out of hand, while avoiding the need for psychotropic medication to help path of medication. Further, we seek a children gain emotional control. Clinical trials therapy that will engage these children to test the promise of this technology are in a manner that he is comfortable warranted with, making him more receptive and engaged with his therapy. 1. The case examples of John and Emily Explosive episodes unfold rapidly. RAGE Control (Regulate and Gain Emotional When the teacher reminded John Control) is an approach to treating a wide that he was supposed to be silently variety of challenges faced by people every reading, John, he denied that he was day. One of the major disorders that we are talking. As a result, the teacher stood looking at initially is explosive disorders, between John’s desk and the other a psychiatric condition where emotional student’s in an effort to decrease control deteriorates rapidly. The easiest way John’s distractions. Moments later to describe another student approached the

teacher with a question and John began Emily, a 10 year old girl who attends drawing on the desk. This exasperated the an affluent elementary school in the teacher and caused her to tell John to get suburbs, began crying in science class rid of his pen because he didn’t need it. In and refused to continue working on reaction, John then threw the pen across the the class assignment. The class had classroom towards the trash. The teacher been working in small groups of four gave John a disappointed and exhausted students and their initial task was to look, but did not comment on his actions. develop a timeline for a class project. John replayed by saying: “You told me to get Emily, who is a bright girl that excels rid of it. I don’t know why you’re so mad.” academically, quickly came up with John then proceeded to get up from a possible outline for the project. his desk and walk around the classroom. However, one of the girls in her group Another student, frustrated with his actions, didn’t like her proposal and suggested said to him “Just sit down and read already.” an alternative plan. Emily, now standing John began swearing at her and then told and speaking rapidly, insisted that her her to “mind her own business.” John’s timeline was the best way to do the teacher told him to leave, but redirecting his project. The other girls in her group anger towards the teacher, John refused. continued to disagree and asked her The teacher had to call the office and to consider their plan, but Emily would request help from the administration to get not. She continued to plead her case John out of the classroom. As the teacher and grew more and more upset as her waited, John continued to swear at her and other group members continued to the other students. He also began ripping disagree with her. pages out of his notebook and throwing After going back and forth for them on the floor. approximately ten minutes, one of John’s explosive episode rippled the group members said: “We have outward. The teacher’s control of the wasted all this time arguing, just give it classroom was tried as John’s outburst up.” Emily replied by calling her other aroused the interest of the other students. group members stupid and told them John’s verbal accosting of his teacher they were bound to fail the project. and peers put a level of stress in the She then proceeded to walk away environment that was neither conducive from the group, sit at her desk, and to his peers’ education nor fair to his began to cry. When her teacher asked teacher. While his destruction was ultimately Emily what was wrong she would harmless, in the heat of the moment, there is not respond and avoided looking at no way for his fellow students to know that her. Concerned about this incident the student throwing pens and ripping apart and Emily’s past difficulty working his notebooks, all while exploring the base with peers, the teacher called Emily’s elements of the English language is not an mother after school to talk about her immediate impediment to their safety. behavior.

Compare John’s explosion to Emily’s outpatient clinics. In early childhood, sullen withdrawal. At first glance these small amounts of aggression can stories may not seem similar. However, be seen as a normative part of upon closer examination, both cases child development [1]. However, as reveal children ill-equipped to manage the children age, advancement in their everyday stresses of their lives. Although development involves mastering the presentation of their external behavior certain tasks, one of which is the in the face of adversity differed slightly, the capacity to better self-regulate when internal states of these two children were encountering stress. Children who remarkably similar. For instance, as was are unable to master this task face evident by their nervous and impulsive numerous challenges in adolescence dispositions, both John and Emily were and later adulthood. The Diagnostic faced by situations that called for them and Statistical Manual, 4th addition (DSM to focus their efforts and inhibit impulses, IV) [2] describes several disorders trying to engage the brain systems required that can lead to disruptive and to accomplish this was impeded by the aggressive behavior, including Anxiety negative physiological arousal they each disorders, Attention Deficit Hyperactive felt. For each of them the battle between Disorder (ADHD), Disruptive Behavior negative arousal and attempts to control it Disorder (DBD), Oppositional Defiant failed and led to their loss of behavioral as Disorder (ODD), Bipolar Disorder, and well as emotional control. Conduct Disorder (CD). Disruptive, tional control. impulsive, and aggressive children For nervous and impulsive children such are at high risk for rejection by their as John and Emily, levels of anxiety that peers, poor school adjustment and accompany focusing attention to accomplish academic underachievement. They challenging tasks can trigger negative show marked deficits in self-esteem emotional and physiological responses and problem solving abilities. These which inhibit attention causing failure at children are more likely to drop out the task. The reciprocal feedback where of school, develop delinquency, negative emotion inhibits brain attentional and fail in adult work and social systems which then causes more negative relationships [3, 4, 5, 6, 7]. Psychotropic emotions quickly spirals out of the child’s medication is often prescribed so control and is converted into uncontrollable as to reduce emotional dyscontrol nervousness or aggression towards others. to a level that these children can engage in psychotherapy. In recent 2. Challenges facing children with years the rate at which psychotropic externalizing disorders medication is prescribed to children Behavioral difficulties among children and has increased dramatically and adolescents similar to John and Emily are a become a major source of societal major mental health concern and a common concern 8. Development of alternative issue faced by clinicians at hospitals and therapies that can reduce the need

to use psychotropic medication in children processes required by techniques deserves a high priority. like CBT, sometimes called concrete operations, are typically only available 3. Cognitive behavioral therapy to children only reaching adolescence. There are a number of different approaches They also require that the children to treating disorders characterized with be willing to engage in learning the impulsive aggression and emotional relaxation techniques and seeing the dyscontrol. However one of the most value of applying them when they empirically validated treatments in the are most emotionally aroused. The literature is for Cognitive Behavioral Therapy techniques themselves often require (CBT) [9, 10, 11]. In CBT, the therapist interacts that the child disengage from the task with patients in a problem solving manner, with which they are wrestling to then providing the child with skills that he or she apply the relaxation technique and can use to help overcome maladaptive when calmer return to the task. The behaviors. The therapeutic skills taught by most behaviorally impaired children are CBT therapists to children and adolescents the ones that are hardest to motive to presenting with impulsive aggression and learn these techniques and who have emotional dyscontrol can vary to some the most trouble seeing the value of degree. However, one of the primary goals inhibiting their anger long enough to for these patients is to obtain a better ability apply them. to self-regulate their behavior and emotions. The theory behind RAGE Control In CBT, this skill is often obtained through is that a child’s desire to do well in a the use of relaxation techniques. Relaxation video game can be harnessed to give techniques include Deep Breathing and him or her an opportunity to see the Progressive Muscle Relaxation (PMR) [12, value of maintaining emotional control 13]. CBT often makes use of biofeedback and practice maintaining it in the midst or providing patients with information on of a challenging and frustrating task. To indices of their state of arousal such as heart succeed at the game of RAGE Control rate, electrodermal conductance, or skin the child must apply the relaxation temperature. Biofeedback is particularly techniques while stimulating their useful in relaxation training [14]. Showing brain attentional and rapid response patients their level of physiological arousal systems. This is a more ecologically helps them learn to control their emotional valid application of relaxation than state. practicing relaxation in the calm of a The limitations of CBT and CBT-based therapist’s office. It is hoped that RAGE techniques can be traced back to acronym. Control will provide a bridge from the Cognitive behavioral therapy presumes a use of relaxation in the office to its use certain amount of cognitive operations on in difficult situation in real life. behalf of the patient. Starting with the work of Piaget [15], developmental psychologists have learned that the type of cognitive

4. Challenges facing therapist by the classic Space Invaders. The Relaxation and biofeedback training is plot of Space Invaders, to use a effective in reducing anxiety and other generous word, runs about as deep externalizing behaviors among children. as any of the pioneering arcade However, the challenge therapists often games. A hero's world is under attack face in treating patients with these types of by an alien armada. The hero gets behaviors, like John and Emily, is their level into his spaceship, and forms the last of interest to actively participate therapy. line of defense between everything Some patients dislike this training. Some he holds dear and alien annihilation. patients are too hyperactive to sit calmly The gameplay is equally simple, but in a therapist’s office and focus on a PMR compelling. The aliens traverse the script being read by a therapist. For other screen vertically, starting at the top, patients, they may feel uncomfortable doing making way to the player who sits at relaxation because it doesn’t feel natural to the bottom of the screen. The hero them and they feel uncomfortable trying to moves horizontally across the screen, do it. Patients may struggle because they firing bullets. Points are awarded for can’t see how relaxation is effective or how shooting aliens, and the game ends it is going to be useful for them. Some are when an alien succeeds in crashing oppositional and do not see the value in into the hero, or the aliens cross in engaging with their therapist at all [16]. sufficient numbers to destroy the home world. 5. RAGE Control From our point of view, Space In response to the above challenges it Invaders offers an attractive starting is important to develop innovative and point, blending solid game play with effective strategies to teach these relaxation exceedingly simple controls. In fact, in skills to patients who otherwise are not the traditional implementation of Space motivated to learn them, and to give all Invaders, there are three controls: patients the opportunity to apply what they drive left, drive right, and fire. The task learned in a situation that more closely is equally simple to understand. Get approaches the clinical situations where under an approaching alien, and fire. they need to gain emotional control. Avoid the descending aliens, and don't Therefore we have developed a new let them by. The interface and task method to teach emotional control which are elegant in their simplicity. This is is to teach patients relaxation and how not to say that they are boring. Clones to apply it during a challenging task. An of Space Invaders are still available instantiation of this method is a video game on web-based gaming sites and still we are calling RAGE Control (Regulate enjoy interest in an age of highly and Gain Emotional Control). It is our sophisticated three-dimensional games first implementation of biofeedback and with elaborate tasks and goals. relaxation during a challenging task. We From our point of view, Space start with a traditional video game, inspired Invaders offers an attractive starting

point, blending solid game play with expected. Should the heart rate go exceedingly simple controls. In fact, in the above the threshold, they begin to fire traditional implementation of Space Invaders, 'blanks:' visually smaller, slower bullets there are three controls: drive left, drive that will not damage the attacking right, and fire. The task is equally simple aliens. to understand. Get under an approaching Other tasks are modified from the alien, and fire. Avoid the descending aliens, space invader game. We require that and don't let them by. The interface and the child intermittently inhibit a potent task are elegant in their simplicity. This is not impulse to fire. For this we introduce to say that they are boring. Clones of Space a number of friendly craft that enter Invaders are still available on web-based the game board at random moments. gaming sites and still enjoy interest in an age Along with aliens entering from the of highly sophisticated three-dimensional top of the screen, 'friends' of the games with elaborate tasks and goals. hero do as well, and the player now RAGE Control, while building on the needs to avoid shooting their friends. template of Space Invaders, makes several These must not be shot. In the game key departures not only from Space narrative, we describe this as the Invaders, but the traditional approach to player's friends fleeing from the alien gaming. The most prominent of these onslaught. From a design perspective, changes is the input device. The user still this completes a tidy task matrix makes use of a traditional input, in out case presented to the user. a keyboard. But unlike any game found in an arcade or on a living room console, Table 1: Task matrix for RAGE Control Hit the user also tethers him/herself to the computer using a heart rate monitor. The Hit Passed user's own physiology becomes part of the Alien Correct Hit Incorrect gaming experience, and the physical link (+100) rejection immediately reinforces the idea that the (β-error; -100) game's narrative now depends on control Friend Incorrect Correct of heart rate, a physiological variable. RAGE hit (Î±-error; rejection -500) (+100) Control currently uses a pulse oximeter for

heart rate input, which clips onto the users finger. The other inputs of the game are After several iterations, we unchanged. A keyboard controls left and decided that, as an introduction to right movement and firing. RAGE Control, users only play for a The activity of firing a bullet is moderated high score. Thus, aliens striking or by heart rate. At the onset of the game, a passing the player have no effect on threshold heart rate is calculated as sitting game play, other than detracting from heart rate plus seven beats per minute. So the score, while shooting aliens and long as the user is under their heart rate allowing friends to pass increase the threshold, they can fire their weapon as score. Shooting friends carries the

highest penalty. This design decision was adolescents are more likely to acquire relaxation made to ensure that users would have a skills using RAGE Control is because it grounds chance to become familiar with the game them in a computer game which is oftenalready and train themselves to regulate their heart an interest of this population. Therefore, therapists rate. will be able to reach patients who may not What does the design of an active respond to the therapists walking them through biofeedback game like RAGE Control traditional relaxation training. The figure below is accomplish? Patients increase their ability a design brief for Psychiatry Invaders. It is meant to regulate emotion and behavior under to capture the game from the user's perspective, stressful conditions. Players of RAGE Control describing the games goals, inputs and outputs. experience a number of challenges to their autonomic nervous systems (ANS). The Table 2: RAGE Control Game Description sympathetic and parasympathetic nervous Goals Active tasks Destroy incoming enemies systems of the ANS acts as the fight or flight Inhibitory Don't destroy friends mechanism within the body. The sympathetic tasks nervous system responds to excitement and Inputs Traditional Left arrow - drive left fear whereas the parasympathetic works to Right arrow - drive right Space bar - fire bullets control relaxation restoring a person’s body Physiological Oximeter - heart rate to a normal physiological state. Outputs Under Shot fired - large, effective bullet RAGE Control begins by having players threshold attend to one active task, shooting aliens. Hit Passed As the game progresses, players face Alien +100 -100 Friend -500 +100 increased ANS challenges corresponding Over Shot fired: slow, ineffective bullet with increased levels of the game. The threshold Shot fired - large, effective bullet next challenge player’s encounter is their friends flying on the screen. This is an Hit Passed inhibitory task asking players to avoid hitting Alien 0 -100 Friend 0 +100 certain spaceships. As the levels increase

the numbers of aliens and friends multiply 6. RAGE Control Utility and begin flying at a greater velocity. The promise of RAGE Control are that we will Adding more challenges to players ANS’s increase the ability of children to regulate their we believe the game provides players emotions even while under stress and this will with motor, emotional and performance reduce the need to administer psychotropic challenges, which replicates the stressful medication. These medications come with two- challenges they will encounter in day to fold cost to the patient and the health care day situations. Mastering the ability to utilize system. First, the system is responsible for the relaxation with the game will generalize to direct costs associated with the medication. other stressful encounters players face in However, many psychotropic medications come their lives. The reason why children and with severe side effects, which are a burden on

the patient, their family, and the system. The treatment longer, be able to tackle use of powerful psychotropic medication to more emotionally charged issues, and treat common childhood disorders leading have better outcomes. to explosive episodes is a matter of deep The challenges addressed in societal concern. Our hope is that RAGE an intervention that includes RAGE Control can augment a treatment plan in Control are faced by enormous a way that can teach the patient valuable numbers of people. Because of this coping skills while mitigating and maybe it is easy to image RAGE Control even eliminating the use of psychotropic expanding to help a variety of people medication for many of these children. beyond our initial target population of However, this is just the beginning of the adolescents in clinical settings. Stress benefits we hypothesize for RAGE Control. can be a good thing. An autonomic Clinically, we expect that RAGE will response can heighten the senses have particular utility with adolescent and increase performance. But this boys. In addition to providing an in vitro same autonomic response can elevate environment for the child to learn how to and impair judgment and degrade self-regulate emotion, we believe RAGE performance. When one finds oneself Control will also help to strengthen the in this situation, it would be valuable to therapist-child therapeutic alliance. Research have rehearsed skills that help them has suggested that early therapeutic overcome these challenges. alliance is associated with later treatment RAGE Control does not need outcomes, but for children and adolescents to be used in one-on-one settings. the therapeutic alliance becomes more We envision building a multi-user complicated with the therapist needing to cooperative game version of RAGE form and maintain an alliance not only with Control. This version could be used the patient, but with the patient’s parents/ in group and family therapy settings. caregivers as well. Many families report One example is a social skills group, that the reason they terminate therapy was a group-based therapy where a small quite straightforward: the child did not like group of patients acquire and practice it. RAGE Control is a fun activity for patients social skills in a controlled setting. to use while in therapy, that challenges Using this cooperative multi-user RAGE them to take the skills they acquire with Control would require group members their therapist and put them to use in an to support each other in maintaining environment in which they are familiar. We concentration and calm so that every believe this will make coming to therapy player can contribute to the group more appealing for patients who previously succeeding at the game. This means may have been reluctant to come engage that other people in the room would in therapy. We think this will help to build need to refrain from distracting others a stronger therapeutic alliance between and also from upsetting others even the patient and the therapist. By forming as they share information in order to a stronger alliance, patients will remain in succeed. These skills are often a goal

of social skills groups because children instantiation and in potential require these skills when in school and future instantiations. The current adults in their work and family lives. Another prototype application is being used aspect of the game involving social skills at Children’s Hospital, Boston in happens at the conclusion of the group’s the outpatient psychiatry clinic, the turn playing the game. This is an opportunity inpatient psychiatry unit and the for each player to give other players positive Emergency Psychiatric Department. feedback on his or her performance. RAGE RAGE Control can be used as a one Control offers a number of features group time intervention but is more likely members are able to comment on including to be effective as part of ongoing how well each player was able to keep psychotherapy. RAGE Control has there heart rate low, how well they were the best chance at making an impact able to shoot the aliens, how well they when the psychotherapist provides the were able to avoid shooting their friends, tools (relaxation techniques) the child and how well they worked together. This requires to succeed at RAGE Control helps teach group members how to search and then helps the child see the link for positive attributes of each player that between using relaxation techniques helps to increase members’ social skills. to gain emotional control to succeed Taking these skills into the home and at the computer game and using school settings will help members develop them to succeed in difficult situations better peer relations which is an important or conflicts in their lives. Future protective factor against other mental health instantiations of the idea behind RAGE problems in the future. Control will likely include more realistic In this light, it is easy to picture RAGE virtual reality games which could Control, ported to a hand-held device, increasingly mimic the actual situations providing skills on an everyday level. where the child often looses emotional Possible applications range from the student control. who has difficulties self-regulating during a test, or an executive trying to navigate References particularly demanding circumstances. [1] Blake, C., & Hamrin, V. (2007). However, there are other uses that are Current approaches to the assessment particularly valuable in the domain of public and management of anger and health. For example, populations of at-risk aggression in youth: A review. Journal expecting fathers could use the self-control of Child and Adolescent Psychiatric training of RAGE Control and then use RAGE Nursing, 20(4), 209-221. Control to teach self control to their children. [2] American Psychiatric Association. It is even possible that RAGE Control could (1994). Diagnostic and statistical help with the impulse control in addiction manual of mental disorders recovery. (4th ed.). Washington, D.C.: Author. RAGE Control offers a tremendous amount of versatility, both in its current

[3] Barry, C. T., Frick, P. J., & Killian, A. L. [10] Kendall, P. C., (1994). Treating (2003). The relation of Narcissism and self- anxiety disorders in children: Results esteem to conduct problems in children: A of randomized control trial. Journal preliminary investigation. Journal of Clinical of Consulting Clinical Psychology, 62, Child and Adolescent Psychology, 32(1), 139- 100-110. 152. [11] Kendall, P. C., Flannery-Schroeder, [4] Erhardt, D., & Hinshaw, S. P. (1994). Initial E. C., Panichelli-Mindel, S, et al. (1997). sociometric impressions of attention-deficit Therapy for youths with anxiety hyperactivity disorder and comparison disorders: A second randomized boys: Predictions from social behaviors and clinical trial. Journal of Consulting from nonbehavioral variables. Journal of Clinical Psychology, 65, Consulting and Clinical Psychology, 62(4), 366- 380. 833-842. [12] Bornman, B. A., Mitelman, S. A., & [5] Fraser, M., Day, S., Galinsky, M., Hodges, Beer, D. A. (2007). Psychotherapeutic V., & Smokowski, P. (2004). Conduct relaxation: How it relates to levels of aggression in a school within inpatient problems and peer rejection in childhood: A child psychiatry. A pilot study. Arts in randomized trial of the making choices and Psychotherapy, 34, 216-222. strong families program. Research on Social [13] Davis, M., Eshelman, E. R., Work Practice, 14(5), 313-324. McKay, M., & Winemiller, V. (2008). [6] Hinshaw, S. (1992). Externalizing behavior The relaxation and stress reduction problems and academic underachievement workbook, 6th edition. Oakland, CA, in childhood and adolescence: Causal England: New Harbinger Publications. relationships and underlying mechanisms. [14] Critchley, H.D., Melmed, R.N., Psychological Bulletin, 111 (1), Featherstone, E., Mathias, C.J., & 127-155. Dolan, R.J. (2001) Brain activity during [7] Keenan, K., Loeber, R., & Green, S. biofeedback relaxation: A functional (1999). Conduct disorder in girls: A review neuroimaging investigation. Brain, of the literature. Clinical Child and Family 124(5), 1003-1012 Psychology Review, 2(1). [15] Piaget, J., & Inhelder, B. (1966). La [8] Thomas, C.P., Conrad, P., Casler, R. Psychologie de l’Enfant. Paris, France: Godman, E. (2006) Trends in the Use Quadridge of Psychotropic Medications Among [16] Hawley, K. M., & Weisz, J. R. (2005). Adolescents, 1994 to 2001. Psychiatr. Serv. Youth versus parent working alliance 57, 63-69 in usual clinical care: Distinctive [9] Kendall, P. C., Hedtke, K. (2006). Cognitive associations with retention, satisfaction, Behavioral therapy for anxious children: and treatment outcome. Journal Therapist Manual. 3rd edition. Ardomore, PA: of Clinical Child and Adolescent Workbook Publishing. Psychology, 34(1), 117-128.

Teresita Chapter 25: Shaping a Healthy Future: supply and consumption, lifestyle, and Hernandez / Shaping a Megabyte, Not Mega bite! the prevalence of chronic diseases Healthy Future Teresita B. Hernández, Ph.D. that could be associated with obesity. in World Health Strategy” President, Health Technomics, Inc, Worldwide food availability expressed eBook, www. Annandale, VA, USA as kilocalories per capita per day Futureofhealth. org (Ed.) Renata increased from 2358 in the mid 1960’s G. Bushko, FHTI, Abstract to 2803 in the late 1990’s. Among 2016. Original Chapter From: he globalization of obesity is not a developing countries, the increase was Intelligent and myth. Scientific and technologic from 2054 to 2681 over the same Extelligent Health advances have increased food period; the increase was specially Environment T production and availability while decreasing pronounced in East Asia where the (Ed.) Renata G. Bushko, IOS demand for physical activity. These food energy supply increased by Press 2005 developments, in turn, have contributed to almost 1000 kilocalories per capita per peoples’ cognitive and behavioral day. There is no question that with food relationship with food selection and availability and rising income, obesity consumption. The more you see, the more has now become a major concern in you want. Although disparities in food both developing and highly developed distribution and personal economics still countries. exist, the problem of over consumption is becoming widespread among low income 2. Part of the Problem—Technology groups in developed countries and among Technology has increased food the high income in developing countries. production and has made packaging The development of innovative technologies and transportation faster and easier. such as described in this chapter may help Indeed, there is an economic research ebb the tide of obesity and improve the report that concludes that 40% of the global future of health. weight gain of the U.S. population in the past two decades may be 1. The Obesity Problem—A Global Concern explained by lower food prices due to The 21st century ushered in a public health agricultural innovations, and 60 % may concern that had had a low profile until the be due to a decline in physical activity popular media gained insight into the because of technological innovations increasing prevalence of overweight and in the home and in the workplace.3 An obesity among the US population. The immediate consequence of adage “big is beautiful” has lost its attraction; technological innovations in agriculture instead the term “obesity epidemic”1 has and the food industry is the “super- been added to the public health vocabulary. sizing” of foods and beverages served The 2003 report of World Health in restaurants, fast food stores and Organization (WHO) on Diet, Nutrition and food courts. Sizes of containers of the Prevention of Chronic Diseases2 ready-to-eat snacks and sweetened provides the global statistics that show drinks have also been enlarged.4,5 changes over the past four decades in food

If consumers were conscious of how versus market-based—are not always technology has affected their lifestyle, if they explicit, even in many of our health and knew what to do about it, and if they nutrition messages and have therefore recognized that weight gain has a large become a source of confusion for the behavioral component, then the obesity public. epidemic might have been prevented. There was a time when parents Research on the increase in portion sizes of admonished their children at mealtime food and beverage consumed by the U.S. “Take only what you can eat” followed population over the past two decades by “Eat everything on your plate.” In supports the economic research findings. this scenario, serving equaled portion. This is especially true for energy-dense but However, especially in this country, the nutrient-deficient foods and beverages such abundance of the food supply and the as salty snacks, beer, and sweetened busy lifestyle that has led to the growth carbonated drinks.6,7 Between 1989 and of the “grab and go” food industry have 1996, data from two independent national made traditional meal preparation and surveys (NHANES and CSFII) show mean serving almost obsolete. USDA reports portion intake of cola-type soft drink that the frequency of dining out rose (excluding sugar-free, or low-calorie) from sixteen percent of all meals and increased from 11.6 to 14.78 fluid ounces for snacks in 1977-78 to twenty seven all users; at the 95th percentile, the change percent in 1995.9 In 1970, the food- is from 18 fluid ounces in 1989-91 to 35 fluid away-from-home sector captured ounces in 1994-1996.8 about a quarter of total food spending and in 1995, about forty percent of the 3. Providing a Solution With Technology food budget was spent on food away With creative, science-based instructional from home.10 These developments and behavioral modification tools, and the have also changed the meaning of willingness of health professionals to “small”, “medium” and “large” in relation maximize the use of such tools, technology to serving sizes. can empower individuals in fighting obesity. A small informal survey that we As the title of this Chapter implies, the focus conducted recently indicated that most is on using computer technology for portion (about ninety percent) dietitians and size definition and control. Within the limits of nutrition students use the terms serving this chapter, there is no intent to address the and portion synonymously. This is problem of obesity in its entirety. The aim is highly influenced by a serving size to emphasize the need for recognizing the defined in reference to the Diabetic difference between food exposure (serving) Exchange, the Food Guide Pyramid, and personal behavior or choice (portion), and sometimes the Nutrition Facts and further illustrate the difference between Label. On the other hand, consumers a health-based serving size and a market- are continually exposed to serving based serving size. These concepts— sizes in the marketplace. These sizes serving versus portion, and health-based get bigger and bigger in response to

consumers’ concept of “value”, meaning sold in bakeries weigh about 5 ounces. “more for your money”. The food industry And among foods for which pyramid uses this concept when introducing a new servings are not clearly defined, for product or promoting sales. The opening of example, soft drinks, “super-sizing” of a new “burrito” restaurant in a college town containers is the growing trend. As part in Maryland advertised its main attraction as of our project to develop an interactive huge (four-inch diameter) rolls! A famous desktop reference for serving sizes, cookie maker sends mail advertisement for we made many trips to fast food its nine-inch cookie! places, kiosks, food courts, and other convenience stores. This is a sampling 4. What This Chapter Is All About of what we found among containers for This Chapter offers a new framework for soft drinks: the old 8 ounce “Dixie” cup defining serving size from two is now called “kiddies”; a 16 ounce cup perspectives—one health-based, and the is “regular” or “medium”; 22-24 is other, market-based. Health-based refers to “large”, “Big Gulp” is 32, “Magnum” is serving sizes as defined according to the 44, and “Double Gulp” is 64 fluid Diabetic Exchange, the Food Guide Pyramid, ounces. And if the container is filled to and the Nutrition Facts Label guidelines. the brim, these volumes can increase Market-based refers to single serving sizes by another 2-4 fluid ounces. encountered at grocery and convenience Unfortunately, there is no requirement stores, at fast food counters, and in diners to label the capacity of containers. If and full-service restaurants. It is important to shown, it usually appears encoded at note that serving size for a given food item the bottom of the cup. So if you want to varies even among the health-based know how much you had, you either references. For example, a serving size for have to finish the contents or spill it! orange juice is 4 fluid ounces in the Keeping track of how much one American Diabetes Association’s (ADA) eats and drinks is a difficult task. Even Exchange List for Meal Planning, 6 fluid among professionals who are trained ounces in the US Department of in food science and nutrition, few, if Agriculture’s (USDA) Food Guide Pyramid, any, can accurately slice a 3 oz piece and 8 fluid ounces in the Food and Drug of meat or pour 8 fluid oz of juice Administration’s (FDA) Nutrition Facts Label without measurement tools. In the real guidelines. However, it is even more world of food consumption, we must important to note the large difference first acknowledge that the cognitive between the health-based and the market- skills used in estimating sizes and based serving sizes. For example, the food amounts are not simple skills. They are guide pyramid size for steak is 2 to 3 ounces brain functions—perceptual, cooked (100g raw), whereas a restaurant mathematical, memory storage and serving size could be 3 to 4 times as large retrieval—that differ from individual to (See Figure 1). The pyramid size for muffin is 1 individual. The degree to which these ounce while muffins served at airports or skills contribute to the accuracy of

quantitative estimates is an area of research programs that displays photographs of that we have only begun to address about 300 typical foods and 100 food systematically. No professional group to date and beverage containers commonly has defined an acceptable error rate in food used in the U.S. Employing digital measurement. Previous studies suggest that photography and a programming using visual portioning anchors tended to language that has both computational result in overestimation more frequently than and pictorial database management underestimation for all types of food—solid, capabilities, a pictorial database of at amorphous, or liquid—when estimation is least two sizes for each food or done in real time or short-term recall.11,12,13 In container was created. Food was an attempt to establish a basis for a rational weighed and measured immediately expectation of accuracy in portion before photographing. Foods with estimation, our recently completed research inedible parts, such as peel or bone, suggests that cognitive adaptation to food were again weighed and measured exposure is a dominant influence in how after photographing to obtain the consumers perceive portion sizes.14,15 edible portion weight. Capacity Beyond these cognitive issues of of containers was measured to the top measurement, scientists are beginning to and to about two centimeters document the effect of food exposure on from the top personal consumption starting in early To communicate a health-based childhood.16, 17 To ebb the tide of obesity, it is serving, a photograph of the USDA important to explore the extent to which pyramid serving size for selected foods technology can assist as early in the in each of the five food groups is formative years as possible. Our approach is available for display in the program. A to get both health professionals and the universally recognized secondary public to think visually, recognize the anchor, a nine-inch paper plate serves difference between health-based and to reinforce size perception without market-based serving sizes, and make a having to use a ruler. Weights, distinction between serving (what you SEE, dimensions, and volume, where in other words, exposure) and portion (what applicable, are available for each you PARTAKE, in other words, personal photograph in both English and Metric behavior or choice). We have developed systems. visual tools to promote this common Photographs were taken under reference for communication. The Health standardized studio settings. To Technomics Computer-based Portion maintain constant camera position for a Anchors (HTCPA) is one of these tools. specific view, several measurements were made for: a) the camera angle, b) 5. The Health Technomics Computer- position of the contextual anchor, and based Portion Anchors (HTCPA)18 c) the tripod position. The product is: The Health Technomics Computer-based testable, portable, upgradeable, and Portion Anchors (HTCPA) is a suite of adaptable for multiple uses.

HTCPA can be used for education and counseling, as measurement aids for dietary assessment, and for conducting cognitive research. Portion Basics, is the primary program for use in educational settings, or as a stand-alone visual aid during dietary assessment. For purposes of education or nutritional counseling, the teacher/student/ client can browse the list of foods or containers and choose an item to view in two or more sizes. For foods, weights and Figure 2. Portion Counts: When Calories Matter measures can be displayed on demand. For container, dimensions and volume capacity The third and most comprehensive can be displayed on demand. For some program, Portion Plus, has all the foods, there is also a picture of pyramid size functions of Portion Basics and Portion serving for comparison with market servings Counts, plus additional functions for as illustrated for steak below. data collection, storage, and retrieval. Thus, beyond educational and clinical uses, the program can serve as a tool for cognitive research in portion size estimation. For cognitive research, the user compares the size or amount of an actual serving of food placed beside the computer with what is displayed on the screen. Figure 1. Portion Basics: Your Choice For research on the effect of memory The second program, Portion Counts, on portion size estimation, or for is the clinical version for use in weight use as a measurement aid in dietary management, diet management in diabetes, assessment, the user compares the or meal planning for heart healthy meals. size or amount of food eaten at an Portion Counts allows the user to view earlier time with what is displayed on the calories, carbohydrates, protein, fat, the screen. Amount in every case can cholesterol and fiber content of each food be expressed as a fraction or multiple displayed. It serves not only as a counseling of the amount shown on the screen. tool, but can also provide reinforcement A portion estimation screen in Portion when installed on the client’s computer. Plus is shown in Figure 3. Figure 2 shows a computer screen from this program.

and at Tennessee State University by S. Godwin and C. Thompson. Dietitians in the Washington DC metropolitan area conducted the beta testing for operability and usability.

References [1] Obesity in Science, Special Issue, February 7, 2003 [2] Diet, Nutrition and the Prevention of Chronic Diseases, Technical Report Series 916, WHO, Geneva, 2003 Figure 3. Portion Plus: Size Estimation [3] Lakdawalla, D. and Philipson, T., The Growth of Obesity and Technological n 6. Conclusio Change: A Theoretical and Empirical While the problem of obesity and the Examination, National Bureau of phenomenon of “super-sizing” have become Economic Research Working Paper No. political as well as legal pursuits, and have created media frenzy, it is important for W8946, May, 2002 scientists to continue basic and applied [4] Hernández T, Kim K, Wilder L, and research on this topic. There is still a long Sebrechts M, Serving versus Portion: way to go in improving the quantitative Is there a difference? Does it matter? aspects of portion size estimation and Fourth International Conference on dietary assessment methods. But with a Dietary Assessment, Tucson, AZ, multidisciplinary approach and the use September, 2000 of appropriate technology to address [5] Young, L., and Nestle, M. The the cognitive and behavioral issues in Contribution of Expanding Portion quantifying food intake, I am confident Sizes to the US Obesity Epidemic, Am that we are on the right track in shaping a J Public Health. 2002; 92:246-249 healthy future, megabyte by megabyte, not [6] Neilsen, S. and Popkin, B. Patterns mega bite! and Trends in Food Portion Sizes,

JAMA. 2003; 289: 450-453 Acknowledgments [7] Smicklas-Wright, H. et al., Foods Small Business Innovation Research grants from the USDA made HTCPA development Commonly Eaten in the United States, and testing possible. Co-developers are 1989-1991 and 1994-1996: Are portion D.Kuehn for photography, K. Rubotzky, sizes changing? J. Am. Diet. Assoc. programming, and L.Wilder for content 2003; 103:41-47 development and alpha test. Consumer testing at the University of Maryland was coordinated by P.Moser-Veillon and C. Wang,

[8] Hernández, T. “Tracking intake of Core [15] Hernández T, Wilder L, Kuehn Food- cola carbonated beverage, 1989- D, and Rubotsky K, Moser-Veillon P, 1996”, in Use of the Core Food Model Godwin S, Thompson C, and Wang to Estimate Mineral Intakes, J. Food C. Portion Size Estimation and Composition and Analysis. 2001, 14: 305-307 Expectation of Accuracy, 28th National [9] Lin, Biing-Hwan, Frazĩo, Elizabeth Nutrient Data Conference, Iowa City, and Guthrie, Joanne, Away-From-Home IA, June 24, 2004; Submitted for Foods Increasingly Important to Quality of publication, J. Food Composition and American Diet. Food and Rural Economics Analysis, July, 2004 Division, Economic Research Service, U.S. [16] Fisher, JO, Rolls, B. and Birch, L. Department of Agriculture, Food and Drug Children’s bite size and intake of an Administration, U.S. Department of Health entrée are greater with large portions and Human Services. Agriculture Information than with age-appropriate or self- Bulletin No.749. selected portions. Am J Clin Nutr 2003; [10] Putnam J, and J Allshouse, Food Cons 77:1164-70. mption, Prices, and Expenditures, U.S.D.A., [17] Rolls B, Engell D, Birch L, Serving Econ. Res. Serv., SB-928, April 1996. portion size influences 5-year old but [11] Chambers E,. McGuire B, Godwin S, not 3-year old children’s food intakes. J Edwards E. Cognitive Methods, CDC, DHHS Am Diet Assoc 2000; 100:232-4. Working Paper Series No. 27, 1999. [18] Hernández T, Wilder L, Kuehn D, [12] Hernández T, Kim K, Wilder L, Godwin and Rubotsky K, Portion Perception: S, and Sebrechts M. Computer based The Missing Link. Fifth International anchors and portion size estimation, Food Data Conference/ National Fourth International Conference on Dietary Nutrient Databank Conference, Assessment, Tucson, AZ, September 2000. Washington, DC, July 1, 2003 [13] Knous, B. et al., Grain-based foods portion size recall compared to portion photo selection, FASEB, San Diego, CA, April, 2003. [14] Hernández T, Wilder L, Moser-Veillon P, Godwin S, Thompson C, and Wang C. Cognitive Adaptation and Portion Size Estimation: Is there a connection? Experimental Biology 2004, Washington, DC. April 18, 2004

A. Stibe / Chapter 26: Persuasive Cities: any well-designed environment can Persuasive Cities: Health Health Behavior Change at Scale become a strong influencer of what Behavior Agnis Stibe people think and do. There is an Change at Scale in “World Health MIT Media Lab, Cambridge, MA, USA endlessly dynamic interaction between Strategy”, Renata a person, a particular behavior, and G. Bushko (Ed.) eBook Abstract an environment in which that behavior FHTI 2016. an you imagine a city that feels, is performed. The persuasive cities FutureofHealth. org understands, and cares about your research leverages this knowledge to Cwellbeing? Future cities will reshape engineer persuasive environments for human behavior in countless ways. New altering human behavior on societal strategies and models of urban spaces levels. are required for creating future cities The proposed research reflects to properly respond to human activity, on novel ways of how persuasive environmental conditions, and market technology [3] and socially influencing dynamics. Persuasive urban systems will systems [4-5] enable mechanisms play an important role in making cities to perpetually support motivation of more livable and resource-efficient by individuals comparing to conventional addressing current environmental problems methods, such as those that are and enabling healthier routines. Drawing on based on carrots and sticks. Instead, socio-psychological theories and integrating persuasive urban systems harness them with new concepts for urban design, social influence from crowd behavior the persuasive cities research focuses on to craft influential messaging aimed improving wellbeing across societies. This at shifting behavior and attitude of research presents an ecosystem of future an individual, who naturally is an cities, describes three generic groups of integral part of the same crowd. Such people depending on their susceptibility to continuous interplay can ultimately persuasive technology, explains the process result in an ongoing process that of defining behavior change, and provides reshapes communities and societies tools for social engineering of persuasive without any other incentives. cities. Further research should continue exploring how urban design in combination 2. Emergence of Persuasive Cities with socially influencing systems could Ongoing research streams focus on encourage healthy and sustainable sensible cities (researching sensing behaviors at scale. technologies to read human behavior in urban spaces) and smart cities 1. Perspective (analyzing big data to classify groups As population in cities continue grow of people based on their distinct exponentially the architecture and design behavioral patterns), however there is of future urban places will become more a lack of knowledge about perspective dominant in impacting human behavior [1]. ways to achieve persistent behavioral According to social cognitive theory [2], changes at scale. Therefore, the

proposed research extends an ecosystem are and what they do on daily basis, of future cities (Table 1) by introducing the thus many behavioral interventions notion of persuasive cities that aims to might fail in attempts to influence advance and refine influential strategies this group of individuals. Self-driven designed for intentionally reshaping how people (the green circle) typically people think and act in urban environments. have comparatively high levels of motivation and can achieve everything Table 1. Ecosystem of future cities. that they have envisioned. Thus, these people most likely are not looking for Role Character Technology additional sources of encouragement, Change Care PERSUASIVE Socially and therefore persuasive technologies Influencing might become unnecessary for this Systems group. Classify Understand SMART Big Data Analytics However, there is another group Read Feel SENSIBLE Sensor of people that oftentimes would like Networks to change their routines, but rarely succeed in doing so. That reminds of Each layer of future cities has its role, New Year’s resolutions that in many character, and supportive technology. cases end around February. Therefore, Sensible cities employ sensor networks this group is entitled as January 1st to read crowd behaviors. In other words, (the yellow circle) and seem to be the these cities feel human movements. These most welcoming towards technology crowd behaviors further serve as an input supported behavioral interventions for big data analytics that smart cities apply designed to help achieving target to classify groups of people according behaviors. Although, Fig. 1 presents to similar behavioral patterns (profiles). all three groups as equal circles, in When that is accomplished, the groups reality the size of each group might having better routines can be exemplified significantly vary depending on the to other underperforming groups through context and particular behavior. intentionally designed socially influencing systems, which are at the core of persuasive cities.

3. Susceptibility to Persuasive Technology People generally can fall into one of the three generic categories depending on their susceptibility to persuasive technology (Fig. 1). Self-contained people (the red circle) most likely are not open for changing anything in Figure 1. Susceptibility to persuasive technology. them. They are fully satisfied with who they

4. Defining Behavior Change The principles are interlinked and To achieve an envisioned target behavior, have potential to exert stronger the process and components of behavior effects depending on the context change have to be well understood and of a particular behavioral challenge. clearly defined. In the process of defining Normative influence and social behavior change, there are three main comparison seem to be more effective components, namely the target group, its to achieve involvement of the target present behavior, and its envisioned future group as the two principles focus on behavior (Table 2). attitudinal changes. Cooperation and social facilitation seem to be more Table 2. The three main components for defining effective to make individuals participate behavior change. and do the envisioned future behavior even without a formed attitude towards Target Group Current Behavior Future Behavior it. Competition and recognition seem A group of Description An ultimate people currently A certain future behavior to be more effective in engaging the having an behavior of the of the target target group to do the future behavior unsatisfactory target group group that is as the principles focus on both attitude behavior. It is that currently is envisioned to be important to not in line with more beneficial and behavior simultaneously. For narrow down an envisioned for everyone. example, the effects several socially the target group future behavior influencing principles have already as precise as in a given possible. context. been studied in the context of urban There are MIT Example They could mobility, e.g. bicycling [6]. faculty members. Who currently commute by commute alone bicycles instead in their private whenever cars. possible.

5. Tools for Social Engineering Earlier research on persuasive technology [3] describes several ways how social dynamics can influence human behavior, which have been further refined and structured as a framework for Socially Influencing Systems (SIS) [4], depicted in Fig. 2. The SIS framework is a useful tool for scholars and practitioners aiming at improving future cities by introducing persuasive urban interventions targeted to support wellbeing. Figure 2. Socially Influencing Systems (SIS) The framework describes seven framework. socially influencing principles that can support persuasive urban interventions.

References [6] Wunsch, M., Stibe, A., Millonig, A., [1] Stibe, A., Chatterjee, S., Schechtner, Seer, S., Dai, C., Schechtner, K, and K., Wunsch, M., Millonig, A., Seer, S., Chin, R.C.C.: What Makes You Bike? Chin, R.C.C., and Larson, K.: Empowering Exploring Persuasive Strategies to Cities for Sustainable Wellbeing. Adjunct Encourage Low-Energy Mobility. Proceedings of the 11th International Lecture Notes in Computer Science, Conference on Persuasive Technology, 9072, Persuasive Technology, pp. pp. 76–79 (2016) 53–64 (2015) [2] Bandura, A.: Social Foundations of Thought and Action: A Social Cognitive Theory. Prentice Hall, Englewood Cliffs (1986)

[3] Fogg, B. J.: Persuasive Technology: Using Computers to Change What We Think and Do. San Francisco: Morgan Kaufmann (2003)

[4] Stibe, A.: Towards a Framework for Socially Influencing Systems: Meta- Analysis of Four PLS-SEM Based Studies. In: MacTavish, T., Basapur, S. (eds.) Persuasive Technology. LNCS, vol. 9072, pp. 171–182. Springer, Heidelberg (2015)

[5] Stibe, A.: Advancing Typology of Computer-Supported Influence: Moderation Effects in Socially Influencing Systems. In: MacTavish, T., Basapur, S. (eds.) Persuasive Technology. LNCS, vol. 9072, pp. 251–262. Springer, Heidelberg (2015)

Benjamin L. Chapter 27: Future of Diagnostics for market (and to cover development Miller / Future of Diagnostics Personalized Medicine costs for the vast majority of drug for Personalized Benjamin L. Miller, Ph. D. candidates that never make it all Medicine in World Health Department of Dermatology, University of the way through the development Strategy” Rochester, Rochester, New York process). eBook, www. Futureofhealth. We are at the dawn of a sea change org (Ed.) Renata Abstract in medical diagnosis and therapy, G. Bushko, FHTI, 2016. From nprecedented advances in our driven by exceptional advances in Strategy for the understanding of the molecular world our understanding of the molecular Future of Health (Ed.) Renata G. around us and within us have the makeup of ourselves and of the world Bushko, IOS U potential to drive a revolution in health care. around us (Figure 1). The "-omics" Press 2009 A key aspect of bringing this revolution to fields (genomics - the study of all the fruition is streamlining and simplifying our genes in an organism; proteomics, ability to detect and quantify molecules metabolomics, glycomics - the of biomedical relevance. New “sample study of proteins, metabolites, and in – answer out” diagnostic systems, some carbohydrates, respectively) are with the potential to detect even single providing an avalanche of information viruses or single copies of molecules, are about the molecules that are present under development in many academic and interact with each other as a part and industrial laboratories worldwide. of “normal”, healthy biology. Likewise, This chapter discusses our efforts at these sciences are beginning to reveal the University of Rochester towards the molecular signatures of human biology development of three complementary gone haywire, and of the infectious molecular detection systems, with agents that attack us. In principle, applications from allergy diagnosis to we can use this information to make monitoring infectious disease. precise determinations about the state of our health, and likewise prescribe Introduction therapeutic regimens based on unique Medical practice has historically centered molecular profiles – a field now known on deductive reasoning drawn from as “personalized medicine”. With observations; a physical exam is a structured regard to infectious disease, these method of acquiring these observations. techniques will allow for the more rapid Because these macroscopic measures are recognition that an infectious bacterium often relatively low resolution (although is resistant to certain antibiotics (or at obviously important), medical practice has an even more basic level, will permit generally relied on a "one size fits most" identification of a bacterial infection treatment strategy. The extraordinarily high in hours or minutes, as opposed to cost and long lead times of pharmaceutical current methods that require several development reinforces this model, since days). corporations need large patient populations to recoup the cost of getting a drug to

such capabilities are almost exclusively located in core laboratory facilities. Pushing our pull up-observing analogy a bit, this is analogous to needing to photograph someone doing pull ups, sending the film in for development, and waiting for the picture to come back before being able to make an observation. Time delays in diagnosis have negative consequences in terms of patient health, and dramatically Figure 1: Internal and external influences on our increase patient costs. The situation health. Having the ability to “see” these molecules in a simple fashion would allow us to more precisely with infectious disease (in particular, and rapidly respond to health challenges. nosocomial bacterial infections) is a particularly stark example of this, and Over the long term, we can envision a future one to which we will return later in the in which the molecular signatures of health chapter. However, rapid detection of and disease are as simple to observe and internal disease biomarkers also has analyze as our current “macroscopic” health the potential to dramatically improve cues. However, the gulf between these patient care. Having the potential to two modes of observation is broad: at the carry out rapid molecular profiling will macroscopic level, we make judgments be a key factor in the development of about the health of those around us on a “personalized medicine”: therapeutic continuous basis just by looking. If I watch strategies and drugs precisely tailored someone doing pull-ups, for example, I can to an individual’s needs. Of course, immediately come to some reasonable similarly dramatic changes in the way conclusions about their overall health. we discover, develop, get regulatory In contrast, I know nothing about their approval for, and prescribe drugs will molecular health: do they have a gene for be the second essential component of a particular kind of cancer? Do they carry the personalized medicine revolution. antibiotic-resistant Staphylococcus aureus (e.g. MRSA) on their skin? Getting at this The road to continuous molecular sort of information currently requires (for monitoring and a personalized the most part) expensive instrumentation medical future: what are the barriers? operated by highly trained personnel – and requires even more highly trained personnel In a previous chapter in this series, I to interpret the results such instrumentation discussed a future in which implanted produces. or ambient sensors were used to Just as critical as the problems monitor - and act on - a person's mentioned above, the complexity of today’s health.1 From a technical perspective, molecular analysis equipment means that many aspects of this scenario (one

version of the technological changes of development are shown in Table described in this chapter) are beginning to 1. In some cases, biomarkers can be come in view, and progress in many areas is macroscopic: for example, obesity occurring at a remarkable pace. It's useful, is a biomarker for heart disease however, to begin to look at the question of and diabetes. Our primary interest what barriers remain (at least in this author’s here, however, is in molecular view) before the personalized medical biomarkers: genetic, protein, and future is a reality. Many of these barriers are small-molecule signatures of disease. societal and regulatory, rather than technical. Each of the tens of thousands of different molecules present in the Scientific hurdles human body is a potential biomarker. Determining which of these alone or One of the primary obstacles in the path in combination correlate usefully with of continuous health monitoring and particular disease states will require personalized medicine is the identification basic biological experimentation on a of biomarkers (in the broadest sense of massive scale. the word) for particular disease states, and pairing these biomarkers with actions that produce a health benefit. A “biomarker”, in its broadest sense, is a biological observable linked to some known (or Table 1: Selected biomarkers, the disease hypothesized) health state. Representative with which they’re associated, and their examples of biomarkers at various stages development status.

Biomarker Type Condition Health Status Reference state Cholesterol Small Elevated Atherosclerosis Validated 2 molecule

p53 gene DNA Mutated Cancer Validated 3

Brca1 DNA Mutated Breat cancer Validated 4

Prostate-specific Protein Elevated Prostate cancer Validated, 5 antigen but (PSA) controversial Survivin Protein Elevated Prostate cancer Candidate 6

Once biomarkers are identified and The combination therapy strategy has validated, the actual therapeutic response even attracted notice as a business needs to be determined as well. That is model. Drug discovery companies to say, a biomarker is only as useful as its such as CombinatorX are examining clinical relevance, or our ability to modify the utility of using mixtures of drugs to therapy based on the biomarker state. The take advantage of drug interactions for Her2/neu story is a particularly successful several indications. example of this idea.7 Breast cancer patients with tumors overexpressing the Her2 Diagnostic hurdles protein, a marker for highly aggressive Of course, before one can prescribe cancer, can now be treated with an antibody a new, biomarker-based “personalized” specifically targeting Her2. This therapeutic therapy, one must be able to detect antibody has dramatically improved the (and in many cases quantitate) that survival of patients with late-stage breast biomarker accurately, sensitively, and cancer. The Her2 story will need to be quickly. Monitoring biomarkers on a repeated hundreds – or thousands – of continuing basis following therapy will times as new biomarkers are discovered be an important health-maintenance and validated. strategy in many instances as well. The possibility of thousands of Development of such technology, biomarkers, with thousands of biomarker- essentially the extension of our senses specific therapeutic agents, brings forward to the molecular level, has been a several questions. One of these is that particular focus of my laboratory and as the number and complexity of different the laboratories of my collaborators inputs increases, how is this to be sorted at the University of Rochester, and out? One therapeutic strategy that's therefore will be discussed in much already attracting notice is the application greater detail below. of "combination therapies". We're mostly familiar with this from the negative Regulatory hurdles perspective (anyone who's taken even Our current method for approving common over-the-counter cold and flu drugs, medical devices, and other remedies is familiar with the idea of drug forms of treatment is incompatible interactions), but combination therapies with a personalized medical future. have become essential in many areas While this is an area that is clearly not of human health. Treatment of HIV, for within this author’s primary expertise, example, routinely employs a number of it is quite clear that carrying out different therapeutic agents simultaneously, full FDA-style clinical trials (Phase a so-called “cocktail” of drugs. As our I, Phase II, Phase III, etc.) is very understanding of biomarkers increases, it is difficult when the available patient likely that the number of therapeutic agents population is small, as will be the needed to be deployed based on what case as increasingly high-resolution those biomarkers tell us will be extensive. molecular disease signatures become

available. Likewise, the financial burdens Addressing the technological and of such studies are untenable even today content front: advances in biosensors for all but the most common conditions. A and diagnostics at the University of foreshadowing of this problem is visible Rochester today in the “orphan drug” field. In the United States, the Orphan Drug Act A crucial aspect of expanding the provides specific protections for companies range and applicability of diagnostic developing therapeutic agents for diseases systems centers on the need to affecting fewer than 200,000 people.8 As produce technologies able to sense personalized medicine becomes a reality, the presence of molecules with molecular signatures may allow every new diagnostic utility. Currently, such therapy to fall within what are now “orphan” sensing methods primarily fall into guidelines, since individualized disease two categories: simple lateral-flow states will be defined with higher and higher tests (the home pregnancy test being resolution. one example), which generally don’t provide much in the way of quantitative Societal issues information, and highly complex A personalized health future implies that systems capable of multiplex analysis. an ever-increasing amount of data will be Both modalities obviously give useful gathered, possibly continuously, about our information, and have been critically health. As in many areas of health research, important in bringing us to the state questions arise regarding how this data of health we enjoy today. However, will be safeguarded, but also how it will be as we move forward, we need to made available to people (researchers? do better. This section will focus regulators? doctors?) who can use it to do in particular on systems able to do the most good. multiplex analysis. This is a concern that in part may resolve A photograph of typical equipment itself through societal changes that have used in modern diagnostic laboratories already begun to happen with respect to is shown in Figure 2. In these systems, personal privacy and data security. Many of a “chip” of some sort bearing a capture us are astounded (and somewhat frightened) molecule specific to the target of by the amount of personal data many interest is treated with a clinical sample people make available on social networking (or alternatively, the clinical sample web sites. Will Bob's table of cancer risk is added to a solution containing factors join pictures of Bob's weekend the capture molecule). The capture keg stand on MySpace or Facebook? It is molecule is typically a DNA sequence possible that people may in the future have (for genetic analysis) or an antibody a comfort level with making this information (for protein analysis). After a period of public that those of us coming to adulthood time to allow molecules in the clinical in a much more privacy-seeking time do not sample to interact with the molecules have. on the surface of the detection chip,

the chip is rinsed to remove materials that does not permit going in to all of do not bind. A primary problem with current these in detail, and therefore we will diagnostic tools is that this does not yet focus on our own work, and that of provide useful information in most cases. our collaborators at the University of Rather, the chip must then be treated with Rochester, as representative examples. a labeled reagent, typically a secondary antibody carrying a fluorescent group or yet Targeting nosocomial infections with another molecule that’s used to capture an the DNA NanoLantern™ enzyme for a colorimetric reaction (DNA is Bacterial infections acquired in typically labeled as part of an amplification hospitals following surgery (nosocomial process that occurs prior to its introduction infections) have become a problem to the chip). It is only after this multi-step of nearly epidemic proportions. Of process that one can actually observe particular concern is the rising fraction whether the capture molecules on the chip of these infections that are resistant bound (captured) anything from the clinical to common antibiotics. Patients who sample. acquire a drug-resistant infection as a result of their hospitalization present a significant cost burden to the health care system, and obviously have to suffer through the burden of a longer hospital stay and more complex therapeutic regimen (let alone the increased possibility of death). The problem is in many Figure 2: “Standard” automated medical diagnostic ways self-reinforcing: patients who equipment. While triumphs of modern technology, exhibit any evidence of a bacterial these systems require expensive reagents to infection are often prescribed broad- operate and extensive operator training. spectrum antibiotics. Overuse of these

antibiotics in turn leads to an increase One way to improve this process is to in resistant bacteria, and therefore develop sensors that respond directly to the patients are prescribed stronger, binding event. We have been pursuing this front-line antibiotics, which leads to goal on several fronts, and have successfully more resistant bacteria…and so on, developed platform technologies allowing in a never-ending cycle. The case of the direct, label-free detection of both Staphylococcus aureus (or “staph”) proteins and DNA. I should note at the is illustrative of the problem. As outset that many other research groups shown in Figure 3, penicillin-resistant world-wide have been pursuing analogous Staphylococcus emerged shortly after goals, and several have developed highly the introduction of penicillin, and the innovative strategies for molecular detection evolutionary pressure provided by that may prove to be useful in the clinical antibiotic use has led to a continuing setting (and eventually at home). Space

escalation in the antibiotics-vs.-bacteria war.9 Vancomycin, once the drug of last resort, is now prescribed much more readily, and as of 2002 cases of vancomycin- resistant Staphylococcus had begun to appear. Unfortunately, a patient with vancomycin-resistant Staphylococcus is rapidly running out of therapeutic options. Figure 4: The DNA NanoLantern™. A hairpin DNA probe molecule bearing a fluorescent group at one end is immobilized on a metal film. When brought into contact with a target DNA sequence, formation of the DNA Figure 3: Timeline for the evolution of antibiotic double-helix causes the fluorescent group resistance in Staphylococcus aureus (data based on to move away from the metal film, allowing Reference 9 and after CDC agency graphics). light to be emitted following excitation with a light source. Right: representative data Guidelines established by the CDC clearly state showing NanoLantern™ signal before and after that surveillance and the development of rapid application of target DNA. diagnostics are critical components of improving our 10 record against drug-resistant bacteria. If an infection The NanoLantern™ system is only as good as is diagnosed more rapidly, and with higher precision the probe DNA sequences it uses, however, (i.e. rather than getting an initial indication of Gram-(-) and so a few years ago we developed a vs. Gram-(+) bacteria, and waiting days to weeks to method for identifying useful DNA probes from find out species and resistance profile via traditional genomic sequences.12 In brief, raw genomic microbiological methods, but instead getting all of sequence information is fed into a computer this information in a matter of hours), doctors can program that predicts how the sequence immediately apply the correct therapy as needed. will fold. This is a complicated problem, as How then can one accomplish this goal? each individual DNA base has many potential Bacteria are defined by their genes, and in pairing partners from which to choose. many cases genetic information encoding common Fortunately, David Mathews and his research mechanisms of resistance are also well known. One group, colleagues of ours at the University of the techniques we have developed over the of Rochester, have developed software tools past several years serves as a platform for rapidly simplifying this part of the process.13 Next, we 11 detecting these genetic signatures. Termed the identify regions of the predicted lowest-energy “DNA NanoLantern™”, this technology relies on two fold that “look like” our DNA hairpin probes. key phenomena: first, a method we have developed This can be done by inspection (as in Figure to identify DNA probes shaped like hairpins for target 5, where candidate hairpins were readily organisms of interest, and second, the ability of metal identifiable in the folded genetic sequence), or films to quench (turn off) fluorescence. The system automatically with software. Candidate hairpin works as follows (Figure 4): a DNA hairpin probe probes are then computationally “excised” immobilized on a metal film (usually gold, but other from the full sequence, re-folded, and their metals work as well) is “off”. No light emits from the predicted energies checked against a set of sensor until target DNA binds to the probe, opening criteria for effective probe characteristics. In up the hairpin, moving the fluorescent group away the case of methicillin-resistant Staphylococcus from the metal surface, and allowing fluorescence to aureus, folding the mecR gene (responsible occur. This conceptually simple method turns out to for the resistance phenotype) yielded a probe work extraordinarily well, providing highly selective molecule subsequently demonstrated to work and sensitive detection of target DNA. effectively with a synthetic DNA target.

bacterial infections, with a particular focus on urinary tract infections (UTI). However, one can envision extension of the NanoLantern™ system beyond infectious disease, to rapid human genetic analysis as well.

MRSA detection. Detection of synthetic DNA served as an effective “proof-of-principle”, but what about detecting actual bacteria? To demonstrate this, PCR was used to amplify the target DNA sequence from cultured MRSA. The Figure 6: A DNA NanoLantern™ microarray. product of the PCR reaction was applied Images are before (left) and after (right) to a NanoLantern™ chip bearing the MRSA addition of target DNA. The dimensions of this array are approximately 90 microns by 90 probe, while in parallel the same process microns, or 0.000012 square inches. was carried out on Staphylococcus aureus lacking the methicillin resistance gene. Monitoring the human immune system As expected, a positive response was with Arrayed Imaging Reflectometry obtained for MRSA, while drug-sensitive The NanoLantern™ system is Staphylococcus gave no signal.14 proving to be exceptionally useful for Moving forward, we can anticipate detecting DNA targets, but what about incorporating arrays of NanoLantern™ probes proteins? Proteins are somewhat into chips able to detect and diagnose a more complicated to detect than broad range of pathogens. Figure 6 shows DNA, for several reasons. First, a preliminary experiment demonstrating there is unfortunately no analog of array capability, with identical spots of the the polymerase chain reaction (PCR), MRSA-targeted probe arrayed using a so amplification of the amount of a BioForce Nano-eNabler. Each spot of this particular protein present in a sample array is roughly 10 microns in diameter, is not possible. As proteins may be making the entire array roughly 100 microns present in serum over a very large on a side (0.1 mm, or somewhat less than range of concentrations (up to 12 the size of the period at the end of this orders of magnitude), this means sentence). Efforts in our laboratory are that detection techniques must have currently centered on the production of high dynamic range as well as high chips able to diagnose a broad range of sensitivity. Second, proteins are much

more fragile than DNA: “rough handling” can In early efforts, we demonstrated that irreversibly degrade them. Third, although AIR could be used for the detection of one can read off proteins from enteropathogenic E. coli, One method under development in validating the platform as a method for our laboratories, termed Arrayed Imaging bacterial detection.16 More recently, Reflectometry, or “AIR”, takes advantage we have extended these efforts to a of the optical and chemical properties broad range of human proteins. We will of silicon, the commodity material of the discuss two examples, as they illustrate microelectronics industry. As shown in the two aspects of how such technology instrument schematic in Figure 7, AIR relies might be useful in the future. on our ability to create an antireflective The human immune system is an coating on the surface of a silicon chip: by extraordinarily complex system. One choosing the proper thickness of silicon aspect of the immune system responds dioxide and capture molecules, we can set quickly and generically to the presence up a condition whereby polarized laser light of external agents, whether bacterial, interacting with the chip at a particular angle viral, or completely inanimate, and is destructively interferes with itself within the also responsible for the inflammatory coating, preventing any light from reflecting response to injury. Proteins produced back off the chip. When a target protein as part of this inflammatory response, binds to the capture molecule on the surface termed cytokines, are in essence an of the chip, that destroys the antireflective amplified response to the presence condition, and light is observed reflecting off of an injury, irritant, or infectious agent the chip. Although conceptually simple, this (among others). These proteins act as method turns out to work exceptionally well.15 signaling molecules to activate other portions of the immune response. Because of their importance as early indicators of inflammation and disease, we tested our AIR protein detection system by preparing a series of cytokine arrays.17 First, antibodies to individual cytokines and other immune Figure 7: Arrayed Imaging Reflectometry system markers were immobilized on (Schematic). Left: The AIR instrument AIR chips, and their ability to detect consists of a few simple optical components target protein in a buffered solution and a CCD camera. Laser light interacting of excess bovine serum albumin (as with an antireflective coating on a chip a simplified analog of what would be (shown at right) undergoes partial reflection found in the complex milieu of human as a function of the amount of target serum) measured. As shown in Figure biomolecules bound to the surface. 8, this experiment was successfully

completed for 11 targets. Importantly, currently resembles a medieval torture detection sensitivity for several targets process. Rather than placing a grid was comparable to that observed using an of antigen scratches on the back of a ELISA assay (the “gold standard” for protein person being tested and waiting for detection, ELISA uses a multistep, labeled an immune response, one would only process analogous to that shown above in need to obtain a small sample of serum Figure 2). Furthermore, cytokine detection from the patient and look for antibodies in doped samples of human serum was binding to an antigen array. found to be straightforward (Figure 8, right). As a first step toward exploring the In combination, these data provided the first utility of the AIR technology for the indication that the AIR technique could serve production of antigen arrays, we have as a suitable method for rapidly detecting carried out preliminary experiments and profiling the concentrations of human using human papillomavirus (HPV) as proteins. a model system. HPV is a widespread infection, and importantly from the perspective of human health is believed to be the primary causative agent of cervical cancer. While estimates vary with regard to the incidence of cervical cancer, many put the rate of new cases world- Figure 8. Array-based detection of cytokines. Left: wide at roughly 500,000. Newly Successful detection of 11 individual cytokines available vaccines show considerable and other immune system proteins with antibody- promise for dropping this number functionalized AIR chips (where “BG” refers to dramatically, but how does one monitor background signal, and “EXP” is the signal produced by the chip in the presence of the target protein in the effectiveness of the vaccine (in a buffered solution of bovine serum albumin). Right: terms of antibody titer) and continue Detection of TNF-alpha and IgG in undiluted human to monitor the virus? To address this serum. question, we have created AIR chips Of course, detection of cytokines provides bearing “virus-like particles” (more on only one measure of the immune system’s that in a moment) from two common response to injury or infection. One can also forms of HPV.18 screen for antibodies produced in response From the purely technical aspect to a particular pathogen. This information is of sensor design, HPV represents a potentially useful as a screening measure particularly interesting challenge to the (for example, if I find a dead crow in my AIR platform. This is because unlike front yard, is it infected with bird flu?), and most of the systems we have worked also as a means of monitoring vaccine with previously, it is not possible to effectiveness. These “antigen arrays” may obtain the HPV coat protein in a stable, also have considerable utility in the field of single-copy form. Rather, this protein allergy testing, dramatically simplifying what self-assembles into a capsule roughly

50 nm in diameter, even in the absence of “traditional” methods of protein any other materials from the virus. These detection. By dramatically simplifying “virus-like particles”, or VLPs, are in fact key the sensing process, we anticipate that elements of the HPV vaccine. However, at sensing methods of this type will prove the outset of our work, it was not at all clear broadly useful. that one could attach such large molecular assemblies to an AIR chip and produce Towards ultrahigh-sensitivity something that would actually function as a biosensors: the two-dimensional sensor. Fortunately, we discovered that it photonic bandgap is indeed possible for chip-tethered VLPs In any scientific field, it is helpful to to function quite well: as shown in Figure define absolutes: zero degrees Kelvin 9, chips bearing VLPs from HPV-11 are able is the absolute minimum temperature; to recognize antibodies to HPV-11 in mouse the speed of light is the absolute ascites fluid, and chips bearing VLPs from upper limit of speed (at least outside HPV-16 are able to recognize antibodies to of science fiction!). For biosensing, the HPV-16. Little cross-reactivity is observed absolute limit of sensitivity is the ability between the two types, suggesting that to detect one copy of a target: one sensors incorporating arrays of different bacterium, one virus, one DNA strand, VLPs will be able to produce highly specific one protein. Several single-molecule patterns of detection with HPV antibodies or single-particle detection schemes have been reported by a number of research groups, suggesting that this “ultimate” goal is in reach. In our case, we have begun exploring the use of two-dimensional photonic bandgap (2DPBG) structures in collaboration with the research groups of Philippe Fauchet and Matt Yates. Conceptually, Figure 9. Left: chip image following treatment with a a 2DPBG confines light to a small 1:200 buffer dilution of mouse ascites fluid containing region of space.19 For example, antibodies to VLP16. The bright spots at the center the 2DPBG shown in Figure 10, indicate positive detection, while other spots serve as controls. Right: Bar graph showing selective constructed in silicon, is roughly one response of anti-HPV11 containing ascites fluid to micron on a side. Confining light within VLP11 AIR chips, and anti-HPV16 containing ascites such a small space allows for detection fluid to VLP16 AIR chips. of extraordinarily small changes in the environment – such as would occur on While considerable development work binding a virus. remains to be done before AIR is a fully automated molecular detection system suitable for hospital, clinic, field, and even home use, the data obtained thus far indicate that it can indeed replace

reality. As that extend our senses to the molecular world, these devices may one day make the early diagnosis of cancer as easy as “looking”. As discussed at the outset of this chapter, however, dramatic advances in basic biomedical research, in the pharmaceutical discovery process, and in regulatory policy are essential to making sure that the information we gain from our new molecular senses is relevant and therapeutically actionable. If this occurs, we will indeed be at the Figure 10: Two-dimensional photonic bandgap dawn of a revolution in health care. sensor. Light is confined within the area of the regular array of “holes” in the silicon; a slightly different-sized hole at the center creates a “defect” in References: the light confinement that shows up as a peak in the [1] Miller, B. L. “Interfacing Biology and optical spectrum. Computing for Health”, in Bushko, Ed. Future of Intelligent and Extelligent Health Environment; Stud. Health Technol. Inform. 2005, 118, 66-78.

[2] Lewington, S.; Whitlock, G.; Clarke, R.; Sherliker, P.; Emberson, J.; Halsey, J.; Qizilbash, N.; Peto, R.; Collins, Figure 11: Optical detection of a single virus-sized latex bead in a 2DPBG. Left: Scanning electron [3] Moreno, C.; Montserrat, E. Blood micrograph (SEM) image of a single latex sphere infiltrated into the center defect of a 2DPBG device. Rev. 2008, 22, 211-219. Right: Optical transmission spectra of the 2DPBG before and after infiltration, showing the shift in the [4] Olopade, O. I.; Grushko, T. A.; primary transmission peak. While acquisition of the Nanda, R.; Huo, D. Clin. Cancer Res. SEM image on the left is arduous and requires very expensive instrumentation, observation of the peak 2008, 14, 7988-7999. shift on the right (as would be used in a diagnostic setting) is relatively straightforward and nearly [5] Vickers, A. J.; Savage, C.; O’Brien, instantaneous. M. F.; Lilja, H. J. Clin. Oncol. 2009, 27, 398-403. Conclusions New methods of biomolecular sensing will [6] Altieri, D. C. Oncogene 2008, 27, serve as important enabling technologies in 6276-6284. bringing truly personalized medicine from the realm of science fiction to everyday

[7] Bazell, R. “Her-2”, Random House, New York, 1998. [17] Mace, C. R.; Striemer, C. C.; Miller, B. L. Biosens. Bioelectron., 2008, 24, [8] Haffner, M. E.; Whitley, J.; Moses, M. Nat. 334-337. Rev. Drug Discov. 2002, 10, 821-825. [18] Mace, C. R.; Rose, R. C.; Miller, B. L. [9] Sievert, D. M.; Boulton, M. L.; Stoltman, G.; Proc. SPIE, 2009, 7167, 71670H. Johnson, D.; Stobierski, M. G.; Downes, F. P.; Somsel, P. A.; Rudrik, J. T.; Brown, W.; Hafeez, [19] Joannopoulos, J. D.; Meade, R. D.; W.; Lundstrom, T.; Flanagan, E.; Johnson, R.; inn, J. N “Photonic Crystals: Molding Mitchell, J.; Chang, S. MMWR Weekly, 2002, the Flow of Light” Princeton University 51, 565-567. Press, Princeton, 1995.

[10] Sievert, D. M.; Rudrik, J. T.; Patel, J. B.; [20] Lee, M. R.; Fauchet, P. M. Optics McDonald, L. C.; Wilkins, M. J.; Hageman, J. Lett. 2007, 32, 3284-3286. C. Clin. Infect. Dis. 2008, 46, 668-674.

[11] a) Du, K; Disney, M. D.; Miller, B. L.; Krauss, T. D. J. Am. Chem. Soc., 2003, 125, 4012; b) Du, K.; Strohsahl, C. M.; Camera, J.; Krauss, T. D.; Miller, B. L. J. Am. Chem. Soc., 2005, 127, 7932-7940; c) Strohsahl, C. M.; Miller, B. L.; Krauss, T. D. Nature Protocols, 2007, 2, 2105- 2110.

[12] Strohsahl, C. M.; Krauss, T. D.; Miller, B. L. Biosens. Bioelectron., 2007, 23, 233-240.

[13] Mathews, D.H., Disney, M.D., Childs, J.L., Schroeder, S.J., Zuker, M., Turner, D.H. Proc. Natl. Acad. Sci. 2004, 101, 7287 – 7792.

[14] Strohsahl, C. M.; Krauss, T. D.; Miller, B. L. Proc. SPIE, 2009, 7167, 71670S

[15] Mace, C. R.; Striemer, C. C.; Miller, B. L. Anal. Chem., 2006, 78, 5578-5583.

16] Horner, S. R.; Mace, C. R.; Rothberg, L. J.; Miller, B. L. Biosens. Bioelectron., 2006, 21, 1659-1663.

Stephen S. Intille, Chapter 28: Designing and Evaluating people connect with friends and Kent Larson / Designing Home-Based, Just-in-Time Supportive family, conduct business, manage and Evaluating Technology resources, learn about the world, Home-Based, Just-in-Time Stephen S. Intille, Ph.D. and maintain health and autonomy as Supportive Technology Director, House_n Consortium, they age. Unfortunately, technologies Technology in “World Health Department of Architecture, Massachusetts that are in the home are typically Strategy” eBook, Institute of Technology, Cambridge, MA, USA developed in isolation, and the general (Ed.) Renata G. Bushko, perception of homeowners is that FHTI, 2016. Kent Larson computer devices are making life Futureofhealth. org - From Director, House_n Consortium, Department more complex and frustrating rather Intelligent and of Architecture, Massachusetts Institute of than easier and more relaxing. People Extelligent Health Technology, Cambridge, MA, USA are wary of the aesthetic, financial, Environments and cognitive challenges of bringing (Ed.) Renata G. Bushko, IOS Abstract new technologies into their homes. Press 2005 t MIT, a multi-disciplinary team of Our multi-disciplinary research team researchers is studying how to create at the Massachusetts Institute of Apervasive computing environments Technology is investigating how the for the home. We are developing home and its related technologies, technologies and design strategies that use products, and services should evolve context-aware sensing to empower people to better meet the opportunities and with information by presenting it at precisely challenges of the future [1]. The “n” in the right time and place. Contrary to many House n represents a variable; we visions of future home environments in the believe there is no single “home of literature, we advocate an approach that the future.” Our focus is on developing uses technology to teach as opposed to design strategies that meet the needs using technology primarily for automated of multiple constituencies. In particular, control. We have constructed a “living we aim to create environments that laboratory” that will provide a unique, flexible are more flexible and that better meet infrastructure for scientifically studying the the physical and cognitive needs of power of pervasive computing for motivating occupants than current environments. learning and behavior change in the home. The spaces we envision seamlessly This facility, called the PlaceLab, is being merge digital information with the used to study technology for creating homes physical environment. Four of the that are supportive. overarching goals of the House n project are to create supportive 1. Changing Places of Living technologies that (1) help people create People spend more time in their homes and customize environments and than in any other space. The home ideally technologies that reflect their unique provides a safe, comfortable environment needs and values, (2) help people in which to relax, communicate, learn, and to live long and healthy lives in their be entertained. Increasingly, it is where homes, (3)

Designing and Evaluating Home-Based, Just-in-Time Supportive Technology 252 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

help people reduce resource consumption, 2. Envisioning Homes of the Future and (4) help people integrate learning into If one is to believe the majority of their everyday activity in the home movies, television, and popular press Our research group is collectively asking articles that mention life in the homes the question, “How can we design spaces of the future, our future homes will with technologies that are more than take care of our every need. Our isolated gadgets, that are easier to use than homes will be so fully automated and today’s technologies, and that provide real “smart” that we will rarely have to think value to people in their homes over long about everyday tasks at all. Nearly all periods of time?” Whenever possible, our of our time in the home will be spent team uses a participatory design approach, engaged in leisure activities because where we involve the stake holders in digital and robotic agents will have the design process. After discussions taken over the mundane chores of with physicians and patients interested in day-to-day life. preventative health care, it became clear Researchers and technologists that the home of the future that would be are more cautious in their predictions, of the most value is one that that does not but a survey of ongoing work still use technology primarily to automatically shows a bias toward creating future control the environment but one that would home environments with the goal of help someone learn how to control the eliminating the need to think about environment. This shift from the “controlling” tasks such as controlling heating and home to the home that is supportive is the lighting, going to the grocery store, focus of this article. cleaning, scheduling home appliances, A byproduct of this shift is that new tools and cooking. Field interviews with are required to study technology in context medical professionals, educators, and of life in the home. Our team has constructed homeowners have led our group in a “living laboratory” to support qualitative a different direction. Simplification or and quantitative studies investigating the elimination of everyday tasks in the relationships between spaces, the behaviors home may be in direct conflict with our of people, and pervasive computing goals of encouraging healthy lifestyles, technologies. This facility, opened in summer resource conservation, and lifelong 2004, is a single family residence with an learning. On the contrary, medical integrated, ubiquitous sensor architecture. professionals suggest that developing This architecture will be used by applications systems that require human effort in to acquire information about context, as ways that keep people as mentally is done in least one existing living lab (i.e. and physically engaged as possible [2]). The laboratory infrastructure will also as they age should be the goal. be used, however, for the quantitative Although there are some instances in measurement and qualitative study of the which we may want to use automation impact of new technologies on the behavior to allow people to accomplish tasks of people actually living in the environment. they can no longer perform on their

Designing and Evaluating Home-Based, Just-in-Time Supportive Technology 253 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

own because of a disability or frailty, our computer-controlled HVAC appliances, primary vision is not one where computer windows, and blinds. technology is ubiquitously and proactively managing the details of the home. 3.1 The automated home Instead, the vision is one where One way to accomplish the goal of computer technology is ever-present but reducing resource consumption is to in a more subtle way – tailored information design a home environment that takes is presented to people at precisely the control of environmental conditions. time and the place when they need it so The home uses a set of optimization that they can learn how to take better care algorithms to simultaneously maximize of themselves, learn how to conserve savings and comfort by automatically resources, or learn about topics that interest controlling the HVAC systems, them. Medical experts tell us that the old windows, and blinds. For instance, on a adage, “use it or lose it,” is applicable to day when the temperature is predicted both physical and mental health as we age. to shift from warm to cool the home We want our pervasive technologies to might determine the optimal cooling empower people with information that helps strategy is to shut down the AC and them make decisions; we do not want to automatically open a set of blinds and strip people of their sense of control, which windows to create an efficient cross has been shown to be psychologically breeze. and physically debilitating [3]. In short, This scenario is relatively simple we are designing pervasive computing compared with other popular “smart environments that do not take over control home” visions. In practice, however, of the environment for the home occupant executing this scenario in an actual as some previous systems have done (e.g. home setting is difficult. The situations [4]) but rather help the home occupant to in which the automatic system might learn how to take control. succeed in optimizing temperature comfort yet fail in “doing the right thing” 3. Control Versus Empowerment: An are many: something noisy is occurring Example outside, someone is smoking outside To illustrate this shift in thinking, consider an the window, someone in the home example. Imagine our goal is to create an is allergic to pollen and the pollen environment that uses pervasive computing count is high, it is raining outside, it is technology to save energy by automatically too quiet for a person reading when controlling the heater-vent-air conditioning the hum of the air conditioner is off, (HVAC) system. We assume that the someone did not want the blinds open environment has embedded sensors that because it throws glare on a computer can infer context such as where people screen, and so on. The system are, what people are doing, and what the designer will be unable to program environmental conditions inside the home common-sense contingency plans for are. We also assume that the home contains all possible contexts, and invariably

Designing and Evaluating Home-Based, Just-in-Time Supportive Technology 254 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

the system will perform in unexpected, indicates that, “it might be a good frustrating, and undesirable ways. idea to open this window right now.” system will actually become less The home thereby non-obtrusively predictable as it acquires more expertise, informs the occupant of actions that and the success of the system some the occupant might take to conserve or most of the time will raise occupant energy or money. A similar approach expectations about what the system is can be taken when the goal is to capable of doing. Inevitably, the system will improve health or introduce learning violate the occupant’s high expectations into everyday life. given the unexplainable “intelligence” the system sometime shows when making these This approach has several advantages control decisions. Because the system is so over proactive control: complex, the occupant will be left feeling • Information can be presented that frustrated – helpless to understand the the occupant can react to without behavior. Why does it keep opening the interrupting ongoing activity in windows when, clearly, the occupant wants potentially irritating ways; this is and needs them closed? Other common especially true if information can scenarios for “smart” automatic control of the be “augmented” onto the physical home suffer from identical problems environment itself using projected light. 3.2 The home that uses subtle reminders Consider an alternative scenario. In this • Leaving the occupant in control of vision of the home of the future, the windows making decisions allows the home include a tiny light that is either embedded to present options based on partial in the window frame (e.g. an LED) or that is information without confusing projected on the window using pervasive the occupant; the occupant will computing display technology (e.g. an IBM naturally consider contexts that the Everywhere Display [6]). This home still home has not and adjust his or her has embedded sensors and optimization actions accordingly. algorithms that compute a strategy for cooling the home by opening a particular set • Algorithms that make suggestions of windows. This home, however, does not can degrade gracefully; algorithms proactively control the home to achieve the that make decisions typically do computed optimal settings. Instead, it uses not. pervasive technologies to teach the home occupant – in a non-obtrusive way – how to • Lack of control over aspects of life achieve the optimal settings. has been shown to diminish health For example, the light on the window [3]; this strategy empowers the will subtly illuminate. It does not interrupt home occupant. the home occupant. When someone in the home notices it, that person knows the light

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The occupant ultimately makes the decision with a control decision made by the whether to open the window. Therefore, home, the user is going to be in a state the task of interpreting the suggestion in of annoyance and primarily interested context rests with the occupant: if it is noisy in counteracting the home’s actions – outside the occupant will simply decide not this is not the best time for the home to open the window, realizing that this is not to present explanatory information to a good time. This is a pervasive computing promote learning. application with an exceptionally simple user A home that leaves the right amount interface. Would a system with such a simple of control to the occupant avoids the interface influence behavior? Yes. Controlled computational challenge of indirectly studies in homes show that using such a inferring occupant intent in order to small, simple light on an AC unit can lead to determine the moment at which to 15% reductions in AC use [7]. teach. The extraordinary power of pervasive computing can come into 3.3 The teaching home and pervasive play when an occupant decides to take information display an action such as opening the window. The example above of the light on the This is a “point of behavior” that can be AC may lead to some behavior change easily identified by detecting a specific but it does so in a way that relies on the event (the opening of the window). technology to be present. Fortunately, The occupant has already made a pervasive computing can be used to not decision to stop whatever he or she only motivate the behavior but to teach at was doing to do a recommended task. the moment when the behavior is being The home can safely infer directly undertaken. from sensor data that the occupant is Systems that automatically make control opening the window and therefore is decisions generally miss this opportunity. likely to be receptive to information Occupants can become complacent if the that helps him or her determine how system is functioning perfectly. Although to do so. The occupant is also likely a computer system might try to present to be curious about why the home is the occupant with educational messages making this recommendation. Finally, to explain the actions it is taking, to do the occupant will have moved to the this without interrupting and irritating the physical location of the object, which occupant is a challenge. The system must presents a good opportunity to teach compute when a reasonable time to present by overlaying digital information on the information might be. Even for relatively the physical space. In this scenario, simple help applications this has proven to at precisely the moment when the be difficult to do (e.g. ClipIt, the Microsoft system determines that the occupant Paperclip attempts just-in-time help but does has decided to take action, information so in ways that often requires the occupant can be overlaid on the real world to to divert attention from the current task). On educate the occupant about how to the other hand, if an occupant is unhappy create the most effective cross breeze.

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Even if the occupant does not have time cooling to occur; understanding the to stop and study information, it is possible best times and places to establish to present feedback that results in learning. intake air; knowing how to use fans to For example, as the window is opened, facilitate cross-breeze cooling. These information might be projected onto the are things that most people do not nearby wall that estimates the magnitude know how to do because there is no of the breeze to be created. The person one to instruct them on how to do it may notice that, counter-intuitively, opening when they are in need of guidance the window further does not always result at the point of behavior. Presentation in a stronger cross breeze. The occupant’s of information at the point of behavior task has not been interrupted, so even if the by a pervasive computing system occupant is completely uninterested in the can fill this need. The challenge then information, no attentional disruption has becomes to develop algorithms been created. Immediately after the point of that can recognize the right time action the information could be removed. and select a presentation strategy It is the potential impact on behavior of suitable for the given context. We this non-intrusive, “just-in-time” learning that have been conducting small user our group is studying. We are interested in studies with mockup displays and three points in time: the point of decision, the are now implementing prototypes point of behavior, and point of consequence of some of the examples. Figure 1a [8]. How can we use computers to educate shows a display that might appear on people about how to take control of a wearable PDA or projected near their environment by using sensors to the window at the moment a person automatically detect these specific (and is opening or closing a window: the sometimes fleeting) moments in time? In “teachable moment.” An open question this particular example, as the occupant that we plan to explore is how the occasionally follows the recommendation way that information is presented of the home he or she will gradually learn and the current context influences how to efficiently control the temperature the persuasive impact of educational in the environment in sophisticated ways. messages. Occupants will understand that the reason the lights appear on their windows is because it is cool enough outside to setup a cross breeze. They will also gradually learn how to create a cross breeze given the geometry of their house and the prevalent wind direction: using window inlets and outlets that maximize cooling through the home; understanding how to open window inlets and outlets to maximize air flow; understanding how long it will take for

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closed to encourage awareness of energy conservation. People who are informed that their behavior is out of line with community standards will often naturally change their activity; in this case a greater awareness of the need to keep the door shut may result.

4. Design of the PlaceLab: A Living Laboratory The shift in focus from creating automatic (“smart”) environments to Figure 1. (a) This image shows a message that might environments that help the occupant be displayed within eyesight of a person just as that person opens a window in order to help that person learn how to take self control impacts learn how to conserve energy. (b) This message not only the type of technology we could be displayed on the refrigerator or on a are designing but also our outlook wearable wrist computer just as someone closes the on how we must conduct research to refrigerator door. evaluate our work. We could construct An important consequence of using a mockup space that simulates a pervasive computing technology for just-in- home and then show that in particular time teaching rather than control is that the situations the home can automatically information people learn in that environment control the physical and digital will transfer to other environments environments. Several of the pervasive where there is no computer technology. computing environments built in the Additionally, the just-in-time teaching last several years have or are doing scenario may still use automatic control of just that (e.g. [4], [2], [9]), and we have the windows but in a way that encourages our own test environment. people to use their physical abilities: a However, pervasive environments young healthy person would be encouraged that help people learn how to take (using pervasive computing messaging) to to take control themselves cannot exercise muscles by opening the window, be evaluated independently of the whereas a frail, elderly person who cannot people using them. We need to study lift the window would be encouraged to the people using the technology in go to the window and push a real or virtual realistic, non-laboratory settings for automatic button. We are also studying how long periods of time and then measure to present persuasive, pervasive messaging whether our interventions are leading to motivate small behavior changes during to learning and behavior change. everyday activities. For instance, Figure 1b To meet this need, we have shows a message that could be displayed designed and built an apartment-scale on a refrigerator door (or on a wearable residential observational facility called wrist computer) just after the door has been the PlaceLab, an MIT and TIAX, LLC

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initiative. The PlaceLab serves as a “living While they occupy the facility, a rich laboratory” to study how people respond dataset is collected on the behavior to new technologies. The facility is located of the subjects. Researchers have a few blocks from MIT in a residential the capability to monitor nearly every condominium building, and it opened in July aspect of life in the home, particularly 2004. The 1000 square foot lab consists what people are doing and the of a living room, dining area, kitchen, small interior and exterior environmental office, bedroom, full bath and half bath. This conditions in the space. Tools for the facility serves two primary functions: (1) to semi-automatic annotation and pruning provide an environment in which life in the of data aid researchers in studying home can be scientifically studied, and (2) to the enormous amounts of data that provide a means for evaluating whether new are acquired daily by the laboratory. types of pervasive computing interventions A suite of portable tools have also have a long-term and meaningful impact on been developed that supplement the behavior in the home, especially behavior capabilities of the PlaceLab and permit related to health and well-being. studies where subjects are monitored in their own homes before and/or after 4.1 Ubiquitous sensing they enter the PlaceLab, permitting The PlaceLab uses a cabinet-based studies that investigate pre- and post- integrated interior infill system [10]. Despite occupancy behavior changes. ubiquitous sensing technology, the Place- The facility is managed as a multi- Lab looks like a nicely designed home to disciplinary shared scientific tool the resident without any visible technologies in the tradition of other scientific other than standard home electronics. facilities developed to study unique Embedded within each cabinet in the environments such as telescopes, microscopes, and undersea vessels. PlaceLab is a suite of sensors, as marked on Researchers from many fields can Figure 2b. The sensors in the PlaceLab are submit proposals to a multi-disciplinary used for two purposes: (1) the development review board. These proposals are of algorithms that infer what people are reviewed and ranked. High quality doing from sensor data, and (2) observation proposals are those that (1) can only be of activity in the space for research accomplished with the unique facilities purposes. The PlaceLab is not intended to of the PlaceLab, (2) will fundamentally be a demonstration “home of the future.” increase scientific understanding of Instead it is a laboratory to study people in issues related to life in the home, and (3) consider the long-term the home setting. implications of the technology, system, or architecture being studied and 4.2 Using the PlaceLab potential to create societal change. The PlaceLab is occupied by volunteer As in existing telescope facilities, subjects who agree live in the home complimentary and non-interfering for periods of days, weeks, or months, studies are piggybacked to fill the depending upon the studies being run. facility calendar.

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Figure 2. (a) Kitchen of the PlaceLab. Each cabinet contains a sensor infrastructure. (b) Living room of the PlaceLab. (c) Locations of some of the sensors built into a typical cabinet

The PlaceLab is already being used to To do so, we are developing tools investigate questions such as, (1) What that will use the Place-Lab’s sensing influences the behavior of people in their infrastructure to acquire and semi- homes? (2) How can technology be effective automatically annotate data of interest in the home context for long time periods?, to researchers. (3) Can technology and architectural design The infrastructure of the PlaceLab motivate life-extending behavior changes?, has been designed so that video, and (4) What new innovations for the home audio, and appliance-level data would most fundamentally alter the way can be continuously acquired from we live our everyday lives? In summary, every part of the environment. For the PlaceLab is a multi-disciplinary, shared instance, the PlaceLab permits a research facility for the study of people researcher studying eating behaviors and their relationship with their living to make a request such as, “I’d like environments. to see all the video and audio data of activity in rooms just before and 4.3 Studying life in the home and physical/ after a subject opens a cabinet or digital interactions appliance that relates to food storage Relatively little research has been done on or consumption.” The researcher the relationship between the home and can collect and identify only the technology given the importance of the small subset of data relevant to that home in life [11]. We are using the PlaceLab’s researcher’s study. An algorithm ubiquitous sensing for the quantitative and developer can use the PlaceLab qualitative study of human behavior in the to acquire probabilistic data about home – with and without new technologies. the movement of people around

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environments throughout typical days. The such as the Hawthorne effect must be lab provides an excellent resource with carefully addressed. However, our which to study how certain technologies discussions with researchers in fields disrupt activity in the home [5]. The as disparate as preventative medicine combination of sensor data and audio- and product development have led video recording (e.g. [12]) creates a powerful us to believe the PlaceLab will enable tool set for the researcher interested in studies that can take place in no other evaluating technology designed for the way. home with people actually living in a home. For instance, we have built a prototype system that uses a PDA 4.4 Measuring effectiveness of device and context recognition (in this applications case location within the environment The last function of the PlaceLab is to and proximity to large objects) to allow for the evaluation of certain types monitor for the onset of congestive of pervasive computing applications. We heart failure (CHF) [13]. The software are particularly interested in studying how uses a Bayesian framework not only to context impacts the presentation and integrate evidence for CHF onset but motivational impact of information presented to select meaningful questions to ask in the home environment over long intervals a person in a home given the context. of time. Cameras monitor the environment The PlaceLab has being designed so and detect contextual cues (e.g. in that pervasive com-putting applications that the kitchen, at the desk). A diagnosis present digital messages at the right time system pools evidence acquired over and place can be created without substantial the last month and, at any moment, amounts of system engineering. Our goal can determine which question that is not to develop new sensors for every is appropriate for the given context situation but to investigate what can be will yield the most valuable evidence. accomplished with a given set of ubiquitous The home occupant carries a.PDA sensors that could be realistically retrofitted device. Whenever the person pulls it into existing living environments. out to use it, a simple question may be Our group consulted with researchers displayed that is meaningful given the in a diverse set of fields as we developed occupant’s current context. The person the Placelab. Our goal has been to design quickly clicks one multiple-choice a facility and infrastructure that leads to answer with almost no interruption verifiable and quantifiable advances in to the intended task. Meanwhile, the understanding how to use pervasive system adds this new evidence to the computing in homes by measuring the preventative diagnosis information. impact of a set of implemented examples. If the system detects a progression Studies run in this lab have a limited sample towards CHF onset, the person or a size (i.e. one house and a small set of long- medical monitoring service can be term occupants), and experimental problems notified.

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Will systems that present motivational to new technologies and design information and ac-quire data for strategies. We invite researchers who preventative diagnosis such as our CHF may be interested in using this shared system work when placed in the complex scientific tool in their own work to environment of the home? Why or why contact us. not and to what degree? How does context impact the way the information is Acknowledgements received and attended to? This is the type The ideas presented here benefited of investigation we, along with our other greatly from discussions with Chuck collaborators, foresee occurring in the Kukla and Dan Carlin. The PlaceLab PlaceLab. The experimental protocols that is a collab-oration between MIT and may be used differ based on the problems TIAX, LLC. being studied. Our goal has been to design a tool that allows researchers from a variety References of disciplines to design and execute studies [1] House n, “Changing Places / House that cannot be accomplished without the n: MIT Home of the Future Consor- home’s ubiquitous sensing infrastructure. tium,” Access date: April 15 2002, http:// One of the computer science challenges architecture.mit.edu/house n. is to enhance the sensor infrastructure so it [2] C. Kidd, R. Orr, G. Abowd, C. can support more advanced event detection Atkeson, I. Essa, B. MacIntyre, E. over time. Mynatt, T. Starner, and W. Newstetter, “The Aware Home: A living laboratory 5. Summary for ubiquitous computing research,” We are interested in creating design in Proceedings of the Second strategies for environments that use International Workshop on Cooperative pervasive displays and context-aware Buildings - CoBuild’99, 1999. sensing to empower people with information [3] J. Rodin and E. Langer, “Long- presented at precisely the right time and term effects of a control-relevant place. Unlike many other visions for future intervention with the institutionalized home environments, we advocate an aged,” Journal of Personality and approach that uses technology primarily to Social Psychology, vol. 35, no. 12, pp. teach as opposed to only for automated 897–902, 1977. control. Therefore, we are developing new [4] M. Mozer, “The Neural Network technologies but also new tools that permit House: an environment that adapts to us to evaluate our technology interventions its inhabitants,” in Proceedings of the in natural settings. AAAI Spring Symposium on Intelligent We have designed and built the Environments, ser. Technical Report PlaceLab, an MIT and TIAX, LLC initiative. SS-98-02. Menlo Park, CA: AAAI Press, The PlaceLab is a flexible, sensor-rich 1998, pp. 110–114. residential research facility that enables researchers to study how people respond

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[5] W. Edwards and R. Grinter, “At Home with [13] S. Intille, K. Larson, and C. Kukla, Ubiquitous Computing: Seven Challenges,” “Just-in-time context-sensitive in Proceedings of the Conference on questioning for preventative health Ubiquitous Computing, 2001, pp. 256–272. care,” in Proceedings of the AAAI 2002 [6] C. Pinhanez, “The Everywhere Displays Workshop on Automation as Caregiver: Projector: A device to create ubiquitous The Role of Intelligent Technology in graphical interfaces,” in Proceedings of the Elder Care, ser. AAAI Technical Report Conference on Ubiquitous Computing, ser. WS-02-02. Menlo Park, CA: AAAI LNCS 2201, G. Abowd, B. Brumitt, and S. Press, 2002. Shafer, Eds. Berlin Heidelberg: Springer- Verlag, 2001, pp. 315–331. [7] C. Seligman, L. Becker, and J. Darley, “Behavioral approaches to residential energy conservation,” Energy and Building, vol. 1, pp. 325–337, 1978. [8] B. Fogg, “Persuasive technologies and netsmart devices,” in Information Appliances and Beyond, E. Bergman, Ed., 2000, pp. 335–360. [9] M. Coen, “Design principles for intelligent environments,” in Proceedings of the Fifteenth National Conference on Artificial Intelligence. AAAI Press, 1998. [10] K. Larson, “Places of Living: Integrated Components for Mass Customization,” Massachusetts Institute of Technology,” Changing Places Technical Report, March 2002. [11] D. Hindus, “The importance of homes in technology research,” in Proceedings of the Second International Workshop on Cooperative Buildings- CoBuild’99, V. Hartkopf, N. Streitz, J. Siegel, and S. Konomi, Eds., 1999. [12] S. Intille, C. Kukla, and X. Ma, “Eliciting user preferences using image-based experience sampling and reflection,” in Proceedings of the CHI’02 Extended Abstracts on Human Factors in Computing Systems. New York, NY: ACM Press, 2002, pp. 738–739.

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Robert A. Freitas Chapter 29: The Future of about to enter a golden new era," / The Future of Nanofabrication Nanofabrication and Molecular Scale announced Richard E. Smalley, winner and Molecular Devices in Nanomedicine of the 1996 Nobel Prize in Chemistry, Scale Devices in Nanomedicine Robert A. Freitas Jr. in recent Congressional testimony in World Health Research Scientist, Zyvex Corp. [1]. On June 22, 1999, Smalley Strategy” eBook, www. spoke in support of a new National Futureofhealth. Abstract Nanotechnology Initiative before the org (Ed.) Renata G. Bushko, FHTI, anotechnology is engineering and Subcommittee on Basic Research of 2016. Chapter manufacturing at the molecular the U.S. House Science Committee from Intelligent and Extelligent scale, and the application in Washington, DC. "We are about to Health N of nanotechnology to medicine is be able to build things that work on Environment (Ed.) Renata G. called nanomedicine. Nanomedicine the smallest possible length scales, Bushko, IOS subsumes three mutually overlapping and atom by atom," Smalley said. "Over Press 2005 progressively more powerful molecular the past century we have learned technologies. First, nanoscale-structured about the workings of biological materials and devices that can be nanomachines to an incredible level fabricated today hold great promise for of detail, and the benefits of this advanced diagnostics and biosensors, knowledge are beginning to be felt targeted drug delivery and smart drugs, in medicine. In coming decades we and immunoisolation therapies. Second, will learn to modify and adapt this biotechnology offers the benefits of machinery to extend the quality and molecular medicine via genomics, length of life." Smalley founded the proteomics, and artificial engineered Center for Nanoscale Science and microbes. Third, in the longer term, Technology at Rice University in Texas molecular machine systems and medical in 1996. But he became personally nanorobots will allow instant pathogen interested in the medical applications diagnosis and extermination, chromosome of nanotechnology in 1999, after he replacement and individual cell surgery was diagnosed with a type of non- in vivo, and the efficient augmentation Hodgkin's lymphoma (the same sort and improvement of natural physiological that killed King Hussein of Jordan). function. Current research is exploring the Smalley then endured an apparently fabrication of designed nanostructures, successful course of chemotherapy nanoactuators and nanomotors, microscopic that caused all the hair on his head to energy sources, and nanocomputers at fall out. the molecular scale, along with the means "Twenty years ago," Smalley to assemble them into larger systems, continued, "without even this crude economically and in great numbers. chemotherapy I would already be dead. But twenty years from now, 1. Nanotechnology and Nanomedicine I am confident we will no longer "There is a growing sense in the scientific have to use this blunt tool. By then, and technical community that we are nanotechnology will have given us

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specially engineered drugs which are said -- to locate medical problems. In nanoscale cancer-seeking missiles, a February 2000, John Hopcroft, dean of molecular technology that specifically targets the College of Engineering at Cornell just the mutant cancer cells in the human University, announced plans for a new body, and leaves everything else blissfully 150,000-square-foot nanotechnology alone. To do this, these drug molecules research center. The facility already will have to be big enough -- thousands of has $12 million per year of earmarked atoms -- so that we can code the information funding and is expected to support into them of where they should go and what 90 local jobs and approximately 110 they should kill. They will be examples of graduate students. "The implications an exquisite, human-made nanotechnology of this research are enormous," of the future. I may not live to see it. But, Hopcroft asserted, and include "the with your help, I am confident it will happen. development of mechanical devices Cancer -- at least the type that I have -- will that can fight disease within the human be a thing of the past." body. The term "nanotechnology" generally In May 2000, the National Cancer refers to engineering and manufacturing at Institute signed an agreement with the molecular or nanometer length scale. (A NASA, the U.S. space agency, to study nanometer is one-billionth of a meter, about the medical potential of nanoparticles. the width of 6 bonded carbon atoms.) The Nanoscience has also attracted the field is experiencing an explosion of interest. attention of the U.S. National Institutes Nanotechnology is so promising that the U.S. of Health (NIH), which hosted one President, in his January 2000 State-of-the- of the first nanotechnology and Union speech, announced that he would biomedicine conferences in June seek $475 million for nanotechnology R&D 2000. In July, the National Science via the National Nanotechnology Initiative, Foundation (NSF) announced a effectively doubling federal nanotech Nanoscale Science and Engineering funding for FY2001. The President never Initiative to provide an estimated $74 referred to "nanotechnology" by name, but million in funding for nanotechnology he gushed about its capabilities, marveling research. Northwestern University in at a technology that will someday produce Evanston, Illinois will spend $30 million "molecular computers the size of a tear on a new nanofabrication facility of drop with the power of today's fastest its own, joining existing operations supercomputers." such as the Stanford Nanofabrication After the President's speech, Walter Facility (started in 1985 with $15 million Finkelstein, president and CEO of NanoFab of backing from 20 industrial sponsors) Inc. in Columbia, MD, agreed that it was and the Cornell Nanofabrication conceivable that the technology could Facility, expected to attract 450 be used to develop computers chips so researchers in 2000, half of them small that they could be injected into the visiting scientists. Cornell is spending bloodstream -- "Fantastic Voyage-like," he $50 million on a new building for the

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Facility, and has just won a $20 million, five- nanotechnology, using nanostructured year grant from the NSF to operate a new materials, are already being tested in a nanobiotechnology center which will make wide variety of potential diagnostic and nanoscale tools available to biologists. therapeutic areas. Burgeoning interest in the medical applications of nanotechnology has led 2.1 Tagged Nanoparticles to the emergence of a new field called For example, fluorescent tags are nanomedicine [2, 3]. Most broadly, commonplace in medicine and biology, nanomedicine is the process of diagnosing, found in everything from HIV tests treating, and preventing disease and to experiments that image the inner traumatic injury, of relieving pain, and of functions of cells. But different dye preserving and improving human health, molecules must be used for each color, using molecular tools and molecular color-matched lasers are needed to knowledge of the human body. get each dye to fluoresce, and dye It is most useful to regard the emerging colors tend to bleed together and field of nanomedicine as a set of three fade quickly after one use. "Quantum mutually overlapping and progressively dot" nanocrystals have none of more powerful technologies. First, in the these shortcomings. These dots are relatively near term, nanomedicine can tiny particles measuring only a few address many important medical problems nanometers across, about the same by using nanoscale-structured materials size as a protein molecule or a short that can be manufactured today. This sequence of DNA. They come in a includes the interaction of nanostructured nearly unlimited palette of sharply- materials with biological systems -- in defined colors, can be excited to June 2000, the first 12 Ph.D. candidates fluorescence with white light, and can in "nanobiotechnology" began laboratory be linked to biomolecules to form work at Cornell University. Second, over the long-lived sensitive probes to identify next 5-10 years, biotechnology will make specific compounds. They can track possible even more remarkable advances biological events by simultaneously in molecular medicine and biobotics tagging each biological component (microbiological robots), some of which are (e.g., different proteins or DNA already on the drawing boards. Third, in the sequences) with nanodots of a specific longer term, perhaps 10-20 years from today, color. the earliest molecular machine systems Quantum Dot [4], the manufacturer, and nanorobots may join the medical believes this kind of flexibility could armamentarium, finally giving physicians the offer a cheap and easy way to screen most potent tools imaginable to conquer a blood sample for the presence of a human disease, ill-health, and suffering number of different viruses at the same time. It could also give physicians 2. Medical Nanomaterials a fast diagnostic tool to detect, say, The initial medical applications of the presence of a particular set of

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proteins that strongly indicates a person and assays, and in biosensors and is having a heart attack. On the research chemosensors, because such surfaces front, the ability to simultaneously tag will selectively adsorb from solution multiple biomolecules both on and inside only the specific protein whose cells could allow scientists to watch the complementary shape has been complex cellular changes and events imprinted, and only at the specific associated with disease, providing valuable place on the surface where the shape clues for the development of future is imprinted. The RESIST Group at the pharmaceuticals and therapeutics. In mid- Welsh School of Pharmacy at Cardiff 2000, Genentech began evaluating the dots University [7] and others have looked for commercial utility in a variety of cellular at how molecularly imprinted polymers and molecular assays. A related technology could be medically useful in clinical called PEBBLES (Probes Encapsulated applications such as controlled drug by Biologically Localized Embedding) release, drug monitoring devices, [5], pioneered by Raoul Kopelman at the and biological and antibody receptor University of Michigan, allows dye-tagged mimics. nanoparticles to be inserted into living cells to monitor metabolism or disease conditions. 2.3 Dendrimers Dendrimers represent yet another 2.2 Artificial Molecular Receptors nanostructured material that may soon Another early goal of nanomedicine is to find its way into medical therapeutics. study how biological molecular receptors Starburst dendrimers are tree-shaped work, and then to build artificial binding synthetic molecules with a regular sites on a made-to-order basis to achieve branching structure emanating specific medical results. Buddy D. Ratner outward from a core. Dendrimers at the University of Washington in Seattle form nanometer by nanometer, so has researched the engineering of polymer the number of synthetic steps or surfaces containing arrays of artificial "generations" dictates the exact size of receptors. In a recent series of experiments the particles in a batch. Each molecule [6], Ratner and his colleagues used a new is typically a few nanometers wide but radiofrequency-plasma glow-discharge some have been constructed up to 30 process to imprint a polysaccharide-like film nanometers wide, incorporating more with nanometer-sized pits in the shape of than 100,000 atoms. The peripheral such biologically useful protein molecules as layer of the dendrimer particle can albumin (the most common blood protein), be made to form a dense field of fibrinogen (a clotting protein), lysozyme and molecular groups that serve as hooks ribonuclease (two important enzymes), and for attaching other useful molecules, immunoglobulin (antibodies). Each protein such as DNA, which hunker down type sticks only to a pit with the shape of that amongst the outermost branches. protein. Ratner's engineered surfaces may In 1998, James R. Baker Jr. co- be used for quick biochemical separations founded the Center for Biologic

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Nanotechnology at the University of Kyoto University, who has designed Michigan to bring together doctors, medical a novel drug molecule that releases researchers, chemists and engineers to antibiotic only in the presence of pursue the use of dendrimers as a safer an infection [11]. Suzuki started with and more effective genetic therapy agent the common antibiotic molecule [8]. For Baker, these nanostructures are gentamicin and bound it to a hydrogel attractive because they can sneak DNA into using a newly developed peptide cells while avoiding triggering an immune linker. The linker can be cleaved by response, unlike viral vectors commonly a proteinase enzyme manufactured employed today for transfection. The by Pseudomonas aeruginosa, a dendrimer molecule is decorated with Gram-negative bacillus that causes specific snippets of DNA, then injected into inflammation and urinary tract infection, biological tissue. Upon encountering a living folliculitis, and otitis externa in humans. cell, dendrimers of a certain size trigger a Tests on rats show that when the process called endocytosis in which the hydrogel is applied to a wound site, cell's outermost membrane deforms into a the antibiotic is not released if no tiny bubble, or vesicle. The vesicle encloses P. aeruginosa bacteria are present. the dendrimer which is then admitted into But if any bacteria of this type are the cell's interior. Once inside, the DNA is present, then the proteolytic enzyme released and migrates to the nucleus where that the microbes naturally produce it becomes part of the cell's genome. The cleaves the linker and the gentamicin technique has been tested on a variety of is released, killing the bacteria. "If the mammalian cell types [9], and Baker hopes proteinase specific to each bacterium to begin clinical human trials of dendrimer [species] can be used for the signal," gene therapy in 2001. Donald Tomalia, writes Suzuki, "different spectra of another co-founder of the Center for antibiotics could be released from the Biologic Nanotechnology, recently reported same dressing material, depending on using glycodendrimer "nanodecoys" to trap the strain of bacterium." This specificity and deactivate influenza virus particles [10]. of action is highly desirable because The glycodendrimers present a surface the indiscriminate prophylactic use that mimics the sialic acid groups normally of antibiotics is associated with found in the mammalian cell membrane, the emergence of strains of drug- causing virus particles to adhere to the resistant bacteria, and most antibiotics outer branches of the decoys instead of the apparently have at least some toxicity natural cells. for human fibroblasts. Immunotoxins are another class 2.4 Smart Drugs of smart drugs, in this case activating Medical nanomaterials also may include only in the presence of cancer cells. "smart drugs" that become medically active An immunotoxin molecule is an only in specific circumstances. A good engineered hybrid of functional protein example is provided by Yoshihisa Suzuki at modules fabricated from two different

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 268 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

types of proteins: a toxin and an antibody. University of California at Berkeley Toxin proteins are normally produced employed bulk micromachining to and released by infectious bacteria. The fabricate tiny cell-containing chambers protein binds to the surface of a host cell, within single crystalline silicon wafers. penetrates it, and kills it. Toxin molecules The chambers interface with the are so potent that just a few of them can kill surrounding biological environment a cell. Antibodies are proteins produced through polycrystalline silicon filter by the immune system to recognize and membranes which are micromachined bind to specific foreign materials. An to present a high density of uniform immunotoxin molecule is made by fusing nanopores as small as 20 nanometers a part of the gene encoding a toxin with in diameter. These pores are large a part of the gene encoding an antibody enough to allow small molecules that recognizes surface features on cancer such as oxygen, glucose, and insulin cells. This creates a novel gene that can to pass, but are small enough to be used to express a new synthetic protein impede the passage of much larger molecule. This new molecule will bind immune system molecules such as only to a cancer cell (via a module from the immunoglobulins and graft-borne virus antibody protein), then penetrate it and kill it particles. Safely ensconced behind (via modules from the toxin protein). The first this artificial barrier, immunoisolated experiments with mice showed that these encapsulated rat pancreatic cells may engineered proteins successfully eliminated receive nutrients and remain healthy certain tumors. Then early in 2000, National for weeks, happily secreting insulin Cancer Institute researchers confirmed that back out through the pores, while an immunotoxin made from a truncated form the immune system remains blissfully of Pseudomonas exotoxin was cytotoxic to unaware of the foreign cells which it malignant B-cells taken from patients with would normally attack and reject. hairy cell leukemia [12]. A second clinic trial Ferrari believes that microcapsules at the Universitaet zu Koeln in Germany containing replacement islets of also found that a ricin-based immunotoxin Langerhans cells -- most likely had moderate efficacy against Hodgkin's easily-harvested piglet islet cells lymphoma in some patients [13]. -- could be implanted beneath the skin of some diabetes patients. This 2.5 Nanopore Immunoisolation Devices could temporarily restore the body's Mauro Ferrari, director of the Biomedical delicate glucose control feedback Engineering Center at Ohio State University loop without the need for powerful and chairman of the BioMEMS Consortium immunosuppressants that can on Medical Therapeutics, has created what leave the patient at serious risk for could be considered one of the earliest infection. Supplying encapsulated therapeutically useful nanomedical devices new cells to the body could also [14]. Ferrari and his collaborators at the be a valuable way to treat other Biomedical Microdevices Center at the enzyme or hormone deficiency

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 269 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

diseases, including encapsulated neurons of a living cell [17]. As early as 1996, which could be implanted in the brain and the researchers had determined that then be electrically stimulated to release the individual nucleotides comprising neurotransmitters, possibly as part of a future the polynucleotide strands must be treatment for Alzheimer's or Parkinson's passing single-file through the 2.6 diseases. nanometer-wide nanopore, and that changes in ionic current could be used 2.6 Nanopore Sensors and DNA to measure polymer length. By 1998, Sequencing Branton had shown that the nanopore The flow of materials through nanopores could be used to rapidly discriminate can also be externally regulated. The first between pyrimidine and purine artificial voltage-gated molecular nanosieve segments (the two types of nucleotide was fabricated by Charles R. Martin and bases) along a single RNA molecule. colleagues [15] at Colorado State University In 2000, the scientists demonstrated in 1995. Martin's membrane contains an the ability to distinguish between array of cylindrical gold nanotubules with DNA chains of similar length and inside diameters as small as 1.6 nanometers. composition that differ only in base pair When the tubules are positively charged, sequence. A similar research effort positive ions are excluded and only negative at the University of California at Santa ions are transported through the membrane. Cruz has produced nanopore devices When the membrane receives a negative with read rates potentially up to 1000 voltage, only positive ions can pass. Future bases per second [18]. Because similar nanodevices may combine voltage nanopores can rapidly discriminate gating with pore size, shape, and charge and characterize DNA polymers at low constraints to achieve precise control of copy number, future refinements of this ion transport with significant molecular experimental approach may eventually specificity. In 1997, an exquisitely sensitive provide a low-cost high-throughput ion channel switch biosensor was built by an method for very rapid genome Australian research group [16]. The scientists sequencing. estimated that their sensor could detect a minute change in chemical concentration 3. Biotechnology Devices equivalent to a single sugar cube tossed Biotechnology originally contemplated into Sidney harbor, or roughly one part in a the application of biological systems billion billion. and organisms to technical and Daniel Branton at Harvard University industrial processes, but in recent has conducted an ongoing series of times the field has expanded to experiments using an electric field to include genetic engineering and drive a variety of RNA and DNA polymers the emerging fields of genomics, through the central nanopore of an alpha- proteomics, transcriptomics, gene hemolysin protein channel mounted in a chips, artificial chromosomes, and lipid bilayer similar to the outer membrane even biobotics. Biotechnology now

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 270 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

takes as its ultimate goal no less than the in 2000 using clinical dosages. The engineering of all biological systems, even next step would be to add genes to completely designed organic living systems, the bacterium to produce anticancer using biological instrumentalities or "wet" proteins that can shrink tumors, or to nanotechnology. There are many good modify the bacteria to deliver various summaries of biotechnology elsewhere, enzymes, genes, or prodrugs for tumor so here we focus on efforts to engineer cell growth regulation. natural nanomachines to create new cellular In 1998, Glen Evans, then at the devices. University of Texas Southwestern During the 1990s, bioengineered viruses Medical Center, described the possible of various types and certain other vectors construction of synthetic genomes routinely were being used in experimental and artificial organisms. His proposed genetic therapies as "devices" to target strategy involved determining or and penetrate certain cell populations, designing the DNA sequence for the with the objective of inserting therapeutic genome, synthesizing and assembling DNA sequences into the nuclei of the genome, then introducing the human target cells in vivo. Retrovirally- synthetic DNA into an enucleated altered lymphocytes (T cells) began to pluripotent host cell to create an be injected into humans for therapeutic artificial organism. Genome engineers purposes. Another example was the use, could modify an existing microbe by Neurotech (Paris), of genetically modified by adding a biochemical pathway cerebral endothelial cell vectors to attack borrowed from other organisms, glioblastoma. This was the first therapeutic though this remains a difficult task use of genetically engineered endothelial because tailoring an existing system cells in humans; Phase I/II clinical studies to match unique requirements were underway in 2000. demands detailed knowledge about Engineered bacteria were also being the pathway. But ultimately, says pursued by Vion Pharmaceuticals in Adam P. Arkin at Lawrence Berkeley collaboration with Yale University. In their National Laboratory, "we want to learn "Tumor Amplified Protein Expression to program cells the same way we Therapy" program [19], antibiotic-sensitive program computers." Some genome Salmonella typhimurium (food poisoning) engineers have started by building bacteria were attenuated by removing the the biological equivalent of the most genes that produce purines vital to bacterial basic switch in a computer -- a digital growth. The tamed strain could not survive flip-flop. "Cells switch genes on and off very long in healthy tissue, but quickly all the time," observes MIT's Thomas multiplied 1000-fold inside tumors which are F. Knight, Jr., who has pioneered rich in purines. The engineered bacteria some of this research. A cellular were available in multiple serotypes to avoid toggle switch, made of DNA and potential immune response in the host, and some well-characterized regulatory Phase I human clinical trials were underway proteins, might be devised to turn

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 271 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

on a specific gene when exposed to a Besides their direct medical particular chemical. These could be used applications, biobots might be in gene therapies -- implanted genes might employed in molecular construction. be controlled with single doses of specially Gerald J. Sussman at MIT notes that selected drugs, one to switch the gene on, when computer parts are reduced another to switch it off. to the size of single molecules, Arcady Mushegian of Akkadix Corp. engineered microbes could be [20] has looked at the genes present in the directed to lay down complex genomes of fully sequenced microbes to electronic circuits. "Bacteria are like see which ones are always conserved in little workhorses for nanotechnology; nature. He concludes that as few as 300 they're wonderful at manipulating genes are all that may be required for life, things in the chemical and constituting the minimum possible genome ultramicroscopic worlds," he says. for a functional microbe. An organism "You could train them to become containing this minimal gene set would be electricians and plumbers, hire them able to perform the dozen or so functions with sugar and harness them to build required for life -- manufacturing cellular structures for you." biomolecules, generating energy, repairing damage, transporting salts and other 4. Medical Nanorobotics molecules, responding to environmental The third major branch of chemical cues, and replicating. The minimal nanomedicine -- molecular microbe -- a basic cellular chassis -- could nanotechnology (MNT) or nanorobotics be specified by a genome only 150,000 [2, 22] -- takes as its purview the nucleotides bases in length. Glen Evans, engineering of all complex mechanical now at Egea BioSciences, can already medical systems constructed from the produce made-to-order DNA strands that molecular level. Just as biotechnology are 10,000 nucleotide bases in length [21] extends the range and efficacy of and is striving to increase this length by at treatment options available from least a factor of ten. The engineered full- nanomaterials, the advent of molecular genome DNA, once synthesized, would then nanotechnology will again expand be placed inside an empty cell membrane enormously the effectiveness, comfort -- most likely a living cell from which the and speed of future medical treatments nuclear material had been removed. while at the same time significantly These artificial biobots could be designed reducing their risk, cost, and to produce useful vitamins, hormones, invasiveness. MNT will allow doctors enzymes or cytokines in which the patient's to perform direct in vivo surgery on body was deficient, or to selectively absorb individual human cells. and metabolize into harmless endproducts harmful substances such as poisons, toxins, 4.1 Early Thinking or indigestible intracellular detritis, or even to The first and most famous scientist to perform useful mechanical tasks. voice these possibilities was the late

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 272 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Nobel physicist Richard P. Feynman, who object that maneuvers at that level!" worked on the Manhattan Project at Los Extending nanomedicine to Alamos during World War II and later taught molecular machine systems will at CalTech for most of his professorial career. probably require, among many other In his remarkably prescient 1959 talk "There's things, the ability to build precise Plenty of Room at the Bottom," Feynman structures, actuators and motors proposed employing machine tools to make that operate at the molecular level, smaller machine tools, these to be used in thus enabling manipulation and turn to make still smaller machine tools, and locomotion. For example, in 1992 so on all the way down to the atomic level K. Eric Drexler of the Institute for [23]. Feynman prophetically concluded Molecular Manufacturing theorized that this is "a development which I think that an efficient nanomechanical cannot be avoided." Such nanomachine bearing could be made by bending tools, nanorobots and nanodevices could two graphite sheets into cylinders of ultimately be used to develop a wide different diameters, then inserting the range of atomically precise microscopic smaller one into the larger one [22]. instrumentation and manufacturing tools -- By 2000, John Cumings and Alex Zettl that is, nanotechnology. at U.C. Berkeley had demonstrated Feynman was clearly aware of the experimentally that nested carbon potential medical applications of the new nanotubes do indeed make technology he was proposing. After exceptionally low-friction nanobearings discussing his ideas with a colleague, [24]. Feynman offered [23] the first known proposal for a nanomedical procedure 4.2 DNA-Based Nanodevices to cure heart disease: "A friend of mine But early mechanical nanorobots (Albert R. Hibbs) suggests a very interesting might be made, at least in part, of possibility for relatively small machines. He DNA. The idea of using DNA to says that, although it is a very wild idea, build nanoscale objects has been it would be interesting in surgery if you pioneered by Nadrian Seeman at New could swallow the surgeon. You put the York University [25]. Two decades mechanical surgeon inside the blood vessel ago, Seeman recognized that a and it goes into the heart and looks around. strand of DNA has many advantages (Of course the information has to be fed as a construction material. First, out.) It finds out which valve is the faulty it is a relatively stiff polymer. Its one and takes a little knife and slices it out. intermolecular interaction with other Other small machines might be permanently strands can be readily predicted and incorporated in the body to assist some programmed due to the base-pair inadequately functioning organ." Later in his complementarity of nucleotides, the historic lecture in 1959, Feynman urged us fundamental building blocks of genetic to consider the possibility, in connection with material. DNA also tends to self- biological cells, "that we can manufacture an assemble. Arbitrary sequences are

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 273 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

readily manufactured using conventional using three single strands of artificial biotechnological techniques, and DNA is DNA which, when placed together, readily manipulated and modified by a large find their complementary partners number of enzymes. During the 1980s, and self-assemble to form a V-shaped Seeman worked to develop strands of DNA structure [27]. The open mouth of this that would zip themselves up into more and nanotweezer can be made to close more complex shapes -- first tiny squares, by adding a special "fuel" strand which then three-dimensional stick-figure cubes binds to the single-stranded DNA comprised of 480 nucleotides each, then dangling from the ends of the arms of a truncated octahedron containing 2550 the tweezers and zips them closed. A nucleotides. By the mid-1990s, Seeman special "removal" strand, when added, could fabricate nanoscale DNA stick figures binds to the fuel strand and pulls it of almost any regular geometric shape, by away, opening the nanotweezers the billions per batch. again. The cycle may then be In 1999, Seeman reported yet another repeated. breakthrough -- the construction of a mechanical DNA-based device that might 4.3 Nanotweezers serve as the basis for a nanoscale robotic In 1999, Philip Kim and Charles Lieber actuator [26]. The mechanism has two at Harvard University created the first rigid double-stranded DNA arms a few general-purpose nanotweezer [28]. nanometers long that can be made to rotate Its working end is a pair of electrically between fixed positions by introducing a controlled carbon nanotubes made positively charged cobalt compound into the from a bundle of multiwalled carbon solution surrounding the molecules, causing nanotubes. To operate the tweezers, the bridge region to be converted from a voltage is applied across the the normal B-DNA structure to the unusual electrodes, causing one nanotube Z-DNA structure. The free ends of the arms arm to develop a positive electrostatic shift position by 2-6 nanometers during this charge and the other to develop a fully reversible structural conversion, like negative charge. The attractive force a hinge opening and closing. "It's a very can be increased or decreased by simple nanomachine," admits Seeman, "but varying the applied voltage -- 8.5 in the scheme of molecular devices it's volts completely closes the arms, huge because it generates more than four while lower voltages give different times the amount of movement produced by degrees of grip. Using the tool, Kim typical molecular devices." A large version and Lieber have successfully grasped of the device might function as an elbow, 500-nanometer clusters of polystyrene while smaller devices could serve as finger spheres, about the same size scale joints. as cellular substructures. They were Bernard Yurke at Bell Laboratories and also able to remove a semiconductor Andrew Turberfield at the University of wire 20 nanometers wide from a Oxford synthesized another DNA actuator mass of entangled wires. At present,

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 274 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

each of the tweezer's arms is about 50 spinning like a field of tiny propellers. nanometers wide and 4 microns long. But The group's first integrated molecular by growing single-walled nanotubes directly motor ran for 40 minutes at 3-4 onto the electrodes, the researchers hope revolutions per second. Subsequent to produce nanotweezers small enough to motors have been operated for hours grab individual macromolecules. continuously by feeding them plenty of ATP. Montemagno has been 4.4 Nanomotors measuring things like horsepower Other researchers are developing and motor efficiency, simple tests that nanomotors for future nanorobots. Most would be familiar to any mechanical notably, Carlo Montemagno at Cornell engineer inspecting a car engine. University has modified a natural biomotor Montemagno is also trying to build a to incorporate nonbiological parts, creating solar-powered, biomolecular motor- the first artificial hybrid nanomotor [29]. driven autonomous nanodevice, Montemagno started with natural ATPase, a wherein light energy is converted into ubiquitous enzyme found in virtually every ATP which then serves as a fuel source living organism and which helps to convert for the motor. "We think we'll be able food into usable energy in living cells. The to make autonomous devices that are moving part of an ATPase molecule is a powered by light on a scale of 1 micron central protein shaft (or rotor, in electric- or less, smaller than bacteria," he says. motor terms) that rotates in response to Montemagno is developing a electrochemical reactions with each of chemical means of switching his the molecule's three proton channels hybrid motors on and off reliably. By (comparable to the electromagnets in engineering a secondary binding the stator coil of an electric motor). ATP site tailored to a cell's signalling (adenosine triphosphate) is the fuel that cascade, he plans to use the sensory powers the molecular motor's motion. system of the living cell to control Using the tools of genetic engineering, nanodevices implanted within the Montemagno added metal-binding amino cell. Montemagno envisions tiny acid residues to the ATPase. This allowed chemical factories operating inside each motor molecule to bind tightly to living cells. He speculates that these nanoscale nickel pedestals prepared nanofactories could be targeted to by electron beam lithography. Properly specific cells, such as those of tumors, oriented motor molecules 12 nanometers where they would synthesize and in diameter were then attached to the deliver chemotherapy agents. Within pedestals with a precision approaching three years he expects to have a 15 nanometers, and a silicon nitride bar a motor assembled within a living cell, hundred nanometers long was bound to with the cell's physiology providing the the rotor subunit of each motor molecule, energy to run it. "My 10-year goal is all by self-assembly. In a microscopic video to make a device that harvests single presentation, dozens of bars could be seen molecules within a living cell, maybe

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 275 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

a cellular pharmacy that produces a drug, Molecular Electronics Corp. in Texas stores it within the cell, and then based and California Molecular Electronics upon some signal, releases it," Montemagno Corp. in California -- have sprung up said in 2000. "For a technology that wasn't with the explicit goal of building the expected to produce a useful device before first commercial molecular electronic the year 2050, I think we've made a pretty devices including memories and good start. But we have a long way to go other computational components before it's safe to turn these little machines of computers, possibly in the next loose in the human body." few years, using techniques of self- Nanomotor research is progressing in assembly. other laboratories as well. For instance, a 78-atom chemically-powered rotating 4.6 Positional Assembly motor was synthesized in 1999 as a proof of As machine structures become more principle by chemist T. Ross Kelly at Boston complex, getting all the parts to College [30]. Ben Feringa at the University spontaneously self-assemble in the of Groningen in the Netherlands has built right sequence will be increasingly an artificial 58-atom motor molecule that difficult. To build such complex spins when illuminated by solar energy [31]. structures, it makes more sense Another potential nanorobot power source to design a mechanism that can is a modified microbial fuel cell -- laboratory assemble a molecular structure by demonstrations of such cells contain captive what is called positional assembly -- bacteria or immobilized enzymes [32] which, that is, picking and placing molecular when fed organic material, convert chemical parts exactly where you want them. A energy into electricity that could be used to device capable of positional assembly power tiny motors. would work much like the robot arms that manufacture cars on automobile 4.5 Nanocomputers assembly lines in Detroit, or which Truly effective medical nanorobots may insert electronic components onto require onboard computers to allow a computer circuit boards with blinding physician to properly monitor and control speed in Silicon Valley. Using the their work. Molecular electronics or positional assembly approach, the "moletronics" is a hot research topic in robot manipulator picks up a part, nanotechnology right now. For example, moves it to the workpiece, installs it, in 2000, a collaborative effort between then repeats the procedure over and UCLA and Hewlett Packard produced the over with many different parts until the first laboratory demonstration of completely final product is fully assembled. reversible room-temperature molecular One of the leading proponents of switches that could be employed in positional assembly at the molecular nanoscale memories, using mechanically scale is Zyvex Corp., a privately- interlinked ring molecules called catenanes held nanotechnology research [33]. Two independent companies -- and development corporation

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 276 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

headquartered in Richardson, Texas [34]. between the inside and the outside Zyvex is the first engineering company with of the bacterial cell. Our bodies also the explicit goal of creating a molecular maintain a population of more than a assembler that uses positional assembly to trillion motile biological nanodevices manufacture atomically precise structures. called fibroblasts and white cells such As a first step toward this goal, in 1998 as neutrophils and lymphocytes, each Zyvex demonstrated the ability to use three measuring perhaps 10 microns in size. independently-controlled inch-long robotic These beneficial natural nanorobots arms to manipulate tiny carbon nanotubes are constantly crawling around inside in three dimensions, under the watchful of us, repairing damaged tissues, eye of a scanning electron microscope that attacking invading microbes, and can monitor objects and motions as small gathering up foreign particles and as 6 nanometers at near-video scan rates. transporting them to various organs for Zyvex still has a very long way to go before disposal from the body. it can assemble nanoscale parts into useful The greatest power of machines, but its work is a small step in the nanomedicine will emerge in a decade right direction and the research continues or two when we learn to design and today. Zyvex engineers are also conceiving construct complete artificial nanorobots and testing various manufacturing using nanometer-scale parts and architectures that may someday enable subsystems including sensors, motors, massively parallel, or exponential, manipulators, power plants, and construction of large batches of identical molecular computers. If we make molecular machines simultaneously. This the reasonable assumption that we might allow vast numbers of nanodevices -- will someday be able to build these ultimately including medical nanorobots -- to complex medical nanorobots, and be produced relatively inexpensively and to build them cheaply enough and in molecular specifications. sufficiently large numbers to be useful therapeutically, then what are the 4.7 Nanomedical Diagnosis and medical implications? We have space Treatment here to describe only a few of the The idea of placing autonomous self- many possibilities [2, 35-38]. powered nanorobots inside of us might One thing that would change seem a bit odd, but actually the human dramatically is clinical diagnostics body already teems with such nanodevices. and treatment. Consider a patient For instance, more than 40 trillion single- who goes to his doctor with a mild celled microbes swim through our colon, fever, nasal congestion, discomfort, outnumbering our tissue cells almost ten and cough. In the nanomedical era, to one. Many bacteria move by whipping taking and analyzing microbial samples around a tiny tail, or flagellum, that is will be as quick and convenient driven by a 30-nanometer biological ionic as the electronic measurement of nanomotor powered by pH differences body temperature using a tympanic

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thermometer in a late 20th-century clinical the infectious microbe is promptly office or hospital. The physician faces exterminated using a patient-inhaled the patient and pulls from her pocket a aerosol of mobile nanorobots which lightweight handheld device resembling the physician has programmed a pocket calculator. She unsnaps a self- to seek out and destroy that one sterilizing cordless pencil-sized probe microbial strain. After a few minutes from the side of the device and inserts the nanorobots have finished their the business end of the probe into the work and are retrieved by the doctor. patient's opened mouth in the manner of A resurvey with the diagnostic probe a tongue depressor. The ramifying probe reveals no evidence of the pathogen. tip contains billions of nanoscale molecular assay receptors mounted on hundreds of 4.8 Improved Human Abilities self-guiding retractile stalks. Each assay Another major change that receptor is sensitive to the chemical nanomedicine will bring is the ability signature of one of thousands of specific to dramatically extend natural human bacterial coats or viral capsids. capabilities. As a simple example, The patient says "Ahh," [35] and a few a few years ago I designed an seconds later a three-dimensional color- artificial mechanical red cell called coded map of the throat area appears on a a "respirocyte" [36]. Still entirely display panel held in the doctor's hand. A theoretical, the respirocyte measures 1 bright spot on the screen marks the exact micron in diameter and just floats along location where the first samples are being in the bloodstream. It is a spherical taken. Underneath the color map scrolls nanorobot made of 18 billion atoms a continuously updated microflora count, precisely arranged in a diamondoid listing in the leftmost column the names structure to make a tiny pressure of the ten most numerous microbial and tank that can be pumped full of up viral species that have been detected, key to 9 billion oxygen (O_2) and carbon biochemical marker codes in the middle dioxide (CO_2) molecules. Later on, column, and measured population counts these gases can be released from the in the right column. The number counts flip tank in a controlled manner using tiny up and down a bit as the physician directs molecular pumps. Gases are stored probe stalks to various locations in the onboard at pressures up to about 1000 pharynx to obtain a representative sampling, atmospheres. with special attention to sores or exudate. After a few more seconds, the data for two 4.8 Improved Human Abilities of the bacterial species suddenly highlight Another major change that in red, indicating the distinctive molecular nanomedicine will bring is the ability signatures of specific toxins or pathological to dramatically extend natural human variants. One of these two species is capabilities. As a simple example, a known, and unwelcome, bacterial a few years ago I designed an pathogen. The diagnosis is completed and artificial mechanical red cell called a

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 278 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

"respirocyte" [36]. Still entirely theoretical, time 100-1000 times faster than the the respirocyte measures 1 micron in natural system. The basic clottocyte diameter and just floats along in the is conceived as a serum oxygen/ bloodstream. It is a spherical nanorobot glucose-powered spherical nanorobot, made of 18 billion atoms precisely arranged 2 microns in diameter, that contains a in a diamondoid structure to make a tiny compactly-folded fiber mesh. Upon pressure tank that can be pumped full of up command from its control computer, to 9 billion oxygen (O_2) and carbon dioxide the device unfurls its mesh packet in (CO_2) molecules. Later on, these gases the vicinity of an injured blood vessel can be released from the tank in a controlled -- following, say, a cut through the skin. manner using tiny molecular pumps. Gases Soluble thin films coating certain parts are stored onboard at pressures up to about of the mesh dissolve upon contact with 1000 atmospheres. plasma water, revealing sticky sections Respirocytes mimic the action of the (e.g., complementary to blood group natural hemoglobin-filled red blood cells. antigens unique to red cell surfaces) Gas concentration sensors on the outside in desired patterns. Blood cells are of each device let the nanorobot know immediately trapped in the overlapping when it is time to load O_2 and unload artificial nettings released by multiple CO_2 (at the lungs), or vice versa (at the neighboring activated clottocytes, tissues). Each respirocyte can store and and bleeding halts at once. While transport 236 times as much gas per up to 300 natural platelets might unit volume as a natural red cell. So the be broken and still be insufficient to injection of a 5 cc therapeutic dose of 50% initiate a self-perpetuating clotting respirocyte saline suspension, a total of 5 cascade, even a single clottocyte, trillion individual nanorobots, into the human upon reliably detecting a blood vessel bloodstream can exactly replace the gas break, can rapidly communicate this carrying capacity of the patient's entire 5.4 fact to its neighboring devices [2], liters of blood. But up to 1 liter of respirocyte immediately triggering a progressive suspension could safely be added to the carefully-controlled mesh-release bloodstream, which could keep a patient's cascade. Clottocytes may perform tissues safely oxygenated for up to 4 hours a clotting function that is equivalent in the event a heart attack caused the in its essentials to that performed by heart to stop beating. Or it would enable a biological platelets, but at only 0.01% healthy person to sit quietly at the bottom of of the bloodstream concentration of a swimming pool for four hours, holding his those cells or about 20 nanorobots breath, or to sprint at top speed for at least per cubic millimeter of serum. Hence 15 minutes without breathing. clottocytes appear to be about 10,000 Similarly, an artificial mechanical platelet times more effective as clotting agents or "clottocyte" [37] could make possible than an equal volume of natural complete hemostasis in just 1 second, even platelets. for moderately large wounds, a response

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 279 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

4.9 Chromosome Replacement Therapy nanomedicine should eliminate Medical nanorobots will also be able to virtually all common diseases of intervene at the cellular level, performing the 20th century, and virtually all in vivo cytosurgery. The most likely medical pain [38] and suffering as site of pathological function in the cell well. Only conditions that involve a is the nucleus -- more specifically, the permanent loss of personality and chromosomes. In one simple cytosurgical memory information in the brain procedure, a nanorobot controlled -- such as an advanced case of by a physician would extract existing Alzheimer's disease or a massive chromosomes from a diseased cell and head trauma -- may remain incurable insert new ones in their place. This is in the nanomedical era. Because called chromosome replacement therapy. aging is believed to be the result of The replacement chromosomes will be a number of interrelated molecular manufactured to order, outside of the processes and malfunctions in cells, patient's body in a laboratory benchtop and because cellular malfunctions will production device that includes a molecular be largely reversible, middle-aged and assembly line, using the patient's individual older people who gain access to an genome as the blueprint. The replacement advanced nanomedicine can expect to chromosomes are appropriately have most of their youthful health and demethylated, thus expressing only the beauty restored. And they may find appropriate exons that are active in the few remaining limits to human longevity cell type to which the nanorobot has been in this wonderfully vigorous state. It targeted. If the patient chooses, inherited is a bright future that lies ahead for defective genes could be replaced with medicine, but we shall all have to work nondefective base-pair sequences, very long and very hard to bring it to permanently curing a genetic disease. fruition. Given the speed with which nanorobots can be administered and their potential rapidity References of action, it is possible that an entire whole- [1] U.S. House Testimony of Richard E. body procedure could be completed in Smalley, 22 June 1999; one hour or less. Robert Austin at Princeton http://www.house.gov/science/ University has also begun early thinking smalley_062299.htm. along these lines, hoping someday to [2] Robert A. Freitas Jr., Nanomedicine, design a nanoprobe capable of identifying Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999; biological markers that are specific for http://www.nanomedicine.com. targeted diseases. "Then you just pop open [3] Robert A. Freitas Jr., "The the cells, remove the bad DNA from that cell, Nanomedicine Page"; http://www. and repair it on a single-cell level," he says. foresight.org/Nanomedicine/index.html. "That's a long way down the road, but it will [4] Quantum Dot Corporation; http:// happen." www.qdots.com/. In the first half of the 21st century,

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 280 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

[5] H.A. Clark, R. Kopelman, R. Tjalkens, M.A. [12] D.H. Robbins, I. Margulies, M. Philbert, "Optical nanosensors for chemical Stetler-Stevenson, R.J. Kreitman, "Hairy analysis inside single living cells. 2. Sensors cell leukemia, a B-cell neoplasm for pH and calcium and the intracellular that is particularly sensitive to the application of PEBBLE sensors," Anal. Chem. cytotoxic effect of anti-Tac(Fv)-PE38 71(1 November 1999):4837-4843. (LMB-2)," Clin. Cancer Res. 6(February [6] H. Shi, B.D. Ratner, "Template recognition 2000):693-700. of protein-imprinted polymer surfaces," J. [13] R. Schnell, E. Vitetta, J. Schindler, Biomed. Mater. Res. 49(January 2000):1-11. P. Borchmann, S. Barth, V. Ghetie, K. [7] C.J. Allender, C. Richardson, B. Hell, S. Drillich, V. Diehl, A. Engert, Woodhouse, C.M. Heard, K.R. Brain, "Treatment of refractory Hodgkin's "Pharmaceutical applications for molecularly lymphoma patients with an anti-CD imprinted polymers," Int. J. Pharm. 195(15 ricin A-chain immunotoxin," Leukemia February 2000):39-43. 14(January 2000):129-135. [8] J.F. Kukowska-Latallo, A.U. Bielinska, [14] T.A. Desai, W.H. Chu, J.K. Tu, J. Johnson, R. Spindler, D.A. Tomalia, J.R. G.M. Beattie, A. Hayek, M. Ferrari, Baker, Jr., "Efficient transfer of genetic "Microfabricated immunoisolating material into mammalian cells using Starburst biocapsules," Biotechnol. Bioeng. 57(5 polyamidoamine dendrimers," Proc. Natl. January 1998):118-120. Acad. Sci. (USA) 93(14 May 1996):4897-4902. [15] Matsuhiko Nishizawa, Vinod P. [9] J.F. Kukowska-Latallo, E. Raczka, A. Menon, Charles R. Martin, "Metal Quintana, C. Chen, M. Rymaszewski, J.R. nanotubule membranes with Baker, Jr., electrochemically switchable ion- "Intravascular and endobronchial DNA transport selectivity," Science 268(5 delivery to murine lung tissue using a novel, May 1995):700-702. nonviral vector," Hum. Gene Ther. 11(1 July [16] B. Cornell, V. Braach-Maksvytis, 2000):1385-1395. L. King, P. Osman, B. Raguse, L. [10] J.D. Reuter, A. Myc, M.M. Hayes, Z. Gan, Wieczorek, R. Pace, "A biosensor that R. Roy, D. Qin, R. Yin, L.T. Piehler, R. Esfand, uses ion-channel switches," Nature D.A. Tomalia, J.R. Baker, Jr., "Inhibition of 387(5 June 1997):580-583 viral adhesion and infection by sialic-acid- [17] A. Meller, L. Nivon, E. Brandin, conjugated dendritic polymers," Bioconjug. J. Golovchenko, D. Branton, "Rapid Chem. 10(March-April 1999):271-278. nanopore discrimination between [11] Y. Suzuki, M. Tanihara, Y. Nishimura, K. single polynucleotide molecules," Proc. Suzuki, Y. Kakimaru, Y. Shimizu, "A new drug Natl. Acad. Sci. (USA) 97(1 February delivery system with controlled release of 2000):1079-1084. antibiotic only in the presence of infection," J. [18] D.W. Deamer, M. Akeson, Biomed. Mater. Res. "Nanopores and nucleic acids: 42(October 1998):112-116. prospects for ultrarapid sequencing," Trends Biotechnol. 18(April 2000):147- 151.

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 281 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

[19] D. Bermudes, B. Low, J. Pawelek, "Tumor- [30] T.R. Kelly, H. De Silva, R.A. Silva, targeted Salmonella. Highly selective delivery "Unidirectional rotary motion in a vectors," Adv. Exp. Med. Biol. 465(2000):57-63. molecular system," Nature 401(9 [20]A.R. Mushegian, "The minimal genome September 1999):150-152. concept," Curr. Opin. Genet. Dev. 9(December [31] N. Koumura, R.W. Zijlstra, R.A. van 1999):709-714. Delden, N. Harada, B.L. Feringa, "Light- [21] "Researchers build huge DNA chains," driven monodirectional molecular rotor," BBC, 27 January 2000; Nature 401(9 September 1999):152-155. http://www.crystalinks.com/biology5.1.html. [32] S. Sasaki, I. Karube, "The [22] K. Eric Drexler, Nanosystems: Molecular development of microfabricated Machinery, Manufacturing, and Computation, biocatalytic fuel cells," Trends Biotechnol. John Wiley & Sons, New York, 1992. 17(February 1999):50-52. [23] R.P. Feynman, "There's Plenty of Room [33] C.P. Collier, G. Mattersteig, E.W. at the Bottom," Engineering and Science Wong, Y. Luo, K. Beverly, J. Sampaio, (California Institute of Technology), February F.M. Raymo, J.F. Stoddart, J.R. Heath, 1960, pp. 22-36. See at: http://nano.xerox. "A [2]Catenane-based solid state com/nanotech/feynman.html. electronically reconfigurable switch," [24] John Cumings, A. Zettl, "Low-Friction Science 289(18 August 2000):1172-1175. Nanoscale Linear Bearing Realized from [34] Zyvex Corporation; http://www. Multiwall Carbon Nanotubes," Science 289(28 zyvex.com. July 2000):602-604. [35] Robert A. Freitas Jr., "Say Ah!" The [25] N.C. Seeman, "DNA engineering and Sciences 40(July/August 2000):26-31; its application to nanotechnology," Trends http://www.foresight.org/Nanomedicine/ Biotechnol. SayAh/index.html. 17(November 1999):437-443. [36]Robert A. Freitas Jr., "Exploratory [26] C. Mao, W. Sun, Z. Shen, N.C. Seeman, Design in Medical Nanotechnology: A "A nanomechanical device based on the B-Z Mechanical Artificial Red Cell," Artificial transition of DNA," Nature 397(14 January Cells, Blood Substitutes, and Immobil. 1999):144-146. Biotech. 26(1998):411-430; [27] B. Yurke, A.J. Turberfield, A.P. Mills, Jr., http://www.foresight.org/Nanomedicine/ F.C. Simmel, J.L. Neumann, "A DNA-fuelled Respirocytes.html. molecular machine made of DNA," Nature [37] Robert A. Freitas Jr., "Clottocytes: 406(10 August 2000):605-608. Artificial Mechanical Platelets," Foresight [28] P. Kim, C.M. Lieber, "Nanotube Update No. 41, 30 June 2000, pp. 9-11; Nanotweezers," Science 286(10 December http://www.imm.org/Reports/Rep018.html. 1999):2148-2150. [38] Robert A. Freitas Jr., "Nanodentistry," [29] C.D. Montemagno, G.D. Bachand, J. Amer. Dent. Assoc. 131(November "Constructing nanomechanical devices 2000):1559-1566. powered by biomolecular motors," Nanotechnology 10(1999):225-231; G.D. Bachand, C.D. Montemagno, "Constructing organic/inorganic NEMS devices powered by biomolecular motors," Biomedical Microdevices 2(2000):179-184.

The Future of Nanofabrication and Molecular Scale Devices in Nanomedicine 282 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Renata G. Chapter 30: Can we build Chromallocyte Bushko / Can we build by 2039? Chromallocyte Renata G. Bushko, M.S. by 2019? in “World Health Founder, Future of Health Technology Strategy” eBook, Institute, Hopkinton, MA, US (Ed.) Renata G. Bushko, FHTI, 2016. 1. Introduction Futureofhealth. org From ust like Edwin Schrodinger, in his paper Strategy for the “What is Life” predicted aperiodic Figure 1. Chromallocyte (early sketch – artists’ Future of Health view) from Robert A. Freitas Jr. , Journal of (Ed.) Renata G. crystals off DNA and Richard Feynman Evolution and Technology - Vol. 16 Issue 1 Bushko, IOS J in his lecture, “There’s Plenty of Room at Press 2009 June 2007 p12, Image © 2006 Stimulacra LLC the Bottom“ conceived nanorobots, Robert (www.stimulacra.net) and Robert A. Freitas Freitas presents chromosome replacement Jr(www.rfreitas.com), used with permission.

in vivo as a painless cure for genetically based disease. “The most essential part 2. Nanotherapeutics: Most Promising of living cell – the chromosome fibre – Health Technology may suitably be called aperiodic crystal. Nanotherapeutic technology was In physics we have delt only with periodic selected as the most important crystals. […] Compared with aperiodic crystal health technology in 2002 FHTI they are plain and dull. […] Aperiodic crystal, survey (Table 1). One of the most in my opinion, is the MATERIAL CARRIER important health technology events OF LIFE.” “What is Life”, Erwin Schrodinger of this decade was the first technical description of a cell repair nanorobot p 4-5 (Prediction of DNA)[2] Sixty five ever published: 94 page paper by years have gone by from the conceptual Robert A. Freitas Jr. “The Ideal Gene description of genes in 1944 and their Delivery Vector: Chromallocytes, Cell discovery by Crick and Watson in 1953 to the Repair Nanorobots for Chromosome fully developed engineering plan by Robert Replacement Therapy,” published Freitas to build chromallocyte. We need 30- in the Journal of. Evolutionary 35 more years to be able to “land Technology in June 2007 [3]. I would chromallocytes on the liver” and replace all like to emphasize its importance and of its cells in vivo. It is our responsibility to make it well known because of its make this happen just like we made landing potential to save 52 million people the man on the moon happen back in 1969. “With annual checkups and cleanouts, and every year and the possibility of 1000- some occasional major cellular repairs fold improvement over our current [using Chromallocyte], your biological age human biological abilities [4]. could be restored once a year to a more or less constant physiological age that you select.” Welcome to The Future of Medicine, Robert Freitas [3]

Table 1. Seven most promising health

technology areas selected by experts. Survey length; displacement volume (mostly method from R. Bushko, Defining Future of Health diamondoid) = 69.250 micron3; dry Technology,. Future of Health Technology, ed. R. Bushko, IOS, 2002. mass = 80 pg; mass with wet cargo = 103 pg. 1 (A) Tissue Bioengineering/ Regeneration & (B) Nanotherapeutic 3.2 What is general structure of the Technologies chromallocyte? Chromallocyte has 10 components: 2 Knowledge Management • Proboscis Manipulator Technologies (including decision • Mobility System support and data mining) • Funnel Assembly 3 Electronic Health Record in a Standard • Chromatin Storage Format with Unique Patient Identifier • Power Supply 4 (A) Powerful yet easy to use Self- • Navigation/Communication diagnostic Technologies & (B) Vaccine • Computers Biology • Sensors 5 Affordable information system access • Consumables with decision support for healthcare • Structural Support professional 6 Internet-driven Technologies 7 Voice Recognition, (B) Psychological Aids & (C) Artificial Intelligence & (D) Controlled Medical Vocabularies

3. Chromallocyte 101 – Basic Design

3.1 What is the shape and size of Figure 2. Chromallocyte (artist’s conception) chromallocyte to minimize volume? with Funnel Partly Extended. from Robert Chromallocytes are not able to free float A. Freitas Jr. , Journal of Evolution and Technology - Vol. 16 Issue 1 June 2007 p16, in the bloodstream so their diameter can Image © 2006 Stimulacra LLC be bigger than 4 microns (size limit for (www.stimulacra.net) and Robert A. Freitas free floating robots). They are restricted Jr(www.rfreitas.com), used with permission to vascular surfaces so they are smaller in volume than erythrocytes (95 microns3 red cells) or granulocytes (1000 microns3 3.3 How is chromallocyte powered? white cells). They are less than 1% of Chromallocyte uses non-chemical typical tissue cell volume and up to 25% power in the form of 10 acoustic power of nucleus volume to be able to penetrate receivers. Each power receiver has cells. Chromallocyte’s dimensions are: 4.18 a 0.4 micron piston throw and can microns x 3.28 microns x 5.05 microns in receive 200 pW. A patient is well-

coupled to a medically-safe 1000 W/m2 to the cell’s nucleus. Probiosis draws 0.5 MHz ultrasound transverse-plane-wave 62 pW of continuous power in normal transmitter. usage. Medical robots can also be powered by glucose fuel cells. Tad Hogg and Robert 3.6 How does chromallocyte get Freitas have just completed a theory and places? simulation study of the in vivo power limits Chromallocyte must walk on vascular on medical nanorobots that use glucose and cell surfaces with up to 150 nm fuel cells. This study combines engineering thickness (intestinal cells). Cell plasma design and the biology of red blood cells membranes are covered with a to identify capabilities of aggregates of fuzzy coat of glycoprotein strands - robots on the inside surface of capillaries. glycocalyx, otherwise known as the The results show that in such aggregates, "sweet husk of the cell" (a network individual nanorobots compete with each of polysaccharides that project from other for power, reducing the power cellular surfaces). Chromallocyte in its available for each robot to several tens of current design, by Robert Freitas, has picowatts. That's enough to operate a 3 1027 telescopic grapple manipulators. MHz nanocomputer continuously inside These manipulators may be shortened each robot or to perform other important or lengthened during each stroke. nanomedical tasks such as sensing or Variable-area end-effectors may be drug delivery or in chromallocyte’s case used to enhance the propulsive effect. - chromatine replacement. Despite their The grapples allow Chromallocyte to high power densities, modest sized groups penetrate vascular, cell membrane, of nanorobots will not significantly heat the and nuclear membrane walls. They are surrounding tissue.[5] stowed in the hull when not used.

3.4 Are there any computers on board? Chromallocytes operate semi-autonomously during most of the mission but can receive various parameters from the physician via acoustic signaling. It has 10 acoustic message receivers, 10 CPU and memory units, 50 megabits of memory and Figure 3. Fully extended grapple - 250 nm (left) and grapple work envelope (right) © 0.01micron3 of total computer volume. Robert A. Freitas Jr. , Journal of Evolution and Technology - Vol. 16 Issue 1 June 200; used 3.5 How does chromallocyte replace with permission. chromatin? It is done with the working unit called Chromallocyte can also swim in tissues Proboscis which: (1) collects old chromatin (histonation) and acelluler tissue from the nucleus, (2) has chromosome spaces (brachiation) where fibrous binding part, (3) transfers new chromatin components are typically spaced up

to 10-100 microns apart. As Robert Freitas 4.2 How is patient prepared for the describes it: “A brachiating nanorobot chromallocyte treatment? can [also] pull itself along individual fibrils, Patient is placed on an ultrasonic changing direction at fibril junctions, vibrating table with comfortable indirectly working its way toward its cellular encapsulated gel interface. The target crudely analogous to the path of a goal of this is to maximize acoustic sailboat tacking into the wind.” [3] power transmission into the body – energy for in vivo chromallocyte 3.7 What if Chromallocyte gets lost? activities. The patient is then sedated Proboscis can be deployed to search for and respirocytes injection follows new handholds (e.g. fibrils) within a ~4 micron while drugs are used to reduce the hemispherical work envelope. The grapples pulse rate. A self-guiding flexible may be operated as cilia, producing slow noncannula in installed directly into the swimming motility in the fluid. Grapples can blood vessel closest to the liver. This be extended or retracted in 0.25 millisec, completes the process and robots are easily allowing execution of a 2 KHz beating inserted into the body (Figure 4). motion similar to that of natural cilia .

4. Landing on the Liver: What are liver therapy stages? In vivo liver chromosome replacement therapy will take about 7 hours and it has five stages: (1) Organ Survey, (2) Chromallocyte Preparation, (3) Patient Preparation, (4) Chromosome Replacement and (5) Patient Figure 4. Chromallocytes (artist’s conception) Post-operative Process. floating in the vascular surface - from Robert A. Freitas Jr. , Journal of Evolution and Technology - Vol. 16 Issue 1 June 2007 - pg 12, 4.1 How many chromallocytes are needed Image © 2006 Stimulacra LLC for total liver replacement? (www.stimulacra.net) and Robert A. Freitas Chromosomes of all 250 billion hepatic Jr(www.rfreitas.com), used with permission. tissue cells must be replaced. Liver cells often have multiple nuclei (typically 1-3) so 4.3 How would we know when to use probably multiple visits to many cells would chromallocytes? be needed. We need to infuse 1 terabot The key of chromallocyte-based (trillion device) chromallocyte dose. This treatment is to avoid painful symptoms. dose would have 69 cm3 of chromallocytes This requires acting before symptoms in 1-liter (7% saline suspension). occur. How can we do that? Robert

Linares in his chapter “Diamond Bio nanorobots (way beyond simpler Electronics” describes molecular diagnostic respirocytes). Many of the challenges devices that will allow ongoing molecular are mentioned in his chapter monitoring (his vision of new bio-electronic “Welcome to the Future of Medicine” in medical era) [6]: this volume. In the manufacturing area, “[ …] Bio-electronic devices, will reside the key technical challenges include: inside the body as opposed to next to the demonstrating Diamond Mechano- bedside or in the lab, and there is a high Synthesis, building nanomachines, degree of real-time information coming building a nanofactory, building from these devices. More importantly, simple nanorobots, and then building the feedback loop from the time of the complex nanorobots. information gathering phase to the therapy/ The first simple diamondoid drug delivery phase can be dramatically medical nanorobots could be built shortened in this model.” by the end of the 2020s, followed by Nanosensing and nanomonitoring based the chromallocytes by the end of the on bio electronics will help us to determine 2030s with a surfeit of funding, to the need to use Chromallocytes before it is build the structure. This is under ideal too late. conditions assuming there would not Diagnostic devices that can monitor be any significant funding or personnel several targets at once - a form of molecular constraints. It would take about 30 redundancy - can potentially increase the years if we optimistically assume that precision with which therapies such as all goes well. Man would never land on the chromallocyte are administered. In the moon if we did not have a dream "Diagnostics for a Personalized Medical with a deadline of 1969. Future: Extending our Senses to the Molecular Scale", Benjamin Miller describes “Although we're not that close to three optical sensor systems that can the operational chromallocyte, we monitor as many as a thousand different should be able to create such things physiological markers at a time.[7] eventually, and they will certainly give us radically new alternative 5. When will chromallocyte be ready for approaches to combating aging and use? other medical problems, and the If you had all the money and brain power chances are high that some of those on Earth, would you be able to build fully alternatives will outperform the more a functional chromallocyte in 10 years? traditional ones.” Aubrey de Grey, According to Robert Freitas 10 years is not 3/2008 possible for any amount of money because there's just too much to do. Chromallocytes are extremely sophisticated and complex

Table 2. Chromallocyte Development: Major past steps and strategic plan for the next 60 years according to interview with Robert Freitas in 2009.

2003 50th anniversary of First mechanosynthesis – key manufacturing technology to DNA discovery build chromallocyte [8] 2007 The first technical description of a cell repair nanorobot ever published: Robert A. Freitas Jr., “The Ideal Gene Delivery Vector: Chromallocytes, Cell Repair Nanorobots for Chromosome Replacement Therapy,” Journal of. Evol. Technology, June 2007. [3] 2008 Direct experiments to build and validate several of mechanosynthesis tooltips. Seminal paper: Robert A. Freitas Jr., Ralph C. Merkle, “A Minimal Toolset for Positional Diamond Mechanosynthesis,” J. Comput. Theor. Nanosci. 5 (May 2008) [9] 2009 40th Anniversary of Nanofactory Collaboration active: coordinate a combine Man landing on the experimental and theoretical R&D program to design and Moon construct the first working diamondoid nanofactory [10] 2019 50th Anniversary of Demonstrating diamond mechanosynthesis in practice Man landing on the Moon 2022 Building Nanofactory 2027 Building Prototypes of simple nanorobots (eg. Respirocyte) 2029 60th Anniversary of Manufacturing of diamondoid medical nanorobots for life Man landing on the extension Moon 2039 70th Anniversary of Building chromallocyte (extremely sophisticated and Man landing on the complex nanorobot) and landing on a human liver – First in Moon vivo liver chromosome replacement. 2069 100th Anniversary of Broad use of chromallocytes: Our biological age restored Man landing on the once a year to a more or less constant physiological age that Moon we select.

6. Chromallocyte on the Map of Strategic Technology Areas 41 different strategic technology areas that will have a profound impact on the entire economy including healthcare sector are listed in Table 3 below [11]. Chromallocytes coupled with telemedical devices and bioelectronics of other kind have potential to redefine medical care.

Table 3. Emerging technology areas that will soon have a profound impact on the entire economy including healthcare sector. Order does not reflect importance.

I Human-Machine Interaction - Requesting Things from Machines 1 Hybrid Brain-Machine Interfaces (HBMI) – Thought to Computer Communication 2 Natural Language Processing 3 Automatic Voice Recognition 4 Mobile, wireless, wearable, and textile computing 5 Computer Implants (connected to tagged smart environment) 6 Neural-mechanical Hybrids 7 Haptics II Machine Intelligence Processing Requests 8 Data and Reality Mining 9 Common Sense Reasoning

10 Reasoning by Analogy 11 Genetic Algorithms 12 Flexible Transistors (e.g. on plastic) Responding to Requests 13 Organic Light Emitting Displays (data glasses, e-paper, smart windows) 14 Speech Generation 15 Affective Computing (emotional communication) 16 Visualization of Data 17 Automatic Summarization /Abstracting Triggering Action 18 Decision Triggers 19 Biomechatronic Interfaces (to cells and biomechanical devices) 20 Electronic Skin III Preservation of Individuality and Security 21 Digital Rights Management 22 Biometrics (Face, Voice, DNA, finger print, behavioral pattern recognition) 23 Biometronics Ethics and Law IV Human-Machine Global Network 24 Adaptive Information Networks with Spontaneous Interoperability 25 Microphotonics (all optical Internet with super high bandwidth) 26 High-temperature Superconductivity (inexpensive power quality devices SMES1) 27 Infinite High-density Data Storage 28 Restructuring Code (Software Engineering) V Intelligent Machines 29 Mobile Robots 30 Nanorobots (Microfluidics, Nanomedicine [12] CHROMALLOCYTE 31 Humanoids (Cyborgs) 32 Machine Vision 33 Machine Learning 34 Human-machine Mergers VI Sources of Energy 35 Batteries, Generators (including Body-heat Batteries) 36 Chemical Molecular Energy (e.g. ATP, Glucose Fuel Cells) 37 Geothermal Energy 38 Tidal Energy (Earth’s tides) 39 Wind /Turbine Energy 40 Solar Energy 41 Superconductive Generators

7. How can we prepare for health care to our genes thus preventing aging. with Chromallocytes available? It could reduce suffering, save lives According to Gianfranco Zaccai’s holistic and enhance human potential. By design principle "we should start preparing analogy to the successful effort to put for the nanorobot era now[…]. We can man on the moon, we should aim at expect technological marvels and chromallocyte landing on the liver by saved lives, but much of this opportunity 2039 – to commemorate the 70th will be wasted unless design plays an anniversary of 1969 man landing on essential role. From the holistic design the Moon. Same strategic planning of nanofactories to the holistic design principles could be applied. We need of a radically different patient/doctor/ dreams with deadlines and funding to family experience, people will still need make progress, dreaming is just not to work and cooperate with each other enough. We need a strategy to get to analyze, diagnose, communicate, and there just like Mercury, Appollo and heal. And since there will be much overlap Gemini research program had strategy between current medical techniques and to put man on the moon in 1969. nanomedicine, we will need to design both the overlap and the transition so that the References solutions do not cause new problems. What [1] http://www.rfreitas.com treatment could be more “transparent” than [2] Erwin Schrodinger, “ What is Life” nanotechnologies operating on their own, Cambridge University Press, 1967. undetectable by the patient? Yet they will [3] Robert A. Freitas Jr., “The Ideal still interact with individual human beings— Gene Delivery Vector: Chromallocytes, both patients and caregivers—who will Cell Repair Nanorobots for have individual logistical, social, emotional, Chromosome Replacement Therapy,” and physiological needs and different J. Evol. Technol. 16 (June 2007):1-97. motivations and levels of understanding. It http://jetpress.org/v16/freitas.pdf will be the task of design to optimize this [4] Robert Freitas, “Welcome to the future experience for all the people who are Future of Medicine”, in R. G. Bushko Ed. involved." [16] Strategy for the Future of Health, IOS Press 2009. 8. Conclusions [5] Tad Hogg & Robert A. Freitas Recently, The most important technological Jr.,"Chemical Power for Microscopic event was the technical description of Robots in Capillaries" (submitted for chromallocyte - nanorobot that would be publication) 2009 http://arxiv.org/ capable of replacing chromosomes on a abs/0906.5022 cell by cell basis in vivo, throughout the body by Robert Freitas [3]. Significance of chromallocyte comes from its ability to painlessly reverse the effects of genetic disease and other accumulated damage 1 Superconducting Magnetic Energy Storage

[6] Robert Linares, Patric Doering, Bryant Linares, “Diamond Bio Electronics”, in R. G. Bushko (Ed.) Strategy for the Future of Health, IOS Press 2009. [7] Benjamin Miller, “Diagnostics for a Personalized Medical Future: Extending our Senses to the Molecular Scale”, in R. G. Bushko Ed. Strategy for the Future, IOS Press 2009. [8] Noriaki Oyabu, Oscar Custance, Insook Yi, Yasuhiro Sugawara, Seizo Morita, “Mechanical vertical manipulation of selected single atoms by soft nanoindentation using near contact atomic force microscopy,” Phys. Rev. Lett. 90 (2 May 2003):176102 [9] Robert A. Freitas Jr., Ralph C. Merkle, “A Minimal Toolset for Positional Diamond Mechanosynthesis,” J. Comput. Theor. Nanoscience, May 2008. [10] The Nanofactory Collaboration: http:// www.MolecularAssembler.com/Nanofactory [11] R. G. Bushko Defining Future of Health Technology, in R. G. Bushko (Ed.) Future of Health Technology, IOS Press 2002 [12] http://www.nanomedicine.com [13] Tad Hogg, Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids, in Renata G. Bushko Ed. Strategy for the Future of Health, IOS Press 2009. [14] Rob Burgess,“Medical Applications of Nanoparticles and Nanomaterials”, in Renata G. Bushko (Ed.) Strategy for the Future of Health, IOS Press 2009. [15] James D. Watson with Andrew Berry, “DNA: The Secret of Life”, Knopf, 2003. [16] Gianfranco Zaccai, “Designing the Future of Healthcare”, Strategy for the Future of Health, Ed. Renata. G. Bushko, IOS Press 2009

Rob Burgess / Chapter 31: Nanotechnology and its 1. Nanotechnology and Its Impact on Nanotechnology and its Impact Impact on Medicine Medicine on Medicine in Rob Burgess, Ph.D. Nanotechnology refers the use and World Health Strategy” eBook, Chairman and President application of particles and/or devices (Ed.) Renata Medical Nanotechnologies, Inc. which are less than 500 nanometers G. Bushko, FHTI, 2016. (nm) in size (1). Nanomedicine is Futureofhealth. Abstract defined as the medical application org From Strategy for the urrent clinical diagnostics and of nanotechnology (2), which Future of Health therapeutics platforms are often spans a broad-based plethora of (Ed.) Renata G. Bushko, IOS limited by borderline sensitivity or methodologies for tackling some of Press 2009 C efficacy levels. These limitations result from medicines most difficult problems. low or minimal specificity for the intended Already, a great deal of progress has target cell or organ, span a multitude been made in this area with respect of physiological disorders and result in to the application of nanomaterials nominal success rates for diagnosis or and, more specifically, nanoparticles treatment in many cases. Diagnosis and for diagnostic and therapeutic treatment of diseases such as cancer or applications, which are defined by viral infections require next generation the Royal Society and Royal Academy medical methods. Nanotechnology has of Engineering as being a size of the potential to significantly address <100nm. Many researchers now diagnostics and therapeutics sensitivity share a forward vision in the field and resulting unwanted side effects by regarding nanotechnology’s eventual providing extremely precise reagents and significant impact on the field of tools that allow for unparalleled detection medicine. Dr. Peter Searson, Director and treatment at the clinical level. This is for the Johns Hopkins Institute for accomplished through extremely controlled Bionanotechnology, stated: nanofabrication methodologies which result in the generation of molecularly defined Very simply, we will develop new nanoscale materials and devices that harbor scientific tools and create new known physical properties unique to each technologies for the diagnosis and material in question and useful for particular treatment of diseases and medical medical applications. The further precise conditions. We will develop new targeting of these materials to specific sites tools that will allow us to develop within the body allows for an added layer a better understanding of how of accuracy and potency. Research in cells function and misfunction, at this area is quickly advancing to the point the molecular level. Research will of providing a comprehensive portfolio also focus on the development of of nanotechnology-based diagnostic new diagnostic and therapeutic and therapeutic platforms that will be strategies, for example, for the early unparalleled in sensitivity, specificity and detection and treatment of cancer elimination of unwanted side effects. (3).

It is clear that the advantages of 200 companies worldwide have nanoparticles and nanomaterials over other introduced a total of 38 approved platforms, such as their large surface-to- products classified as nanomedicines mass ratio and ability to bind and carry that have resulted in approximately other molecules and absorption properties, $6.8B USD in sales. These products provide a unique opportunity to diagnose were the result of approximately $3.8B and treat a variety of human disorders with USD in research and development higher efficacy and fewer side effects than expenditures (6). Thus, while the NIH that exhibited by existing platforms. This has funded a major attempt at the chapter focuses on the current advances study and classification of nanomaterial and future prospects for nanoparticles and and nanoparticle properties, private nanomaterials as they relate to detection, industry has turned this fledging prevention and treatment of disease. In science into a revenue-generating these areas it has been estimated that as far opportunity. This trend will no doubt back as 2006, around 130 nanotechnology- continue as nanomedicine not only based therapeutics or delivery systems becomes a reality but nanoparticles were under development worldwide (4). To become accepted for their unique and this end, in 2005 the United State National beneficial physical properties as they Institutes of Health (NIH) established a relate to therapeutic applications. national network of eight Nanomedicine Development Centers “which serve as the 2. Nanoparticles and Medical intellectual and technological centerpiece Applications of the NIH Nanomedicine Roadmap Initiative Given their small size, even relative (5).” These centers have a central focus to to individual cells and viruses, probe the physical properties of nanoscale nanoparticles represent an ideal materials and biological structures in order platform for the delivery of therapeutic to glean a thorough understanding of platforms at the molecular level. their utility and potential toxic properties. Nanoparticles of a variety of different Such an understanding will create a solid origins may be utilized for effective foundation for the use and application drug delivery or may act directly as the of these materials in diagnostics and therapeutic agent through combined therapeutics-related endeavors. While this applications with external fields such initiative has a projected completion date as near infrared light or radiofrequency of 2010, a second phase has already been waves (Table 1). The particles may approved to turn this acquired knowledge be delivered nonspecifically through into fundamental platforms for understanding natural accumulation in a particular and treating disease. physiological site or through site- Others in industry are considerably specific targeting via a variety of ahead of the curve in driving practical agents such as antibodies, aptamers, applications of nanotechnology in medicine. peptides or other small molecules. It has been estimated that as of 2004, over

Table 1. Examples of high-profile nanoparticles Perhaps the largest focus in the currently under study as potential carrier, therapeutic area of nanoparticle-based drug and/or imaging agents. delivery has been on biodegradable polymers that release a drug over time. Composition of Potential Clinical Clinical Nanoparticle Uses Trials A number of these have been pursued Underway since late 2002 and include chitosan, Carbon Direct No gelatin, hydrogels, magnetic iron oxide, Nanotubes Therapeutic, PLGA and solid lipid formulations Drug Delivery, among others (8). For example, Imaging researchers at the Albert Einstein Lipid-PFCs Imaging No Centre in Nottingham, UK Liposomes Drug Delivery Ye s demonstrated effective nasal delivery Gold Nanoshells Direct No of insulin utilizing a chitosan Therapeutic nanoparticle-based carrier platform (9). Cascone and colleagues in the Micelles Drug Delivery Ye s Department of Chemical Engineering Paramagnetic Direct Ye s at the University of Pisa, Pisa, Italy Nanoparticles Therapeutic, developed and optimized a system Drug Delivery, based on nanoparticles of gelatin for Imaging the delivery of methotrexate. In order Quantum Dots Imaging No to assess the general properties of gelatin nanoparticles, particle size, 2.1 Nanoparticle-Based Drug Delivery drug encapsulation efficiency and The efficacy of a drug and its successful, release rates were extensively specific and contained delivery within the characterized in vitro (10). Gupta et al. human body is limited by the composition of at the University of Glasgow in the drug itself, any adjuvants used and the Scotland have formulated a hydrogel drug’s half-life after delivery. A platform that composed of pullulan nanoparticles for enhances such parameters as site-specific delivery of nucleotide-based delivery and biocompatibility while reducing therapeutics thus opening the door to toxic effects has the potential to become the reality of nanoparticle-mediated influential in a number of therapeutic areas. gene therapy. These studies could All in all, the ultimate goal of most if not all open the door to realistic nanoparticle- nanomedicine initiatives is to significantly based gene therapy platforms. The increase the therapeutic index, which is a same group has studied the comparison of the amount of a therapeutic application of superparamagnetic iron agent that causes the therapeutic effect to oxide nanoparticles (SPIONs) for drug the amount that causes toxic effects (7). delivery, combining the hydrogel and Nanotechnology provides multiple iron oxide approach by coating methodologies to address each of these SPIONs with pullulan to reduce critical issues. cytotoxicity and enhance cellular

uptake (11). Poly (D,L-lactic-co-glycolic) acid advantages and disadvantages with (PLGA) is a biodegradable nanoparticle naturally occurring coatings lacking polymer widely studied as a drug delivery binding specificity and synthetic vehicle. Most recently, researchers at coatings posing toxicity issues. Wayne State University in Detroit optimized Implementing organic linkers, magnetic this polymer to function as a carrier for siRNA nanoparticles have successfully therapeutic molecules, demonstrating yet delivered both gene- and drug-based another avenue for nucleotide-based therapeutics platforms. As early as therapeutics delivery using nanotechnology 2000, Cathryn Mah and colleagues at (12). Solid lipid compositions at the the University of Florida constructed nanoscale have also been formulated for magnetic nanoparticles coated with an topical delivery applications. Wissing et al. at adeno-associated virus (AAV) the University of Berlin, for example, have containing DNA sequences coding for developed a novel sunscreen delivery green fluorescent protein (GFP). They system based on the incorporation of demonstrated that the combination of tocopherol acetate into solid lipid the virus and nanoparticle yielded nanoparticles, illustrating this platform as significantly improved GFP expression a superior delivery system than more in vitro and in mice (18). More recently, conventional agents (13). Wilson et al. at the University of Other non-biodegradable nanoparticles California at San Francisco performed have also been studied for their properties a successful clinical trial by targeting in the delivery of both drugs and nucleotide- the anticancer drug doxorubicin linked based therapeutics. Magnetic nanoparticles, to magnetic carriers to hepatocellular for example, were proposed for drug carcinomas using magnets to draw the delivery as early as the 1970s (14, 15). The particle/drug complexes to cancerous properties of these particles include a tissue (19). magnetic core that could encompass a All of the above examples of metal or polymer coating to which drugs nanoparticle-based drug and could be attached. The function of these therapeutic delivery depend upon a coatings allows for the attachment of drugsNanotechnology number and its of physical factors. Even that may act in various therapeutic scenarios.Impact on Medicinesubtle differences in particle size, for Perhaps the most popular of these magnetic example, may significantly affect the nanoparticles is iron-oxide, fairly nontoxic delivery system’s ability to present a after removal of metals used to catalyze its therapeutic moiety inside cells or even synthesis. To prevent corrosion and inside various organelles within the cell promote biocompatibility, iron oxide such as lysosomal compartments. nanoparticles may be coated with naturally Even particles with a similar size may occurring polymers such as carbohydrates have varying biocompatibility and and protein or synthetic organic polymers therapeutic delivery efficiencies due to including, but not limited to, PEG and variations in shape and chemical polyvinyl alcohol (PVA) (16, 17). Each has its composition. Other physical

properties, such as sensitivity to applied diffuse efficiently across the cell external fields, may actually aid in the membrane (22). Larger nanoparticles release of therapeutic agents once the site have been optimized for intracellular of intervention is reached. Gold entry via endocytic mechanisms nanoparticles and carbon nanotubes, for through coating with polymers such as example, are sensitive to near infrared light PEG and PLGA (23, 24). (near IR) and radiofrequency (RF) waves, Delivery of nanoparticle/drug emitting intense heat upon exposure to complexes to the surface of specific these fields (20). Rapid heating of these cell types has been successfully nanoparticles could act as a methodology accomplished by a number of for dissociation and activation of attached researchers both nonspecifically and inactive drugs. Other thermosensitive specifically targeted to unique cell nanoparticle polymers such as polyethylene surface receptors. The attachment of glycol (PEG) and poly-L-lactide (PLLA) have ligands which bind general classes of shown increased cytotoxicity in a cancer carbohydrates to the surface of model following delivery of doxorubicin and nanoparticles has been demonstrated an increase in local temperature from 37 to increase nonspecific cell surface deg. C to 42 deg. C (21). binding (25). Carbon nanotubes have The use and application of nanoparticles successfully targeted tumor cells in as treatment delivery vehicles follows a vitro via the attachment of antibodies long-held desire to more specifically and which specifically recognize unique accurately provide access to therapeutic receptors expressed by these cells molecules by cells within the body. Delivery (26). In vivo, targeting of nanoparticles to or within subcellular compartments may to individual cell types has been be accomplished via nonspecific diffusion or accomplished by a number of groups. endocytic mechanisms, or through the use Bourges et al. at the National Institute of targeting moieties that drive the of Health and Medical Research in nanoparticle/therapeutic entity to precise Paris, France have targeted retinal locations on the surface or within cells. pigment epithelial (RPE) cells with Depending upon the physical nature and nanoparticle/ocular drug complexes composition of the nanoparticle/drug through diffusions and transretinal complex, it may end up intracellularly within movement (27). Tada and colleagues endosomes or lysosomes and be degraded at Tohoku University in Japan have over time, thus releasing the therapeutic shown highly efficient targeting of agent gradually as may be desired quantum dot nanoparticles to tumor depending upon the mechanism of action. cells in mice using monoclonal The surface composition and size of the antibodies which bind the HER2 nanoparticle plays an important role in the receptor uniquely expressed on these mechanism and efficiency of entry. cells (28). The specific targeting of Nanoparticles of less than 20nm, for nanoparticles and nanoparticle/drug example, have been demonstrated to complexes to particular cell types

within the body and even concise organelle Liposomes, small vesicles targeting within these cells will no doubt composed of phospholipids, are have a significant influence on the perhaps the most extensively studied optimization of their therapeutic efficacies in this arena due to enhanced and reduction of unwanted side effects. biocompatibility and efficiency at delivering water-soluble drugs. In 2.2 Nanoparticles for Targeted Cancer addition, liposomes elicit no toxic Drug Delivery or antigenic reactions. This artificial Perhaps one of the most exciting areas of phospholipid vesicular system (50nm therapeutic potential involving the use and - 1000nm in size) can be effectively application of nanoparticles is the treatment loaded with numerous water-soluble of cancer. Particles of various material drugs within the internal aqueous origins have been studied extensively core. Targeting of liposomes, as as carriers for cytotoxic drug delivery to with other nanoparticles, can be cancer cells in the body. These include accomplished with antibodies, true nanoparticles such as dendrimers and peptides or ligands that bind specific quantum dots as well as nanoparticulate receptors uniquely expressed on compositions of nanoparticles like solid the surface of cancer cells. Recent lipids, micelles, microcapsules and research has suggested, however, that lipoproteins (for review see 8). The liposome immunocomplexes have a desired advantages of using nanoparticle- short half-life in the circulatory system based drug delivery platforms over more and thus much attention has been conventional adjuvants or carriers are to focused on the use of polyethylene minimize drug degradation and inactivation, glycol (PEG)-coated liposomes, which to increase drug availability and to tend to be significantly more stable reduce side effects by targeting the drug upon administration (29). A number preferentially to the site of treatment. of liposome/drug platforms have now As mentioned above, both been approved for clinical investigation biodegradable polymers and non- or are undergoing clinical evaluation biodegradable metal nanoparticles have for the treatment of different types of been successfully implemented to deliver cancers including Kaposi’s sarcoma, drugs for cytotoxic purposes in the treatment recurrent breast cancer, non-Hodgkin’s of cancer. Perhaps the most thoroughly lymphoma, ovarian cancer, solid characterized to date have been liposomes, tumors, metastatic melanoma and polymeric nanoparticles and micelles, due some forms of leukemia (8). to their drug encapsulation efficiencies and For water-insoluble drugs, micelles biodegradation properties. All of these have shown promise as effective delivery platforms can encompass unique carriers. Micelles are nanoparticulate and specific surface modifications that compositions of surfactants of between increase biocompatibility and allow for the 5nm and 100nm, significantly smaller efficient attachment of targeting agents. than liposomes. This small size not

only aids in stabilizing water-insoluble drugs Table 2. Examples of targeting moieties and but enhances spontaneous penetration into their applications in cancer therapeutics (Courtesy Medical Nanotechnologies, Inc., interstitial body compartments that have Richardson, Texas). leaky vasculature, a hallmark of tumors. It Targeting Targeting Cancer Known has been demonstrated that water-insoluble Agent Agent Application Example(s) cytotoxic anticancer drugs incorporated Monoclonal Cell Breast, Herceptin, into micelles preferentially accumulated into Antibody Surface or Colorectal, Erbitux, tumors as opposed to non-target tissues Internalized Head and Avastin, (30). This is termed “passive targeting” Neck, Rituximab Lymphoma Tarceva, and can be a very effective delivery Iressa methodology to tumorigenic tissues (31). Small Cell Lung Tarceva, Targeting cancer cells in the body with Molecule Surface, Iressa anticancer drugs has been a central focus Intracellular of cancer research for the past several Aptamer Renal, Lung Renal, Lung AS1411 (in decades. Generally strong cytotoxins, dev.) anticancer drugs kill cells they come into Peptide Cell Breast, RGD (in Surface, Thyroid dev.) contact with, whether those particular Intracellular cells are tumorigenic or not. The basis of chemotherapy is to kill rapidly dividing Tumor cells overexpressing the HER2 cells in the body. Unfortunately this applies receptor, for example, have been to many normal cell types, such as those effectively targeted with liposomes of epithelial origin like skin and the lining conjugated with anti-HER2 antibodies. of the stomach, and thus the premise of Park et al. at the University of California chemotherapeutic treatment is to kill the - San Francisco demonstrated that cancer cells before you kill the patient. these immunoliposomes showed Targeting cytotoxic drugs specifically to superior cytotoxic effects both cancer cells will no doubt increase efficacy in vitro and in rats compared to and decrease unwanted side effects such non-targeted liposomes and the as death. Ligands that bind to cancer enhanced therapeutic activity was cells have been attached to a number of attributed, at least in part, to receptor- nanoparticle/drug delivery compositions mediated endocytic delivery of and have been shown to target tumorigenic the anticancer agent inside the cells in vitro and in vivo. Table 2 lists some cells. Other successful targeting of the more prominent examples of targeting formulations of immunoliposomes agents that have been studied for homing in include GD2-targeted fenretinide on unique types of cancer cells in the body to neuroblastoma and melanoma to exert a drug’s cytotoxic effects. cells and anti-VEGFR2 liposome targeting of human cancer cells in vitro (32, 33). PEGylated poly(lactic acid) immunoparticles have also been successfully targeted with anti-

transferrin receptor antibodies to cell lines identity of the nanoparticles utilized in expressing the transferring receptor (34). the studies. Folate receptor nanocarrier targeting has also received much attention as many tumor Magnetic Nanoparticles cells preferentially overexpress this receptor during oncogenesis. Liposomes containing As early as 1957, researchers either daunorubicin or doxorubicin have studied the use of magnetic fields been targeted both in vitro and in mouse in combination with an absorption xenograft models to a number of tumor platform as a method for enhanced cells and been shown to exhibit increased delivery of hyperthermic conditions cytotoxicity in comparison to administration to specific parts of the body. In these of the non-targeted complexes (35, 36). studies, researchers developed a Amphiphilic micelles containing paclitaxel, strategy to apply heat to cancer- a lipophilic anticancer compound, were positive lymph nodes through the targeted with high efficiency to folate localization of fine magnetic particles receptor-expressing Hela cells in vitro and within the lymph nodes followed demonstrated subsequent cytotoxic effects by “selective heat induction” via (37). The intense focus of targeting cancer the application of a magnetic field. cells with cytotoxic drugs will only increase This resulted in the eradication of as nanotechnology-based delivery platforms lymph node-specific cancer cells continue to show encouraging results. (38). Nanoparticles such as iron oxide, Fe3O4, and magnetite absorb 2.3 Thermal Ablation and Cancer magnetic fields at very high efficiency. The study and application of nanoparticles This absorption ultimately results in for the treatment of cancer is not limited energy emission in the form of heat. to drug delivery. In certain instances, The interplay between magnetic depending upon composition and physical nanoparticles and magnetism has properties, the nanoparticles themselves now been exploited by a number may act as the therapeutic agents. of researchers for its applications in Much attention has been paid to certain the hyperthermic ablation of cancer nanoparticles’ ability to absorb energy cells. In vivo studies of iron oxide upon exposure to external fields such as nanoparticles administered into SCID magnetism, light or radiofrequency waves. mice implanted with human breast The absorption of this energy is ultimately adenocarcinoma cells followed by emitted in the form of heat (hyperthermia), exposure to an alternating current with the efficiency of absorption and (AC) magnetic field were successful emission depending upon the nanoparticle in inducing coagulation and necrosis composition and the field of energy to which specific to tumor cells (39). Johannsen it was exposed. Below are descriptions and colleagues at the Charite- of some of the latest and most high profile Universitatsmedizin in Berlin, Germany research in this area categorized by the have shown that thermo-ablative

temperatures can be achieved with high resulted in a significant increase in efficiency in a Phase I clinical trial of ten cytotoxic effects of B16 melanoma cells patients where iron oxide nanoparticles in compared to irradiation or use of the solution were introduced into the prostates chemotherapy alone. The researchers of patients followed by successive exposure took the study a step further in vivo to an alternating current magnetic field and demonstrated an additive effect (40). In industry, the concept of magnetic of 4-S-CAP/MCL and magnetic nanoparticle applications in cancer field-inducing hyperthermically and treatment has reached the industrial level. chemically induced cytotoxicity The company Triton Biosystems, now following Intratumoral injections of known as Aduro Biotech, in Berkeley, CA the complex in mice (43). The same has developed the NTTM and TNTTM researchers recently developed a proprietary cancer therapeutics platforms combination therapeutic platform of which are based upon the use of iron liposomes complexed with anti-HER2 oxide nanoparticles and externally applied receptor antibodies and containing magnetic fields to induce hyperthermic magnetite nanoparticles. Anti-HER2 ablation of cancer cells. The relatively low antibodies not only specifically target toxicity of iron oxide may allow for high HER2 expressing cells but also inhibit doses of the nanoparticles to accumulate the proliferative capacity of these cells. within the tumor site. Clinical trials are This combination of hyperthermic expected to begin in 2009 (41). induction via alternating current In addition to the sole use of magnetically magnetic exposure of the magnetite induced heat to ablate cancer cells, nanoparticles with anti-HER2 antibody combination therapeutics in which both effects resulted in a striking efficiency nanoparticle-based hyperthermia and proliferative reduction and cytotoxicity chemotherapy are applied in concert in the breast cancer model cell line has yielded some exciting results (for SKBr3 (44). Similar effects were also review see 42). Magnetite nanoparticles shown in vivo (45). combined with chemotherapeutic agents in liposomes have been used with striking Nanoshells success to treat malignant melanoma. Specifically, Ito and colleagues at Nagoya Considered the best nanotechnology University in Japan developed magnetite discovery for 2003 by Nanotech cationic nanoparticles complexed with Now (46), gold nanoshells were first the chemotherapeutic agent 4-S-CAP considered as a cancer therapeutics (4-S-CAP/MCL), which acts to induce the platform by the researchers Naomi killing of both melanocytes and melanoma Halas and Jennifer West at Rice cells. The in vitro study demonstrated that University in Houston, Texas. They the combination of efficient hyperthermic showed that silica nanoparticles induction by alternating current magnetic surrounded by thin gold nanoshells field of the nanoparticles with 4-S-CAP could be tuned to optimally absorb

light in the near-infrared range and convert We believe AuroLase Therapy will this energy to therapeutic levels of emitted have broad applications in cancer. heat. SKBr3 breast cancer cells were We will initially focus on head and effectively ablated in vitro upon exposure to neck cancer to fill the significant near IR light when cultured in the presence unmet medical need in this serious of gold nanoshells. The researchers also cancer, and then expand to other demonstrated in vivo therapeutic efficacy cancers after FDA approval. We using SCID immunocompromised mice hope to start our first human trial injected with canine TVT cancer cells. later in 2006 (51). Intratumoral injection followed by exposure to near IR light yielded significant tumor Therefore it appears that the tissue damage as evidence by coagulation, application of gold nanoshells cell shrinkage and the loss of nuclear combined with near IR-induced staining (47). Halas, West and colleagues hyperthermia for the treatment of also demonstrated successful targeting of cancer has the solid backing of both gold nanoshells to SKBr3 cells using anti- academia and industry and may HER2 antibodies and hyperthermic ablation indeed become a standard therapeutic of these cells in vitro (48). Several groups, procedure for some types of cancers. including West and colleagues, have since expanded on these studies and shown Polymer-Solubilized Carbon efficacy in ablating a variety of different Nanotubes types of cancer cells both in vitro and in vivo. These include medulloblastoma, Due to its inherent small size and glioma, and prostate cancer cells (49, 50). extreme sensitivity to external fields, One drawback of this technology lies in the polymer-solubilized carbon the inability of near IR light to effectively nanotube (CNT) provides one of the penetrate beyond several centimeters most promising nanoparticle platforms below the skin’s surface. Thus deep tissue for the hyperthermic treatment of therapeutics may be hindered by ineffective cancer. Carbon nanotubes are nanoshell excitation and heating. allotropes of carbon atoms arranged As is the case for the magnetic in a chicken wire-like configuration nanoparticle cancer therapeutics platform, rolled back upon itself. CNTs typically gold nanoshells and their application to the have a length to diameter ratio greater treatment of cancer have been taken on than 1,000,000 and have been by industry and are now the central focus pursued for use in a variety of materials of the Rice University spinout Nanospectra applications due to extremely high Biosciences. J. Donald Payne, the strength to mass ratios. In addition, company’s President and CEO, made the based in their physical properties, point that nanoparticles may affect a broad CNTs rapidly heat up in the presence spectrum of cancer phenotypes, stating: of radio frequency (RF) waves or near infrared light. These properties make

CNT-based hyperthermic ablation of cancer cells a possibility and much research has been conducted in this area to date. One of the first studies carried out to assess the use of CNTs and near IR light demonstrated the delivery of oligonucleotides inside cells by CNTs. Exposure to light of a specific infrared Figure 1. Carbon nanotube functionalized with KenteraTM (Courtesy Zyvex Performance wavelength resulted in endosomal release Materials, Columbus, Ohio for which Kentera is of oligonucleotides into the cytoplasm and a trademark). hich Kentera is a trademark). nuclear translocation, but it also revealed efficient induction of cell death due to A great deal of effort by Zyvex Performance hyperthermic conditions (52). Materials’ researchers has been focused on Carbon nanotubes can exist as both multi- the efficient solubilization of MWCNTs and walled CNTs (MWCNT) or single-walled CNTs SWCNTs in water. Formulation of a unique (SWCNT), with the greatest limitation for utility and proprietary version of Kentera containing as their tendency to tightly clump, primarily as aliphatic side chains has resulted in extremely a result of van der Waals interactions between efficient water dispersion of both SWCNTs and the carbon atoms (53). This bundling effects MWCNTs (Figure 2). The dispersion is stable, results in considerable insolubility in a variety and even appears to aid in the CNT’s ability of solvents, including water, and has been the to absorb RF waves and emit heat (54). Other focus of major industrial efforts to develop polymer compositions are also effective at polymers that allow for the solubilization of dispersing CNTs in an aqueous environment. both MWCNTs and SWCNTs in a variety of Rocky Draper and colleagues at the University solvents. Zyvex Performance Materials (ZPM), of Texas at Dallas have identified peptide- based in Columbus, Ohio, is at the forefront of based polymers that solubilize CNTs in an this effort, developing a proprietary polymer, aqueous environment with a similar efficiency termed to that of Kentera (55). In addition, Nish and “Kentera” (Greek for “bridge”), that allows colleagues at Oxford University, Oxford, for a significant reduction in van der Waals U.K., have performed an extensive analysis interactions between the CNTs. Kentera acts of aromatic polymers and their efficiencies by binding to individual CNTs through non- at dispersing carbon nanotubes and covalent electron stacking and thus masks demonstrated that different polymers possess and minimizes van der Waals attractions the ability to discriminate between nanotube (Figure 1). In addition, Kentera’s side chains species with respect to chiral angle or even can be customizable to allow for unique tube diameter (56). interactions with virtually any type of solvent, thus allowing for relatively universal and efficient CNT soluble dispersion. The side chains can also be modified efficiently to attach receptor-specific targeting agents like antibodies and small molecules. Figure

of Kentera-SWCNT dispersions and exposure to the 13.56 MHz RF field massive tumor-specific cell death was observed as evidenced by thermal necrosis of the tumor tissue. In Figure 2. Kentera-mediated multi-walled carbon nanotube dispersion in water. A. SEM image of addition, the studies suggested no raw, bundled MWCNTs. B. SEM image of 2% wt/vol observable toxic effects resulting from MWCNTs after dispersion in water with Kentera. C. exposure to the polymer or carbon MWCNTs in water in the absence (left) and presence nanotubes themselves (57). It should (right) of Kentera (Courtesy Zyvex Performance Materials, Columbus, Ohio). be noted that the Kanzius RF signal generator has been successfully used The ability to effectively disperse carbon to demonstrate proof-of-concept, nanotubes in an aqueous environment in vitro and in vivo, for hyperthermic allows for their possible applications in ablation of tumor cells using other human therapeutics, as they now may types of nanoparticles such as gold be effectively introduced into the body nanoshells (58). at high concentrations and under normal While non-targeted localized physiological conditions. The inherent introduction of the hyperthermic agent sensitivity of CNTs to either near infrared remains promising, light or radiofrequency waves allows for it is also nonspecific and will in most the possibility of hyperthermic ablation cases result in the unwanted death of unwanted cells in the body following of surrounding tissues, as evidenced introduction of dispersed CNTs and by the research cited above. To exposure to an external field. Researchers address this detrimental non-specificity, at the University of Texas M.D. Anderson researchers at the University of Texas Cancer Center, in collaboration with Zyvex Southwestern Medical Center in Dallas, Corporation which supplied Kentera- Texas have focused on targeting solubilized SWCNTs, showed highly efficient carbon nanotubes to tumor cells using ablation of human cancer cells in vitro and in moieties attached directly to the CNTs, vivo. Specifically, human hepatocellular and which bind specifically and tightly to adenocarcinoma cells were grown in tissue receptors on the surface of cancer culture and treated with Kentera-SWCNT cells. In these studies, Ellen Vitetta and dispersions followed by exposure to a colleagues demonstrated the specific radiofrequency wave of 13.56 MHz using a binding of polar lipid solubilized anti- variable power RF signal generator invented CD22-CNTs to Daudi lymphoma cells by the late John Kanzius of Therm Med, which express the CD 22 receptor. LLC (Erie, PA). Enhanced bulk heating was Exposure of these cells to near IR light observed, followed by massive cytotoxicity. resulted in very specific and efficient The studies were expanded upon in New killing in vitro (59). Taken together, Zealand white rabbits inoculated with VX2 these findings suggest that there are tumors. Following intratumoral injection a multitude of dispersion and targeting

methodologies that will allow for specific contrast agents either within the access to and ablation of, cancer cells within liposomal core or external in the the body. hydrophobic membrane pending the use of a metal chelating agent (60, 61). 2.4 Nanoparticles and Cancer Diagnostics Polyethylene glycol (PEG)-based micelles were also used Current noninvasive imaging techniques to carry paramagnetic Gd and for for the diagnosis of tumors such as both MRI and scintigraphy imaging magnetic resonance imaging (MRI), gamma (62). In addition to biocompatibility, scintigraphy or computed tomography (CT) another advantage of both liposomes require a certain level of signal intensity and micelles is their small size, which with respect to the lesioned area over allows for accumulation at very high healthy tissue to be effective at diagnosis. concentrations within the tumor. Even with enhanced image processing and other optimization techniques, often the Quantum Dots - Nonspecific successful diagnosis of a tumor with MRI or CT requires a relatively large pathological Quantum dots are composed of an area. Recent years have seen the advent elemental core, such as cadmium or of contrast agents that interact with external mercury, surrounded by a metal shell fields to heighten the sensitivity of the and they typically emit fluorescent light diagnostic procedure by absorbing external in the range of 400nm to 2000nm due field signals much more efficiently than to electron excitation (63). Quantum surrounding tissues. Yet even a further dots are superior to other types concentration of contrast agents at the of fluorescent molecules due to a tumor site has been desired and thus logarithmically increased ability to nanoparticles have been pursued as carriers resist photo-bleaching, compared to to increase contrast agent concentration. fluorescent compounds of organic Some of the more high-profile nanoparticle- origin (64). A great deal of study on the based cancer diagnostics platforms, both utility of quantum dots in the analysis non-specific and targeted, are discussed of basic cell biology to lymph system below. marking has been undertaken over the last several years (For review see 65). Liposomes and Micelles - Nonspecific In addition, much attention has been directed at fine tuning quantum dots Liposomes and micelles have received to fluoresce in the near IR spectra to much attention in this area due to favorable overcome auto-fluorescence and lack biocompatibility and conjugation properties. of tissue penetration which typically Tilcock and colleagues in the Department occurs in the visible range. Parungo of Biochemistry at the University of British et al in the Division of Cardiac Surgery Columbia in Vancouver have shown that at Brigham and Women’s Hospital in liposomes may be used to carry metal Boston have shown that these NIR

tuned quantum dots can act as effective St. Louis, MO demonstrated the use of diagnostics tools in several animal models, lipid-coated perfluorocarbon specifically within the lymph system (66). It (PFC) nanoparticles as excellent should be noted that quantum dots have targeted ultrasonic contrast agents one important disadvantage in that their with potentially broad biomedical heavy metal core remains highly toxic. Thus, applications. Specifically, they outer coatings that ensure safety will have to detected fibrin clotsin vivo using be developed. This is discussed in further an antifebrin monoclonal antibody detail in Section 2.8. conjugated PFCs (68). These studies have since been expanded upon to Gold Nanoshells - Nonspecific address cancer diagnostics using the same basic system. Kereos, Inc., also Similar to that of quantum dots, the of St. Louis, is a company founded to engineering process for gold nanoshells capitalize on the application of lipid- allows them to be optically tuned for coated PFCs for diagnostics purposes maximum diagnostics effectiveness in the with a focus on using the same system IR, UV and visible spectra. In addition, to deliver drug payloads. The company nanoshells lack the heavy metal toxicity now has a number of diagnostic and issues underlying quantum dots. Non- therapeutic molecules based on lipid- targeted nanoshells have been shown PFC nanotechnology in the preclinical by researchers at Texas A&M University pipeline (69). and Nanospectra Biosciences to be good contrast agents for both computerized and Magnetic Nanoparticles - Nonspecific photo-acoustic tomography in vivo (67). Finally, the combination of their hyperthermic Superparamagnetic nanoparticles and optical properties makes gold have been extensively studied as nanoshells a platform that may allow for dual alternative contrast agents to that simultaneous diagnostics and therapeutics of gadolinium, for example, due to endeavors. As mentioned above, it should a greater propensity for magnetic be noted that gold nanoshells rely on near susceptibility. In addition, their small infrared light as the external field which does size, 50nm - 100nm, has been shown not penetrate further than a few centimeters to allow for more extensive tissue below the skin’s surface, thus limiting the distribution (70). A great deal of clinical nanoparticles’ utility for deep tissue imaging research has been performed in this or treatment. area with a focus on the use of iron oxide nanoparticles to characterize Lipid-PFCs - Targeted lymph node status for patients with a variety of cancers including As early as the mid-nineties, a pioneering breast, lung, prostate, endometrial group of researchers lead by Samuel and cervical cancers. Keller and Wickline at the Barnes-Jewish Hospital in colleagues at the Institute of Diagnostic

Radiology in Zurich, Switzerland evaluated syncytial virus (RSV) and allow for its superparamagnetic iron oxide (SPIO) efficient detection both in vitro and in enhancement for preoperative axillary lymph vivo (76). Nanoshells conjugated with node staging in breast cancer patients. anti-HER2 antibodies were targeted They found in two cases that preoperative to tumor cells in vitro that express the findings using SPIO led to a change in HER2 receptor and detected via near therapeutic approach due to increased IR optical computerized tomography sensitivity (71). A multicenter clinical trial (77). The anti-HER2 system was of SPIO for the evaluation of mediastinal also used successfully with iron lymph nodes in patients with primary lung oxide nanoparticles to specifically carcinoma also revealed a sensitivity of bind HER2/neu positive cancer correct diagnosis at 92% (72). These studies cells in vitro followed by detection have also been expanded upon for lymph in a magnetic field. A similar result node analyses in patients with endometrial, was demonstrated using luteinizing cervical and prostate cancer thus suggesting hormone releasing hormone (LHRH) that SPIO may become a diagnostic conjugated iron oxide nanoparticles. standard for nonspecific clinical evaluation of This allowed for specific binding to potential lymph node metastases properties LHRH receptors on cancer cells in vitro in cancer patients (73, 74). followed by magnetic field detection (78). Finally, telomerase is an enzyme Other Targeted Nano-diagnostics synthesized by cancer cells that allows them unlimited division capacity The key to effective and sensitive diagnosis through specific DNA sequence is the ability to home nanoparticles in synthesis. Researchers at the Center to the precise locale of the cancerous for Molecular Imaging Research cell type and to eliminate the diagnostic at Harvard Medical school have reagent from other healthy tissues within developed iron oxide nanoparticles the body. A pioneering study conducted by that change their magnetic state upon Shuming Nie’s group at Georgia Institute of binding to the telomerase synthesized Technology demonstrated the localization DNA sequence TTAGGG thus allowing of three different targeted quantum dot for magnetic imaging of telomerase- types to tumor sites in mice using copolymer active cancer cells (79). encapsulated quantum dots tagged with targeting ligands that bind specifically to 2.5 Nanoparticles and Toxicity - The tumor cells (75). Efforts have also been Question Remains expanded beyond cancer diagnostics to The potential toxic effects of utilize quantum dots for the detection of nanoparticles remains a controversial viral particles. Researchers at the University subject and depends on a multitude of Georgia, for example, have developed of factors including the identity of nanoparticles functionalized with monoclonal the nanoparticle, the dosage and antibodies that recognize respiratory final concentrations used, clearance

rates and biocompatibility, just to name a (89). Thus, residual amounts of metal few. Some interesting findings with respect catalysts in the finished SWCNT and to toxicity for a few key nanoparticles are MWCNT concentrates could promote described below. toxicity during therapeutic applications. In addition, the rapid uptake of carbon Gold Nanoshells nanotubes by cells, and the fact that they are non-biodegradable, raises Two independent groups have shown that some issues regarding long-term gold nanoparticles present no observable biodistribution. In vitro, a number cytotoxic effects upon entry into cells (80, 81). of studies have suggested carbon Gold nanorods, however, which carry small nanotube cytotoxicity using various amounts of the stabilizer CTAB no matter cell types such as keratinocytes and how stringent the purification, have exhibited bronchial epithelial cells as model some cytotoxic effects determined to be due systems. Effects observed included to the stabilizer itself as demonstrated by radical oxide synthesis, oxidative Niidome and colleagues in the Department stress responses, reduction in of Applied Chemistry at Kyushu University mitochondrial function and changes in Fukuoka, Japan (82). Nanoshells of a in cell morphology (90, 91). Studies gold/copper heterogenous makeup have by Draper and colleagues at the also been studied for cytotoxic properties University of Texas at Dallas have and exhibited none unless acted upon by shown that carbon nanotubes an external laser to achieve the desired solubilized by the polymer PEDOT/ ablation of tumor cells in vivo (83-85). PSS are rapidly ingested by cells via endocytosis and appear to accumulate Single-Walled and Multi-walled Carbon in endocytic vesicles (see figure 3 Nanotubes below). Whether this accumulation has a long-term detrimental effect on cell In recent years carbon nanotubes have viability remains to be determined. In been perhaps the most controversial of vivo, intratracheal instillation of carbon all nanoparticles with respect to toxicity nanotubes at high doses in rodents concerns. Synthesized as either single caused chronic lung inflammation walled (SWCNT) or multi-walled and fibrosis, although these studies (MWCNT), these nanotubes present several are considered flawed and largely characteristics that cause concern. Methods dismissed due to the extremely high employed to generate carbon nanotubes concentrations of carbon nanotubes include arc discharge, chemical deposition utilized (92, 93). Other studies and laser ablation, and each requires metal indicate an asbestos like effect of catalysts to perform effective synthesis carbon nanotubes when these are (86-88). These catalysts, such as cobalt introduced into the abdominal cavity or nickel, have been demonstrated to be of mice, yet again the high non- highly cytotoxic at certain concentrations physiological concentrations used in

this study suggest further research in this fullerenes are known as Buckminster area is needed to definitively determine fullerenes, or buckyballs, and all the mesothelioma-inducing properties of have properties that may suggest MWCNTs. Contradicting these findings, their role as potent antimicrobial Liu and colleagues at Peking University in agents due to their potential for Beijing, China have performed long-term reactive oxidation induction during (three month) studies on the effects of photoexcitation (95). Perhaps the SWCNTs injected into the main organs of most concerning toxicology issues mice and have shown low toxicity, with only surrounding fullerenes lie not in slight inflammation observed (94). the effect on human but rather, the environment. Discharge of fullerenes into the ecosystem could possibly have detrimental environmental impacts due to the very antimicrobial effects that are thought to aid in the treatment of infections. For example, the median lethal concentration, LC50, for C(60) in Daphnia, a small, planktonic crustacean, was between 460 and 800ppb, raising concerns about general ecotoxicity (96, 97). In higher organisms such as largemouth bass, brain-localized lipid peroxidation was observed two days after treatment with nC60 at 0.5ppm, but the high concentrations of fullerenes used in Figure 3. PEDOT/PSS-mediated intracellular uptake this study suggest further research in of single-walled carbon nanotubes by HEK293 this area is needed (98). cells. Arrows denote dynamic cytoplasmic endocytic vesicles containing carbon nanotubes (Courtesy Quantum Dots Rocky Draper and Austin Edmiston, The University of Texas at Dallas). As mentioned above, quantum Fullerenes dots are semiconductor-based nanoparticles that have unique optical Fullerenes are nanoparticles composed properties which allow the particles to entirely of carbon atoms that exist in various act as extremely valuable diagnostic forms including planar, ellipsoid, tubular agents. Dots of different sizes emit and spherical. They were discovered different light patterns, and dot shape by Richard Smalley and colleagues at may also play a role in color emission Rice University and Harold Kroto at the properties although this has yet to be University of Sussex in 1985. Spherical definitively determined (99). Studies

on the potential toxicity of quantum dots of dendrimers branches, often at very suggest the nanoparticles promote the high concentrations (104). Toxicology formation of reactive oxygen species, which studies on dendrimers and their may play a role in damaging cell membranes derivatives are currently very limited. and the nuclear envelope as well as One example involves the evaluation detrimentally affecting mitochondrial function of polypropylenimine dendrimers (100). As toxicity is a major concern, many conjugates on cultured endothelial groups have made efforts to coat quantum cells. These conjugates resulted dots with biocompatible surfaces. Wang et in significant DNA damage, yet this al, for example, coated cadmium selenium, damage could be minimized or in CdSe, quantum dots with polyethylene some cases completed eliminated glycol casings and observed a reduced following chemical modification of the cytotoxic effect on Caco-2 enterocyte cells parental dendrimers surface amines compared with free uncoated nanoparticles to a neutral state (105). Researchers (101). It is speculated that the toxicity in the Center for Nanomedicine and observed with direct exposure of cells Cellular Delivery at the University of to naked Cd is actually the result of the Maryland - Baltimore noted a similar formation of free radical Cd2+ ions. Adding phenomenon for polyamidoamine to the controversy, other researchers have (PAMAM) dendrimers following surface published data on a variety of quantum acetylation (106). Given the unique dot compositions that demonstrate no nature of each dendrimer composition, observable in vitro or in vivo toxicity (102). it is difficult to perform toxicology studies on this broad class of Dendrimers nanoparticles or to make wide-ranging conclusions. Highly branched molecules of primarily a carbon composition, dendrimers have 3. Nanomaterials and Clinical shown much promise in their application and Neuroscience use for therapeutics purposes. Dendritic The effect treatment of branches allow for the presentation of neurodegenerative disorders such unique functional groups for both the as Alzheimer's and Parkinson's efficient encapsulation of functional diseases as well as amyotrophic molecules and to aid in biocompatibility. lateral sclerosis (AML) is perhaps the Thus, therapeutic agents which are primary focus of clinical neuroscience often hydrophobic in nature can be and represents an area of medicine made biocompatible through coating where nanotechnology can truly have with dendrimer compositions that have an immense and positive impact (for hydrophobic internal cores and hydrophilic review see 107). These disorders external functional groups (103). Drugs which are usually based upon the loss have biocompatible/hydrophilic properties of cells present within the brain or may also be coated on the external surfaces spinal cord that play critical roles

in the "wiring" of the nervous system. In bind specifically to BBB transporting addition, neurodegeneration is often a receptors. These lipid bilayers are secondary effect of such conditions as small enough to cross the BBB yet stroke and head or spinal column trauma. also designed to carry possible gene The accurate diagnosis and treatment of therapies or even large drug payloads neurodegenerative disorders is hampered (111). Solid colloidal nanoparticles by a number of challenges unique to made of biodegradable polymers this field of study. The central nervous have also been shown to deliver a system is defined by a very complex and number of therapeutic agents across heterogeneous population of cell types the BBB. Typically less than 100nm and support matrices. This complicates the in size, these particles can be coated delivery and overall efficacy of diagnostic with substances that make them both platforms or therapeutic drugs. Some of soluble and stabile in the blood. For the efforts at combating neurodegenerative example, Kreuter et al. at the Institut diseases with nanotechnology have been für Pharmazeutische Technologie focused on the use of nanomaterials, in Frankfurt, Germany showed that specifically carbon nanotubes, as scaffolds polybutylcyanoacrylate (PBCA) upon which neurite outgrowth can be nanoparticles coated with a surfactant encouraged (108). Matsumoto and successfully delivered a number of colleagues at Toyo University in Gunma, therapeutic agents across the BBB Japan have expanded on these findings including analgesics, anti-cancer using carbon nanotube scaffolds coated agents and anticonvulsants (112). Other with brain-derived neurotrophic factor examples include pegylated PLA or (BDNF) to stimulate the growth of neurons. PLGA. These and other encouraging Biocompatible nanopolymers such as poly( findings have solidified nanoparticles -hydroxy acids)-poly(lactic acid) (PLA) have and nanomaterials as promising agents also been demonstrated to be effective as of tomorrow for the ultimate treatment scaffolds promoting tissue regeneration CNS disorders. after spinal cord injury. Specifically, mouse brain-derived progenitor cells differentiated 4. Nanofibers and Tissue Engineering into mature neurons in the presence of Perhaps one of the most exciting areas PLA (109). With respect to the brain, the of convergence for nanotechnology blood-brain barrier (BBB) further hinders and medicine is that of tissue delivery of macromolecules such as engineering. Cell/tissue transplantation diagnostic agents or drugs (for review see is often the only mode of therapeutic 110). Delivery across this barrier, however, intervention, especially for burn victims. could be accomplished by basing the Yet the practice of both auto- and delivery platform on nanotechnology. allograft procedures has limitations Immunoliposomes, for example, have been that warrant the pursuit of tissue used to deliver exogenous genes to the engineering/regeneration alternatives. brain using attached antibodies which Given the properties of many types

of nanoparticles and nanomaterials, it isn't mineralization and type I collagen surprising that some mimic the biological synthesis which suggests the scaffolds environment and have been shown to aid in may be utilized for bone tissue the engineering of various living tissues in engineering (119). Li and colleagues vitro. As discussed for clinical neuroscience, in the Department of Biomedical scaffolding of nanomaterials is the primary Engineering at the University of basis for their use in tissue engineering Wisconsin-Madison demonstrated applications. Electrospun nanofibers have that PCL-based nanofiber scaffolds shown the most promise in this area and seeded with fetal bovine chondrocytes can be synthesized from a wide variety maintained their chondrocytic of natural and synthetic biomaterials. The phenotype and expressed several electrospinning process produces fibers cartilage specific genes including of a three-dimensional nature that have aggrecan and collagen type II been used effectively as scaffolds for the (120). Significant advancements engineering of skin, vasculature, neural and have also been made in the musculoskeletal tissue and as carriers for area of skin tissue engineering the delivery of proteins, nucleic acids and using nanofibers. Min et al in the drugs Bioengineering and Biotechnology (for review see 113). Nanofibers have been Center at Tufts University developed spun from a variety of natural polymeric silk nanofibers which, given their materials that offer the advantage of being high porosity and surface area to quite similar to macromolecules present volume ratio, were found to promote in the body. This allows for an increased keratinocyte and fibroblast adhesion probability that introduction of the foreign and spreading when coated with nanofibers into a biological environment type I collagen (121). Engineering of will be met favorably. Collagen, chitosan, the vasculature may also be aided hyaluronic acid (HA) and gelatin/PCL are by the use of nanomaterials. This some examples of natural polymers from field has been a major focus of tissue which nanofibers have been successfully engineering researchers as they generated and utilized in the context of seek new methods and materials tissue engineering (114-117). Yoshimoto to promote blood vessel formation. and colleagues at Massachusetts General A biodegradable PLLA-CL (75:25) Hospital investigated the interactions of nanofibrous scaffold was developed mesenchymal stem cells (MSCs) seeded as a scaffold to mimic the natural ECM onto gelatin/PLC nano-scaffolds and and shown to form a well defined revealed that these cells migrated inside architecture for smooth muscle cell the scaffold and subsequently produced adhesion and proliferation (122). While extracellular matrix (ECM), a natural support these studies are encouraging, the component for virtually all tissues (118). future of nanomaterials as they apply These studies were expanded upon in a rat to tissue engineering will depend model implant of the scaffolds demonstrating upon critical factors such as safety,

biocompatibility, biodegradability three- industry standardization of cell culture dimensional architecture and long-term protocols. To circumvent issues such delivery of factors needed to support as animal component-containing cell adherence, growth, migration and substrates and substrate variability, a differentiation. number of researchers have begun exploring the use and application of 5. Nanomaterials and Stem Cell Culture nanomaterials as support matrices for The efficient culture, expansion and directed human stem cell culture. Kommireddy differentiation of embryonic stem cells and colleagues in the Institute for have been at the forefront stem cell-based Micromanufacturing at Louisiana Tech therapeutics development for the last twenty University in Ruston, Louisiana have years. The ability to maintain stem cells focused on surface topography as in a pluripotential state and prevent the one of the most important factors introduction of chromosomal abnormalities influencing the attachment and has been especially difficult with human spreading of mesenchymal stem cells. embryonic stem cells. These cells require Their studies using titanium oxide a unique set of growth factors, media (TiO2) nanoparticle thin films showed formulations and attachment substrate upon that these particles could be used which to adhere that ideally would mimic successfully as adherence substrates the in vivo environment (for review see 123). and in general rougher surfaces While progress has been made utilizing promoted enhanced attachment mouse embryonic feeders and substrates and expansion (125). Mesenchymal such as Matrigel, these components contain stem cells have also been exploited animal by-products which raises issues for bone tissue engineering regarding the safety of cell therapeutics using magnetic cationic liposome resulting from such culture. As such some nanoparticles as substrates for growth. progress has been made with the utilization Specifically, magnetized cells were of human fibroblast feeders yet these drawn to an attachment surface with cells were originally derived using animal a 4000G magnet and demonstrated byproducts thus again raising concerns to differentiate into osteoblasts, regarding derived therapeutic cells from adipocytes and chondrocytes, a safety and FDA approval perspective depending on the media conditions. (124). Finally, the use of undefined animal Sheets of MSC's layered in this fashion components often introduces yet another were transplanted into nude mice level of unwanted variability in the cell and resulted in new bone formation culture process. Defined substrates are (126). Emphasizing the importance of thus needed to more reproducibly culture serum-free culture of stem cells, Sefcik cells and maintain certain phenotypes. This and colleagues in the Department would allow for more efficient and reliable of Biomedical Engineering at the cell culture and manipulation of embryonic University of Virginia - Charlottesville and adult stem cells and provide a basis for designed a system for the application

of electrospun collagen nanofibers 230 times the efficiency of a natural assembled in a 3D matrix as a biomimetic red blood cell. Other medically substrate for the efficient differentiation relevant nanobots include "clottocytes", of human adipose-derived stem cells into also conceived by Freitas, which osteogenic lineages (127). Others have at 2 microns in diameter and due focused on the maintenance of pluripotency to its incredibly efficient compact of human embryonic stem cells in the fiber mesh design, could offer absence of substrate feeder layers. Studies clotting performance similar to that using liposomal ceramide nanoparticles of biological platelets but at 0.01% of as an attachment platform promoted the the same bloodstream concentration survival of healthy, pluripotent hES cells (130). At the molecular level, Nadrian at the expense of differentiated cells due Seeman, Professor in the Department to a resistance to the apoptotic effects of of Chemistry at New York University ceramide specific to undifferentiated cells and a pioneer in the area of nucleic (128). In the future it can be speculated that acid self-assembly, has developed a wide range of nanoparticle substrates will computer-based methodologies for be utilized to both maintain pluripotency and the design and assembly of three- drive selected and directed differentiation of dimensional DNA structures that these cells towards particular differentiated take advantage of nucleotide base lineages. These advances will both pairing properties. Specifically, his eliminate cell culture variability and provide lab has successfully applied these animal component-free alternatives for algorithms to assemble both a cube matrix attachment. and a truncated octahedron from DNA (Figure 4). Seeman's group has also 6. Nanorobotics and Medicine demonstrated the operation of a DNA Robert A. Freitas, Jr., who has written robot arm inserted into a 2-dimensional numerous books and publications on the DNA crystalline substrate (131). These subject of nanomedicine and is considered nucleic acid-based primitive robotic one of the world's experts in this area, structures are biocompatible and stated, "In the first half of the 21st century, could theoretically be utilized as the nanomedicine should eliminate virtually all basic building blocks for construction common diseases of the 20th century, and of nanorobots such as a respirocyte virtually all medical pain and suffering as or clottocyte for use in medical well" (129). This is a bold statement, yet applications. It it highlights the potential of a universal and is clear that the use of nucleic acids permanent impact of nanotechnology on and their base-pairing properties medicine. While targeted carbon nanotubes will no doubt profoundly impact the or gold nanoshells could be considered development and application of therapeutic "nanobots", others could include nanobots for biological and therapeutic Freitas' conceptual artificial "respirocyte", uses in the near future. which theoretically could function at over

As it stands, this is an exciting time Acknowledgements for both nanotechnology and medicine. The author would like to thank Zyvex Major breakthroughs and basic scientific Performance Materials of Columbus, knowledge in these areas are accumulating Ohio for the contribution of Figures at an unprecedented pace, and each 1 and 2, Rocky Draper and Austin field is rapidly evolving to produce new Edmiston of the University of Texas at tools and technologies that will have Dallas for the contribution of Figure broad applications across multiple 3 and Nadrian Seeman of New York disciplines. Eventually, it is inevitable that University for the contribution of Figure nanotechnology and medicine will mature 4. and permanently merge to bring about new and superior diagnostic and therapeutic References platforms to effectively address a variety 1. M. Ferrari, "Cancer nanotechnology: of debilitating illnesses and disease, thus opportunities and challenges," Nat Rev increasing the quality of life and perhaps Cancer. 2005; 5(3): 161-71. even extending life for millions of individuals. 2. RA Freitas, "Nanomedicine, Volume I: Basic Capabilities," 1999; Landis Bioscience Publishers. 3. Peter Searson Interview, Nanomaterials and Nanotechnology, March 19, 2007. 4. Editorial. (2006). "Nanomedicine: A matter of rhetoric?". Nat Materials. 5(4): 243. 5. National Institutes of Health, US Department of Health and Human Services http://nihroadmap.nih.gov/nanomedicine/. 6. RRH Coombs and DW Robinson, "Nanotechnology in Medicine and the Biosciences," 1996; Taylor & Francis, Inc. Publishers. 7. Therapeutic Index as defined by Wikipedia, http://en.wikipedia.org/wiki/ Therapeutic_index. 8. V.P. Torchilin (editor), "Nanoparticulates as Pharmaceutical Carriers," 2006; London, UK: Imperial College Press. 9. A.M. Dyer, M. HInchcliffe, P. Watts, J. Castile, I. Jabbal-Gill, R. Nankervis, A. Smith, L. Illum, "Nasal delivery of insulin Figure 4. A 3-dimensional DNA-based cube (upper using novel chitosan based formulations: panel) and DNA-based truncated octahedron (lower a comparative study in two animal models panel). See text for descriptions. between simple chitosan formulations and chitosan nanoparticles," Pharm Res. 2002; 19: 998-1008.

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Robert Linares, Chapter 32: Diamond Bio Electronics for bio-electronics. This generation Patrick Doering, Bryant Linares Robert Linares, Ph.D., Patrick Doering, Bryant Linares of diamond based bio-electronic / Diamond Bio Apollo Diamond, Inc., Boston, MA, USA devices would contribute substantially Electronics in “World Health to ushering in a paradigm shift for Strategy” eBook, Abstract medical science, leading to vastly (Ed.) Renata G. Bushko, he use of diamond for advanced improved patient diagnosis, decrease FHTI, 2016. applications has been the dream of of drug development costs and risks, Futureofhealth. org From mankind for centuries. Until recently and improved effectiveness of drug Strategy for the T this dream has been realized only in the delivery and gene therapy programs Future of Health (Ed.) Renata G. use of diamond for gemstones and abrasive through better timed and more Bushko, IOS applications where tons of diamonds are customized solutions. Press 2009 used on an annual basis. Diamond is the material system of choice for many 1. The Vision of Bio-Electronics applications, but its use has historically The realistic vision for bio electronics been limited due to the small size, high has been with us for a number of cost, and inconsistent (and typically poor) decades. Since the advent of the quality of available diamond materials computer chip in the 1960’s, the until recently. The recent development of thought or dream of putting electrical high quality, single crystal diamond crystal components in the body has moved growth via the Chemical Vapor Deposition from the purview of science fiction to (CVD) process has allowed physcists and a reasonable near term quest for this increasingly scientists in the life science segment of life science in the early area to think beyond these limitations parts of this century. Some of the early and envision how diamond may be used applications of this branch of medicine in advanced applications ranging from have already manifest themselves quantum computing, to power generation throughout our society in early and molecular imaging, and eventually even applications such as pace makers and diamond nano-bots. identification sensors used in animals. Because of diamond’s unique properties While these devices are functional, as a bio-compatible material, better they are in general large, somewhat understanding of diamond’s quantum effects cumbersome, and limited relative to and a convergence of mass production, the new generation of bio devices that semiconductor-like fabrication process, is currently envisioned. As electronic diamond now promises a unique and and optical devices continue to shrink, powerful key to the realization of the bio- a new generation of bio-electronic electronic devices being envisioned for devices is taking shape that will usher the new era of medical science. The in an era of bio –electronics where combination of robust in-the-body diamond these devices will become ubiquitous based sensors, coupled with smart bio- in our society and persons. functionalized diamond devices may lead to diamond being the platform of choice

Clemson University’s C3B group, Center of Bio Electronics, Bio-Sensing and Bio Chips bio-electronics defines the space as:

..the interface of microelectronics, materials chemistry, molecular biology and information technology. These new technologies are leading to high performance devices and instruments that find application as test and measurement systems in the service of health and Figure 1. Conventional Medicine medicine. They find application in The goal of the 3B trend (bio- such areas as functional genomics electronics, biosensor, biochips) is (gene discovery), genetic screening, to dramatically change the paradigm pharmacogenomics (high throughput in which the four target goals are drug screening and drug discovery), and achieved to improve accuracy, molecular diagnostics. increase speed, reduce risk, and Established firmly on such manufacturing reduce cost. Bio-electronics allow all principles as four to be done more effectively and miniaturization, modularization, systems with better efficacy than conventional integration, parallelism, and redundancy, processes. Over time they collectively these technologies promise to vastly revolutionize the healthcare space. reduce the cost of drug development, Medical diagnostics, information accelerate the rate of human genomics gathering, therapy development and research, and enable new modes of solutions management fall generally analysis of analytes not easily measured into three eras. and at sites previously unprecedented. CLEMSON UNIVERSTY, C3B Group[1] Conventional Human to Patient Naturally, the systematic realization of these Medicine Interaction program goals will profoundly impact and improve the four traditional aspects of Modern Human and medical science. Medicine Machine to Aspects of Conventional Health Care Patient Interaction Process 1. Collect medical information from the patient Bio-Electronics Human/ 2. Interpret information with best possible Era Medicine Machine to speed Patient/Machine 3. Develop a therapy solution for the Interaction patient 4. Deliver the therapy to the patient

Conventional Medicine has been with us lab. Similarly, therapies are derived for centuries, and generally deals with the in external environments and follow collection of information and its interpretation testing and approval procedures that through the interaction of the care giver- are somewhat disconnected from the doctor and the patient. The physician patient audience at the time of delivery. gathers empirical information usually through The benfits of this era have been: observation and creates a diagnosis a) A radical shift of complex from knowledge held by that individual, monitoring and analysis to the collegeages or in a data base. Without bedside , taking anything away from the importance and benefits of human to human interaction, b)Improvement in accuracy and this process (from a technical analysis speed-up of diagnosis and solution standpoint, and solution delivery standpoint) delivery, is slow and generalized. Human diagnosis and decision making leads to rapid problem c) Emergence of semi-custom but solving for certain types of problems but generalized drug and therapy lacks in good diagnosis of less common development. or more complicated health issues. The While it may be suggest that this era resolution of the data is low on the diagnosis began in earnest with the discovery side and mostly deals with the interpretation of penicilian it has reached a degree of symptomatic information which may be of maturity over the past few decades out of phase or time delayed from the root that has led to large drug development cause of the issue. Incomplete and time programs and more targeted delayed feedback loop during therapy and drug therapies. An unintended delays for drug development ultimately lead consequence of this era however are to a major ‘trial and error’ component to this the drug resistant strains of bacteria approach. and organisms that remain after the Modern Medicine, the second era, generalized therapy. This outcome which is at the tail end of its growth curve, of our success in drug development involves the increasingly sophisticated use requires ever faster speeds to detect of computers and equipment to collect and these drug resistant species and better catalog information taken from the patient processes to develop new drugs and systematically analyze it and create and new approaches to defeat this drug therapies based upon the information. evolutionary process. This analysis and therapy solution is usually Current standards for the speed done in a manner where biological data and accuracy of patient diagnosis, drug and samples are taken, removed from research and therapy customization the individual and analized in a remote will be considered slow with the roll- location. Most of the tools needed to out of the bio-electronics era. properly analyze the imaging information are large and need to be done in the

Aspects of Bio-Electronic Era Health Care Customizable and personalized drug Process delivery will be possible in the latter 1. Robust information at the molecular and phases of this stage as bio factories nano scale take advantage of molecular scale 2. Information gathering and therapy sensing and fabrication capabilities. inside the body Effectively these chips will be able to 3.Integration and match of the therapy/ sense, and output detailed molecular drug delivery to the exact intentions of the level information in real time. drug as dictated at the time of the drugs Bio-chips running internal therapy development solutions can match the effectiveness 4.Customized delivery and tailoring of of the given therapy at the molecular therapy timing, intensity and details level to models generated on living cells from the drug development Solutions Must Have: bio compatibility, stage, and subsequently change or molecular scale sensing and actuation, tailor the course of therapy “on-the- and flexible tool kit of semiconductor type fabrications and capabilities fly” depending on the results. The results will be a revolution in medical information, drug development and therapy The resulting speed of information collection and analysis will dramatically increase with this new era. Some forecasters of our medical future such as Ray Kurzweil believe that this information flow will mimic in healthcare what happened in the computer sciences during the last three decades with devices becoming increasingly Figure 2: Bioelectronics Era Medicine miniaturized to the size of nano- The result of these trends is a radical shift scale devices. With this increasingly in the speed and detail of diagnosis and systematized and information based improved efficacy of the treatment. In health care and discovery system, general, the medical devices of this era, it is also expected that the pace bio-electronic devices, will reside inside the of medical discovery and therapy body as opposed to next to the bedside or increasing at an exponential rate. in the lab, and there is a high degree of real- Radical improvements will occur at an time information coming from these devices. increasingly faster rate. This has been More importantly, the feedback loop from described as the Moore’s Law for the time of the information gathering phase health care. to the therapy/drug delivery phase can “An analysis of the history of technology be dramatically shortened in this model. shows that technological change is exponential, contrary to the common-sense

“intuitive linear” view. So we won’t experience 100 Complex fabrication techniques years of progress in the 21st century - normally reserved for semiconductor - it will be more like 20,000 years of progress (at today’s rate). The “returns,” such as chip fabrication such as photolithography speed and cost-effectiveness, also increase and ion-implantation techniques are exponentially… being used on diamond in order …There are a great many examples of the to tailor its properties for specific exponential growth implied by the law of accelerating returns in technologies as varied applications. This means that as DNA sequencing, communication speeds, development of diamond for advanced electronics of all kinds, and even in the rapidly applications can take advantage of shrinking size of technology.” Ray Kurzweil, Law of the large body of equipment and Accelerating Returns [2] processing that have been developed 2. Diamond based Bio Electronics for the silicon based microelectronics Diamond offers a unique and robust platform industry. Additionally, recent advances for biotechnology applications. Its material in single crystal diamond growth properties make it an ideal material for in- techniques (namely the CVD process) the-body devices. Because of its versatility, now make high purity, single crystal and robustness, a wide variety of sensor, diamond a material which can be and bioelectronics functions can be considered alongside other advanced envisioned on a diamond bio-chip. In some semiconductor materials such as cases these devices have already been Gallium Arcinide, Gallium Nitride demonstrated. and Silicon Carbide but with full bio compatibility that other semiconductor 2.1 The Role of Diamond in Bio-Electronics materials lack. Diamond has three roles as a major material Each of these single crystal type in the life science and bio-electronics area. of diamond are all grown by the CVD 1. Diamond serves as a macro scaffold or process and each plays a different role device platform upon which traditional in the type of Bio-electronic device and semiconductor or optical devices may be its functionality and utility. built, 2. Diamond may act as a macro scale 2.2 Why is Diamond a Platform of device platform upon which nano Choice for Bio Electronics? scale segments of the material are Single Crystal Diamond has a number functionalized, of features that individually present 3. Diamond may be grown in the macro- the researcher and medical device scale with consistent, engineered developer a superior platform for properties and then be reduced down to the use of the material. Collectively, the nano scales so that the free standing diamond offers a series of benefits that nano-sized diamond has the engineered are unavailable in any other material. properties and orientation of the larger crystal but on the nano-scale.

2.2.1 Bio Compatible Material opto-electrical. MEMS structures and Diamond is one of the most stable materials etching are possible as well as light known to man. One of the stellar features of emission in certain crystal structures. the material is that it does not break down 2.2.6 Micro Structures in most chemicals. It remains entirely stable Micro pipes, reservoirs, wave-guides in the body. This is probably the singularly and diving boards can be fabricated on the most important key attribute for a bio- the surface of and inside single crystal electronics platform. diamond with techniques similar to those used with other semiconductor 2.2.2 Toxicology materials. (see ‘Structures Formed in Since diamond does not break down and Diamond’, US patent 7,122,837 Linares, remains stable in the body, it is not toxic et al, Oct 17 2006)[3] to the body. Unlike other semiconductor materials that breakdown and subsequently 3. A Quick Background of Diamond toxify the patient, diamond remains intert and healthy for the body. 3.1 Varieties of Diamond 2.2.3 Effective bio functionality of Diamond is quite possibly the highest diamond utility material known to man. Its Diamond can be functionalized to attach relative scarcity in pure varieties organic compounds, DNA and proteins. however has prevented it from These structures have proven to be robust entering the roadmap for high tech and stable in hostile environments. The applications until recently. Some stability of these structure are shown to be natural diamond have very good more stable that carbon platforms. purity levels and crystal features but 2.2.4 Nano-molecular and bio scale are generally small and expensive. information High temperature / high pressure Recent work focusing on the Nitrogen diamond (developed in the 1950’s) is Vacancy (N-V) Center in diamond have very prevalent with over 1 billion carats shown that it can be used to enable produced annually. Unfortunately, High Molecular resolution imaging of various Pressure diamond process limitations types of organic and inorganic compounds. require large amounts of nitrogen as These prototype imagers have the well as magnetically active impurities possibility of providing us with realtime to be used. This creates a highly ‘You Tube’ video of molecular and nano- doped, nitrogen saturated diamond scale movements, change, fatigue and that is limited in both size, and crystal interactions of living cells and non-organic consistency. devices such as artificial heart valves or artificial joint replacements. 3.2 Types of CVD Diamond 2.2.5 Effective Fabrication Techniques Chemical Vapor Deposition (CVD) Device fabrications in diamond are currently diamond represents the current state- similar in resolution and process to early of-the-art in diamond crystal growth.

This type of process allows large crystals and optically identical to high quality of diamond to be grown with controlled diamond crystals found in nature. impurities and a high degree of crystal Carbon atoms along the entire perfection. Diamond can now be grown crystal structure are all oriented in with the CVD process in a variety of crystal the same direction. This diamond sizes ranging from nano-scale crystals to can be selectively doped and crystal large single crystals in excess of 25 mm structures are close to flawless. The with controlled impurities. In addition, single crystal diamond may be grown engineered structures can be grown via in thin films less than 1 micron or in CVD consisting of nanometer thick layers of crystals over 2 mm’s thick. diamond having varied dopants levels and/ CVD remains the best diamond or 12C / 13C. growth system to grow single crystal The following types of process and diamond of different crystal sizes. equipment represent current CVD diamond Tailored nanometer sized diamond growth configurations. particles for cell sensors may be produced by this method as well as larger single sized pieces of diamond. Furthermore, these crystals can be tailored using the CVD process to engineer the diamond crystals with dopants or selective impurities for electrical, optical, and quantum properties. Depending on the bio application, one of these two types of CVD diamond will be most appropriate. Nano-crystaline has proven to be a good MEMS platform, and a coating Figure 4. CVD Techniques, J.Butler NRL [4] material for hardened bio applications, Poly (nano)-Crystalline Diamond – This is a while single crystal diamond has been sheet of diamond which consists of millions shown to have excellent properties for of diamond crystals of different orientation quantum spin states, electrodes, and bonded together by carbon. The benefits sensors. of this type of CVD diamond is that large surface areas can be coated with a coating of diamond crystals. The negatives are that each diamond crystal is oriented in a different crystallographic direction and is bonded to the next crystal with carbon. Single Crystalline Diamond – These diamond crystals are chemically, physically

4.1 Table of Diamond Properties

Property Value Hardness (kg/mm2) 10,000 Sound Velocity (m/s) 18,00 Density (gm/cm3) 3.52 Young’s Modulus (GPa) 1.22 Coefficient of Friction 0.02 Thermal Expansion 1.1 (ppm/oK) Thermal Conductivity 20 Figure 5. Top View CVD Single Crystal with HPHT (W/cm- oK) Seed Debye Temperature 2,200 (oK) Optical Index @ 591 nm 2.41 Optical Transparency UV to far IR Range Loss Tangent @ 40 Hz 0.0006 Dielectric Constant 5.7 Bandgap Energy (eV) 5.45 Resisitivity (undoped, 1013-1016 Ohm-cm) Note Growth Steps on CVD Material. Shape Chemical Compatibility Highly Resistant and size of steps controlled by Chemistry, to Corrosion Bio- Substrate Temperature, and presence of Compatible

impurities Table 1. Properties of Single Crystal Diamond Figure 6. Side View, CVD Single Crystal with HPHT Seed 5. Useful Features in Diamond (the toolkit) 4. Known Diamond Properties 5.1 Acoustic Waves Diamond excels in a number of properties Because of its rigidity, Diamond has making it the material of choice for a number the distinction of being the best of high requirement applications. The needs material for the passing of fast, high of bio-electronics applications require a frequency sound waves. Diamond material that not only exists in the body but SAW devices can be operated at does things that other materials cant. The gigahertz frequencies and at high tool kit of material attributes make diamond the ideal material for building bio-electronic power levels. Low levels of signal devices. noise and distortion are possible due to the diamond’s stable atomic

structure. Changes in the optical or the most electrically insulating materials electrical output signal can be seen when known to man. Once doped with different impurities attach to the surface of boron, diamond becomes electrically the diamond. Diamond is currently being conductive, making an excellent used as a material of choice for high-end semiconductor. Recent research audiophile tweeters. has shown that heavy boron doping turn diamond into a low temperature 5.2 Light-wave absorption superconducting material. Diamond in its intrinsic undoped form is fully transmissive to most forms of light and 5.5 Light Emission energy frequencies. The doping of diamond Light emission has been shown on the however allows the diamond to absorb 111 crystal orientation of diamond when radiation of varioys frequencies. Absorption it is doped with phosphorous. Laser cells utilizing total internal reflection can cavities have also successfully be detect very low levels of impurities using constructed in diamond resulting in a a wide range of wavelengths, including, diamond Raman laser amplifier. ultraviolet, visible, near infrared, and far infrared. 5.6 Surface conductivity in diamond The chemical termination of the 5.3 Engineered Defect Centers diamond surface can be controlled A vacancy is a point in the atomic structure by various chemical treatments of of the diamond where a carbon atom the surface. The two primary surface is missing. This often occurs when an terminations of interest are hydrogen impurity atom such as nitrogen causes a terminated and oxygen terminated displacement in the carbon lattices shape because they represent the extremes because of a lattice mismatch caused by of surface properties which can be the introduction of the non-carbon atom. attained on diamond (Nebel, AIST These vacancy defect centers cause optical, [5]). Two important properties which and electrical changes to the diamonds can be controlled by controlling the properties. The unique stability of the surface termination are the surface diamond’s structure enables viewing of energy (wettability) and the electrical quantum effects in these vacancy centers conductivity of the surface. The at room temperature and for long periods hydrogen terminated diamond of time. N-V concentrations of 1010 to 1012/ surface is electrically conductive and cc have been achieved in diamond. T2 is hydrophobic, while the oxygen spin lifetimes in excess of 100ms have been terminated surface is electrically observed in this type of diamond at room insulating and is hydrophilic. In temperature. addition, the hydrogen and oxygen terminated surfaces have very 5.4 Electrical Insulation and Conductivity different chemical activity and this In its intrinsic, pure form, diamond is one of allows the diamond surface to be

chemically modified/functionalized in a sites can then be attached which will in controlled manner. In addition, the surface turn attract specific organic species. termination of diamond can be controllably 6. Current Applied Research in patterned (regions of hydrogen and oxygen Diamond termination) using standard semiconductor patterning processes, and the surface 6.1 Harvard University – Walsworth, termination are very stable under a wide Yacoby, Lukin Groups range of chemical and thermal conditions. A collaboration of Harvard University This makes the diamond surface a unique is unlocking some very practical tool for use in sensing and modifying and interesting features of diamond biological activity. defects called vacancy centers. These vacancy center defects can capture Diamond Surface Sheet Resistance an optically read magnetic spinstate that has many useful functions that could revolutionized a wide variety of fields from quantum computing to drug discovery.

Nano scale magnetic sensing with an individual electronic spin in diamond “Detection of weak magnetic fields Figure 7. Diamond Surface (Sheet) Resistance vs. with nanoscale spatial resolution is an Oxidation Temperature – outstanding problem in the biological as the surface becomes oxygen (vs hydrogen) and physical sciences. For example, terminated, the surface conductivity is reduced by more than 7 orders of magnitude (H. at a distance of 10 nm, the spin of a Gamo [6]) single electron produces a magnetic field of about 1 micro Tesla, and the 5.7 Bio Functionalized surfaces corresponding field from a single Diamond can be functionalized by a variety proton is a few nano Tesla. A sensor of means. The crystalline carbon surface of able to detect such magnetic fields the diamond can be terminated with oxygen with nanometer spatial resolution or hydrogen atoms creating a surface to would enable powerful applications, which other compounds can be joined. ranging from the detection of magnetic Hydrogen surfaces create hydrophobic resonance signals from individual surfaces and oxygen creates hydrophilic electrons or nuclear spins in complex surfaces. Once a diamond surface is biological molecules to readout of terminated, the termination is very stable. classical or quantum bits of information In addition, the surface terminationDiamond can be Bio Electronicsencoded in an electron or nuclear patterned using standard micro-electronic spin memory. Here we experimentally techniques. Once a surface has been demonstrate an approach to such terminated in the desired manner, active nanoscale magnetic sensing, using

coherent manipulation of an individual 6.2 Waseda University / Kawarada electronic spin qubit associated with a Group nitrogen-vacancy impurity in diamond at Dr. Kawarada’s group from Waseda room temperature. Using an ultra-pure University in Japan are world leading diamond sample, we achieve detection researchers and pioneers in the area of 30 nT magnetic fields at kilohertz of diamond applications. A number of frequencies after 1s of averaging. In addition, their current research directions focus we demonstrate a sensitivity of 0.5 mT/Hz1/2 on the bio-functionality of diamond for a diamond nanocrystal with a diameter and the use of semiconductor device of 30 nm. Diamond Nitrogen vacancy spin design to create life science solutions states in diamond” in diamond. The Kawarada/Waseda Amir Yakoby presentation, Rutgers web-site describes a portion of their University, Condensed Matter Seminar, work as follows: March 10, 2009 [7] DNA sensor with diamond surface “Harvard’s ‘diamond’ camera’, described “My research topic is the development ..in the journal Nature, consists of a special of DNA sensor to detect the single- “flaw” in diamonds that can be manipulated nucleotide-polymorphisms (SNPs). The into sensitively monitoring magnetic signals DNA is fabricated by the sequence from individual electrons and atomic nuclei of four kinds of bases (A, T, G, C) placed nearby. and which codes the synthesis of The new work represents a dramatic protein. Generally, the two strands of sharpening of the basic approach used in complementary DNA makes the A-T or nuclear magnetic resonance (NMR) and G-C pairs in these bases and form the magnetic resonance imaging (MRI), which double-helix structure (which is also ascertain chemical structures and image called Watson-Crick structure). The inside human bodies by scanning the SNP is the site where the two bases in magnetic activity of billions of individual each DNA strands cannot fabricate the nuclei. The new diamond-based magnetic pair such as A and G or C and T etc. sensor could enable novel forms of The existence of SNP is controlling the imaging, marrying NMR’s noninvasive controlactability for such diseases and nature with atomic-scale spatial resolution, the affectability of some medicine. potentially benefiting fields ranging The merits of fabricating the sensor from materials science, spintronics, and with diamond substrate are the high quantum information to structural biology, biocompatibility, simply modification neuroscience, and biomedicine” Medical on surface and the high stability both News Today, October 2008 [8] in air and in aqueous solution. And [9] Walsworth, Yakoby, Lukin Groups; the semiconductor devices can be Harvard University, Department of Physics fabricated on the diamond substrate because the hydrogen terminated

surface natively has the p-type surface radically change healthcare as we conductive layer. currently know it. New studies into We fabricate the FET-type DNA sensor understanding the quantum effects which operates stably in electrolyte of diamonds atomic and nano scale solution to apply these attractive merits of features will lead to a ubiquitous use semiconductive diamond surface. The gate of diamond in health care and our surface of diamond FET is directly exposed broader society. Healthcare is on to the electrolyte solution and the DNA is the verge of a sea-change with the immobilized on this surface. This FET is ushering in of the Bio-electronics operated as the sensor to measure the Medicine Era. We expect that surface potential on gate surface, while FET diamond will play a leading role in this generally operates as the “switch” controlling revolution. the drain-source current by the applied As we see diamond play an gate voltage. The surface potential on gate increasing leading role in our life’s becomes more negative when the single extension, and become ubiquitous strand DNA (target DNA) is hybridized with in health care in the form of sensors, immobilized single strand DNA (probe DNA), bio-chips and diamond-nano-bots, our because DNA is natively negatively charged appreciation for diamond will rise to by the ionization of phosphate groups in it. a new level, transforming our view of This surface potential change induces the diamond from “A Diamond is Forever’ more holes in the surface conductive layer to “ A Diamond Helps Us Live Forever”. and the conductivity of gate channel (the conductance between drain and source References electrode). The detection of target DNA [1] Guiseppi-Elie, Clemson University, Center for Bio Electronics, Bio-Sensing and Bio-Chips, by the electrolyte solution gate FET is (2009),(www.clemson.edu/c3b) applied to detect the mismatched DNA. …” [2] R. Kurzweil, “Law of Accelerating Returns”, (2002), Kawarada Group, Waseda University Japan, (ww.kurzweilai.net) [3] Linares et. al., “Structure formed in Diamond”, US Web Site [10] Patent 7,122,837, ( 2007) [4] J. Butler, Diamond Growth Materials, U.S. Naval Research Laboratories (2008) 7. Summary and Conclusion [5] C.E. Nebel et.al., J.R. Soc. Interface, p. 439, (2007) Diamond fits the prerequistite requirements [6] H. Gamo, et. al, J. Phys: Conf. Ser. 61, p. 332 for a bio-electronics platform. It is 100% bio- (2007) [7] Yakoby, Harvard University, Department of compatible, and has useful semiconducting Physics, (2009) and optical properties. Additionally, diamond (www.physics.harvard.edu/people/facpages/yacoby. has a device fabrication and modeling tool html) [8] Lukin, Walsworth, Yakoby, Harvard-Smithsonian kit that has been utilized in mass computer- Center for Astro Physics, Harvard University chip production. Department of Physics, (2009) (www.cfa.harvard. These techniques, and the increasing edu/Walsworth) [9] Medical News Today, (October 2008) (www. availability of large area, high purity medicalnewstoday.com/articles/123944.php ) diamond, give researchers and application [10] H. Kawarada, Waseda University, Department of Electronics, “DNA Sensing in Bio Functionalized engineers new ideas on how to extend and Diamond”, (2009), (www.kawarada-lab.com)

Tad Hogg / Chapter 34: Maintaining Your Health targets. More ambitious future Maintaining Your Health from from Within: Controls for Nanorobot developments of the technology Within: Controls Swarms in Fluids should allow for the manufacture of for Nanorobot Swarms in Fluids Tad Hogg, Ph.D. much more complicated devices, in “World Health HP Labs particularly programmable machines Strategy” eBook, (Ed.) Renata comparable in size to bacteria and G. Bushko, Abstract able to sense and modify their FHTI, 2016. Futureofhealth. olecular electronics and nanoscale environments. Such microscopic robots org From chemical sensors could enable the (“nanorobots”) could provide significant Strategy for the Future of Health construction of microscopic sensors medical benefits by operating within (Ed.) Renata G. M capable of detecting patterns of chemicals the body [1, 2], greatly extending the Bushko, IOS Press 2009 as they flow passively in a fluid. Information capabilities of today’s much larger from a large number of such devices allow ingested or implanted medical devices. the estimation of properties of tiny chemical These current medical devices include sources in a macroscopic tissue volume. pill-sized cameras to view the digestive Although such devices cannot yet be tract, as well as implanted glucose and fabricated, estimates of plausible device bone growth monitors to aid treatment capabilities in small blood vessels allow the of diabetes and joint replacements, evaluation of their performance for typical respectively. Such devices gather chemicals released by tissues in response information continually over a period of to localized injury or infection. The devices time, in contrast with the more limited can readily discriminate a single cell-sized monitoring possible with a series of chemical source from the background conventional laboratory tests. chemical concentration, providing high Nanorobots would be small resolution sensing in both time and space. enough to move through the tiniest By contrast, such a chemical source would blood vessels. For example, the be difficult to distinguish from background robots could operate as passively when diluted throughout the blood volume circulating sensors to detect patterns as obtained with a blood sample. These of chemicals. Communicating results microscopic, programmable devices could to external detectors would allow real- also aid treatments, such as precisely time in vivo monitoring of many cells. targeting drug delivery and improving speed The robots could also act on their and accuracy of microsurgery. environments, e.g., releasing drugs at locations with specific chemical 1. Introduction patterns or mechanically manipulating Nanotechnology can potentially objects for microsurgery. revolutionize health care. A current example Realizing these benefits requires is the medical uses of nanoparticles, fabricating the robots cheaply and capsules containing drugs or imaging in large numbers. Such fabrication enhancers whose surface chemistry is beyond current technology. preferentially binds to specific biological Nevertheless, ongoing progress

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in engineering nanoscale devices could for all, or even most, robots to do eventually enable production of such so. This observation contrasts with robots. One approach is engineering teams of larger robots with relatively biological systems, e.g., bacteria executing few members, such as robot soccer simple programs [3]. However, biological or surveillance: incorrect behavior by organisms have limited material properties even a single robot can significantly and computational speed. Instead we focus decrease team performance. on machines based on plausible extensions To illustrate the potential of of currently demonstrated molecular-scale microscopic robots for medicine, electronics, sensors and motors [4, 5, 6, 7, this paper describes plausible robot 8, 9] as early versions of components for capabilities from early nanotechnology stronger and faster microscopic robots than based on extrapolations from is possible with biological organisms. These current laboratory demonstrations nonbiological robots contain nanoscale of nanoscale devices. The physical sensors and electronics within a protective, properties of task environments are biocompatible shell. Of particular interest then discussed in the context of a are biomedical applications requiring only prototypical diagnostic task of finding a modest hardware capabilities, as those small chemical source in a multicellular applications will likely be among the first organism via the circulatory system. uses of the technology as it develops. Theoretical studies suggest these Understanding the behaviors of such “first robots can give significantly better generation” nanorobots will identify design performance than current medical tradeoffs among hardware capabilities, technology, not only for diagnostics control methods and task performance. but also for interventions such as drug A major challenge for nanorobots arises delivery and aiding microsurgery. from the physics of their microenvironments Thus we can expect benefits from and the hardware limitations of the robots, even relatively early developments which differ considerably from experience of nanotechnology, which will in turn with today’s larger robots. For example, the pave the way for more significant physical environment will often consist of applications as the technology cells in fluids dominated by viscous forces. matures. Second, thermal noise is a significant source of sensor error and Brownian motion limits 2. Capabilities of Microscopic Robots the ability to follow precisely specified Minimal robot capabilities needed for paths. Third, relevant objects are often biomedical tasks include chemical recognizable via chemical signatures rather sensing, computation and power. than visual markings or shape. Fourth, the Additional capabilities, enabling tasks involve large numbers of robots, each more sophisticated applications, with limited abilities. Moreover, a task will include abilities to stick to specific cell generally only require a modest fraction of surfaces, to communicate and to move. the robots to respond appropriately, not

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 336 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

2.1 Sensing 2.2 Communication Large-scale robots often use sonar or Several forms of communication could cameras to sense their environment. These be useful for nanorobots. The simplest sensors locate objects from a distance, form of communication is receiving and involve sophisticated interpretation electromagnetic or acoustic signals algorithms. In contrast, microscopic robots broadcast from outside the body. for biological applications will mainly use Such signals could activate robots chemical sensors, e.g., the selective binding only within certain areas of the body, of molecules to receptors altering the perhaps within centimeter length electrical characteristics of nanoscale wires. scales. Microscopic robots and bacteria face Mutual communication between similar physical constraints in detecting nearby robots and detectors outside chemicals [10]. For example, diffusion of the body require more difficult the chemicals and Brownian motion of the fabrication and increase robot power sensors make it difficult to determine the use compared to robots that just direction of a chemical source directly. receive broadcast signals, but such Nevertheless, random motion modulated communication abilities increase the by the detected concentration can allow for range of tasks for the robots. For the tracking of chemical gradients to their instance, acoustic communication sources. Current molecular electronics [9] among nearby robots (e.g., within and nanoscale sensors [11, 12, 13] indicate about 100¹m of each other [1]) allows for that even today’s sensors are effective at coordination of their activities. detecting concentrations well below those For limited communication with the of many chemicals in the body that may attending physician, the robots could prove medically interesting. carry nanoscale structures with high In addition to chemical sensing, robots response to some external signals. could sense other properties of their Such structures could respond to environment, such as, measuring fluid flow light of particular wavelengths when rates at speeds relevant for biomedical tasks near the skin, or give enhanced [14], allowing robots to examine microfluidic imaging via MRI or ultrasound. Such behavior in small vessels. Since boundaries visualization mechanisms, combined significantly alter fluid behavior far into the with a selective ability to stick to vessel vessel [15], several such sensors, extending walls, allows for the detection of a small distance from the robot surface in aggregations of devices at specified various directions, could detect changes locations near the surface of the in the vessel geometry. Such estimates of body. This visualization technique local geometry might, for example, help could be useful even if the tissue distinguish normal vessels from leaky new volume of interest is too deep to vessels formed within tumors. image effectively at high resolution. In particular, robots could use various

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 337 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

areas near the skin (e.g., marked with various robot motion, giving smooth flow with light or ultrasound frequencies) at centimeter different physical behaviors than those scales as readout regions during operation. of larger organisms and robots [16, 17, For example, robots that have detected 15]. For instance, robots applying a certain chemicals could aggregate at the locomotive force quickly reach terminal corresponding readout location, which velocity in the fluid, i.e., applied force would then be visible externally. Robots is proportional to velocity rather than could choose how long to remain at the the more familiar proportionality to aggregation points based on how high a acceleration of Newton’s law F = ma. concentration of the chemical pattern they By contrast, a swimming person has detected. Robots with local communication Reynolds number about a billion times capabilities could compare observations larger, and viscous forces are minor. while in these aggregation regions, Another physical effect, Brownian allowing further computation to influence motion, randomly changes location the communicated result, e.g., by changing and orientation of microscopic robots, how long the devices remain at the readout thereby limiting the time over which location or whether they aggregate in other they can reliably compare different locations at a later time. This indication of locations or directions. This behavior whether, and (at a coarse level) what, the contrasts with long range path planning devices have found could help decide with maps of the environment often how long to continue treatment. These used for larger robots. aggregation points could also be used to signal to the devices, e.g., instructing them 2.4 Power to switch to another preprogrammed mode Robots require power. To quantify of operation. power requirements of microscopic robots, moving through the fluid at 2.3 Locomotion 1mm=s dissipates about a picowatt Biomedical applications will typically [18] to overcome fluid drag and involve robots operating in fluids. A key the inefficiencies of locomotion. physical property is the ratio of inertial Communication could use power to viscous forces for an object moving of a similar order of magnitude. For in fluid, which depends on the size and comparison, a typical person at rest speed of the object. This ratio is called uses about 100 watts. For tasks of the Reynolds number. Using typical values limited duration, onboard fuel created for density and viscosity (e.g., of water or during robot fabrication could suffice. blood plasma) and noting that reasonable Otherwise, the robots could use speeds for robots with respect to the fluid energy available in their environment, [1] are comparable to the fluid flow speed such as converting externally in small vessels, i.e., ≈1mm/s, motion of a generated vibrations to electrical 1-micron robot has Reynolds number of energy [19] or chemical generators, about 10-3. Thus, viscosity dominates the e.g., a fuel cell using glucose and

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 338 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

oxygen in the bloodstream [1]. semiconductor fabs routinely produce 3. Tasks for Microscopic Robots chips with about that many transistors. This section describes some task scenarios As a point of comparison, a billion of enabled by the robot capabilities described the microscopic robots discussed here above. would have a total mass of only a few A prototypical task is responding to milligrams and a total volume of a few chemical signals, e.g., released in the cubic millimeters. This volume of robots blood by tissue injury [20] or monitoring is about a millionth of a person’s total chemical behaviors within individual cells blood volume. [21, 22]. The robots may detect signals and initiate response more rapidly than 3.1 Diagnosis natural mechanisms (e.g., immune cells). The robots could detect localized They could also identify the signal’s cause high concentrations that become too (e.g., a type of infecting bacteria) and, low to distinguish from background unlike cells, communicate that information concentrations when diluted in the to an attending physician [1], providing whole blood volume as obtained earlier and more accurate diagnosis. As an with a sample for laboratory analysis. example, Fig. 1 illustrates the environment Moreover, if the detection consists of robots operating in small blood vessels. of the joint expression of several The number of robots involved in the chemicals, each of which also occurs task determines the time required for from separate sources, the robot each vessel to have likely had at least could identify the spatial locality, which one robot pass through it. For example, would not be apparent when the a person has several billion capillaries chemicals are mixed throughout the and circulation takes about a minute to blood volume. Similarly if the chemical complete a transit through the body. For is released in bursts, sensors nearby high resolution diagnosis involving low during a burst would encounter much concentration chemicals released into higher local concentrations than a few tiny vessels, using about a billion the time averaged concentration. robots would give several opportunities Furthermore, by recording events for passing robots to detect the chemical over time (e.g., minutes to days), the during operation time of about an hour. sensors could collect information Using multiple detections is important for on changes (e.g., in response to an reducing false positives due to sensor external stimulus such as introduction errors and a low background concentration of a drug) that would be impractical to of the chemical in the bloodstream [23]. obtain from repeated blood samples. A billion robots is considerably more than By collecting enough measurements, are used today with teams of larger robots, the robots could distinguish between a e.g., for robot soccer. However, such large strong source and many weak sources numbers should be manufacturable as producing the chemical at the same nanotechnology develops, just as today’s total rate. The strong source would

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 339 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

give high count rates for a few robots (those correlation of chemical detections with passing near the source) while multiple properties of the flow and the vessel weak sources would have some detection geometry (e.g., branching and changes in a larger fraction of the robots. Thus robots in vessel size or permeability to fluids). could not only determine whether sources The robots could also detect some of a specified pattern of chemicals exist, properties of cells outside but near the but also provide information about their small blood vessels, such as electrical structure. activity of nearby nerve cells [25]. Fig. 2 illustrates the problem of The information retrieved from distinguishing a single source from two, the robots could be analyzed in a nearby weaker sources. The combined conventional computer with far more chemical production from the two weaker computational resources than available sources is the same as of the single to any individual microscopic robot. stronger source. In this example, fluid flows This computer would have access to through branching vessels passing near the information from many robots, allowing source(s). The chemical from the source(s), evaluation of aggregate properties of taken to have a diffusion coefficient of a the population of cells that individual small protein, diffuses to the nearby vessels robots would not have access to, and into the moving fluid within them. The e.g., the number of cells presenting chemical moves downstream through the a specific combination of chemicals. vessels as it continues to diffuse in the This combined information allows for fluid. The concentration patterns in the the estimation of spatial structure and two cases are similar, with only slightly strength of the chemical sources, in more variation along the vessel with two analogy with reconstructing tissue sources compared to the single one. At structure from a series of X-rays at low concentrations typical of chemicals various angles as used with computer- released into the blood in response to initial aided tomography (CAT) scans. stages of infection or minor injury [24], the robots would typically encounter only a few 3.2 Modifying Microenvironments dozen molecules of the chemical with their Chemical sensing, as used for the sensors. Thus, observations from multiple diagnosis task, forms the basis for robots passing through these vessels are more complex tasks. Specifically, needed to reliably determine number and robots able to locate chemically strengths of the sources. This example distinctive microenvironments illustrates a benefit of a swarm approach to in the body could modify those diagnosis: a combination of observations environments. from multiple robots in nearby vessels For example, the robots could carry to improve diagnostic accuracy. Robots specific drugs to deliver only to cells with other types of sensors could provide matching a prespecified chemical additional information about the sources. For profile [1, 26]. Robots could achieve example, fluid flow sensors would allow for this aggregation if they can alter their

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 340 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

surface properties to stick to the vessel many cells with behavior determined wall or through active locomotion to follow according to a program computed the chemical gradient to the source. This within the devices in response to local aggregation process is another opportunity environmental conditions. to benefit from the coordinated behavior of The robots could monitor several robots. In particular, fluid flow moves environmental changes due to their the chemical downstream of the source so actions, thereby documenting the robots will tend to detect the chemical only progress of the treatment in far greater after they have already passed the source. detail than is possible today. With Attempting to follow the chemical gradient to external communication, the treating the source would then require considerable physician could monitor the robots’ power use to move a bit upstream against progress and decide whether and the flow. A cooperative approach can be when they should continue to the next more effective; instead of the robot that step of the procedure. Using a series detects the chemical then moving upstream of steps, with robots continuing with to the source, it can emit an acoustic the next step only when instructed signal to other robots further upstream by the supervising person, maintains in the vessel. Such robots, notified of the active human control of the robots. detection, can then move to the vessel wall and approach the source with, rather than 4 Evaluating Robot Behaviors against, the fluid flow [23]. Because it is not yet possible to As another application, robots fabricate nanorobots, studies of their aggregated at chemically identified targets behavior must rely on theory and could perform precise microsurgery at the simulations. As technology develops to scale of individual cells. Since biological fabricate early versions of the robots, processes often involve activities at simple experiments with them will help molecular, cell, tissue and organ levels, validate the simulations. This section such microsurgery could complement describes some of these evaluation conventional surgery at larger scales. For possibilities. instance, a few millimeter-scale manipulators, built from micromachine (MEMS) technology, 4.1 Theoretical Studies and a population of microscopic devices A variety of theoretical approaches could act simultaneously at tissue and allow estimating the task performance cellular size scales. An example involving of nanorobots with the capabilities microsurgery for nerve repair with plausible described in this paper. The simplest biophysical parameters indicates the approach relies on estimates of potential for significant improvement in individual capabilities to indicate the both speed and accuracy compared to the plausible range of tasks the robots larger-scale machines acting alone [27, 28]. could perform [1]. More detailed Such detailed manipulations extend current studies consider the combination of efforts [29] to simultaneous actions on robot capabilities and the physical

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 341 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

properties of the task environment. One process, early nanorobots, with limited such theoretical approach estimates typical capabilities, could help quantify behavior of the robots using a statistical these properties, thereby leading to approximation [30]. This method has been more accurate behavior models and applied successfully to teams of small improved robot designs. Thus much numbers of large robots. Microscopic remains to be done in developing robots, with limited computational detailed theoretical evaluation capabilities, will likely use simple controls, of nanorobots. Nevertheless, with minimal dependencies on events in current studies suggest robots, individual robot histories, for which this even with limited capabilities of statistical approximation is ideally suited. early nanotechnology fabrication, The approach can also readily incorporate should give improved diagnosis spatial variations such as fluid speeds and and treatment, both in speed and chemical concentrations [31] relevant for spatial resolution. For example, they nanorobot tasks. Simulations of groups of could rapidly aggregate at cell-sized robots provide a more detailed look at their chemically distinctive locations or aid behaviors. These simulations can include larger machines with microsurgery. The various levels of detail, giving a tradeoff precision of localization and the robots’ between physical accuracy and computation programmability gives them a degree required to simulate large numbers of of flexibility to alter microenvironments, robots over relevant time scales. Such e.g., by releasing drugs, well beyond simulations can readily include individual that possible with either large robot histories and correlations in behavior scale surgery or nonprogrammable that are not easily treated with the statistical chemically-targeted drug delivery approximation discussed in the previous with nanoparticles. The full range of paragraph. biomedical situations that could benefit Theoretical studies identifying tradeoffs from this flexibility, e.g., nerve repair among control complexity and hardware [28], remains to be seen. capabilities can aid future fabrication. Specifically, control can compensate for 4.2 Validation Experiments limited hardware (e.g., sensor errors or As technology advances to power limitations), providing design freedom constructing early versions of to simplify the hardware through additional microscopic robots, experimental control programs. Thus the studies can help evaluations will supplement theoretical determine minimum hardware performance studies. capabilities needed to provide robust One such experiment is embedding systems-level behavior. the devices in bacterial biofilms to One challenge for theoretical studies monitor chemical signals exchanged is the poorly characterized physical among the bacteria. In this case, parameters of the microenvironments the the robots could be fabricated on robots will operate in. In a bootstrapping a surface and the film grown over

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 342 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

them, greatly simplifying constructing the By performing the task in stages, the robots. The surface could provide power person deploying the robots remains and communication during operation. in the decision loop, especially for the This experiment would test the ability of key decision of whether to proceed the chemical sensors and the onboard with treatment (e.g., release a drug) computation to detect patterns of chemical based on diagnostic information activity, as well as the durability of the reported by the robots. Information robots. Another early validation experiment retrieved during treatment can also is operating the robots in manufactured indicate how well the procedure is microfluidic channels [15]. This would test working and provide high-resolution the robots’ ability for independent operation documentation of what was done, without direct connections to external thereby helping improve future devices for power or communication. treatments. More generally, this control Such studies would allow testing the approach illustrates an important robots’ ability to infer properties of their technique for using microscopic microenvironments, such as vessel robots: local, distributed control to branching, based on fluid flow nanoscale achieve robust responsive behaviors sensors, and calibrating the chemical on small scales in space and time, sensors with known concentrations combined with feedback from a slower, introduced in the fluid. The robots could larger central control (e.g., a person) to also demonstrate the ability to aggregate verify performance and consider global at chemically defined locations. After such constraints using information from in vitro experiments, early in vivo tests many devices. could involve robots acting as passive Safety is important for medical sensors in the circulatory system. The applications of microscopic robots. chemical patterns found would quantify Thus, evaluating a task protocol properties of microenvironments in the should consider its accuracy allowing body. Such nanorobots will be useful not for errors, failures of individual only as diagnostic tools and sophisticated devices or variations in environmental extensions to drug delivery capabilities [32], parameters. For the tasks discussed but also as an aid to develop robot designs in this paper, statistical aggregation of and control methods for more active tasks. many robots’ measurements provides These free-floating devices could extend robustness against these variations; current capabilities based on sensors a technique recently illustrated using tethered to nanowires introduced through DNA computing to respond to patterns the circulatory system [25]. of chemicals [33]. Furthermore, the devices must be compatible with 5. Discussion their biological environment [34, 35] The nanorobot capabilities and tasks for enough time to complete their described in this paper highlight key task. Appropriately engin surface control principles for microscopic robots. coatings and structures should prevent

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 343 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

unwanted inflammation or immune system Figures and Captions reactions during robot operation [34, 36]. Despite the simplifications used to model nanorobot behavior in current studies, the estimates with plausible biophysical parameters show even relatively modest molecular hardware could provide useful in vivo sensing and manipulation capabilities [1, 28, 20]. These capabilities give far more rapid, flexible and specific performance than is possible with today’s larger devices. While engineering challenges for manufacturing Figure 1: Schematic interior view of a small these robots preclude definite estimates of blood vessel with red blood cells (≈7μm when they might be available, quantifying diameter) and a bacteria-sized robot (small their benefits compared to existing cylinder near the wall at upper left). The cells technology can guide and motivate occupy about 1/5-th of the vessel volume, a typical case for small blood vessels. investment in their development. Moreover, early versions of microscopic robots will enable detailed quantitative research studies of tissue microenvironments well before the robots are ready for clinical use. The improved understanding will, in turn, identify tasks for more capable robots and appropriate tradeoffs between size and capability for hybrid systems combining coarse centralized control with the flexibility of cell-sized robots in biological microenvironments.

Acknowledgments I thank A. Cavalcanti, R. Freitas Jr, P. Kuekes, and D. Sretavan for helpful comments.

Figure 2: Example of chemical concentration in branching vessels near one or two cell-sized sources (indicated by the ovals between the branching vessels). Chemical concentration in the fluid ranges from 0 (black) to a maximum 3 nanomolar solution (white). Fluid flows from left to right, with average speed of a millimeter per second, a typical speed in small blood vessels. The width of the figure corresponds to 100 microns.

Maintaining Your Health from Within: Controls for Nanorobot Swarms in Fluids 344 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

References [12] Fernando Patolsky and Charles [1] Robert A. Freitas Jr. Nanomedicine, M. Lieber. Nanowire nanosensors. volume I: Basic Capabilities. Landes Materials Today, 8:20– 28, April 2005. Bioscience, Georgetown, TX, 1999. Available [13] Paul E. Sheehan and Lloyd J. at www.nanomedicine.com/NMI.htm. Whitman. Detection limits for nanoscale [2] Kelly Morris. Macrodoctor, come meet the biosensors. Nano Letters, nanodoctors. The Lancet, 357:778, March 10 5(4):803–807, 2005. 2001. [14] Shankar Ghosh et al. Carbon [3] Ernesto Andrianantoandro, Subhayu nanotube flow sensors. Science, Basu, David K. Karig, and Ron Weiss. 299:1042–1044, 2003. Synthetic biology: New engineering rules for [15] Todd M. Squires and Stephen R. an emerging discipline. Molecular Systems Quake. Microfluidics: Fluid physics at Biology, 2(msb4100073):E1–E14, 2006. the nanoliter scale. Reviews of Modern [4] C. P. Collier et al. Electronically Physics, 77:977–1026, 2005. configurable molecular-based logic gates. [16] E. M. Purcell. Life at low Reynolds Science, 285:391–394, 1999. number. American Journal of Physics, [5] H. G. Craighead. Nanoelectromechanical 45:3–11, 1977. systems. Science, 290:1532–1535, 2000. [17] Steven Vogel. Life in Moving Fluids. [6] Joe Howard. Molecular motors: Structural Princeton Univ. Press, 2nd edition, adaptations to cellular functions. Nature, 1994. 389:561–567, 1997. [18] Howard C. Berg. Random Walks [7] J. Fritz et al. Translating biomolecular in Biology. Princeton Univ. Press, 2nd recognition into nanomechanics. Science, edition, 1993. 288:316– 318, 2000. [19] Xudong Wang et al. Direct-current [8] Carlo Montemagno and George nanogenerator driven by ultrasonic Bachand. Constructing nanomechanical waves. Science, 316:102–105, 2007. devices powered by biomolecular motors. [20] Tad Hogg and Philip J. Kuekes. Nanotechnology, 10:225–231, 1999. Mobile microscopic sensors for [9] S.-Y. Wang and R. Stanley Williams, high-resolution in vivo diagnostics. editors. Nanoelectronics, volume 80, New Nanomedicine: Nanotechnology, York, March 2005. Springer. Special issue of Biology, and Medicine, 2:239–247, Applied Physics A. 2006. [10] Howard C. Berg and Edward M. Purcell. [21] X. Sunney Xie, Ji Yu, andWei Physics of chemoreception. Biophysical Yuan Yang. Living cells as test tubes. Journal, 20:193–219, 1977. Science, 312:228–230, 2006. [11] Z. Li et al. Silicon nanowires for [22] Tuan Vo-Dinh, Paul Kasili, and sequence-specific DNA sensing: Device Musundi Wabuyele. Nanoprobes fabrication and simulation. Applied Physics and nanobiosensors for monitoring A, 80:1257–1263, 2005. and imaging individual living cells. Nanomedicine: Nanotechnology, Biology, and Medicine, 2:22–30, 2006.

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[23] Tad Hogg. Coordinating microscopic [31] Aram Galstyan, Tad Hogg, and robots in viscous fluids. Autonomous Agents Kristina Lerman. Modeling and and Multi-Agent Systems, 14(3):271–305, mathematical analysis of swarms of 2007. microscopic robots. In P. Arabshahi [24] Charles A. Janeway et al. and A. Martinoli, editors, Proc. of the Immunobiology: The Immune System in IEEE Swarm Intelligence Symposium Health and Disease. Garland, New York, 5th (SIS2005), pages 201–208, 2005. edition, 2001. [32] Thresa M. Allen and Pieter R. [25] Rodolfo R. Llinas et al. Neuro-vascular Cullis. Drug delivery systems: Entering central nervous recording/stimulating the mainstream. Science, system: Using nanotechnology probes. J. of 303:1818–1822, 2004. Nanoparticle Research, 7:111–127, 2005. [33] Yaakov Benenson, Binyamin Gil, Uri [26] Robert A. Freitas Jr. Pharmacytes: Ben-Dor, Rivka Adar, and Ehud Shapiro. An ideal vehicle for targeted drug An autonomous molecular computer delivery. Journal of Nanoscience and for logical control of gene expression. Nanotechnology, 6:2769–2775, 2006. Nature, 429:423– 429, 2004. [27] D. Sretavan, W. Chang, C. Keller, and M. [34] Robert A. Freitas Jr. Nanomedicine, Kliot. Microscale surgery on axons for nerve volume IIA: Biocompatibility. Landes injury treatment. Neurosurgery, 57(4):635– Bioscience, Georgetown, TX, 2003. 646, 2005. Available at www.nanomedicine.com/ [28] Tad Hogg and David W. Sretavan. NMIIA.htm. Controlling tiny multi-scale robots for nerve [35] Andre Nel et al. Toxic potential of repair. In Proc. of the 20th Natl. Conf. on materials at the nanolevel. Science, Artificial Intelligence (AAAI2005), pages 311:622–627, 2006. 1286–1291. AAAI Press, 2005. [36] Amanda M. Schrand et al. Are [29] Scott P. Leary, Charles Y. Liu, and diamond nanoparticles cytotoxic? Michael L. J. Apuzzo. Toward the emergence Journal of Physical Chemistry B, of nanoneurosurgery: Part iii-nanomedicine: 111:2–7, 2007. Targeted nanotherapy, nanosurgery, and progress toward the realization of nanoneurosurgery. Neurosurgery, 58:1009– 1026, 2006. [30] Kristina Lerman et al. A macroscopic analytical model of collaboration in distributed robotic systems. Artificial Life, 7:375–393, 2001.

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Ray Kurzweil and Chapter 35: Fantastic Voyage: Live Long Emerging technologies in rational Terry Grossman/ Fantastic Enough to Live Forever The Science drug design, tissue engineering, Voyage: Live Behind Radical Life Extension Questions gene therapy, and nanobots (among Long Enough to Live Forever and Answers others) promise a future of automated - The Science Ray Kurzweil life extension. The use of such Behind Radical Life Extension Inventor and Author technologies, and the resulting Questions and and dramatic increases in productivity in all Answers in “World Health Terry Grossman, M.D., areas of human endeavor, will enable Strategy” eBook, Medical Director, Frontier Medical Institute us to live in a world in which all our (Ed.) Renata G. Bushko, physical needs can be met. FHTI, 2016. Abstract Futureofhealth. org utting an end to human aging is now Printed with permission of Rodale From Strategy becoming a reality, and immortality Books for the Future of Health (Ed.) is no longer just a dream. Through Renata G. P what we are calling “Fantastic Voyage,” we 1. What’s the key message? Bushko, IOS Press 2009 provide a guide to achieving life extension We make the scientific case that through various means, thereby slowing immortality is within our grasp. We down aging and disease processes. explain how to slow down aging and The three components of Fantastic disease processes to such a degree Voyage are: Bridge One - Aggressively that you can remain in good health applying today’s knowledge. Bridge Two until the more radical life-extending - Putting biotechnology, such as gene and life-enhancing technologies – now technologies, to use with therapeutic in the research and testing pipeline – cloning and rejuvenation medicine. Bridge become available. Three - Putting nanotechnology to use by developing a means to rebuild our bodies 2. What sort of life-extending and brains with nanobots. technology are you referring to? Many of these technology solutions Fantastic Voyage is a guide for can be simulated today through the use aggressively applying today’s of targeted supplements, designed to knowledge – we call it Bridge One – to address the specific needs of an individual, enable you to live long enough to take such as insulin resistance, cholesterol and advantage of the full development of homocysteine levels, and inflammation. the biotechnology revolution – Bridge To slow aging now, we propose a Two. program of supplementing aggressively, eating foods that impede aging and disease 3. What are some examples of this? processes, and reversing inflammation Biotechnology is providing the means through diet. We also provide guidance to actually change your genes: not to customize each program to the specific just designer babies but designer needs of the individual. baby boomers. We’ll also be able to rejuvenate all of your body’s tissues

and organs by transforming your skin cells to live long enough to live forever into youthful versions of every other cell by aggressively reprogramming our type. Already, new drug development is biochemistry to forestall aging and precisely targeting key steps in the process disease processes. of atherosclerosis (the cause of heart disease), cancerous tumor formation, and 7. Where is this ultimately going to the metabolic processes underlying each take us? major disease and aging process. The Within a quarter century, nonbiological biotechnology revolution is already in its intelligence will match the range and early stages and will reach its peak in the subtlety of human intelligence. It second decade of this century. will then soar past it because of the continuing acceleration of information- 4. And this will bring radical life extension? BASED technologies, as well as the Well, biotech is Bridge Two, which, in turn, ability of machines to instantly share will allow you to reap the benefits of the their knowledge. Intelligent nanorobots nanotechnology-AI (artificial intelligence) will be deeply integrated in our bodies, revolution – Bridge Three – which does our brains, and our environment, have the potential to allow you to live providing vastly extended longevity, indefinitely. With nanotechnology, we can full-immersion virtual reality go beyond the limits of biology, and replace incorporating all of the senses (like your current “human body version 1.0” with a the “Matrix”), “experience beaming” dramatically upgraded version 2.0, providing (like “Being John Malkovich”), and radical life extension. vastly enhanced human intelligence. The result will be an intimate merger 5. And how does that work? between the technology-creating The “killer app” of nanotechnology is species and the technological “nanobots,” which are blood-cell sized evolutionary process it spawned. robots that can travel in the blood stream destroying pathogens, removing debris, 8. How do I slow down aging now? correcting DNA errors, and reversing aging • The most unique aspect of processes. The nanotechnology revolution our program is to supplement will reach its peak in during the 2020s. aggressively. Our bodies evolved in a different era when short life 6. Haven’t there been promises in the past spans were in the interest of the along these lines? species, thereby freeing up scarce Until recently, there was relatively little that resources for the young and those could be done about our short life span, caring for them. So we need to other than to rationalize this tragedy as “a reprogram our biochemistry to good thing.” But that is now changing. We change the ancient programs in have devised a new program that enables our genes. We provide a detailed even older baby boomers like ourselves guide to which supplements will

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contribute to your health and slow down plans and schedules. Rather, by truly aging based on your particular health understanding how your body works, situation. you can set your own priorities, and devise your own customized program. • Eat foods that slow down aging and disease processes. For example, sugars 9. Can we really forestall diseases and simple starches increase insulin like heart disease and cancer? resistance, a key source of aging, so we The leading causes of death – heart recommend a low “glycemic index” diet. disease, cancer, stroke, respiratory Sugar and starch also promote what’s disease, kidney disease, liver disease, aptly called AGEs (advanced glycation and diabetes – do not appear out of end-products), which are damaging the blue. You don’t catch them walking cross links that form between the body’s down the street one day. They are proteins. the end result of processes that are decades in the making. We help • Chronic inflammation underlies every you understand how longstanding step in heart disease, and promotes imbalances in the metabolic processes all major degenerative diseases, but underlying life functions can lead to you can reverse inflammation with disease. anti-inflammatory foods. For example, Conventional medical care is it’s important to emphasize the anti- geared toward dealing with long-term inflammatory fats found in such foods as degenerative processes fish, nuts, and extra virgin olive oil. only after they erupt into advanced clinical disease. But by this time it is • Each of us is different, so we provide often too late. It’s like approaching a guidance on how to customize your cliff, but walking backward. You need program based on test results, including to recognize that you’re getting closer genomic tests. We also provide to the edge and stop. Once you fall guidance on exercise and stress off, it’s difficult to do anything about management. it. That’s what Fantastic Voyage is all about: to provide the knowledge This sounds complicated. and the specific steps to take, sooner rather than later, to extend your life, Fantastic Voyage is not a one-trick pony. your vitality, and your well-being. Many popular health books provide a single key idea. But our bodies are complex, 10. Why are you delivering this and no one message captures the key to message now? slowing down aging. There are a dozen Technical progress progresses important aging and diseases processes, exponentially, and we’re just now and we provide programs to address reaching the rapid part of the each one. So we don’t give you menu curve. Our paradigm shift rate – the

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rate of technical progress – is doubling similar metabolic changes as caloric every decade. The capability of specific restriction, even though the animals technologies such as genetic sequencing were not eating less. and nanotechnology is doubling even faster: every year. These emerging transformations 13. So how have you guys done in in technology will usher in powerful new the aging department? tools to expand your health and human Ray: My father’s premature death at powers. Eventually, the knowledge age 58 from heart disease and my represented in Fantastic Voyage will be own diagnosis of type II diabetes at automated within you. Today, however, you the age of 35 defined my early health have to apply that knowledge yourself. concerns. The conventional medical treatment made my diabetes worse 11. Give me a surprising idea to slow down and did little to alleviate my concern aging. about a genetic predisposition to heart Supplement with phosphatidylcholine (PtC), a disease. As an inventor, I studied the fatty substance that is a major component of literature, devised my own program, cell membranes. As you age, the PtC in your overcame my diabetes, and wrote a cell membranes diminishes dramatically, and best-selling health book about the is replaced with hard fats and cholesterol. experience. More recently, I have This is one important reason that an elderly become aware of a more insidious person’s skin is less supple, and organs less challenge: middle age. Working with effective. Supplementing with PtC can stop Terry over the past five years, we and even reverse this process. applied the same belief in the power of ideas to the problem of aging. 12. What’s another one? The prescription drug metformin can I take 250 supplements a day and significantly reduce the effects of insulin really feel that I’m reprogramming resistance. One adult in three has what’s my biochemistry, just like I would called the “metabolic syndrome,” also reprogram my computers. known as “Syndrome X,” which results in a serious inability to process sugar and I’m 56 chronologically, but my refined carbohydrate foods like pasta and biological age, according to an bread. Most people who have this are not extensive set of tests, is about 40, not even aware of it. Moreover, almost all adults much changed from 16 years ago. In develop some level of insulin resistance many ways, I’m healthier and younger as they age, which is a major contributor to than I was 20 years ago. I have no heart disease, stroke, and other diseases. indications of diabetes. My glucose, Metformin combats this aging process. In HgA1c (a test of glucose levels animal tests, metformin (and an earlier over the past 90 days), cholesterol, version of this drug called phenformin) homocysteine (test of methylation extended life spans, and produced processes), C-reactive protein (test of

Fantastic Voyage: Live Long Enough to Live Forever The Science Behind Radical Life Extension Questions and Answers 350 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

inflammation levels), and other test levels 15. Your book promises the end of are all at ideal levels. My overall feeling: aging, not just slowing it down. Is so far, so good. Terry: It is said that among that realistic? the things you can do to enjoy a long and We are in the early stages of multiple healthy life, it is best to start by “picking your profound revolutions spawned by the parents wisely.” I am fortunate that both are intersection of biology, information alive and well at 80 years of age. They are science, and nanotechnology. With physically and mentally active and enjoy a the decoding of the genome and our varied social and cultural life. So it would efforts to understand its expression appear that I started life with “a leg up” on in proteins, many new and powerful longevity, thanks to their genes. Things technologies are emerging. These aren’t always so straightforward in medicine, include rational drug design (drugs however. My genomic testing revealed that designed for very precise missions, I harbor several harmful genetic tendencies. with little or no side effects), tissue Although I have enjoyed excellent health so engineering (regrowing our cells, far, I am now at the stage of my life where tissues, and organs), reversal of aging one’s genetic predispositions have a way processes, gene therapy (essentially of manifesting themselves as “full blown” reprogramming our genetic code), diseases. But with the genetic information I nanobots (robots the size of blood now possess, I’ve been able to take specific cells built from molecules placed in our measures to maintain my health, using the bodies and bloodstreams to enhance best of the Bridge One ideas we present in every aspect of our lives), and many Fantastic Voyage. I am very optimistic about others. what the future Bridge Two and Bridge Three therapies will be able to do for both 16. Isn’t it a bit of hyperbole to say myself and the rest of humankind. you can live forever? Consider the metaphor of maintaining 14. Isn’t it natural to age? a house. How long does a house It may be “natural,” but we don’t see last? The answer obviously depends anything positive in losing our mental agility, on how well you take care of it. If you sensory acuity, physical limberness, sexual do nothing, the roof will spring a leak desire, or any other human ability. We view before long, water and the elements disease and death at any age as a calamity, will invade, and eventually the house as problems to be overcome. Until recently, will disintegrate. But if you proactively there was relatively little that could be take care of the structure, repair all done about our short life span other than to damage, confront all dangers, and rationalize this tragedy as a good thing. We rebuild or renovate parts from time now have another option. to time using new materials and technologies, the life of the house can essentially be extended without limit.

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The same holds true for our bodies and 18. Tell me more about bridge two: brains. The only difference: while we fully biotechnology. understand the methods underlying the As we are learning about the maintenance of a house, we do not yet fully information processes underlying understand all of the biological principles biology, we are devising ways of of life. But with our rapidly increasing mastering them to overcome disease comprehension of the biochemical and aging and extend human processes and pathways of biology, we potential. One powerful approach are quickly gaining that knowledge. We is to start with biology’s information are beginning to understand aging, not backbone: the genome. With gene as a single inexorable progression, but as technologies, we’re now on the a group of related biological processes. verge of being able to control how Strategies are emerging for fully reversing genes express themselves. We now each of these aging progressions, using have a powerful new tool called RNA different combinations of biotechnology interference (RNAi), which is capable techniques. In the meantime, we can slow of turning specific genes off. It blocks each aging process to a crawl, using the the messenger RNA of specific methods outlined in this book. genes preventing them from creating Many experts, including the authors, proteins. Since viral diseases, cancer, believe that within a decade we will be and many other diseases use gene adding more than a year to human life expression at some crucial point in expectancy every year. At that point, with their life cycle, this promises to be a each passing year, your remaining life breakthrough technology. Ultimately, expectancy will move further into the future. we will actually be able to add new genes by “infecting” our cells with 17. Aren’t the designs of nature optimal? specially designed viruses that insert Biological systems are remarkable in their new genes in our genome in just the cleverness. In the 15th century, Leonardo da right place. Vinci wrote, “Human ingenuity may make Another important line of attack is various inventions, but it will never devise to regrow our own cells, tissues, and any inventions more beautiful, nor more even whole organs, and introduce simple, nor more to the purpose than nature them into our bodies without surgery. does; because in her inventions nothing One major benefit of this “therapeutic is wanting and nothing is superfluous.” We cloning” technique is that we will be share da Vinci’s sense of awe at the designs able to create these new tissues and of biology, but we do not agree with him on organs from versions of our cells our inability to improve on nature. Da Vinci that have also been made younger was not aware of either biotechnology or – the emerging field of rejuvenation nanotechnology, and it turns out that nature, medicine. For example, we will be able for all its apparent creativity, is dramatically to create new heart cells from your suboptimal. skin cells and introduce them into your

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system through the blood stream. Over Despite the elegant way our red blood time, your heart cells get replaced with these cells carry oxygen in our bloodstream new cells, and the result is a rejuvenated and deliver it to our tissues, it is a “young” heart with your own DNA. very slow and cumbersome system. Drug discovery was once a matter of There’s a design for such robotic red finding substances that produced some blood cells called “respirocytes” by beneficial effect without excessive side Rob Freitas, a nanotechnology expert, effects. This process was similar to early which are thousands of times more humans’ tool discovery, which was limited to efficient than biological red blood simply finding rocks and natural implements cells. Analyses show that with these that could be used for helpful purposes. respirocytes, you could sit at the We are learning the precise biochemical bottom your pool for four hours without pathways that underlie both disease and taking a breath. aging processes, and are able to design There is another Freitas design drugs to carry out precise missions at the that will be able to augment your molecular level. The scope and scale of immune system, basically robotic white these efforts is vast. bloods. It will have the capability to destroy any virus, cancer cell, or other 19. And Bridge Three? invader hundreds of times faster than As we peer a couple of decades into the our biological immune system. We’ve future, nanotechnology will enable us to actually watched our own white blood rebuild and extend our bodies and brains cells destroy a bacterium through a and create virtually any product from mere microscope. Although our white blood information and inexpensive raw materials, cells are clever, they are very slow, the resulting in remarkable gains in prosperity. process of killing a germ takes over We will develop means to vastly expand our an hour. The robotic versions will do a physical and mental capabilities by directly more thorough job in seconds. They interfacing our biological systems with will be able to download software human-created technology. from the Internet to combat specific As one example, the interneuronal types of pathogens. If that sounds connections in our brains compute at only particularly futuristic, we’d point out that 200 transactions per second, millions of we already have brain implants, such times slower than even today’s electronic as the FDA approved neural implant circuits. Circa late 2020s, billions of for Parkinson’s Disease, that can nanobots traveling in the capillaries of the download new software from outside brain will interact directly with our biological the patient. neurons providing a vast expansion of The reality is that biology will never human intellect. They can also provide be able to match what we will be full immersion virtual reality from inside the capable of engineering, now that we nervous system by shutting down the signals are gaining a deep understanding of from our “real” senses and replacing them biology’s principles of operation. with the signals that are appropriate for a virtual environment. Another example is our red blood cells.

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20. What about government opposition to were going to change. The three new technologies such as stem cell therapy? intertwined revolutions of biotechnology, Is that going to hold things up? nanotechnology, and “strong AI” (artificial These obstacles end up being stones in the intelligence at human levels and beyond) river of progress; the broad progression of will result in other transformations technology just flows around them. Stem that address this issue. For example, cell research is a good example of this. The nanotechnology will enable us to research has continued despite opposition create virtually any physical product from the government and elsewhere. from information and very inexpensive And the controversy has only served to raw materials, leading to radical wealth accelerate other ways of accomplishing the creation. We’ll have the means to meet same thing, which ultimately will provide the material needs of any conceivable superior approaches. For example, there size population of biological humans. has been substantial recent progress on Nanotechnology will also provide the transdifferentiation: turning one type of cell, means of cleaning up environmental such as a skin cell, into another type. After all, damage from earlier stages of what’s the difference between a skin cell and industrialization. In recent years, gains a pancreatic Islet cell, or a heart cell? They in prosperity have resulted in declines in all have the same genes. The difference is population growth, although a dramatic that different genes are expressed, and we’re drop in the death rate will reverse that to learning the molecular triggers that control some extent. But dramatic increases in gene expression. By adding certain chemicals productivity will enable us to provide for such as peptides and short RNA molecules all of our physical needs. to cells, we can transform their cell type. This has already been demonstrated. If you want 22. Won’t it get boring to live many new heart cells, creating them from your own hundreds of years? cells has important advantages: you’ll have an If humans lived many hundreds of years inexhaustible supply of them, and these new with no other change in the nature cells will have your DNA, thereby avoiding an of human life, then, yes, that would immune system response. lead to a deep ennui. But the same In general, opposition to technology nanobots (robots the size of blood tends to focus narrowly on very specific cells) in the bloodstream that keep us techniques. The flow of progress in healthy (by destroying pathogens and biotechnology, nanotechnology, and other reversing aging processes) will also new methodologies is so broad and diverse vastly augment our intelligence and that these types of controversies do not experiences. By traveling noninvasively significantly affect the overall rate of advance. into the capillaries of the brain, these nanobots will interact directly with 21. If people stop dying, isn’t that going to our biological neurons to create full- lead to overpopulation? immersion virtual reality experiences A common mistake that people make from within the nervous system, and when considering the future is to envision provide intimate connection to greatly a major change to today’s world, such as enhanced intelligence. We won’t be radical life extension, as if nothing else bored.

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Aubrey D.N.J. Chapter 36: What are Similarities and in all probability, mutually exclusive. de Grey/ in “World Health Differences between the Singularity and The singularity is one; the demise of Strategy” eBook, Methuselarity? humanity is the other. Hence my choice (Ed.) Renata G. Bushko, Aubrey D.N.J. de Grey, Ph.D. of the indefinite article: the singularity is FHTI, 2016. [email protected] not “the” uniquely unique event in Futureofhealth. org From Methuselah Foundation humanity’s future, because it may not Strategy for the occur, but if it does occur, nothing Future of Health (Ed.) Renata G. Abstract comparable will either precede or Bushko, IOS ging, being a composite of follow it. Press 2009 innumerable types of molecular The singularity has been defined in Aand cellular decay, will be defeated many related but subtly distinct ways incrementally. I have for some time predicted over the years, so let me begin my that this succession of advances will discussion of it by making clear what I feature a threshold, which I here christen mean by the term. I adhere to the the “Methuselarity,” following which there following definition: “an asymptotically will actually be a progressive decline in rapid increase in the sophistication of the rate of improvement in our anti-aging technology on whose behaviour technology that is required to prevent a humans depend.” I do not use the rise in our risk of death from age-related word to mean, for example, “the causes as we become chronologically older. technological creation of smarter-than- Various commentators have observed the human intelligence” (which is the similarity of this prediction to that made definition currently given by SIAI, the by Good, Vinge, Kurzweil and others Singularity Institute for Artificial concerning technology in general (and, in Intelligence1) – despite my agreement particular, computer technology), which they with the view that the technology most have termed the “singularity.” In this essay I likely to bring about the singularity compare and contrast these two concepts. (and, indeed, the one that was originally used to define it) is precisely 1. The singularity: a uniquely unique event the one that SIAI study, namely in humanity’s future recursively self-improving artificial “Unique” is, of course, an over-used word to intelligence (of which more below). I am describe momentous events – arguably, sticking to the more abstract definition even more over-used than “historic.” How, partly because it seems to me to then, can I dare to describe something as encapsulate the main point of why the uniquely unique? singularity is indeed uniquely unique, Well, I will begin by pulling back a fraction and partly because it will help me to from that description. There are actually, in highlight what distinguishes the my view, two possible events in humanity’s singularity from the Methuselarity. future that merit this description. But I do not One aspect of my definition that feel very bad about this qualification, may raise eyebrows is its use of the because I believe that those two events are, word “asymptotically” rather than

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“exponentially.” I feel sure that von happen at all? Not if we merely Neumann2 would agree with me on this: the proceed according to Moore’s law, mere perpetuation of Moore’s Law3 will not because that does not predict infinite bring about the singularity. A gravitational rates of progress at any point in the singularity, which is of course the future. But wait – who’s to say that etymological source of the term, is the progress will remain “only” centre (not, I stress, the event horizon) of a exponential? Might not progress black hole: the point at which the force of exceed this rate, following an inverse gravity is infinite – or, to be more precise, the polynomial curve (like gravity) or even point arbitrarily near to which gravity is an inverse exponential curve? I, for arbitrarily strong. The distance between the one, don’t see why it shouldn’t. If we singularity and any point of interest (inside or consider specifically the means outside the event horizon) at which gravity is whereby the Singularity is most widely finite is, of course, finite. This is an expected to occur, namely the asymptotic relation between distance and development of computers with the strength: if point X is distance Y from the capacity for recursive improvement of singularity, it is not possible to travel from X, their own workings,4 I can see no along the line between X and the singularity, argument why the rate at which such a by a distance greater than Y, and experience computer would improve itself should continuously increasing gravity. Exponential not follow an inverse exponential (though not inverse exponential! – see curve, i.e. one in which the time taken below) relations are not like this: they have to achieve a given degree of no asymptote. If the force of gravity exerted improvement takes time X, the time by a particular body were exponential taken to repeat that degree of (though still increasing with decreasing improvement is X/2, then X/4 and so distance from the body), the relation on. between distance from that body and gravity Why does this matter? It might exerted by it would be defined in terms of matter quite a lot, given that (in most distance from the point furthest away from it people’s view, anyway) the purpose of (“on the other side of the Universe”). Call the creating computers that are smarter gravity exerted at that point X and suppose than us is to benefit us rather than to that the gravity exerted at half that distance supersede us. Human intelligence, I from the body is 4X (which is the same as for believe, will not exhibit a super- gravity in real life). Then the gravity exerted exponential rate of growth, because by the body at a point arbitrarily close to it is our cognitive hardware is incompatible not arbitrarily large – it is just 16X, since that with that. Now, I grant that I have only point is exactly twice as far away from the rather wishy-washy intuitive reasons for point of minimum gravity as the 4X point is. this view – but what I think can be quite Having belaboured this point, I now hope safely said is that our ability to “keep to justify doing so. Will the technological up” with the rate of progress of singularity, defined as I define it above, recursively self-improving computers

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will be in inverse relation to that rate, and regions, of sufficiently deep snow in thus that super-exponentially self-improving just the right places to save the lives of computers will be more likely to escape our reckless mountaineers, and so on – control than “merely” exponentially self- but we will not dwell on it, and quite improving ones will. Computers have soon we will take it for granted. hardware constraints too, of course, so the A reasonable question to ask is, formal asymptotic limit of truly infinite rates of well, since even a super-exponentially improvement (and, thus, truly infinite self-improving AI will always have finite intelligence of such machines) will not be intelligence, might it not at some point reached – but that is scant solace for those create an even more rapidly self- of us who have been superseded (which improving system that could supersede could, of course, mean “eliminated”) some it? Indeed it might (I think) – but, from time previously. There is, of course, the our point of view, so what? If we have distinct possibility that even exponentially succeeded in creating a permanently self-improving systems would similarly friendly AI, we can be sure that any supersede us, but the work of SIAI and “next-generation” AI that it created others to prevent this must be taken into would also be friendly, and thus (by the account in quantifying that risk. previous paragraph’s logic) largely Let us now consider the aftermath of a invisible. Thus, from our perspective, “successful” singularity, i.e. one in which there will only be one singularity. recursively self-improving systems exist and In closing this section I return to my have duly improved themselves out of sight, claim that the singularity and the but have been built in such a way that they demise of humanity are, in all permanently remain “friendly” to us. It is probability, mutually exclusive. Clearly if legitimate to wonder what would happen our demise precedes the singularity next, albeit that to do so is in defiance of then the singularity cannot occur. Can Vinge.5 While very little can confidently be our demise occur if preceded by the said, I feel able to make one prediction: that singularity? Almost certainly not, I our electronic guardians and minions will not would say: the interval available for our be making their superintelligence terribly demise between the development of conspicuous to us. If we can define “friendly recursively self-improving AI and the AI” as AI that permits us as a species to attainment by that AI of extremely follow our preferred, presumably familiarly thorough ability to protect us (even dawdling, trajectory of progress, and yet also from, for example, nearby supernovae) to maintain our self-image, it will probably do will be short. (I exclude here the the overwhelming majority of its work in the possibility that the singularity will occur background, mysteriously keeping things via the creation of AI that is not friendly the way we want them without worrying us to us, only because I think humanity’s about how it’s doing it. We may dimly notice life expectancy in that scenario is so the statistically implausible occurrence of very short that this is equivalent from hurricanes only in entirely unpopulated our point of view to the singularity not

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occurring at all.) The “area under the curve” Humans are very, very good at of humanity’s probability of elimination at any adjusting their aspirations to match time after the singularity is thus very small. I their expectations. When things get am, of course, discounting here the better, people are happy – but if they possibility that even arbitrarily intelligent and stay better and show every sign of powerful systems cannot protect us from continuing that way, people become truly cosmic events such as the heat death blasé. Conversely, when things get of the Universe, but I agree with Deutsch6 worse people are unhappy, but if they that this is unlikely given the time available. stay worse and show every sign of continuing that way, people become 2. The Methuselarity: the philosophical. This is why, by all biogerontological counterpart of the measures that have to my knowledge singularity been employed, people in the In a recent interview, Watson was asked developed world are on average what would be the next event in the history neither much happier nor much less of biology that would compare in happy now than they were when things significance to his and Crick’s discovery of were objectively far worse. This is a the structure of DNA, and he replied that good thing in many ways, but in at least there would never be one.7 I think he was one way it is a problem: it dampens our correct. However, I agree with him only if I ardour to improve our lives more am rather careful in defining “biology” as the rapidly. In particular, it depletes the discovery of features of the living world, and ranks of “unreasonable men” to whom excluding biotechnology, which for present Shaw so astutely credited all progress.8 purposes I define as theexploitation of such There are far too few unreasonable discoveries. In biotechnology I believe that men and women in biology, and there will certainly be a counterpart, especially in biogerontology. I am something that will outstrip in significance proud to call myself an exception: every other advance either predating or someone who is comfortable devoting following it: the Methuselarity. his life to the most important problems For almost a decade following my of all, even if they appear thoroughly graduation in 1985, I conducted research in intractable.9 In my youth, I felt I could artificial intelligence. I switched fields to make the most difference to the world biogerontology shortly after becoming by helping to develop intelligent aware that the defeat of aging was vastly computers; but when I discovered the less on biologists’ agenda than I had hitherto truth about biologists’ attitude to aging I presumed. I was not, at that time, aware of knew that I could make even more the concept of recursively self-improving AI difference in that field. and the singularity, though perhaps I should Why is aging so important? Aging have been. But even if I had been, I think I kills people, yes, but so do quite a few would still have made the career change other things – and moreover, life is that I did. Why? about quality as well as quantity, and

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intelligent machines might very greatly policy-makers’ minds on the ever- improve the quality of life of an awful lot of dependable lure of lucre associated people, not least by virtue of providing with keeping people youthful, rather essentially unbounded prosperity for all. than on the moral imperative.11 Even if we take into account the fact that But this is in the process of aspirations track expectations, such that changing – indeed, of being turned on what really matters is to maintain a good rate its head. This is for one reason and of improvement of (objective) quality of life, it one only: it is becoming appreciated is hard to deny that the development of that aging may be amenable to super-intelligent machines will be of comprehensive postponement by astronomical benefit to our lives. But let’s be regenerative medicine.12,13 And the clear: quantity of life matters too. There is a reason that makes all the difference is well-established metric that folds together because it creates the possibility – the quality and quantity benefits of a given indeed, the virtual certainty – of the technological or other opportunity: it is the Methuselarity. “quality-adjusted life year” or QALY.10 Having tantalised you for so long, I Historically, mainstream biogerontologists cannot further delay revealing what the have been publicly cautious regarding Methuselarity actually is. It is the point predictions of the biomedical consequences in our progress against aging at which of their work, though this is gradually our rational expectation of the age to changing. But even privately, few which we can expect to live without biogerontologists have viewed aging as age-related physiological and amenable to dramatic change: they have cognitive decline goes from the low been aware that it is a hugely multi-faceted three digits to infinite. And my use here phenomenon, which will yield only of the word “point” is almost accurate: incrementally to medical progress if it yields this transition will, in my view, take no at all. This places them in a difficult position longer than a few years. Hence the – when arguing for the importance of their superficial – similarity to the singularity. work relative to other supplicants for I have set out elsewhere, first biomedical research resources. Yes, there is qualitatively14 and then quantitatively,15 always a benefit to a QALY, and yes, the details of my reasons for believing progress against aging will deliver QALYs – that the application of regenerative but the force of this argument is diminished medicine to aging will deliver this cusp; by two key factors, namely the probability of thus, here I will only summarise. success (which biogerontologists cannot Regenerative medicine, by definition, is provide a conclusive case for being high) the partial or complete restoration of a and the entrenched ageism in society, which damaged biological structure to its pre- views it as “fair” to deprioritise health care damaged state. Since aging is the for the elderly. This quandary is well accumulation of damage, it is in theory illustrated by the current “Longevity a legitimate target of regenerative Dividend” initiative, which seeks to focus medicine, and success in such a

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venture would constitute bona fide Methuselarity will occur at all: the rejuvenation, the restoration of a lower Methuselarity is, simply, the one and biological age. (The bulk of my work over only point in the future at which LEV is the past decade can be summarised as the achieved. elaboration of that “theory” into an increasingly detailed and promising project 3. The singularity and the plan for actual implementation16 – but I Methuselarity: some key differences digress.) This rejuvenation would not be Having described the singularity and total: some aspects of the damage that the Methuselarity individually, I now constitutes aging would be resistant to these examine how they differ. I hope to therapies. But not intrinsically resistant: all communicate that the superficial such damage could in principle be reversed similarities that they exhibit evaporate or obviated by sufficiently sophisticated rather thoroughly when one delves repair-and-maintenance (i.e., regenerative) more deeply. interventions. Thus arises the concept of a Perhaps the most important contrast rate of improvement of the between the singularity and the comprehensiveness of these rejuvenation Methuselarity is the relevance of therapies that is sufficient to outrun the accelerating change. In the first section problem: to deplete the levels of all types of of this essay I dealt at some length with damage more rapidly than they are the range of trajectories that I think are accumulating, even though intrinsically the plausible for the rate of improvement damage still present will be progressively of self-improving artificial intelligence more recalcitrant. I have named this required systems – but it will have been rate of improvement “longevity escape apparent that all the trajectories I velocity” or LEV.14,15 discussed were accelerating. It might It is important to understand that LEV is intuitively be presumed that, since not an unchanging quantity, as it might be if it aging is a composite of innumerable were a feature of our biology. Rather, it will types of damage that accumulate at vary with time – and exactly how it will different rates and that possess probably vary is a topic I address in the next different degrees of difficulty to section. LEV will, however, remain non-zero remove, our efforts to maintain youth in for as long as there remain any types of the face of increasing chronological damage that we cannot remove or obviate. age will require an accelerating rate of Thus, the formal possibility exists that we will progress in our biomedical prowess. at some point achieve LEV but that at some But this is not correct. subsequent date our rate of progress The central reason why progress against aging will slip back below LEV. need not accelerate is that there is a However, I have claimed that this will almost spectrum not only in the recalcitrance certainly not happen: that, once surpassed, of the various types of damage that LEV will be maintained indefinitely. This claim constitute aging but also in their rates is essentially equivalent to the claim that the of accumulation. As biomedical

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gerontologists, we will always focus on the be far more momentous than the highest-priority types of damage, the types singularity. that are most in danger of killing people. How can this be? Surely I have just Thus, the most rapidly-accumulating types of shown that the Methuselarity will be the damage will preferentially be those against consequence of only quite modest which we most rapidly develop repair-and- (and, thereafter, actually decreasing) maintenance interventions. There will, to be rates of progress in postponing aging, sure, be “spikes” in this distribution – types whereas the singularity will result from of damage that accumulate relatively rapidly what for practical purposes can be and are also relatively hard to combat. But regarded as infinite rates of progress in we are discussing probabilities here, and if the prowess of computers? Indeed I we aggregate the probability distributions of have. But when we focus on humanity’s the timeframes on which the various types of experience of the world and its view of damage, with their particular rates of itself, what matters is not how rapidly accumulation and degrees of difficulty to things are changing but how rapidly combat, are in fact brought under control, those changes affect us. In the case of the conclusion is clear: we are almost certain the singularity, I have noted earlier in to see a progressive and unbroken decline this essay that if we survive it at all (by in the rate at which we need to develop new virtue of having succeeded in making anti-aging therapies once LEV is first these ultra-powerful computers achieved. (I do not mean to say that this permanently friendly to us) then we will progression will be absolutely monotonic – move from a shortly-pre-singularity but the “wobble” in how rapidly progress situation in which computers already needs to occur will be small compared to make our lives rather easy to a the margin of error available, i.e. the margin situation in which they fade into the by which the average rate of progress background and stay there. I contend exceeds LEV.) This conclusion is, of course, that, from our point of view, this is really subject to assumptions concerning the not much of a difference, distribution of these types of damage on psychologically or socially: computers those two dimensions – but, in the absence are already far easier to use than the of evidence to the contrary, a smooth (log- first PCs were, and are getting easier normal, or similar) distribution must be all the time, and the main theme of that assumed. progression is that we are increasingly The other fundamental difference able to treat them as if they were not between the singularity and the computers at all. It seems to me that Methuselarity that I wish to highlight is its the singularity may well, in this regard, impact on “the human condition” – on merely be the icing on a cake that will humanity’s experience of the world and its already have been baked. view of itself. I make at this point perhaps my Compare this to the effect of the most controversial claim in this essay: that in Methuselarity on the human condition. this regard, the Methuselarity will probably In this case we will progressively and

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smoothly improve our remaining life To summarise my view, then: the expectancy as calculated from the rate of singularity will take us from a point of accumulation of those types of damage that considerable computing power that is we cannot yet fix. So far, so boring. But wait mostly hidden from our concern to one – is that the whole story? No, because what of astronomical computing power that will matter is the bottom line, how long is just slightly more hidden. The people think they’re actually going to live. Methuselarity, by contrast, will take us These days, people are notoriously bad from a point of considerable medical at predicting how long they’re going to live. prowess that only modestly benefits There is a strong tendency to expect to live how long we can reasonably expect to only about as long as one’s parents or live, to one of just slightly greater grandparents did (just so long as they died medical prowess that allows us of old age, of course).17 This is clearly absurd, confidence that we can live indefinitely. given the rapid rise of life expectancies The contrast is rather stark, I think you throughout the developed world in the past will agree. half-century and the fact that, unlike the previous half-century, that rise has resulted 4. Epilogue: the Methuselarity and from falling mortality rates at older ages the singularity combined rather than in infancy or childbirth. It persists, Those who have followed my work I believe, simply because the rise in life since I began publishing in expectancy has been rapid only by historical biogerontology may have noticed a standards: unless one’s paying attention, it’s subtle change in the way that I typically not been rapid by the standards of progress describe the Methuselarity’s impact on in technology, so it easily goes unnoticed. lifespans. Early on, I used to make This will not last, however. As the rate of probabilistic assertions about future life improvement in life expectancy increases, expectancy; now I make assertions so the disparity between that headline about how soon we will see an number and the age which someone of any individual (or a cohort) achieve a given particular age can expect to reach also age. increases. But here’s the crux: these two The reasons for this shift are many; quantities do not increase in proportion. In some are down to my improved sense particular, when the rate of improvement of of what does and does not scare life expectancy reaches one year per year people. But an important reason is that – which, in case you didn’t know, is only a my original style of prediction few times faster than is typical in the incorporated the implicit assumption developed world today18 – the age that one that the Methuselarity would occur in can expect to reach undergoes a dramatic the context of a continued smooth, and shift, because the risk of dying from age- relatively slow, rate of reduction in our related causes at any given age suddenly risks of death from causes unrelated to plummets to near zero. And that is (another our age. I only belatedly realised that way of defining) the Methuselarity. this assumption is unjustified – indeed,

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absurd. And the singularity is what makes it alter these considerations.) particularly absurd. One of my “soundbite” predictions Roughly speaking, we prioritise our effort concerning the Methuselarity is that the to avoid particular risks of death on the basis first thousand-year-old is probably less of the relative magnitude of those risks. than 20 years younger than the first Things that only have a 0.01% risk per year of 150-year-old. The above killing us may not be considered worth considerations lead to a working very hard to avoid, because even supplementary prediction. I think it is multiplied up over a long life they have only abundantly likely that the first million- a 1% chance of being our cause of death. year-old is less than a year younger This immediately tells us that such risks will than the first thousand-year-old, and move altogether nearer to the forefront of the first billion-year-old probably is too. our concerns as and when the Methuselarity The singularity and the occurs (or is even widely anticipated), Methuselarity are superficially similar, because the greater number of years but I hope to have communicated in available to get unlucky means that the risk this essay that they are in fact very of these things being our cause of death is different concepts. Where they are elevated. It seems clear that we will work to most similar, however, is in the do something about that – to improve the magnitude of their impact on humanity. efficiency with which we develop vaccines, The singularity will be a uniquely to make our cars safer, and so on. But there dramatic change in the trajectory of would appear to be only so much we can do humanity’s future; the Methuselarity will in that regard: first of all there are things that be a uniquely dramatic change in its we really truly can’t do anything about, such perception of its future. Together, they as nearby supernovae, and secondly there will transform humanity… quite a lot. are quite a few moderately risky activities that quite a lot of us enjoy. References The singularity changes all that. What the 1. Singularity Institute for Artificial singularity will provide is the very rapid Intelligence. What is the Singularity? reduction to truly minute levels of the risk of http://singinst.org/overview/ death from any cause. You may have whatisthesingularity (retrieved 25th thought that my earlier mention of snow August 2008). reliably saving careless mountaineers was in 2. Ulam S. Tribute to John von jest; indeed it was not. Moreover, the Neumann. Bulletin of the American residual risk that our rate of improvement of Mathematical Society 1958; 64(3 part medical therapies against aging will at some 2): 1-49. point fall below LEV will also essentially 3. Moore GE. Cramming more disappear with the singularity. (Clearly the components onto integrated circuits. possibility also exists that the singularity will Electronics 1965; 38(8): no pagination. precede, and thus bring about, the Methuselarity – but that does not materially

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4. Kurzweil R. The Singularity Is Near: When interventions. AGE 2007; 29(4):133-189. Humans Transcend Biology. New York: 16. de Grey ADNJ, Rae M. Penguin, 2006 (ISBN: 0143037889). Ending Aging: The rejuvenation 5. Vinge V. The Coming Technological biotechnologies that could reverse Singularity. In: Vision-21: Interdisciplinary human aging in our lifetime. New York, Science & Engineering in the Era of NY: St. Martin’s Press, 2007, 416pp, CyberSpace, proceedings of a Symposium hardcover (ISBN 0-312-36706-6). held at NASA Lewis Research Center (NASA 17. Banks J, Emmerson C, Oldfield Conference Publication CP-10129), 1993. Z. Not so brief lives: longevity 6. Deutsch D. The fabric of reality. New York: expectations and wellbeing in Penguin, 1998 (ISBN: 014027541X). retirement. In: Seven Ages of Man and 7. Weatherall D. Was there life after DNA? Woman (Stewart I and Vaitilingam R, Science 2000; 289(5479):554-555. eds.), Swindon: Economic and Social 8. Shaw GB. Maxims for Revolutionists. In: Research Council, 2004, pp. 28-31. Man and Superman, 1903. 18. Oeppen J, Vaupel JW. Broken 9. de Grey ADNJ. Long live the limits to life expectancy. Science unreasonable man. Rejuvenation Res 2008; 2002;296(5570):1029-1031. 11(3):541-542. 10. Pliskin JS, Shepard DS, Weinstein MC. Utility Functions for Life Years and Health Status. Operations Research 1980; 28:206- 224. 11. Olshansky SJ, Perry D, Miller RA, Butler RN. Pursuing the longevity dividend: scientific goals for an aging world. Ann N Y Acad Sci 2007; 1114:11-13. 12. de Grey ADNJ, Ames BN, Andersen JK, Bartke A, Campisi J, Heward CB, McCarter RJM, Stock G. Time to talk SENS: critiquing the immutability of human aging. Annals NY Acad Sci 2002; 959:452-462. 13. de Grey ADNJ. A strategy for postponing aging indefinitely. Stud Health Technol Inform 2005; 118:209-219. 14. de Grey ADNJ. Escape velocity: why the prospect of extreme human life extension matters now. PLoS Biol 2004; 2(6):723-726. 15. Phoenix CR, de Grey ADNJ. A model of aging as accumulated damage matches observed mortality patterns and predicts the life-extending effects of prospective

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L. Alonso-Pastor, Chapter 38: Use of a 3D-printed punch on the application of comparable M. Gonzalez- Andrades, template for multiple wounds within a pressure on the punch and the J. Mauris, A. single tissue culture well, in order to generation of a concentric incision Cruzat, C.H. Dohlman, P. establish a barrier function in a novel in groove in the tissue culture plate Argueso, K. vitro model of stratified epithelial wound around the punch wound. In this injury Larson / Use of a 3D-printed healing model, the use of a 3D-printed punch punch template Author 1: Luis Alonso-Pastor t0emplate facilitated the generation of for multiple Changing Places Research Group, Media multiple wounds within a single tissue wounds within Lab, Massachusetts Institute of Technology, a single tissue culture well. culture well, Cambridge, Massachusetts. in order to Author 2: Miguel Gonzalez-Andrades establish a Institution, City, Country Schepens Eye Research 1. Introduction barrier function Institute and Massachusetts Eye and Ear, The first 3D printing patent application in a novel in Department of Ophthalmology, Harvard Medical vitro model was filed by a Dr Kodama in Japan, of stratified School, Boston, Massachusetts. epithelial wound Author 3: Jerome Mauris in 1980 [1]. In 1984, Charles W ‘Chuck’ healing in “World Institution, City, Country Schepens Eye Research Hull made, in effect, the world’s Health Strategy”, Institute and Massachusetts Eye and Ear, first 3D printer under the US patent Renata.G. Department of Ophthalmology, Harvard Medical Bushko number US4575330, and with the (Ed.) eBook School, Boston, Massachusetts. FHTI, 2016 Author 4: Andrea Cruzat name: "Apparatus for production futureofheath.orgInstitution, City, Country Schepens Eye Research of three-dimensional objects by Institute and Massachusetts Eye and Ear, stereolithography" [2]. Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. The first main impact of 3D printing Author 5: Claes H. Dohlman in healthcare came in 1999 when, Institution, City, Country Schepens Eye Research using the technology developed at the Institute and Massachusetts Eye and Ear, Wake Forest Institute for Regenerative Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Medicine, a laboratory-grown organ Author 6: Pablo Argüeso was successfully transplanted into Institution, City, Country Schepens Eye Research a patient for the first time [22]. Since Institute and Massachusetts Eye and Ear, then, many different steps have been Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. done and many research, healthcare Author 7: Kent Larson applications and commercial uses Changing Places Research Group, Media on this very promising field: Wohlers Lab, Massachusetts Institute of Technology, Associates as well as some industry Cambridge, Massachusetts. observers forecast that the 3D printing market will generate revenues of Abstract $20 billion by 2020, and an impact of e describe a straightforward in between $230 and $550 billion per vitro wound assay to evaluate the year by 2025 [3]. The largest impact Whealing and restoration of barrier will be on consum-er users ($100 to function in stratified human corneal epithelial $300 billion), direct manufacturing cells. In this assay, the reproducibility and ($100 to $200 billion) and the creation uniformity of these injuries was dependent of tools and molds ($30 to $50 billion)

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 365 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

[4]; this last market niche is where the 3D-printed punch template fits. In the other hand, the repair of wounds through collective movement of epithelial cells is a fundamental process in multicellular organisms [5]. In stratified epithelia such as the cornea and skin, healing occurs in three steps that include a latent, migratory, and reconstruction phases. Several simple and inexpensive assays have been developed to study the biology of cell migration in vitro Figure 1. Definition of the design process of [6]. However, these assays are mostly based the 3D-printed 6-hole punch template. A) First on monolayer systems that fail to reproduce drafts and ideas. B) Production Issues: The the differentiation processes associated to number of holes made the template a very high precision element, and the MakerBot print multilayered systems [6, 7]. process stopped. C) The template is made On this paper we link the design and by polylactic acid (PLA) filament. A calibration low cost potential of a conventional 3D of the autoclave is needed in order to clean printer and the biomedical needs in order to and reuse the template without damaging it. D) Example of a 3D-printed 6-hole punch develop a simple and inexpensive assays template. E) Evolution of the template design: to study the biology of cell migration in from a matrix of 300-holes into a matrix of vitro in the Re-epithelialization process. Re- 10-holes, and finally a 6-hole matrix. epithelialization is an essential biological process critical to restore an intact barrier in The 3D-printed 6-hole punch template organ systems such as the cornea, skin and (Fig. 1) was learning by doing iterative gastrointestinal tract following a wound [5]. design process. From the beginning of the design the goal was to create 2. Design process a template as efficient (in number of The 3D template was modeled using holes) and as eco-friendly as possible, AutoCAD Mechanical design software with a conventional 3D printer. (Autodesk; San Rafael, CA). Models were The first iteration was designed exported as STL-files and processed using with polylactic acid and 300-holes ReplicatorG (MakerBot Industries; Brooklyn, matrix, but after several productions NY). 3D printing was carried out on a (print process stopped), structural (Fragility of the template), and material MakerBot Replicator 2 (MakerBot Industries) issues (autoclave calibration), the final using polylactic acid (PLA) filament. template was made with a 6-hole matrix.

3. Biomedical approach Re-epithelialization is an essential biological process critical to restore

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 366 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

an intact barrier in organ systems such as the cornea, skin and gastrointestinal tract following a wound [5]. Numerous models and methods of injury have been described to study the migratory process in corneal epithelial cells [6]. Human corneal ex vivo models have been developed, but their use has been hampered by the difficulty of obtaining healthy human donor tissue and poor Figure 2. Morphometric analysis of epithelial standardization due to cornea-to-cornea wounds. Stratified cultures of human corneal variability [6, 7]. The use of in vitro models epithelial cells were injured by rotation using a plastic or metal tip (rotating scratch can simplify the characterization of specific model), or using dermal punchs (0.5, 1.0, 1.5 biological processes that are difficult to or 2.0 mm diameter) followed by epithelial study in vivo because of their complexity. For debridement (punch model). Morphology of this purpose, tissue engineered scaffolds the injured area was analyzed by measuring main parameters of the wound shape, have been developed, but are expensive including circularity, area, perimeter and and difficult to produce and manipulate Feret diameter. The area and perimeter of [3]. Culture models using human corneal the wounds ranged from 0.3 to 3.3 mm2 and epithelial cell lines, on the other hand, offer a 2.9 to 7.0 mm, respectively. The values for circularity and Feret diameter ranged from series of advantages such as simplicity, high 0.48 to 0.87 and 0.8 to 2.1 mm, respectively. level of reproducibility and relatively low Use of plastic or metal tips produced modest costs [6, 7]. results in terms of shape and circularity. Punch Unfortunately, most culture models injuries followed by epithelial debridement using a disposable plastic tip (i.e., 1.0, 1.5 and evaluating human corneal epithelial cell 2.0 mm punch) produced consistent shapes migration are based on monolayer cultures, and high circularity values. Results are which fail to reproduce the three phases displayed as mean +/- SD (N=9). Significance of epithelial healing. The aim of this study was determined using one-way ANOVA with Bonferroni’s post-hoc test. *p<0.05; ***p<0.001. was to develop and characterize a simple ns, non-significant. and reproducible in vitro model of wound healing that could potentially be used to On the other hand, punch injuries, study the different phases of healing in particularly those followed by epithelial stratified epithelium. debridement using a disposable plastic tip (i.e., 1.0, 1.5 and 2.0 mm punch), 4. Biomedical results produced consistent shapes that were Analyses of the wound morphology associated with high circularity values. revealed that use of plastic or metal tips in rotating scratch injury models produced modest results in terms of shape and circularity (Fig. 2).

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 367 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

appeared within the concentric incision groove around the punch wound, but not in actively migrating cells, a phenomenon known as migration- proliferation dichotomy (Fig. 4b).

On the other hand, punch injuries, particularly those followed by epithelial debridement using a disposable plastic tip (i.e., 1.0, 1.5 and 2.0 mm punch), produced consistent shapes that were associated with high circularity values.

The reproducibility and uniformity of these injuries was dependent on the application of comparable pressure on the punch and the generation of a concentric incision groove in the tissue culture plate around the punch wound. In this injury model, the use of a 3D-printed punch template facilitated the generation of multiple wounds within a Figure 4. Serum promotes re-epithelialization and wound closure. Circular wounds of 1 mm in single tissue culture well (Fig. 3). diameter were made using a punch template. (a) Morphometric analysis demonstrated that the extent of re-epithelialization was enhanced 4.1 Promotion of wound closure in the presence of culture media containing In our experiments, the wound closure serum. In the absence of serum, none of the was significantly promoted following wounds was able to completely re-epithelialize at 72 h, whereas in the presence of serum, the addition of serum to the cell culture media wounded area was significantly reduced at 48 (Fig. 4a). Here, the wounded area was re- h and completely closed at 72 h. Results are epithelialized by more than 40% at 24 h, by displayed as mean +/- SD (N=18). Significance was determined using the Mann-Whitney approximately 90% at 48 h, and a complete test. ****p<0.0001. (b) In control experiments, closed wound was observed at 72 h. The the presence of proliferative activity was presence of proliferative activity following demonstrated by staining for PCNA (green) in subconfluent cultures of human corneal addition of serum was further demonstrated epithelial cells. Following injury to stratified by staining for proliferating cell nuclear cultures, clusters of PCNA-positive cells appeared within the concentric incision groove antigen or PCNA, a marker of growing around the punch wound (arrowheads), but cells entering the early S phase of the cell not in actively migrating cells (asterisks). Nuclei cycle [8,9]. Clusters of PCNA-positive cells were counterstained using DAPI (blue). Scale bar, 100 μm.

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 368 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Direct visualization of the migratory process Cells at the stratification front moved by time-lapse microscopy revealed an initial behind the leading edge at a slower accumulation of cell mass within the incision average rate of 0.17 μm/min. Both the groove in the tissue culture plate followed leading edge and the stratification by unified sliding of the healing epithelium front maintained similar trajectories and towards the wound (Supp. Movie 1). During relative position (Fig. 5b). this migratory phase, most cells at the leading edge remained at the wound edge 4.2 Restoration of barrier function and were not actively replaced by other Restoration of the transcellular and cells. Cell-tracking experiments showed that paracellular barrier function in in vitro the average rate of migration of cells at the models of wound healing is critical leading edge during this phase was 0.27 to understanding the biological μm/min (Fig. 5a). processes associated with the reconstruction phase of healing. To determine whether wound closure was associated with restoration of transcellular barrier function in our model of stratified epithelial wound healing, we took advantage of the rose bengal penetration assay. In this assay, uptake of rose bengal by the cell culture is dependent on the character of the apical glycocalyx and the ability to synthesize cell surface mucins [10-11]. The presence of a fully functional glycocalyx barrier protects against rose bengal uptake, whereas positive staining of the epithelia indicates the presence of a compromised transcellular barrier. As shown in Figure 6, monolayer cultures Figure 5. Wound healing involves migration by unified of corneal epithelial cells stained sliding of cells at the leading edge and stratification positively with rose bengal. In contrast, front. Circular wounds of 1 mm in diameter were stratified cultures were characterized made using a punch template. The migration of individual human corneal epithelial cells in stratified by the presence of islands of stratified cultures and in the presence of serum was analyzed cells that excluded the dye. Analyses by time-lapse imaging. (a) Cell-tracking experiments of the stratified culture immediately revealed that cells at the leading edge and after wounding (t = 0 h) resulted in a stratification front migrated with an average trajectory speed of 0.27 and 0.17 μm/min respectively. (b) defined staining of the wound margins, Following a wound, epithelial cells indicative of epithelial damage induced by the cutting edge of the

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 369 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

punch. Subsequent to the initial wound, In addition to the transcellular barrier, cell migration was characterized by the the formation of tight junctions is crucial presence of a leading edge of monolayer for the establishment of paracellular cells that stained positively for rose bengal, barrier function in polarized epithelial and a stratified zone behind the edge that sheets. Analyses of stratified cultures contained areas of rose bengal exclusion. immediately after wounding revealed This stratified zone was observed within the abrupt interruption of the tight junction- wound at 24 and 48 h, and mostly covered associated protein occludin at the the entire wound at 72 h. wound margin (Fig. 6b, upper panel). During the migratory phase, epithelial cells at the leading edge of the migrating sheet extended lamellipodial protrusions and were characterized by lack of occludin localization at the cell-cell junction (Fig. 6b, lower panel). However, occludin expression was restored to apical intercellular junctions within the stratification front behind Figure 6. Barrier function is restored as epithelial cells migrate en bloc. (a) Circular wounds of 1 mm the leading edge, indicating that tight in diameter were made using a punch template. junctions are immediately formed after The extent of rose bengal dye penetrance was the epithelium becomes multilayered, assessed at 0, 24, 48 and 72 h following culture in and suggesting the presence of serum-containing medium. Induction of stratification in control cultures resulted in the formation of a reconstruction phase and the islands of stratified cells that excluded the dye. normalization of the barrier function A defined staining of the wound margins was of the epithelial sheet during wound observed immediately after wounding (arrowheads). closure. Epithelial migration was characterized by uptake of dye by cells at the leading edge but not behind the stratification front (dotted line). Closure 5. Generation of wounds of the wound at 72 h was associated with the Two types of corneal epithelial cell complete restoration of barrier function. (b) For injury (rotating scratch and punch) immunofluorescence microcopy, stratified cultures in chambered slides were wounded using a 1.5 were performed in areas equidistant mm punch and manually scraped using a pipette to the center of the culture in six- tip. Occludin (green) was detected at the cellular well tissue culture plates (Corning margin after wounding (arrows), and was restored Inc.; New York, NY). For the rotating to the intercellular junctions within the stratification front during migration. Cells at the leading edge scratch injury, wounds were produced (asterisks) extended lamellipodial protrusions by manually rotating a standard 200 as shown by actin staining (red) and were μl plastic pipette tip (1 mm diameter; characterized by lack of occludin localization at the Eppendorf; Hauppauge, NY) or a 0.5 cell-cell junction. Nuclei were counterstained using DAPI (blue). Scale bars, 50 mm (top), 20 mm (middle), mm titanium-coated diamond burr 100 mm (bottom). (Sona Enterprises, Hangzhou, China) at a 90-degree angle over the culture

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 370 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

for approximately 5 sec. For the punch injury, healing using an immortalized epithelial wounds were produced by pressing (300- cell line grown as a multilayered 450 g/mm2) and rotating (180º) the metal culture. The method enabled us to cutting edge of a 0.5, 1.0, 1.5 or 2.0 mm obtain reproducible wounds that were Miltex dermal punch (Integra Miltex; York, PA) associated with the coherent migration at a 90-degree angle over the culture for of epithelial sheets and the restoration approximately 1 sec. The pressure unit was of barrier integrity. This model may calculated by dividing the weight applied prove a useful system to better on the punch by the surface area covered understanding the factors controlling by the punch. To maintain sharpness, each the different phases of human wound punch was only used for approximately 20 healing in stratified epithelia, and could wounds. Next, cells within the wound were constitute a valuable tool for preclinical scraped for approximately 5 sec by rotation wound healing research of the retractable internal plunger of the punch (0.5 mm punch) or by rotation of a 10 7. Conclusions μl disposable SHARP® Precision Barrier Tip The use of non-expensive 3D printed (Denville Scientific; South Plainfield, NJ). For tools provides an important research the latter, tips were inserted within the punch tool to study the mechanisms leading with the help of a metal rod (1.5 and 2.0 mm to barrier function in stratified epithelia punch) or connected to a 100 rpm cordless and may facilitate the development of power precision screwdriver and inserted future therapeutic applications. within the well with the help of a 3D-printed 6-hole punch template (1.0 mm punch). The We have established a simple 3D template was modeled using AutoCAD and inexpensive in vitro model of Mechanical design software (Autodesk; wound healing that displays features San Rafael, CA). Models were exported as associated with the re-epithelialization STL-files and processed using ReplicatorG of stratified epithelia that include (MakerBot Industries; Brooklyn, NY). 3D unified sliding of cell sheets and printing was carried out on a MakerBot restoration of epithelial barrier function. Replicator 2 (MakerBot Industries) using polylactic acid filament. References [1]Hull C. Apparatus for Production 6. Discussion of Three-Dimensional Object Here, we have established a simple and by Stereolithography. US Patent inexpensive in vitro model of wound healing 4,575,330, 1986. that displays features associated with the re-epithelialization of stratified epithelia that [2] Leukers B, Gulkan H, Irsen SH, include unified sliding of cell sheets and , et al. Hydroxyapatite scaffold for restoration of epithelial barrier function. bone tissue engineering made by 3D In summary, we have developed a simple printing. J Mater Sci Makter Med 2005; and inexpensive in vitro model of wound 16: 1,121–1,124.

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 371 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

[3] Wohlers Associates (2014). Wohlers [10] Argueso P, Guzman-Aranguez A, Report 2014: 3D Printing and Additive Mantelli F, Cao Z, Ricciuto J, Panjwani Manufacturing State of the Industry. Fort N: Association of cell surface mucins Collins, CO. with galectin-3 contributes to the ocular surface epithelial barrier. J Biol Chem [4] McKinsey Global Institute (2013). 2009, 284(34):23037-23045. Disruptive Technologies: Advances that will Transform Life, Business, and the Global [11] Argueso P, Tisdale A, Spurr-Michaud Economy. S, Sumiyoshi M, Gipson IK: Mucin characteristics of human corneal-limbal [5] Raja, Sivamani K, Garcia MS, Isseroff epithelial cells that exclude the rose RR: Wound re-epithelialization: modulating bengal anionic dye. Invest Ophthalmol keratinocyte migration in wound healing. Vis Sci 2006, 47(1):113-119. Front Biosci 2007, 12:2849-2868.

[6] Stepp MA, Zieske JD, Trinkaus-Randall V, Kyne BM, Pal-Ghosh S, Tadvalkar G, Pajoohesh-Ganji A: Wounding the cornea to learn how it heals. Exp Eye Res 2014, 121:178-193.

[7] Alekseev O, Tran AH, Azizkhan-Clifford J: Ex vivo organotypic corneal model of acute epithelial herpes simplex virus type I infection. J Vis Exp 2012(69):e3631. [8] Morris GF, Mathews MB: Regulation of proliferating cell nuclear antigen during the cell cycle. J Biol Chem 1989, 264(23):13856- 13864.

[9] Ghosh P, Beas AO, Bornheimer SJ, Garcia-Marcos M, Forry EP, Johannson C, Ear J, Jung BH, Cabrera B, Carethers JM et al: A G{alpha}i-GIV molecular complex binds epidermal growth factor receptor and determines whether cells migrate or proliferate. Mol Biol Cell 2010, 21(13):2338- 2354.

Use of a 3D-printed punch template for multiple wounds within a single tissue culture well, in order to establish a barrier function in a novel in vitro model of stratified epithelial wound healing 372 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Robert A. Chapter 39: Future of Medical such tasks that could be use-ful for this Greenes / Future of Medical Knowledge Management and Decision purpose. Knowledge Support Management and Decision Robert A. Greenes, M.D., Ph.D. A variety of other issues must Support in World Professor of Radiology and of Health be considered as well, to move Health Strategy” eBook, www. Science & Technology, Harvard Medical beyond source-oriented information Futureofhealth. School, Professor of Health Policy & and knowledge resources, to the org (Ed.) Renata G. Bushko, Management, Harvard School of Public timely and efficient incorporation of FHTI, 2016. Health & Director, Decision Systems Group, targeted resources in problem-specific Chapter from Future of Health Brigham and Women's Hospital, Boston, MA, settings. The common requirement Technology US is for a standards-based approach to book Ed. R. Bushko 2002, taxonomy and interface development. IOS Press Abstract

© 2002 Future nformation and knowledge abound to such 1. The hazards of prognostication of Health an extent that we cannot cope effectively Attempts to predict the future are Technology Institute. 508- with them. Strategies for targeting selected typically off the mark. Beyond the 497-2577 I information and knowledge to the point of challenges of fore- need are greatly needed in many health casting the stock market or the care settings – in clinical practice, to support weather, dramatic instances of problem solving and decision making notoriously inaccurate prog- needs of both the provider and the patient; nostications have been those by the in health care institution management, in US patent office in the late 1800s education;, and in research. The increased about the future of inventions, by need is exac-erbated by the growing Thomas Watson in the 1930s about interdisciplinary and multi-institutional nature the market for large computers, and of practice, education, and research. by Bill Gates in the early 1990s about Some possible models for implementing the significance of the Internet. When such strategies involve the setting of context one seeks to make predictions about for use of in-formation and knowledge health care, one finds that, beyond the by defining the problem and task in usual uncertainties regarding the advance. This requires that information future, additional impediments to and knowledge providers support the use forecasting are the discontinuities of a taxonomy of problem/task contexts introduced by advances in biomedical for access to their resources, and that science and technology, the impact of infrastructure provide support for integration information technology, and the reor- methods that incorporate these resources ganizations and realignments attending into workflow and process that are various approaches to health care compatible with and helpful to the problem delivery and finance. Changes in all solving or decision making task. Guideline three contributing areas themselves modeling is one technology for representing can be measured in “PSPYs”, or workflow and process characteristics of paradigm shifts per year.

Future of Medical Knowledge Management and Decision Support 373 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Despite these risks in forecasting, I distributed, ranging from local believe that certain trends are sufficiently repositories and programs on one’s clear that I am willing to venture a few own desktop, to those within the local predictions. The predictions I wish to make enterprise (hospital, university, practice actually suggest a goal for the future that can networks), to national or international be achieved, if we can align the prevailing sites accessible via the Internet. political, financial, biomedical, and technical Not only is this panoply of sources forces toward that end. Thus, in a sense this distributed, but it is heterogeneous is a call to action, to shape the future rather in format, software platform, mode of than just let it happen. This chapter seeks access, and manner of representation to lay out the direction we are heading or encoding of information. Even in knowledge management and decision within lo-cal enterprise networks, multi- support, and to delineate an information vendor platforms and incompatible technology framework that appears protocols often compli-cate access. desirable. I believe the framework to be Knowledge may be defined as that discussed is of importance to the health which results from the organization, care-related knowledge management and analysis, or extrapolation of data to decision making activities of the consumer derive a higher level conceptualization and patient, the health care provider, and of phenomena or processes. health care de-livery organizations and “Knowledge differs from data or payers. The approach is also relevant to the information in that new knowledge may other dimensions of academic health care be created from existing knowledge institution activities, notably the conduct of using logical inference. If information research and the processes of education is data plus meaning then knowledge and learning. is information plus processing” [1]. Knowledge can be either in human- 2. Information glut is not a good thing readable form only, as are textbook We are not information-starved at present, and journal content, or capable of but it may seem that way. Information being executed in some fash-ion, as comes in many forms, ranging from raw are the rules in knowledge bases of data to summaries of results, from narrative decision support tools. documents such as textbooks and With respect to knowledge journal article, to formal representations resources, as with information more of knowledge, rules and guidelines generally, we are inundated with so encapsulating best practices, or automated many alternatives that it is difficult to sift decision support tools. The information out those particular items that are most focus may pertain to the domains of basic pertinent and of highest quality. Chaos science, clinical practice, preventive reigns in the generation of health care- medicine, public health, health services relevant knowledge – many producers, research, or a variety of specialized arenas. many variations in method, review, The information sources are widely sponsorship, dissemination approach,

Future of Medical Knowledge Management and Decision Support 374 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

and business models. The traditional necessary to assemble different kinds publishing industry is in dis-array [2], libraries of information at the same time. are groping with new roles and missions Yet we note a marked contrast [3], and Internet-based health knowledge between the production and the use of providers are struggling to determine how information – its production is primarily to sustain and grow their activities [4]. The source-oriented, whereas the use of knowledge dissemination industries in the it is primarily problem-oriented (Fig. form of educational institutions are also 1). The production process can be facing upheavals, as virtual classrooms, considered to be the province of a distance learning, and other models of set of vertical silos, those entities and education are refined [5]. services responsible for the creation and distribution of the information. 3. The problem-oriented paradigm as a Settings in which use occurs can coping strategy be viewed as a horizontal set of Although potential users of information cross-cutting planes corresponding are faced with many modes of information to problems or tasks, which ideally access, providers, and types of information, intersect the silos at the precise points they are typically driven by a single problem where information pertinent to the or task. They seek high quality information, problems reside. but restricted to those items relevant for that problem or task. Where the information comes from is less important than its value for the task at hand. The information, in addition, is most useful if it can be made available immediately (“just-in-time”), in the context of the application that is being used for solving the problem or carrying out the task. Ideally, the information resources can be selected automatically based on specific data already known. Furthermore, among Figure 1. The orthogonal relationship of those resources selected, deci-sion support information producers and users. tools can be primed with pre-existing data, can be used to update or collect In this chapter, we shall discuss a additional targeted data, can implement variety of settings in which problem- recommendations, and can facilitate based organization of information workflow. is useful. We then focus on My thesis is that problem-based methodologies for providing the information organization is a particularly necessary in-frastructure to support useful coping strategy, when it is necessary problem-based access and use. to select pertinent items from a vast array of possibili-ties, especially when it is

Future of Medical Knowledge Management and Decision Support 375 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

4. Centrality of information needs in the by the problems to which they relate. academic health sciences university This was proposed both as a means The modern academic health sciences for focusing a clinician’s thinking, when center has a combined mission of education, writing a progress note, making it research, and service, where the latter easier to review a patient’s progress by includes both clinical and non-clinical problem subsequently, and as a means activities. The academic health sciences to tie observations to assessments, are now experiencing the birth of many and assessments to plans, thus new fields, and the integration of previously enhancing the accountability of the separate disciplines, the growth of “big record. Weed and his colleagues science” initiatives, and the establishment developed a computer-based multiple- of physical and virtual collaborations choice problem-oriented data entry spanning multiple disciplines, institu-tions, interface for generating the SOAP note and geographic boundaries. As a result, for many of the problems in internal both the opportunity and the necessity medicine, in the 1970s, although no exist to rethink traditional approaches to published citations are available development of an information infrastructure describing this ambi-tious work; the to support the activities of the academic limited success of this project can be health center. attributed in part to the primitiveness, Integration is the new byword, with most by today’s standards, of the user activities increasingly dependent on the interface technology available at the information infrastructure. Among the new time, rather than to a fundamental flaw interdisciplinary and cross-cutting activities in the concept. While the problem- with such dependency are, for example: oriented mode of record keeping molecular imaging, telesurgery, robotics, has not been popular without use of nano-technology, functional genomics, a computer, many aficionados still do proteomics, drug development, health care maintain their clini-cal records that or biomedical data warehousing, integrated way even manually [8]. With the ability delivery networks, consumer health, to present the same data in multiple distance education, digital libraries, and views, either by source (e.g., progress networked clinical trials. notes vs. labs vs. xrays vs. orders), by chronology, by specialist domain, or 5. Health and health care information by problem, computer systems could today support problem-oriented record 5. 1 The problem-oriented medical record The problem-oriented medical record keeping more effectively. was introduced by Weed in the 1960s [6,7] Another advantage of a problem- oriented view of a patient’s problems as a strategy for clinical record keeping, which has at its core the notion that clinical is that it al-lows one to focus on the observations (Subjective and Objective), other associated information resources Assessments, and Plans (together referred that could be useful. This might to as the SOAP note) should be organized include directories of specialists that

Future of Medical Knowledge Management and Decision Support 376 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

are appropriate for referral for that problem, images must be communicated across bibliographic references or textbook these multiple systems. materials, guidelines, appropriateness Furthermore, because of the criteria, or other decision support resources culture of fiscal restraint and cost- for the physician, as well as educational effectiveness, prac-tices have been materials or instructions for the patient. subjected to increasing scrutiny with Thus delineation of a problem provides a respect to cost, quality, risk, appropri- framework for organizing a wide variety of ateness of services or referrals, information resources. We shall return to this and adherence to clinical practice notion later. guidelines and constraints. Thus, education and decision support 5.2 The Integrated Delivery Network (IDN) must be provided across the IDN to The evolution of the health care reduce errors and increase safety, environment has been a striking example and to promote adherence to “best of the need for integration of information practices”. Purely logistical functions from diverse sources, and focusing them on become more complicated in an IDN, specific problems or tasks. We have seen and help is needed for such tasks as a spate of mergers and affiliations in the getting oriented and navigating among mid-to-late 1990s, resulting in the formation resources, scheduling of services, of integrated delivery networks (IDNs) finding and initiating consultations, [9], motivated by the need for in-creased requesting referrals, and even efficiency and decreased cost. Related learning about transportation and goals have been the need to reduce parking. Communication support is redun-dancy yet attract referring physicians needed across the network for email, and patients with a full range of services, teleconferencing, accessing support improve-ment in economies of scale by groups, obtaining consults, etc. Patient growth of market share and retention of instructions need to be provided patients and providers in the network, and and home care services offered and increased clout for negotiation with payers. coordinated. Yet IDNs introduced a new level of Partners HealthCare System, complexity in health care, necessitating Inc., the IDN formed in 1993 with the assimilation of multiple formerly independent merger of the Brigham and Women’s hospitals, clinics, practices, and specialty Hospital and Massachusetts General services, each with their own cultures, Hospital, plus affiliations and mergers modes of operation, and information of a number of smaller hospitals and systems. With respect to the latter, disparate practices in Eastern Massachusetts, electronic medical record systems might provides an example. While parts of often be operating in the enti-ties to be the information environment were quite assimilated, along with incompatible sophisticated, such as the Brigham information systems and different patient Integrated Computing System (BICS) identification schemes. Clinical data and [10] at the Brigham, there was no con-

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sistent system across the entire IDN. content development, review, edit and As efforts were being devoted to approval, and publication. beginning the integration of the clinical Separate form-based tools or infor-mation systems environment, in 1995, components were used for each the Decision Systems Group focused on a kind of content (Fig. 2). Components different problem for Partners HealthCare, available to editing groups depended that of creating and maintaining a Web site, on the content domains and foci, and called Part-nerWeb, for the IDN’s component as various departments or divisions health care delivery sites, including identified new requirements that we Massachusetts General Hospital and considered suffi-ciently generic, we Brigham and Women’s Hospital. Overall, expanded the range of form tools more than 250 clinical, admin-istrative, available. This approach provided and research departments or divisions a number of advantages, including were producing content. The PartnerWeb a uniform look and feel, ease of system [11] was designed to make available changing the look without redesigning information such as descriptions of individual pages, the ability to select depart-ments and services, directories of resources for presentation for specific specialists, seminars, educational programs, problems or purposes, and reduction research ac-tivities, training programs, news of the need for significant Webmaster and announcements, appointment requests, services. fund raising, and other functions. Our goal was to have a consistent design for the site, to the extent possible, and to make it easy for these entities to contribute content, and to update their information, with-out requiring each to have their own Web staff, or to have a huge central Web development organization. The component- based design, one of the first of its kind for Web site man-agement when it was initially developed in 1995, provided interfaces for authors and edi-tors to tools for providing information about administration and Figure 2. The earliest home page for organization, profiles of staff, descriptions PartnerWeb shows links to a variety of kinds of content resources, the content for each of of services, calendar event entries, news which was managed by a different form tool items, publications, training programs, and editing component, and the Web display of other categories of content. Authors were which was generated dynamically from the organized into editing groups, each with component’s database.

an editor responsible, as determined by the department or division, and a hierarchical process was put into place for

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5.3 Data and knowledge needs of business models for these entities as physicians alternatives to traditional publishers As noted earlier, a practitioner needs to has still been elusive. assemble information that relates to a patient’s specific problem, including past 5.4 The health care consumer / medical history, clinical findings, images, patient diagnoses, and medications, as well as Patients or consumers seek order sets, formularies, lists of relevant information about symptoms, diseases, specialists, knowledge resources (textbook treatments, or proce-dures, as well as and journal articles, appropriateness criteria, about healthy lifestyles and disease guidelines, and other decision aids), and prevention. This may be in the form instructions and materials to provide to the of textbook and magazine articles, patient. Health care information systems discussion lists, chat groups or support typically provide each kind of information as groups, directories of services or a separate resource, or the user must use providers, clinical trials databases, the Web to go outside of the health care logistic information about a health system to find knowledge resources such care facility (directions to it, scheduling as articles or decision aids for problems information, virtual tours, etc.), news when they need such information. The items, interactive risk assessments, organization of material is not generally and other decision aids. Provision of done by problem, and dynamically made information to this market has also available at the point of need, except in been a broad area of activity in the some experimental settings. dot.com sector, with a number of The issue of sorting quality knowledge national sites offering content. Other content from chaff faces the health national providers of content include professional. Believing that there is a disease-oriented societies (such as business in providing this knowledge, the American Diabetes Association and developing a re-lationship with the or the American Cancer Society), health professional, multiple entrants and the government (MedlinePlus have been attracted to this market, with from the National Library of Medicine different production approaches and and HealthFinder from the Depart- business models. The result is that these ment of Health and Human Services, resources tend to be in silos reflecting the coordinated by the Office of Disease various producers – resources for journals, Prevention and Health Promotion. textbooks, news, guidelines, clinical trial For patients, information relevant directories, risk assessment tools, etc. The to the problem should ideally be “dot coms” have epitomized the frenetic organized so as to focus the inquiry exploration of approaches to knowledge and foster easy navigation and generation and delivery to both patients pursuit of relevant subtopics, with in- and providers; as the hard times in this depth exploration where needed, sector have shown, identification of viable and identification of appropriate

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related topics. In addition, a feature lacking quest function, or “virtual tours” offered from most national information sources by some clinical services. Extensive but being increasingly incorporated into usability test-ing and rewriting for portals associated with health care delivery appropriateness of literacy level went organizations, is that information about a into the design. disease or problem should be coupled, Note that without an approach when needed, with resources for follow up that links content to local resources, – including how to obtain care, from whom, health care in-formation is still readily how to schedule it, where to go, and how to obtainable, but the user must make all get there. the links. National health information Thus we believe the emphasis should Web sites have largely provided be on “closing the loop”, i.e., when a content without local linkages; health problem is identified, resources for its care fa-cilities are now seeking to solution are made available, including the provide health information portals means for obtaining local follow up and on their Web sites that do a better care. This was the approach we pursued job of local linkage (to build patient in a 1997 National Library of Medicine- loyalty and to facilitate follow up), and funded contract to develop and evaluate the national sites are changing their HealthAware, a prototype resource business models to offer their content for consumer health information [12,13]. for use in this context through co- Distinct from national health information branding. sites, the aim of HealthAware was to provide access to both generic and locally developed content, through a portal to a health care delivery system, in this case that of Brigham and Women’sHospital, a participant in Partners HealthCare. The HealthAware system was built with the component-based, distributed authoring, dynamic page generation approach used in PartnerWeb, described above. It included in addition to generic content and locally Figure 3. A screenshot from the heart attack topic home page in the cardiovascular developed materials, a number of tools disease section of HealthAware. This shows for interactive risk assessments, finding a the visual layout into hierarchies of subtopics doctor for referral, appointment request, corresponding to horizontal tabs, plus various ask-a-doctor, chat groups, support groups, interactive tools arrayed along the left margin. In addition, the tools are integrated into the search, and problem-specific FAQs (Fig. con-tent at appropriate points. The content 3). It was designed to link to resources organization and tool-specific materials were of the IDN’s Web site, such as the doctor developed through a component-based directory of PartnerWeb, or its lists of approach using a distributed authoring environment with editorial responsibility for educational seminars, its appointment re- editing

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While HealthAware was only a prototype, memorizing facts, which quickly and covered only selected medical problem become outdated. This approach to domains, further evolution of the Web learning of course also builds on the strategy at Partners is now incorporating notion of the problem-based medical many of the features of the above systems record, since the cases are focused plus others, aimed at providing access to on specific problems as instructional an increased range of resources. Yet the paradigms. problem still remains how to best organize In educational contexts in general, information in a problem/context-specific not just those involving clinical way. This involves the development of medicine, it would be useful if study various user interface paradigms and of a topic could be augmented by an models of usage. Experimentation is information environment that could being done for example, in how best to provide, among other things, such support clinical trial information access, resources as: relevant lecture notes, data entry and interface to the EMR of visual materials, references, access to the host environment, and integration of instructors or experts, access to fellow clinical practice guidelines into primary care, students, discussion boards, self-test particularly for chronic disease management. questions, and perhaps databases and software tools for exploration. 6. Health Care Education Ideally, these should be organized Problem-based learning has become and accessible by topic or subtopic a popular form of education of medical primarily, and only secondarily by students, since the introduction of this source. Some Web products are now approach at Harvard Medical School in available that provide collaborative the mid-1980s [14]. The approach is one in support for discussion groups, and for which realistic problem solving scenarios linking resources such as the above, or simulated cases are presented, and to foster the establishment of instant the student must determine how to work communities of individuals pursuing a up, assess, and treat the cases. Case topic of common interest. A course materials are assembled that are relevant repre-sents such an instant community. to a problem, and supporting references Distance learning environments may and related materials are provided, or must find it useful to em-ploy such tools to be found by the student. In so doing, a increase the interactivity and cross- case becomes a springboard for discussing fertilization of learning that is typically underlying pathophysiology, similar or lost in non-classroom instruction. contrasting conditions or related teaching In CME as well, we would like points. Further, in contrast to the traditional to have a curriculum that organizes lecture mode, the student learns how to resources in a problem-specific find and assess appropriate information fashion. It should reflect one’s resources, as he or she would often need specialty, the kinds of cases seen, to do in actual practice, rather than simply the kinds of problems encountered,

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updates about recommended approaches, education can also be used to support self-assessment questions, and other communities of researchers. resources. In the classical study by Covell et al in 1985 [15], it was found that many 8. Group Collaborative Work questions arose in the course of an office A common theme from the above clinical session for which an-swers would discussions is that there is a dual have been useful, although not readily requirement for supporting problem available, not only for the immediate care solving, whether it is in clinical of the patient, but also to enhance the medicine, education, or research. physician’s knowledge. What better time First, it is necessary for relevant to provide such information than when the information resources to be available question is immediate and pertinent? Thus to the individual participant at the CME should be delivered in the context time of need. Secondly, the various of care, and when impractical, should be human participants must often be associated with an offline curriculum that able to be brought together around reflects the real-time context in which the a focus of interest or problem. The questions occurred. problem definition in effect spawns an instant community of interest or 7. Multidisciplinary Research affinity group. Early use of the Web We have discussed the birth of new fields was pri-marily aimed at enabling an and the development of others at the individual to have access to multiple intersection of existing fields. Biomedical information resources. Now the and health care research these days focus is as much on bringing people frequently involves many collaborators, as well as resources together. This multiple disciplines, and often multiple will be important in further evolution institutions. These areas of research share of telemedicine for home/office characteristics with many other fields, and doctor-patient interaction, for medical we will not discuss the domains in detail specialty consultation, for distance- here. The common element, though, based learning, for collaborative appears to be the increase in complexity research, and for a large number of of many fields, and the need for organizing other problem solving activities that both access to information and to people. involve interactions of peo-ple as well Collaborative groups must form, often as access to infromation. in “virtual space”, and must be able to find each other, participate in discussion 9. Requirements for a Knowledge- groups, and provide and access shared Based Infrastructure data and knowledge of common interest. The essential challenge of enabling This is particularly important as a means to problem-based information access is break down geographic and disciplinary to have an infra-structure and tools to boundaries. Collaborative tools such as reconcile the two disparate views of those discussed above for supporting source-oriented produc-er/distributor

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and problem-based user of information 2. Tools must be able to locate and resources. There are thus dual issues in access information resources. achieving problem-specific selective access A variety of kinds of tools might be to relevant information resources: used for this purpose. The component services should have APIs that enable 1. Components: the relevant resources, them to be queried with respect to tools, and services to provide specific their descriptive axes, and searched kinds of in-formation must be available for particular resources. Further, and identifiable. the component services might be required to register themselves with 2. Integration methods: the knowledge respect to lookup services, such as models, workflow models, and interfaces provided in distributed object resource with user environments must underlie environments. The invocation of applications, to be able to incorporate queries might be via agents, bots, information re-sources at appropriate search engines, or other mechanisms. points. The coordination of the development of axes and taxonomies 9.1 Components for indexing of information resources There are two primary issues involved for specific domains and subdomains in designing and providing component needs to be under the aegis of services that function as information sources: editorial boards, ideally convened by 1. The services must be able to identify and professional specialty organizations characterize their information content, in focused on those areas of endeavor. terms of descriptive axes and terminologies Besides their expertise in the areas, that are known by and relevant to such editorial boards are probably applications that will be accessing them. in the best position to assess quality For the Web to be organized to provide indicators. information content as component services, we need to develop standards for encoding 9.2 Integration methods the types of information resources that Two kinds of capabilities must also a service contains, and to describe the exist to enable applications to integrate domain/subdomains to which the information external infor-mation resources into relates. Templates for each of these would problem-based contexts: 1. The application must be able to need to be defined that provide detailed provide a knowledge model that attributes relating to these, such as form characterize its problem solving of resource, language, encoding scheme, approach in terms of the types of terminology scheme used, etc. Attributes information resources that would be that enable quality to be assessed should use-ful, ideally identifying specific points also ideally be standardized, such as s in the process where they are most ponsoring organization type, source of needed. content, how validated, when updated, etc. For example, in a clinical encounter, the SOAP note in the problem-oriented

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paradigm has an implied knowledge sufficiently well structured to enable model, in which identification of a problem them to be directly executed. Not determines what da-ta elements (subjective only are phrases inexact or vague, but and objective) are relevant. Once data logic is not always fully specified, and elements have been recorded, their values the medical data elements and actions should determine what assessments are referred to in decision steps or in appropriate. Having recorded the as- recommendations are impre-cise. sessments, these choices should determine Computer-based guidelines are the appropriate plans for further workup potentially useful in a wide variety of or treatment. Thus there is an underlying applications, including consultation, guideline for management, with a set of rules risk assessment, determination of that go from proble m definition to data, from appropriateness of a procedure or data to assessments, and from assessments a referral, audit and quality review of to plans. care, automated alerts and reminders, A Role for Guidelines: For clinical the specifica-tion of the management practice, we can therefore use clinical protocol of a clinical trial, and in guidelines as a basis for creating the educational simulations. underlying knowledge framework. We are pursuing the goal of trying Associated information resources, such to standardize the representation as the evidence for a particular decision of computer-based guidelines, for or action, a dose calculation tool, or the variety of applications described instruc-tions for the patient regarding side above. Because of the enormous effects of a medication or preparation for effort involved in creating high quality, a forthcoming procedure, can be tied to evidence-based guidelines, and particular steps in a guideline. the even greater effort in structuring We have been carrying out considerable them sufficiently to enable them to work in development of a sharable be automated, it would be useful if representa-tion model for computer- the representation were sharable. interpretable clinical guidelines, called This is because additional adaptation GLIF (GuideLine Inter-change Format) and interfacing is needed to map [16,17]. Clinical guidelines are of interest authoritative guidelines to vendor- for a number of reasons, primari-ly to specific clinical platforms, to their EMRs, encourage best practices and reduce and to local constraints or preferences unjustified practice variation. They can for medical practice, and to revise hopefully reduce medical errors [18] and these adaptations, when the guideline encourage high quality care, and are ideally is updated. GLIF development has evidence-based. While guidelines have been carried out by our group at been produced for decades, and distributed Harvard, in conjunction with medical in read-only form, in textbooks, journal and informatics groups at Stanford and magazine articles, and more recently via Columbia, in a collaborative project CDROM and the Web, they are not typically known as InterMed, funded in part

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by the National Library of Medicine, the For the particular purpose described in Department of the Army, and the Agency for this paper, that of providing a predictive Healthcare Research and Quality. Recently, framework for assembling information the InterMed group initiated cooperation resources for a clinical encounter, with the HL7 standards development guidelines appear promising as a basis organization, to establish a Clinical for representing the knowledge, and Guidelines Special Interest Group within HL7 our research group is pursuing this. to further pursue the definition and adoption This is particularly feasible for settings of a standardized approach to computer- in which a patient’s problem, and the based guidelines (Fig.4). stage of disease and treatment plan are known from the patient’s EMR. Patients with chronic dis-eases, such as diabetes, hypertension, congestive heart failure, or asthma tend to have mul-tiple clinical encounters over the course of their disease. Not only does the patient have a known problem, but he or she is typically in a particular state of evolution or management of that problem (which we term “clinical management state” or CMS) [19], for example, stable hypertension on beta blocker drug therapy with no comorbidities or complications. Patients tend to stay in a CMS for a period of time, further defining the framework for the clinical encounter, in terms of the data needed, likely assessments and plans, and other information resources that may be useful. Patients may transition to other CMSs, in which case the encounter is based on the new CMS. The guideline structure for a CMS can be used to predict what data elements need to be retrieved from Figure 4. A GLIF-encoded guideline for evaluation the EMR, what new data are required, of post-nasal drip syndrome (PNDS) as a cause for what assessments are likely to be cough. Underlying the flow chart view for laying out made (and whether they should be or visualization is a formal representation, based on an object-oriented data model. [Courtesy of M. Peleg, automatically triggered or suggested Stanford University] based on the data), the plans that are

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likely (again, possibly triggered, based on with highlighted assessments the various possible assess-ments), other corresponding to those predicted information resources that may be useful, by the guideline based on values such as instructions or educational materials of the entered data. Subsequently, for the patient, and references, decision forms for entering plans and orders aids, and other materials for the provider. could be generated with highlight- For clinical care, therefore, a knowledge ed plan/order elements based on model can be constructed by combining the particular assessments that have (a) clinical management states identifying been chosen. Infor-mation buttons classes of patients, and (b) clinical guidelines can be associated with elements for for the decision making and process which there are corresponding infor- flow associated with the states. This mation resources in the knowledge framework enables information resources model (Fig. 4). A critical pathways/ to be associated with classes of patients, care plan application would use a and more finely with particular activities guideline to extract pertinent data represented by guideline steps. from the record to match against For other arenas of activity, such as thresholds in the care plan model. education and research, other knowledge An application that used guidelines models and frameworks would of course to determine appropriateness of be needed. To the extent that activities referrals or procedure orders might can be classified by a state model, and the be inte-grated with the order entry or decisions and process flow predicted by a scheduling functions of the information guideline model, the above approach might system, such that a form requesting be useful for them as well. data determined by the guideline to be 2. An interface paradigm must exist for necessary for assessing appropriate- determining how to integrate external ness of the referral or order might information resources into applications, in be displayed, and explanations and a form that is helpful to the user, facilitates other supporting doc-umentation workflow and task performance, and provided. Other clinical and non- does not overwhelm. clinical applications might integrate the Given a knowledge model, we must knowledge in different ways, for which determine how best to integrate the paradigms need to be determined. information access and decision support functions with the workflow and processes of the target application. For example, if the application is one for clinical encounter record keeping, a set of forms can be generated for data entry that are predicted by the guideline. Once data are entered, a set of forms for selecting appropriate assessments can be generated,

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“ownership” of the medical record reside? At present, there is essentially no such thing as a complete patient medical record – portions providing institution- or practice-specific records exist in various places. The whole record would need to somehow be a synthesis of all these disparate sources. This is exactly the reverse of the ideal paradigm, in which the record would exist in toto under the aegis of the patient or some trusted authority, and views of it could be obtained, Figure 4. A prototype user interface for entering assessment into a progress note for a clinical upon authorization, by institutions or encounter in a primary care setting for a patient with practitioners or the patient, based on moderately well controlled diabetes. An underlying a need for specific information; they guideline suggests potential assessments by would then in turn update the primary highlighting selections, based on data that have been entered or retrieved from the EMR about the record with new information as it was patient’s subjective and objective evaluation. The obtained. physician may inspect the rationale for highlighted The “holy grail” of clinical suggestions, and if he or knowledge management and decision 10. Other Issues support is a set-ting in which all patient Many other considerations are important with data are encoded in structured form respect to development of an infrastructure using standard terminology, and to support knowledge management longitudinal records of all patients are and decision making. For example, with maintained. Cross-sectional research respect to privacy and confidentiality of that is ap-propriately monitored to data, how should interactive decision comply with human research study support resources access and interact with requirements could be done on this local data? If the resources are accessed corpus of data. In effect, this would through an API to an external service, how is enable every patient to become part protection of patient data assured? Or must of a clinical trial, since it would be they be operated only as services internal to possible to retrieve the aggregated a health care institution? More fundamental experience of patients with simi-lar issues relating to standardized en-coding findings, in order to determine the of medical data elements must be solved distribution of diagnoses, responses to for generic services to be useful. Further, therapies, and long term prognoses. the data relating to outcomes need to be Knowledge in this setting would be able to be pooled if we are to be able to do able to be dynamically derived from assess ments of the decision support tools such collective experience. We are themselves. For that matter, where should a long way from achieving this goal,

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Acknowledgments [8] Salmon P, Rappaport A, Bainbridge This work was supported in part Grant LM06594 with M, Hayes G, Williams J. Taking the support from the Department of the Army, Agency for problem oriented medical record Healthcare Research and Quality, and the National Library of Medicine, and by contract N01 LM63539 forward. Proc AMIA Annu Fall Symp. from the National Library of Medicine. 1996;:463-467.

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[15] Covell DG, Uman GC, Manning PR. Information needs in office practice: are they being met? Ann Intern Med. 1985 Oct;103(4):596-599. [16] Ohno-Machado L, Gennari JH, Murphy SN, et al. The guideline interchange format: a model for representing guidelines. J Am Med Inform Assoc. 1998;5:357-72.

[17] Peleg M, Boxwala AA, Ogunyemi O, Zeng Q, Tu S, Lacson R, Bernstam E, Ash N, Mork P, Ohno-Machado L, Shortliffe EH, Greenes RA. GLIF3: The evolution of a guideline representation format. Proc AMIA Symp 2000. Philadelphia: Hanley & Belfus. JAMIA (suppl) 2000; 7:645-649.

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Renata G. Chapter 40: AI Introduction to Using this method before automating Bushko/ AI Introduction to Healthcare human work will get us closer to the Healthcare in Renata G. Bushko, M.S. ideal where there is no discontinuity World Health Strategy” Director, Future of Health Technology between design and use of programs; eBook, www. Institute, Hopkinton MA, USA where the technology matches users’ Futureofhealth. org (Ed.) Renata needs perfectly - the world with G. Bushko, FHTI, Abstract humanistic technology and healthcare 2016. Intelligent and Extelligent e work hard on creating AI-wings workers with AI-wings. Health for physicians to let them fly Environment (Ed.) Renata G. higher and faster in diagnosing 1. Is there a Cure for Diagnomania? Bushko, IOS W patients - a task that physicians do not want Diagnomania is an obsession with Press 2005 to automate. What we do not work hard automating medical diagnosis while on is determining the ENVIRONMENT in ignoring a real-world environment which physicians’ AI wings are supposed where diagnosis takes place. Medical to function. It seems to be a job for social/ AI research community suffers business analysts that have their own from diagnomania: it has been separate kingdom. For the sake of all concentrating on the medical diagnosis of us (potential patients!) social/business for more than a decade despite of consultants and their methodologies should the fact that physicians do not want to not be treated as a separate kingdom. The automate it. Diagnomaniacs do not most urgent task is to achieve synergy want to hear what an experienced between (1) AI/Fuzzy/Neural research, (2) neurosurgeon says: “ I will never Applied medical AI, (3) Social/Business decide to operate on a patient based research on medical institutions. We need on a diagnosis of a machine.” They this synergy in order to assure humanistic ignore social setting of medical medical technology; technology flexible practice. Diagnomania, not physician’s and sensitive enough to facilitate healthcare resistance to technology, is the reason work while leaving space for human that “the field of AI, which has attracted pride and creativity. In order to achieve commercial attention recently as humanistic technology, designers should expert systems have been successfully consider the impact of technological implemented in industry has produced breakthroughs on the organizations in only a handful of narrowly focused which this technology will function and the commercial Because of Diagnomania nature of work of humans destined to use healthcare workers do not have AI- this technology. Situated (different for each wings yet and patients do not get organization), Strategic (based on an in- a full advantage of achievements depth knowledge of Healthcare business), of modern computer science. It is and AI-Enhanced (ended with a dynamic time to change that! Diagnomania model) method for introducing technology is not terminal. The cure involves to Healthcare allows identifying areas where internalizing that physicians and technology can make medical work easier. nurses do not deliver patient care in

isolation but they function in communities repositioning of their organizations and of operating procedures) as much as their their work is much like that of clinicians cognitive powers. These structures should but their goal is a healthy organization not be ignored in defining AI projects aimed in addition to healthy patients. CEOs at creating new tools for healthcare! and CIOs define social/business On the contrary, the nature of medical setting for medical practice, thus workplace should drive the type and indirectly affect medical communities of extent of research/application projects practice. in healthcare. In addition, a unique organizational environment of healthcare institutions is what makes medical knowledge elicitation different from knowledge acquisition for other non-medical expert systems. Thus, we can increase both a rate of success of AI projects and Figure 1. Healthcare worker in isolation and in accuracy/speed of medical knowledge a social context acquisition by building models reflecting the nature of medical workplaces. 3. What kind of Tools Can Informate1Medical Work? 2. What is the Nature of the Medical The irregular and ad-hoc nature Workplace? of medical work (clinical and The nature of clinical work in medical administrative) can be addressed by communities of practice is highly nonroutine AI in three ways: (1) achieving high [2] and emergency-driven. It requires adaptability of programs (reasoning constantly inventing new ways to cope by analogy, approximate reasoning, with unforeseen contingencies under machine learning, incorporation of time pressure and with limited resources. neuro-fuzzy work validation methods), Patient care environment forces workers (2) getting automatic programming to “carry out their routine tasks and - often to work (healthcare workers create simultaneously - respond to unforeseen their own decision-support systems); combinations of events [2]”. (3) using social techniques and AI Medical work is based on dynamic, cross- business modeling to precisely identify functional, inter-departmental, and inter- real need for medical decision-support organizational collaboration that requires systems within the reach of current constant communication and effective technology. sharing of professional knowledge. It (1) It is imperative that medical takes place in healthcare institutions that decision-support systems are flexible, are constantly restructuring themselves in order to survive in a turbulent, competitive 1Automating means introducing technology without paying attention to its effect on people; environment. Especially now healthcare Informating goes beyond automating and executives must actively work on strategic prepares people and business process for technological change [9]

non-brittle, and able to do “guessing” given a workplace is to do the “field work”; incomplete knowledge. Research on analogical reasoning in large knowledge experience it - immerse in it and then bases strives to create such adaptive represent it. applications but more work is still needed Thus, in order to understand a [3] [4] [5]. Neural and fuzzy solutions provide real medical community of practice a flexibility but we do not have good ways to researcher/developer must have skills validate them, thus we cannot rely on them of a social scientist who is sensitive to in “main stream” patient care. (2) Automatic the subtleties of motivational factors, programming that could eliminate time/ power struggles, and frustrations within space discontinuity between design and organizations use of programs is not mature enough to handle medical applications. (3) Social/ 4.2 Why Strategic? business modeling (e.g., Situated, Strategic, We need to include knowledge about and AI-Enhanced method) of the medical strategic positioning of a medical workplace, can and should be used NOW institution in an economic environment to define application areas where today’s AI as a part of the workplace analysis can really help by being incorporated into because it affects the way communities an enterprise-wide Integrated Healthcare of practice function and evolve (e.g., by Information System (IHIS). the year 2000, nearly 80% [today 45%] of community hospitals will belong 4. Why do We Need Situated, Strategic, to hospital systems [7] which will and AI-Enhanced Method? change communication patterns within medical communities of practice). A 4.1 Why Situated? structurational model of technology Representing knowledge about technology derived from Gidden’s theory of in medical workplace is difficult because structuration can provide a framework technology has a dual nature: it is easily for building a guidance system for manipulated by humans, but also molds situated and strategic organizational behavior and organizational practice. knowledge representation. Giddens’ “This reciprocal causation of dialectical theory describes reciprocal interaction relationships implies that a general of social actors and institutionalized predictive model of the interaction of social practices [Figure 2]. technology with organizations is not meaningful [6].” The specific institutional context (situation) has to be understood and this is the essence of the situated approach. We cannot count on preexisting, general knowledge relevant to a specific workplace. The only way to represent knowledge about

nature of physician-radiology communication process explicit. Because medical knowledge “happens” in reaction to events (it is not static), an AI modeling tool able to represent this kind of knowledge has to easily support the following: (1) Multiple levels of abstraction, (2) Multiple logical views of the same process - different workers talk about the same process differently, (3) Emulation of dynamic interdependencies among activities and data over time; (4) Self- documentation; (5) Dynamic tracking Figure 2. A Framework for Strategic Knowledge of incomplete information - model Representation assumptions [8].

4.3 Why AI-Enhanced? 5. Expectations Capturing real-time dynamics of a distributed Using Situated, Strategic, and AI- business/medical process in a model Enhanced analysis of the workplace allows for the discovery of bottlenecks in before automating human work information flows and enhances the quality assures that new technology makes and speed of knowledge acquisition. A this work easier and thus users fully knowledge engineer communicates better accept it. Once researchers/designers with healthcare workers if model is used as a get to use this method there will focal point; automatic knowledge acquisition be more medical decision-support tools can reuse “modeling knowledge”. In systems that are actually accepted addition, AI modeling enables technology and used in many areas of practicing designers to create a model of a future medicine (e.g., patient referral, data workflow (e.g., mediated by AI applications) analysis, policy monitoring, lab data before investing in implementation. This analysis, health-education); there will prepares users for the change, facilitates be more enterprise-wide, scaleable AI discovery of possible difficulties, and helps applications integrated with Healthcare planning new applications’ integration Information Systems. It is imperative with Healthcare Information Systems. For that research on new ways to enhance example, modeling healthcare work with SYMMOD2 allowed to encode, hard to 2SYMMOD is a symbolic modeling environment otherwise capture, knowledge about developed at a Digital Equipment Corp. that handling delays in radiology report combines techniques of business analysis and discrete modeling with knowledge-based distribution and made emergency-driven methods

medical work starts from the workplace [7] Shortell, S.M., Morrison E.M., and analysis. AI modeling makes this analysis Friedman, B., Strategic Choices for easier - a dynamic model helps to capture America’s Hospitals, Jossey-Bass Inc. knowledge about the environment in which Publishers, 1990. physicians and nurses work. Environment awareness enhances the quality and [8] Chaney, T., Symbolic Modeling, speed of knowledge acquisition. Situated, Digital Equipment Corp., internal white Strategic, and AI-Enhanced method of paper, 1990. technology introduction will simply give healthcare workers AI-wings that let them [9] Zuboff, S., In the Age of the Smart fly where they want not there AI-designers Machine, Basic Books, Inc., Publishers, think they should. New York, 1988. [3] Greenbaum, J. and King, M., Design at Work, Lawrence References Erlbaum Ass., 1990. [1] Shortliffe, E.H., and Perrault, L.E., Medical Informatics, Computer Applications in [10] McDermott, J., The World Would Healthcare, Addison-Welsley, 1990. be a Better Place if Non-Programmers Could Program, Machine Learning, [2] Kukla, C. and Cash, D., “I Like My Job April, 1989. because Thre’s Nothing Repetitious About It”: On the nonroutine nature of workplaces, [11] Minsky, M., Why People Think that to be published in 1991. Computers Can’t, Technology Review, November, 1983. [3] Bushko, R. G., KRA - Knowledge-Rich Analogy: Adaptive Estimation with Common Sense, MS Thesis, EECS Department, Massachusetts Institute of Technology, 1990.

[4] Lenat, D., and Guha, R.V., Building Large Knowledge-Based Systems, Adison-Wesley Publishing Company Inc., 1989.

[5] Minsky, M., Logical vs. Analogical or Symbolic vs. Connectionist or Neat vs. Scruffy, In Winston, P., Expanding Frontiers: Artificial Intelligence at MIT, MIT Press, 1990.

[6] Orlikowski, W., The Duality of Technology: Rethinking the Concept of Technology in Organizations, CCSTR#105, SSWP#3141, Sloan School of Management, 1990.

Klaus-Peter Chapter 41: Artificial-Intelligence-Based standards. These MLM packages Adlassnig, Alexander Hospital-Acquired Infection Control together with the Arden software Blacky, Walter Klaus-Peter Adlassnig a,b,1, Alexander Blacky , are well suited to be incorporated in Koller / Artificial- Intelligence- Walter Koller medical information systems such as Based Hospital a Section on Medical Expert and hospital information or intensive-care in World Health Strategy” eBook, Knowledge-Based Systems, Medical patient data management systems, (Ed.) Renata University of Vienna, or in web-based applications. In G. Bushko, FHTI, 2016. Spitalgasse 23, A-1090 Vienna, Austria terms of method, Moni contains an Futureofhealth. b Medexter Healthcare GmbH, extended data-to-symbol conversion org From Strategy Borschkegasse 7/5, A-1090 Vienna, Austria with several layers of abstraction, until for the Future c Division of Hospital Hygiene, Clinical the top level defining NIs according of Health (Ed.) Renata G. Institute for Hygiene and Medical to HELICS is reached. All included Bushko, IOS Microbiology, medical concepts such as “normal”, Press 2009 Währinger Gürtel 18-20, A-1090 Vienna, “increased”, “decreased”, or similar Austria ones are formally modeled by fuzzy sets, and fuzzy logic is used to process Abstract the interpretations of the clinically osocomial or hospital-acquired observed and measured patient infections (NIs) are a frequent data through an inference network. Ncomplication in hospitalized patients. The currently implemented cockpit The growing availability of computerized surveillance connects 96 ICU beds patient records in hospitals permits with Moni and offers the hospital’s automated identification and extended infection control department a hitherto monitoring for signs of NIs. A fuzzy- and unparalleled NI infection survey. knowledge-based system to identify and monitor NIs at intensive care units (ICUs) 1. Introduction according to the European Surveillance The increasing availability of digitalized System HELICS (NI definitions derived medical data of patients in a hospital from the Centers of Disease Control and permits comprehensive identification Prevention (CDC) criteria) was developed and monitoring of nosocomial and put into operation at the Vienna General infections. The now routinel used Hospital. This system, named Moni, for information systems in hospitals are monitoring of nosocomial infections contains one of the basic foundations of this medical knowledge packages (MKPs) to procedure. The systems are capable identify and monitor various infections of of storing, transferring and retrieving the bloodstream, pneumonia, urinary tract an ever-increasing body of digitalized infections, and central venous catheter- data concerning the patients’ medical associated infections. The MKPs consist history, the outcome of physical of medical logic modules (MLMs) in Arden examination, the different outcomes syntax, a medical knowledge representation of laboratory tests, and the findings of scheme, whose definition is part of the HL7 various clinical investigations. These

Artificial-Intelligence-Based Hospital- Acquired Infection Control 395 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

systems are known as hospital information Hospital), a number of algorithmic systems (HISs), whose many functions and knowledge-based identification include the administration of data pertaining and monitoring programs for to the admission, transfer and discharge microbiological findings and of patients in order to render these data nosocomial infections have been accessible to medical information systems introduced and implemented on this (MISs) at the different wards and out-patient basis. These have been accompanied departments that contain the medical data of by a number of flexible statistical patients, as laboratory information systems evaluation modules. The systems (LISs) with the respectively gained laboratory include the following: findings, as well as patient data management • Moni/Germ: Germ and antibiogram systems (PDMSs) at ICUs with clinical, monitoring for pre-defined laboratory, equipment-based and nursing species using specifically defined data. resistance patterns in newly High-quality knowledge-based support submitted microbiological reports; for making medical decisions based on • Moni/Cross: Cross-infection these patient data stored in the respective monitoring by collecting information information systems requires that medical as to whether germs with knowledge be represented in a formal resistance patterns are passed manner and stored in a computer system. on, which—within a specific time This may be in the form of interpretations period—have been previously of rare or complex laboratory findings, or registered in a different patient; computer-based definitions of symptoms, diseases and treatment processes, • Moni/Trend: Frequency and trend and their inter-relationships, or rules or monitoring by collecting information tabulated forms of medical decision-making as to whether there have been procedures, to name a few. increases in the frequency of pre- Advances in methods of formal defined germs beyond a “basic representation and processing of medical level” indicative of an epidemic knowledge achieved in the fields of artificial event and how strong these deviations are; and intelligence, fuzzy set theory, and fuzzy logic permit computer-based processing • Moni/Surveillance: Monitoring for of medical knowledge originally available nosocomial infections by collecting in natural language [1]. A few examples of information as to those patients in these are the definitions of nosocomial whom the definitions of nosocomial infections issued by CDC [2–4], HELICS [5], infections represented as complex and KISS [6]. fuzzy rules are completely fulfilled, fulfilled to a certain extent, or not 2. The MONI programs fulfilled at all, as indicated by the At the individual clinics of the Medical collected data in the respective University of Vienna (Vienna General information systems.

Artificial-Intelligence-Based Hospital- Acquired Infection Control 396 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

3. The Moni/Surveillance program Figure 1 shows the methods that constitute the basis of Moni/Surveillance, a comprehensive monitoring program developed for nosocomial infections at ICUs to be surveyed by the infection control team of the hospital. Figure 2. Indication of those ICUs at which All of the Moni programs are directly patients developed a suspected or confirmed connected to the LIS of the microbiology nosocomial infection according to the most department (currently this is the electronic recent data. The color codes indicate whether they were suspected cases, i.e., the HELICS data processing (EDP) system of the definitions of nosocomial infections were Municipality of Vienna; later on it will be the only partly fulfilled, or whether they were MOLIS system of Vision4Health) as well as confirmable cases in which the definitions the PDM systems of the ICUs (here: CareVue were completely fulfilled. classic of Philips). On the one hand, the Moni programs actively provide information about germs and nosocomial infections in the individual patient, give reasons, and permit rapid intervention. On the other hand, the output statistics provide information about existing germs and infections at the wards, out-patient departments, or the entire medical facility.

Figure 3. In one patient at the neurosurgical ICU the definition of a catheter-associated symptomatic urinary tract infection (refer to UTI-B-k above right) is fulfilled by 100%; the underlying originally measured and observed patient data and the intermediate medical concepts derived from these data are shown as explanation, if requested.

Figure 1. Interplay of the applied formal methods in Moni/Surveillance The following screenshots show some steps Figure 4. Tracing the logical conclusion chain of the Moni surveillance system established shows that the patient received a urinary for the clinical department of hospital catheter; this data element was documented hygiene at the Vienna General Hospital: in the PDMS and passed on to Moni/ Surveillance through intermediate steps.

Artificial-Intelligence-Based Hospital- Acquired Infection Control 397 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Figure 5. An increased level of C-reactive protein Figure 7. “Other findings of a urinary tract (CRP) is present 100% as a clinical symptom because infection” can be fulfilled by several means; a determined value of 6 mg/dl (see Figs. 6 and 10) is here pathogens were found in urine. definitely an elevated value.

Figure 5. An increased level of C-reactive protein Figure 8. Definition of septicemia with its (CRP) is present 100% as a clinical symptom because top level concepts that need to be further a determined value of 6 mg/dl (see Figs. 6 and 10) is decomposed into their constituents. definitely an elevated value. 4. Methods When the medical data of a specific Figure 8 shows the implementation of a part patient are mapped in, the individual of the definition of septicemia of the HELICS fuzzy concepts are processed and document [5] into a formal rule. This—like all combined through fuzzy logic. other definitions of nosocomial infections— Technically, the rules and concept exists in natural language. It is “primary definitions are represented by using septicemia with clinical signs of sepsis and the Arden representation scheme two-fold common skin germs in blood.” The [7]. Arden is a medical knowledge elements of this rule are decomposed into representation and rule-based their constituents (Fig. 9). They contain a inference standard supported by HL7 number of sub-definitions of clinical and [8]. The basic building blocks of Arden microbiological concepts that are finally are so-called medical logic modules evaluated by importing data from both, the (MLMs). Each of these modules is PDM systems of the Vienna General Hospital usually responsible for one action to and the LIS of the microbiology department. be taken on the basis of incoming Some of these concepts, as can be seen medical data of a particular patient. in Figure 10 based on the example of “CRP Such an action may be an allergy alert, increased”, are defined as fuzzy quantities. a recommendation for a change in the drug dose, etc. For Moni/Surveillance we created larger building blocks or so-called medical knowledge packages (MKPs). They consist of a number of interwoven MLMs, each contributing to the overall task. Within

Artificial-Intelligence-Based Hospital- Acquired Infection Control 398 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

these MKPs, there are MLMs for simple and fine-tuning phase, the system is mapping and pattern matching tasks, others being evaluated and optimized. for aggregating detailed information, and yet The results obtained thus far others for the final logical inference steps. not only demonstrate the technical At present 47 MLMs form the MKP for Moni/ feasibility of the system; the medical Surveillance. An Arden rule engine residing results already show that it is an on an Arden server attached to a database exceptionally valuable means of with patient data from the connected ICUs identify ing clinical cases of nosocomial holds and processes the MKPs, or MLMs infection in an automated manner respectively (see also [9]). (currently such identification is performed by the inf ec tion control personnel).

Figure 10. The medical concept of “CRP increased” is defined by a fuzzy quantity. Under 1 mg/dl “CRP increased” = 0, i.e., it is not fulfilled. At 3.5 mg/dl “CRP increased” = 0.5, i.e., it is fulfilled to a certain extent (here by 0.5). A CRP value of 6 mg/dl and beyond means “CRP Figure 9. Decomposition of the concept of “clinical increased” = 1 and thus the medical concept is signs of septicemia” for today (t), yesterday (t-1d), and completely fulfilled. tomorrow (t+1d) (for retrospective studies). 6. Conclusion 5. Results By applying methods of artificial Currently we have implemented 24 fully intelligence and fuzzy theory, the computer-based definitions of nosocomial existing identification and monitoring infections as they occur in adult ICU patients program Moni/Surveillance has been according to the European surveillance equipped with knowledge-based system HELICS [5]. There are six forms intelligence that performs complex of septicemia, nine forms of pneumonia analytical steps automatically, acquired at the ICU, six forms of urinary tract substantiates these, and thus infection, and three forms of central venous renders them comprehensible and catheter-induced infection. reproducible. At present, twelve ICUs with adult We believe that routine application patients at the General Hospital of Vienna, of this program will make a significant comprising 96 beds in all, are connected to contribution to quality management Moni/Surveillance. In a currently ongoing test at the Vienna General Hospital. In

Artificial-Intelligence-Based Hospital- Acquired Infection Control 399 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

particular, it will assist the treating physicians [7] G. Hripscak, Writing ARDEN Syntax in reducing the rate of nosocomial infection Medical Logic Modules, Computers in at the ICUs and may therefore potentially Biology and Medicine, Vol. 24, 331– serve as a significant cost-reducing 363, 1994. measure. [8] Health Level Seven, Arden Syntax References for Medical Logic Systems, Version [1] L.A. Zadeh, Fuzzy Logic = Computing with 2.1, Health Level Seven, Inc., 3300 Words, IEEE Transactions on Fuzzy Systems, Washtenaw Ave, Suite 227, Ann Arbor, Vol. 4, No. 2, 103–111, 1996. MI 48104, 2002.

[2] Centers for Disease Control and [9] K.-P. Adlassnig, A. Rappelsberger, Prevention (CDC), http://www.cdc.gov/ Medical Knowledge Packages and their Integration into Health- [3]J.S. Garner, W.R. Jarvis, T.G. Emori, T.C. Care Information Systems and the Horan, J.M. Hughes, CDC Definitions for World Wide Web, Studies in Health Nosocomial Infections 1988, American Technology and Informatics, Vol. 136, Journal of Infection Control, Vol. 16, 128–140, 121–126, 2008. 1988 . [4] J.S. Garner, W.R. Jarvis, T.G. Emori, T.C. Horan, J.M. Hughes, CDC Definitions of Nosocomial Infections. In R.N. Olmsted (Ed.), APIC Infection Control and Applied Epidemiology: Principles and Practice, Mosby, St. Louis, pp. A-1–A-20, 1996.

[5] Hospital in Europe Link for Infection Control through Surveillance (HELICS), Surveillance of Nosocomial Infections in Intensive Care Units – Protocol Version 6.1, (Based on Version 5.0 including technical amendments), September 2004, Project commissioned by the EC / DG SANCO / F/ 4, Agreement Reference number: VS/1999/5235 (99CVF4-025), 1–51, 2004, http://helics.univ-lyon1.fr/helicshome.htm

[6] Robert-Koch-Institut, http://www.rki.de

Artificial-Intelligence-Based Hospital- Acquired Infection Control 400 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Renata G. Chapter 44: Doctor of the Future with patient Dr. Zuzu will develop a long- Bushko/ Framework Knowledge of 1000 Best Physicians and term educational and care plan based for Measuring Medical Traditions from 50 Cultures on personalized interactive movies, Adaptive Knowledge- Renata G. Bushko illustrating major behavioral points that rich Systems [email protected] should be reinforced to maximize life’s Performance in World Health @RenataBushko capacity, length, and pleasure. Strategy” eBook, Founder, Future of Health Technology Dr. Zuzu’s ability to annotate www. Futureofhealth. Institute, Happier, Longer Lives.™ www.fhti. and retrieve from image and video org (Ed.) Renata org libraries will allow a just-in-time health G. Bushko, FHTI, 2016. Intelligent education or compliance program. Dr. and Extelligent n 2057, your personal pharmacists/nurse/ Zuzu will also be able to prescribe and Health Environment physician could very well be Dr. Zuzu, not then develop (in its virtual R&D lab) (Ed.) Renata G. a human at all but a distributed Intelligent personalized drugs just for its patient Bushko, IOS I Press 2005 Caring Creature (ICC) with the combined Dr. Zuzu will help its patients knowledge of 1,000 of the best physicians, not only to maintain good health © Renata pharmacists, and nurses from different but also deal with bad health in a Bushko, medical specialties from 50 cultures. You compassionate and emotional way. 2002 would visit Dr. Zuzu at its office in the Through Dr. Zuzu you will access to Bushko@fhti. Cyberspace the essence of millions of stories of org www.fhti. Dr. Zuzu will be prepared to respond other people going through a given org to many requests related to maximizing condition including: joy and pleasures of life, no longer with a • Encoded mental states focus as in current medicine on reducing • Most common thoughts pain because most diseases have been • Activities and words that helped eliminated and the probability of the rest of them to make it through the rough them was minimized in the neonatal phase experience through chromosome replacement. Effective Dr. Zuzu’s collective common sense preventers (stress reducers) helping ICCs knowledge will allow it to always say also contributed to low-sickness levels. the right thing or to produce a right To facilitate ease of patient-physician virtual companion you can interact with communication, Dr. Zuzu will have multiple through direct retinal projection, in personalities, sex, age, voice and cognitive difficult cases. style depending on the situation and the Dr. Zuzu will charge its patients patient. This includes the ability to become per knowledge injection and per a humanoid version of the best friend successful interaction that will be from high school in order to maximize its automatically recorded based on convincing power and emotional closeness. your positive response recorded This way Dr. Zuzu will be able to relate well in your data stream. The payment to emotional states of its young and elderly will be expected also in the form of patients. knowledge – your permission to use Based on the genetic profile of each your data to further improve Dr. Zuzu’s

Doctor of the Future with Knowledge of 1000 Best Physicians and Medical Traditions from 50 Cultures 401 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

common sense and medical knowledge. – just when you have to change plains This way your personal ICC will revitalize its in Denver.” curing and educational ability. Dr. Zuzu’s will have a rich library What about the patients? of health stories extracted from life- All Dr. Zuzu’s patients will be equipped long medical data. These stories will with computers in their homes and cars in be parsed and represented in the the form of data glasses, windows, mirrors knowledge base for further retrieval and e-wallpaper. In addition, they will have and then turned into video scripts out on-body sensors and nanocomputers inside of which context-specific educational their bodies allowing continuous screening, health movies will be assembled for monitoring and data collection about their other patients in need. physical and emotional state (e.g. EKG, GSR). What if Dr. Zuzu gets sick itself? They will also have bathroom MRI machines, Dr. Zuzu will use self-treatment shower skin mole detectors, toothbrush through knowledge injections. Another protein analyzers, smart beds monitoring option is to call on other Intelligent sleep pattern, and sensors equivalent to a Caring Creatures and get a byte of hospital pathology lab, checking daily basic support. Most of the time Dr. Zuzu is in lab results. perfect shape – never tired and never Their on- and in-body sensors will be competitive or jealous, never anxious able to report pain or any unusual physical or annoyed. or emotional state directly to Dr. Zuzu. They could also do it via a voice-enabled telehealth tool at any time since Dr. Zuzu understands 105 human languages and 1,005 machine languages. Another communication option will be hybrid brain-machine interface, allowing a patient to send a request to Dr, Zuzu just by thinking about requesting an extraordinary virtual experience. Dr. Zuzu will always listen to all its patients (no limit on amount) and will process their vital signs and test results, relating all the findings and looking for unusual patterns. Dr. Zuzu will be able to warn patients about incoming health problem (e.g., pain) using its case-based and memory-based predictive engine. For example, it could warn you: “Please, call your surgery robots before leaving for work, to remove a splinter that will cause pain in three hours and 15 minutes

Doctor of the Future with Knowledge of 1000 Best Physicians and Medical Traditions from 50 Cultures 402 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

D.W. Shaffer, Chapter 45: What is Digital Medicine? 1. Introduction C.M.. Knight, David Williamson Shaffer, M.S., Ph.D. The last two decades have seen the J.J. Kaput, G.S. Gazelle / Lecturer, Harvard Medical School, beginning of a digital revolution that is What is Digital Harvard University Graduate School of creating a new information economy, Medicine? Education, Massachusetts General Hospital and with it new paradigms for business, in “World Department of Dermatology, Boston, MA, US politics, and culture. Not surprisingly, Health Strategy” Colleen M. Kigin, M.S., M.P.A., P.T. the field of medicine is undergoing eBook, (Ed.) CIMIT (Center for Innovative Minimally dramatic change as well. Renata G. Invasive Therapy), Massachusetts General Public conversation about health Bushko Hospital Institute for Health Professionals, care in this time of change has tended FHTI, 2016. Futureofhealth. Boston, MA, US to address questions of policy and org, From James J. Kaput, Ph.D. technology. Politicians, practitioners, Future of University of Massachusetts patients, and the health care industry Health G. Scott Gazelle, M.D., Ph.D. more generally are concerned with Technology (Ed.) Renata G. CIMIT, Harvard Medical School, Harvard access to care, reimbursement policy, Bushko, IOS School of Public Health, Massachusetts improvements in quality of life, and the Press 2002 General Hospital Department of Radiology, role that technology plays in raising or Boston, MA, US lowering the cost and efficacy of medical care. [1] [2] Much of this Abstract discussion has focused on local hanges in health care are a changes, looking at the current state of fundamental part of social and health care in comparison with the Cintellectual evolution. The modern practice of medicine in the past 40 or practice of scientific medicine depends on 50 years. Policy makers ask, for the existence of the written and printed example, whether Health Maintenance word to store medical information. Because Organizations (HMOs) provide care computers can transform information as well that is more or less expensive — and as store it, new digital tools cannot only more or less effective — than the record clinical data, they can also generate employer-based fee-for-service medical knowledge. In doing so, they make insurance system that developed in it possible to develop “digital medicine” that the United States after the Second is potentially more precise, more effective, World War [2] [3] [4]. more experimental, more widely distributed, If we step back not 30-50 years but and more egalitarian than current medical 3000-5000 years, we can see that the practice. Critical steps in the creation of nature of medicine itself is changing. digital medicine are careful analysis of the Technologies of the digital revolution impact of new technologies and coordinated do not just alter the cost of health care, efforts to direct technological development the range of diseases that can be towards creating a new paradigm of medical treated, or overall quality of life for care. patients. These technologies are

fundamentally transforming the practice of fifteenth century physician’s admonition medicine. to “let not the sun go down behind the hill without your having gone out, or if 2. Background - From Healing Art to you can not, take before meals a little Medical Science exercise” [6] is good advice for general Disease and healing have been a part of the health. But these words were offered human condition as far back as the science as a method for avoiding bubonic of archaeology can take us. Skeletal remains plague, against which regular exercise of early hominids show evidence of is little defense. Prescriptions such as disorders such as hypervitaminosis A and this for controlling the interactions of yaws, and excavations have uncovered miasmic vapors and bodily fluids were bodies with evidence of wounds based on the notion of humoral successfully treated, dislocations balance — medical care based on the successfully replaced, and broken bones importance of balancing emotional successfully set. [5] [6] states. [7] This was a theory of disease, The development of scientific medicine is to be sure, but not yet scientific a relatively recent phenomenon, however. It medicine. is only in the last few thousand years (a blip The development of scientific in the span of human evolution) that early medicine as we know it today was medical texts begin to define medicine “as made possible by the invention of the something over and beyond mere healing, printing press. In 1543, just over ninety as the possession of a specific body of years after Guttenberg produced the learning, theoretical and practical, that might first printed bibles, Vesalius published be used to treat the sick.” [6] It is no his seminal text on human anatomy. In coincidence that the distinction of medicine the centuries following Vesalius, as something “beyond mere healing” modern medicine was developed emerges around the same time as the development of writing. The development of through collaborations between medicine as a body of learning was investigators and theorists over time intimately connected with the ability of and across space. While printing was physicians to record observations about not the only factor involved in the specific patients and specific diseases, to creation of scientific medicine, these share these observations, and to theorize collaborations were made possible in about how the human body functions. large part by the publication and Hippocrates and Galen, the giants of early distribution of medical texts. [8] [9] Western medicine, made their marks by Scientific medicine depends on the collecting, extending, and codifying medical recording, collecting, and comparing of knowledge in extensive writings. observations, the formation of theories, By today’s standards, the medicine of and the building of new understanding Hippocrates, Galen, and their successors on the foundation of prior work — all of appears systematic, but not yet scientific. A which are possible on a large scale

only with the ability to store and distribute to communicate these standard information widely. gestures or symbols. The development of language created the next stage of 3. Human Cognitive Evolution cognitive development: a “mythic” In a recent book, Origins of the Modern culture based on the telling of stories Mind [10], psychologist Merlin Donald or narratives that carry important describes the development of human cultural information. Here, then, some cognitive abilities in a series of stages, 300,000 years ago, was the cognitive where new cognitive abilities are built on top origin of the incantations, magic, myth, of — and co-exist with — older forms. These and rituals of healing. [13] stages of cognitive development are Donald identifies the next stage of associated with specific cultural practices, cognitive development as a “theoretic” including the practice of medicine.1 culture based on written symbols and In Donald’s analysis, human cognition paradigmatic thought. Beginning departed from its primate roots some 2 30,000-50,000 years ago, accounting million years ago when early hominids and other complex record keeping began to develop a system for mental drove the development of external representation based on mimesis — the representations. The existence of such ability to represent events using gesture and external representations made it re-enactment. Mimesis is, for example, when possible for literate humans to think we follow someone else’s gaze or pointing analytically by looking for relationships gesture because we understand that the among recorded ideas — and thus to gesture means they want us to look at develop a scientific culture based on something. Recognition that a gesture can external records and external notations refer to an event or object (rather than being for thinking such as writing and the thing of interest itself) makes it possible mathematics. Theoretic culture to communicate intent, and is only possible if requires large-scale storage of the person seeing the gesture and the information, such as the accumulation person making the gesture have a shared of texts in a library. This “external understanding — that is, if each has a model memory field” acts as a medium in of what is taking place in the mind of the which analytic thinking can take place. other. Mimesis made it easier for early Literate people access the cultural humans to coordinate group activities — and record (books and other written also provided the basis for the healing arts materials), use and transform that in gestures of understanding, support, and information to take appropriate actions, sympathy. Donald argues that the social advantages 1Donald’s thesis has been the foundation of of mimetic communication drove the much scholarly discussion, including a range evolution of language. Humans began to of responses in a special issue of Behavioral use ritualized or standardized gestures, and and Brain Sciences [11]. However, despite significant controversy, the substance of language developed as a more efficient way Donald’s argument remains intact [12].

and make new contributions to the external What happens when information corpus of human knowledge. can be transformed externally as well? It is hardly surprising, then, that the To take an example from Shaffer and development of a science of medicine Kaput, computers make it possible for depended on writing and the dissemination a researcher to perform a statistical of medical information made possible by the analysis without making a single printing press. It is not just that the scientific computation by hand. Software does method requires accurate record-keeping. the necessary calculations and The development of scientific thinking itself produces a results table or visual is intimately linked to external recording of representation of data that the information. Anatomy texts and patient charts researcher can use to understand the are not just symbols of modern medicine — phenomena in question. The computer they are essential tools in the development is processing the information so the of scientific medicine in a theoretic culture. researcher can focus on the more Donald’s picture of a theoretic culture interesting problem of interpreting the based on the external storage of information results of the analysis. In the same way, has been extended into the digital age by a clinician who orders a CT or MRI authors such as Shaffer and Kaput [14], who relies on a computer to gather and suggest that new digital tools are creating a process a vast amount of information fifth stage of cognitive evolution where and render it into a useful model of computers and other new media not only internal anatomy. In both cases, the store information for us, but process computer is not just storing information; information as well. This has profound it is taking information in one form and implications for the practice of medicine. returning it in a fundamentally altered form without additional action by the 4. A new stage of development researcher or clinician. Donald’s theoretic culture depends on the We are thus on the verge of a new externalization of memory. Cognitive cognitive culture, dependent on the theorists whose information-processing externalization of symbolic processing perspective matches Donald’s analysis [15] as well as on externalization of explain cognition as an interaction among symbolic representation.2 As humans long-term memory, short term (or working) developed gestural communication, memory, and the process of transforming language, and writing, they created information internally. There is some doubt mimetic, narrative, and analytic ways of as to whether mental activity can be as thinking that interact and compliment cleanly segmented as such a model suggests; [16] however, it is clear from 2We are not suggesting here that information- processing is the only important aspect of Donald’s analysis that theoretic culture mental activity. We argue here that a new depends on external storage of information digital culture is being created as we develop and internal processing of information. new ways to execute well-specified algorithms, which are a limited by important subset of thinking.

each other. Mimetic, mythic and theoretic will be a useful adjunct to clinical cultures, in turn, developed the art of healing practice, but hardly a transformation of into the science of medicine, where the medicine as we know it. experimental method and the other tools of It is true, of course, that computers modern medicine augment — but do not can not imbue data with meaning. But replace — compassion in the delivery of this does not prevent them from health care. The development of transforming information and thus computational media makes possible a making it more available and more digital culture, and with it, we argue, a new useful. As Wendell Berry writes: era of digital medicine. “Knowledge refers to the ability to do or say the right thing at the right time.” 5. Information and Knowledge [17] Knowledge in this sense requires In order to understand how computers will the selection of (and ultimately action create an era of digital medicine, we need to upon) information appropriate to a understand what it means to “process particular context: knowledge is what medical information.” If processing medical remains after the irrelevant and information means only keeping more distracting pieces of information are detailed medical records, or making sure removed and only the useful that a medication delivered matches the information remains.3 medication ordered, then digital medicine

3Theorists of information make distinctions between data, information, and knowledge.[18] Information, they argue, is data combined with “meaning” — with some framework for interpretation. Knowledge is internalized information and the ability to apply that information in action. In this scheme, data is what can be stored on a computer disk. Information is the meaning of that data in “the collective mind of a society.” Knowledge exists in an individual person’s mind. In a theoretic culture, these distinctions are sensible: data is the external memory field which forms the medium of culture and thought. What matters is how people acquire the data (turn it into information) and how they put it to use internally (act knowledgeably). In this view, however, a computer by definition can do nothing more than store data. Data transformed remains data, and only human beings can add value to data by giving it meaning and turning it into knowledge. But in transforming data, computation augments “thinking” as well as “memory.” Instead of data, information, and knowledge, we suggest in the following paragraphs that in digital culture the critical progression is from information, to knowledge, to understanding, and finally to wisdom. These two frameworks can be summarized in the following table:

Digital Information Knowledge Understanding Wisdom Clulture selection creation of a choice of appropriate of context- mental model of actions based on appropriate situation based understanding of situation information on multiple contexts

Theoretic Data Information Knowledge Culture data + meaning information that is internalized and used

By transforming information, computers wisdom [16]. So-called expert systems generate knowledge any time they sort have a terrible track record in medical through, discard, and simplify information diagnosis [19]— and in many other and raise its utility. The table of results from complex domains to which they have the regression is easier to use and more been applied. The first chess playing meaningful to a researcher than listing of the program to beat a human chess master raw data. A CT scan is more useful to a (the famous Deep Blue) was able to clinician than a collection of individual x-ray match human performance in a images. Both are examples of how a relatively simple domain (chess is far computer can generate knowledge. less complex than even a relatively Of course, generating knowledge is not trivial task like doing the dishes after the final step in most activities — clinical or dinner). In the foreseeable future, otherwise. There is a long way to go human beings may come to rely on between completing and interpreting a machines to help generate knowledge statistical analysis and answering a research about the world. But we will almost question, just as conducting a CT scan is certainly rely ultimately on ourselves only one step in the process of diagnosis and on other people to develop and treatment. understanding and act with wisdom. Knowledge is context-appropriate information: a window into a particular 6. So, What Is Digital Medicine? system. We turn knowledge into Put simply: digital medicine is the understanding as we view the same situation transformation of health care that is from enough perspectives to develop a coming about as computer technology robust mental model of the underlying is used in the creation and application system. The goal of a clinician in assembling of medical knowledge. medical knowledge — whether general The traditional role of the clinician is knowledge about physiology and pathology, as the intellectual agent of patient care. or specific information about an individual The clinician examines a patient. From patient — is to come up with an the examination comes a diagnosis, understanding of what is happening in the and from diagnosis a plan for body and why. Finally, understanding leads treatment, which is also carried out by to action. This produces new information, a clinician. At each stage in the which can be turned again into knowledge, process (examination, diagnosis, and then used to refine understanding. planning, treatment), the clinician turns Wisdom is built up from this information into knowledge by accumulatedexperience of creating deciding what data are relevant, what understanding, taking action, and evaluating the data mean for the health of the the outcome in clinical (and other) venues. patient, when and how to use Computers can be good at generating instruments or administer medication. knowledge, but computers are notoriously In digital medicine, technology bad at generating understanding and helps in the process of turning clinical

information into medical knowledge. CT and human performance, such as guiding a MRI scans are digital examinations because micro-catheter through a tortuous distal they collect raw data and produce vessel, or delivering extremely precise segmented images of the underlying bursts of energy to destroy cells along anatomy. Implantable cardiac defibrillators a tumor margin. [29] [30] are digital treatments because they collect Digital medicine, in other words, is information about cardiac function and the augmentation of human abilities determine, based on parameters set by the through the external generation and clinician, whether at a given moment the application of medical knowledge that heart needs artificial stimulus. Modern health will make health care safer and more care policy is digital because computer effective by enhancing our ability to simulations and statistical tools are used to diagnose and treat disease. evaluate cost-effectiveness and quality of life impacts of data too complex to be analyzed 7. The Ten-thousand Foot View using pencil and paper. [20] [21] [22] Tissue It is impossible at this early stage in the engineering, genetic sequencing, and development of digital medicine to telemedicine are digital medicine because predict what specific diagnostic and none are possible without the power of therapeutic techniques will be modern computers to transform complex developed as digital technology information into medical knowledge. [23] [24] transforms medicine. It is possible, [25] however, to identify some of the ways Although digital medicine is made in which digital medicine will differ from possible by advances in information the practice of scientific medicine processing, the changes brought about by overall. digital medicine will be more than just diagnostic and analytic; digital medicine will 7.1 Digital Medicine Will Be More impact therapeutic interventions as well. Precise Minimally invasive techniques such as MR- Digital tools will make it possible to guided therapy and radiation therapy are create knowledge about the human digital procedures because they make it body at a level of detail previously possible to destroy or excise tissue using unimaginable. Computers can collect computer-augmented images of patient information that is difficult to obtain or anatomy more precisely and with less hidden in signals too noisy to interpret, damage to healthy tissue than is possible and then render that information into with traditional instruments alone [26] [27] medically-useful knowledge. [31] [28]. As digital medicine improves our ability Mappings of the human genome have to generate and act upon medical already provided a new class of knowledge using technology, robotically- treatments (gene therapies) [32]. augmented tools will be able to use Minimally-invasive tools make it sophisticated sensors to deliver drugs or possible to deliver drugs, energy carry out procedures beyond the limits of therapies, and devices to more parts of

the body with less disruption to surrounding computing power advances, tissue [33] [34]. New imaging techniques simulations will become more realistic make it possible to diagnose complex and more robust. Data from real conditions quickly and accurately: where patients will make it possible to plan today we can use CT to characterize tumors procedures and tailor treatment and response to therapy, tomorrow we may regimes to individual idiosyncrasies. be able to target specific neurons for pain or High-fidelity simulations will increase as the cause of seizures [35] [36]. As the rate at which new devices and computational technology advances, we will therapies can be developed, as be able to gather more precise diagnostic prototypes can be rapidly created, information and intervene with computer- tested, and adapted in the simulated guided and computer-assisted therapies that environment, and safety and efficacy are less invasive and more effective at can be tested in a virtual patient before treating specific conditions. clinical trials are conducted. Digital tools will make it possible to 7.2 Digital Medicine Will Be More Effective experiment and explore in silico more Digital tools will make it possible to target rapidly and far more safely than is therapies more precisely to specific possible in vitro or in vivo. diagnoses. External generation of medical knowledge is a critical component in the 7.4 Digital Medicine Will Be More emerging sciences of modeling and Distributed decision analysis. [20] [21] [22] As patient As more procedures can be done less data becomes more standardized and more invasively, conditions that once portable,4 and as more sophisticated tools required inpatient hospital stays can be are developed for monitoring the course of done in a doctors office, with the treatments, it will be possible to assess the patient returning home the same day. impact of interventions — and thus to Telemedicine is already making it easy manage conditions — more effectively. to get expert consultations from remote locations [42] [43], and the 7.3 Digital Medicine Will Be More ability of digital tools to transform Experimental information by altering its location One of the most important effects of digital makes it easy to create and access tools is to make it possible to simulate knowledge and expertise across wide anatomy, physiology, pathology, and areas. As digital technology produces therapeutic interventions. Computational new sensors and new communications chemistry has made it possible to generate tools, inexpensive monitors will able to and perform preliminary tests on candidate gather data about patients during the formulations for new drugs [37] [38], and first- generation simulation systems are currently 4 We recognize, of course, the central available to help train clinicians with new importance of protecting patient confidentiality devices and procedures [39] [40] [41]. As as new tools are developed to help clinicians evaluate the impact of treatments.

course of their everyday lives and transmit it Taken together, these the physician. [44] Telecommunications will transformations will potentially change make it possible for examinations to be the role of the clinician in the health carried out from a patient’s home [45], and care system. As medical knowledge is digital networks will make it possible for generated in partnership with digital patients to get high-quality information and tools, clinicians will be able to focus medical advice from virtually anywhere at their attention on their higher calling: virtually any time. [46] the role of the physician will be to manage a wide range of clinical 7.5 Digital Medicine Will Be More resources for the good of the patient, Egalitarian with the emphasis on complex New tools are making it easier for patients to problems of ethics, on the wise make informed decisions about their health application of the power new care options: from pre-packaged medical technology brings, and ultimately on decision support systems [47] to internet making sure that the vast medical forums where patients can “ask the experts”, knowledge of digital tools is grounded chat with people who share their conditions, in human compassion. or look up the latest medical information on a wide range of topics. Home testing kits are 8. Looking ahead available for ovulation, pregnancy, insulin What medicine will become in the level, and other assays that previously digital age is impossible for anyone at required access to a sophisticated this point to say with certainty — just as laboratory. In each case, the delivery of Vesalius himself would not have been context-appropriate information — that is, the able to predict the transformation of generation of medical knowledge — is made medicine made possible by the more accessible by new technology. As development of the printing press. In digital technology makes it easier for the field of health care, it is clear that patients to access medical information — computers and other computational both general medical information, and media will have a tremendous impact information about their own health — the on the practice of medicine. doctor/patient relationship will have the Computers make it possible not just to potential to become more of an equal store medical knowledge, but to create partnership. The clinician will continue to it. In doing so, they make it possible to have specialized knowledge and skills. But develop digital medicine that is patients will increasingly have the potentially more precise, more opportunity to use the doctor as expert effective, more experimental, more advisor, to help them weigh alternatives and distributed, and more egalitarian than make a wise and well-informed decision, modern scientific medicine. rather than relying on the clinician as sole Of course, this process is neither source of medical knowledge. inevitable or deterministic. The development of scientific medicine

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Urs-Vito Chapter 46: How Can We Build increasing, be it for private as well as Albrecht, Ute Trustworthy, Secure and Transparent professional purposes. The health von Jan / How Can We Build Health Apps? sector is no exception. Here, apps Trustworthy, Urs-Vito Albrecht are being used for various reasons: Secure and Hannover Medical School, Peter L. Reichertz to keep fit and to track one’s health Transparent Institute for Medical Informatics of the status or obtain support for those who Health Apps? in World Health Institute of Technology Braunschweig and have to deal with health problems, Strategy” Hannover Medical School, Hannover, but also in professional settings, e.g. eBook, www. Germany for diagnostic or therapeutic purpose. Futureofhealth. Ute von Jan Apps that may be used as reference org (Ed.) Renata G. Hannover Medical School, Peter L. Reichertz are also quite popular. The great Bushko, FHTI, Institute for Medical Informatics of the variability of possible combinations of 2016. Institute of Technology Braunschweig and settings as well as user and application Hannover Medical School, Hannover, types makes it considerably difficult to Germany define specific criteria for “what makes an app a good app”. While there are Abstract always “hard criteria”(often technical) owadays, smartphones, tablets that need to be taken into account, and other “smart” devices along such as compliance to basic standards Nwith the apps running on them with respect to privacy and security, are ubiquitously used in all areas of life. high quality implementation of the Health and medicine are no exception. provided functionalities, integration of However, while undoubtedly offering many evidence based content etc., there exciting possibilities in these areas, using are additional “soft criteria” that must technologies that were originally designed also be taken under consideration. with other purposes in mind holds many These are highly dependent on risks, especially in the highly sensitive the specific circumstances an app context of health. Avoiding risks or mitigating can be used in as well as on the their effects requires efforts on the part of individual requirements of the targeted all parties concerned, i.e. not only users, but users. Even an app that meets the also manufacturers and distributors of apps. aforementioned hard criteria may While there are increasing efforts to educate be problematic if it does not meet the former about potential risks, the latter the demands of its users. Apps that are often unaware of pitfalls they may run are too demanding may easily lead into when developing and distributing apps to operating errors because those that are meant to be used in a health related operating them do not understand context. This paper will point out a number what they are being asked to do. of aspects developers need to be aware of. On the other hand, apps that do not provide the content and functionalities 1. Introduction users expect, i.e. are “too simple, will The popularity of mobile apps is steadily soon lose their user base. Similarly,

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apps that contain “more than the user distributing the final product also bargained for”, e.g. implement functions that took considerable effort. In contrast, are not absolutely necessary for providing developing and distributing a mobile what is promised, such as evaluating the app is a task that can easily be done entrusted data in a manner that does not by almost anyone (based on the benefit the user but rather the manufacturer tools and distribution channels for the or a third party (without telling the users major mobile platforms), contributing about this) will also not have a good towards the rapid growth of the standing [1]. Keeping the balance between mobile app market. While on the all these aspects is not always easily done. one hand encouraging, especially in This paper will consider some of the most the context of health related apps, important factors manufacturers of health this can potentially be problematic: related apps will need to respect in order to Here, depending on the functionality be able to provide trustworthy, secure and they provide and the designation transparent health apps, starting with the a developer gives it (e.g. use for development phase up to the distribution of diagnostics or therapy), an app can the finished product via the app stores. easily enter the domain of so called “medical devices” that require special 2. Current Status attention throughout their lifecycle. The chances of mobile apps are as manifold In an app context, depending on as their risks [2, 3, 4]. While there are many the risk category an app belongs aspects users themselves need to consider to (and the respective jurisdiction), in order making the “app experience” safe, this may for example require quality nowadays, they are often left to their own assured development processes devices when it comes to finding accurate (and documentation thereof) – steps information about an app before installation. that should be respected for any app Since not all manufacturers openly provide development. Additionally, registration sufficient information about their apps, with a “notified body”, extensive their own background, and other relevant testing, and official certification (e.g. aspects. However, transparency is a decisive as demonstrated by the CE mark in factor with the potential of contributing the European Union) or regulatory to an app’s (commercial) success. Thus, approval (as is the case in the United transparency should also be in the best States) may become necessary. interest of those who develop or distribute Often, developers are unaware apps. of the requirements they need to Another aggravating factor is the sheer follow, especially when distributing number of apps available for choosing their apps internationally, which is from. In former times, software development easily the case when using the sales used to be the domain of professional infrastructure provided by the mobile developers – apart from a few non- app stores. User cannot rely on the professional enthusiasts – and successfully stores to recognize test an app’s

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quality or to ascertain whether they may importance. As for software in general fall in the “medical device category” and – independent of whether there is a have undergone the necessary procedures health related area of application – before they are published. While the rules there are a number of norms to be provided by the stores for developers who considered, e.g. the ISO 9001 as well register for distribution commonly specify as the ISO 250xx series of norms and that apps may not cause harm to their users others. Some of these norms define or damage to the devices they run on – and the minimum set of measures to be there are often statements to the effect that taken by developers, and– depending such apps will either be initially rejected on the jurisdiction – following them or removed from the stores, there is often may even be a requirement for no clear definition of what is considered apps that fall into the medical device “harmful”, a “risk” or a “hazard” and which category, although it does not appear measures developers should take to as if any of these norms are commonly prevent them [5, 6]. Also, while the stores applied in an app context. often check for what they consider “explicit While norms are also applicable content”, and developers are also often outside of software development and required to state for which age categories are used in various industries, e.g. their apps are “safe” to use, there are usually for production processes, there are no special provisions for health related also those that specifically apply to content, where potential damages may software rated as a “medical device”. be much more serious and may also have Here, IEC 62304 as well as ISO 13485 lasting (bodily) consequences for users. must be mentioned. “Quality” can be seen from various angles: as described 3. Steps to be Taken by Developers ISO 9001, quality rests on satisfying Due to the low barriers of developing the implicit and explicit needs of apps and only negligible restrictions of the the customers, and on measuring stores when it comes to the quality of apps, customer satisfaction. Extensive developers are mostly on their own when it documentation of all steps taken is comes to developing safe and trustworthy also part of ISO 9001’s understanding apps. On the other hand, they also have of quality. On the other hand, ISO to bear the legal consequences should 13485 takes this understanding of problems with their apps arise. It is their quality to the next level by describing responsibility to inform themselves about how quality management needs to the market conditions, applicable legal and be implemented in medical device regulatory requirements (e.g. with respect to contexts and specifically aims at medical device regulation, data protection ensuring patient safety. Within the laws, etc.) and to implement the necessary European Union, a quality management steps [7]. system implemented according to ISO Also, quality assurance throughout all 13485 fulfills the requirements of the phases of an app’s lifecycle is of utmost medical device directive 94/42 EWG.

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2.1. Use-Case Specific Quality Criteria good usability and that users can trust While not specifically targeting software in that the software performs as they the medical device context, developers of expect (5). The foundation for these health related apps should nevertheless rather “soft” criteria is of course that keep the quality definitions of ISO 25010 in the hard criteria often mentioned in the mind, as these are of importance from the context of software quality are fulfilled users’ point of view. Essentially, five points first. These will be described in the are described as playing a role for high following paragraphs as well as table 1. quality software: First of all, the software should be suitable for the specific use case 2.2. Product Related Quality Criteria (1). Secondly, its focus should not be too As mentioned before, many of the narrow, but rather be adaptable (2). Software relevant product related criteria should also aim at performing efficiently and that developers should respect are effectively (3), while minimizing risks to the described in ISO 25010. Based on user’s financial or social status, his health this norm, but also supplemented by or environment as far as possible (4). It aspects mentioned in PAS 277:2015 should also be of practical benefit and fulfill 4 and guidelines put forth by other the needs of the user in a comfortable and organizations [8], Table 1 lists essential satisfactory manner, and this also includes points to be respected.

Table 1. Quality criteria for software also applicable to health apps. Criterion Explanation Functionality The app needs to fulfill the explicit and implicit needs of its users. Implemented functions need to satisfy these needs as user expect (functional integrity), and they must have been implemented must in a sound and safe manner. Efficiency The app should not make undue use of the available resources. Ideally, it should perform its functions in an efficient manner, including quick reactions to user input and rapid calculation and presentation of the results wherever necessary.

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Compatibility There are two levels that can be counted under “compatibility”. First of all, an app should peacefully coexist with other apps installed on the same device and not interfere with their functions (unless intended). Where it makes sense, interoperability is also an important factor, e.g. by using standardized formats for exchanging data with other apps, as well as non-mobile software and services. Usability Via an appealing and easy to use interface, users should be able to make efficient and safe use of the provided functions. Functions should be easily accessible, and not require too much effort with respect to learning how to use them. An important factor is also the protection against use errors. In order to provide a good experience for all potential users, accessibility need to be taken care off. And finally, an aesthetically pleasing interface is an additional boon. Reliability Reliability includes not only that an app performs satisfactorily under normal conditions. In case of errors (hardware or software), basic functionality should still be available if at all possible (fault tolerance). If there is a temporary interruption or failure, it should be possible to recover the previous state and/or data (recoverability). Data All data entered into an app needs to be Protection/Privacy protected against unauthorized access. This may also make it necessary to implement role based access models if there is a need for multiple users to gain access to the data. It should be possible to track access to data as well as any changes to the responsible party (traceability). Data Security Data must be kept safe not only by providing means to protect against unauthorized access, but also via adequate encryption for storage, as well as transmission. In addition, there should be means to protect against data manipulation.

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Maintainability Apps should be designed to be easily maintainable. A number of factors can contribute to this. Using a modularized approach, an app can be easily extended, or existing modules from other apps can be reused. Of course, this necessitates well-documented code and well-designed interfaces between the modules. This is especially important since even minimal changes in one module may have serious effects on other parts of an app. Also, care should be taken to guarantee that the app and its functionality can be easily analyzed and tested against predefined criteria to ensure its functioning after any changes. Modifications should not lead to any unintentional changes in functionality. Portability To ensure continuing function over a longer period of time, due to the rapid development in mobile technologies, apps should be constructed such that they are easily adaptable to new hard- and software. On a similar note, wherever possible standardized formats should be used for storing/exchanging data in order to allow for easy exchange of data with similar software. User Safety Best practice approaches should be used to ensure that potential health related risks are avoided. In cases where it is not possible to rule out potential risks, protective mechanisms need to be implemented, e.g. via alarm functions. Also, users need to be informed about any potential risks to their health. Compliance with legal and regulatory requirements Developers need to respect legal and regulatory requirements as they are applicable. Since apps distributed via the app stores often target international audiences, developers need to inform themselves about the respective legislation before they put their apps on the market. If necessary, the apps should be restricted to specific markets.

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Transparency Developers need to respect legal and regulatory requirements as they are applicable. Since apps distributed via the app stores often target international audiences, developers need to inform themselves about the respective legislation before they put their apps on the market. If necessary, the apps should be restricted to specific markets. • Imprint: Information about the developer, but also meta-data regarding the app, i.e. version numbers, date of release etc. • Rationale: Information about the purpose the app serves, the users it targets and whether it has been designated as a medical device or not. • Functionality: There should be a clear description of the integrated functions, possible limitations as well as usability aspects and accessibility. • Validity and reliability: Methods employed for quality assurance as well as the information sources used to implement the app’s content and functionalities should be disclosed to allow users to form an opinion about the app. • Data handling: Information about measures used to ensure data protection and privacy, but also about whether the app uses external storage, or shares any data with the developer or third parties.

5. Conclusion the development process. Developers Even though, from a technical point of view, and distributors need to be made it is quite easy to successfully develop and aware that in a health context, there distribute an app, other aspects are not as are many additional aspects to be easily taken care of. There are many legal respected in order to be able to as well as ethical aspects to consider. This is provide save and trustworthy apps. On not only important to protect users, but also their side, this may reduce the risk for developers. For example, apps that were liability, while also protecting the users. not originally designed as medical devices, but later on add functionality making them medical devices, can easily cause regulatory, legal, or financial problems for the developers if adequate documentation and quality assurance were not used throughout

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References [7] M. Brönner, S. Meister, B. Breil and [1]U.-V. Albrecht, O. Pramann and U. von U.-V. Albrecht. Kapitel 15. Orientierung Jan. Chapter 7: Synopsis for Health Apps – für Hersteller von Gesundheits-Apps. Transparency for Trust and Decision Making. In: U.-V. Albrecht (ed.), Chancen In: M. Househ, E. Borycki and A.W. Kushniruk und Risiken von Gesundheits- (ed.), Social Media and Mobile Technologies Apps (CHARISMHA). Medizinische for Healthcare, Medical Information Science Hochschule Hannover, 2016, pp. 320– Reference, Hershey PA, 2014, pp. 93-107. 340. urn:nbn:de:gbv:084-16040812106. http://www.digibib.tu-bs. [2] R. Bierbrier, V. Lo and R.C. Wu, Evaluation de/?docid=60022 of the accuracy of smartphone medical calculation apps, Journal of medical Internet [8] Düsseldorfer Kreis, research 16(2) (2014) e32. Orientierungshilfe zu den Datenschutzanforderungen an App- [3] K.G. Giota and G. Kleftaras, Mental Entwickler und App-Anbieter. Available health apps: innovations, risks and ethical fromhttps://www.lda.bayern.de/lda/ considerations, E-Health Telecommunication datenschutzaufsicht/lda_daten/ Systems and Networks 3 (2014) 19-23. Orientierungshilfe_Apps_201 4.pdf (last accessed 04/17/2016), 2014. [4] K. Huckvale, S. Adomaviciute, J.T. Prieto, M.K.-S. Leow. and J. Car, Smartphone apps for calculating insulin dose: a systematic assessment, BMC Med 13 (2015) 106.

[5] T. Wetter, Consumer Health Informatics: New Services, Roles, and Responsibilities, Springer, 2015.

[6] U.-V. Albrecht, Kapitel 8. Gesundheits- Apps und Risiken. In: U.-V. Albrecht (ed.), Chancen und Risiken von Gesundheits- Apps (CHARISMHA). Medizinische Hochschule Hannover, 2016, pp. 176–192. urn:nbn:de:gbv:084-16040811340. http://www. digibib.tu-bs.de/?docid=60014

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Kevin Warwick Chapter 47: Future of Computer Implant involving animals, for example rat / Future of Technology and Intelligent Human- reward and punishment and maze Computer Implant Machine Systems following tests [1,2] and monkey remote Technology Kevin Warwick, Ph.D. signalling [3]. But where the trials are and Intelligent Professor of Cybernetics, Department of of considerably greater interest is Human- Cybernetics, University of Reading, UK where humans are involved. Various Machine Systems studies have involved the employment in World Health Abstract of implants to try and bring about some Strategy” inking the human nervous system and basic movement or control for those eBook, www. brain directly to a computer opens up who are paralysed, however some of Futureofhealth. org (Ed.) Linnumerable possibilities, not only in the most significant are those by Philip Renata G. the future world of medicine, but also as a Kennedy [4] allowing stroke victims to Bushko, FHTI, potential waya of technically evolving all control basic elements of their local 2016. From: humans. This, however, presents something environment simply by thinking about Intelligent and Extelligent of an ethical problem. Nevertheless, moving. Health the only way to actually find out what is Using implant technology to help Environment realistically possible and what is not is to those who have a mental or physical (Ed.) Renata G. carry out practical experimentation using problem, such as a paralysis, allowing Bushko, IOS Press 2005 implant technology and to witness the them to do things that they would not results. This chapter describes the most ordinarily be able to do, is seen by recent self-experimentation trials carried out most to be a good thing. However, the by the author and his team. same technology can also potentially augment all humans, giving them 1. Introduction abilities over and above those of other Technically, we are now in a position to humans. make a useful direct connection between Clearly this presents something of the human nervous system and computer an ethical issue as to whether the technology. This has come about partly due technology should be developed at all. to significant advances in the means of Indeed it is, in itself, an intriguing establishing a bond between biology and question as to whether it is a good technology. The chances of a body thing or a bad thing to ‘evolve’ humans rejecting technology or of infection setting in a technical, rather than a biological, in, although still not zero, can now be way. regarded as almost negligible if extreme Reasons for wishing to consider care is taken. At the same time, the extending human capabilities are increased capabilities of computers, both in manifold. Indeed it is part of human terms of computing power and networking, nature to try and do so. Nowadays, for have opened up a whole new raft of example, all sorts of possibilities arise possibilities. when the abilities of machine As a result, we have, in recent years, (computer) intelligence are compared witnessed a number of experiments with the finite, limited brain size of

humans – clearly it can be seen that the two on relatively complex electro-chemical entities have distinctly different modes of signals, which are converted into operation and in a number of ways the mechanical signals, sound waves in machine exhibits distinct performance speech or hand movements to operate advantages. a keyboard. In reality such mechanical Obvious examples are the mathematical, signalling is a very slow, error prone number crunching, abilities of a computer means of communication. As a result, and the networked computer’s memory human languages are nothing more base. These are both reasons why we use than finite coding systems that cannot computers as we do now – simply because hope to convey more than a small an individual human brain cannot compete. fraction of what we would really like to Nevertheless, such computer abilities have communicate with another including led to a redefining of, and a change in our our thoughts, wishes, feelings and understanding of intelligence [5]. What was emotions. Problems occur due to the once thought to be an intelligent act in wide variety of different languages and humans, now comes directly into question the indirect relationships and cultures when a machine clearly outperforms a between them. In comparison, human. machine communication is Technology has also been employed tremendously powerful, not only externally to improve on the humans’ limited because of its usually inherent parallel range of sensing the world around them. So nature, as opposed to human serial technology can give a picture of what is communication. going on in the infrared or ultraviolet spectra, Looking at these mental differences even translating X-ray signals into visual between humans and machines, it is images that human brains can understand. clear that humans can benefit Another factor is that human brains have enormously by the use of external evolved to think in at most, three cooperation, as indeed we do now. dimensions, whereas computers are able to However a direct link could offer so ‘think’ in n-dimensions. Space around us is, much more. For example, by linking of course, not three dimensional, as human and machine brains together categorised by humans, but can be could it be possible for us in this perceived in as many dimensions as one Cyborg (part human, part machine) wishes. Machines therefore have the ability form to understand the world around of understanding the world in a more us in twenty or thirty dimensions? Even complex, multidimensional way when four or five dimensions would be worth compared to humans. This is an extremely it. Could it be possible to tap the powerful advantage for machine intelligence. mathematical and memory capabilities Perhaps the biggest performance of computers directly, thereby probably difference, in an intellectual sense, between changing the operation of the human humans and machines is that of part of the Cyborg brain? What will the communication. Each human brain operates human brain make of extra sensory

information being fed directly in? Perhaps we needed something more most importantly of all, by linking the human sophisticated. Hence, as soon as the brain directly with a computer, might it be 1998 tests were concluded, we possible to communicate directly between immediately set to work on a new human and machine, and even person to implant experiment. person purely by electronic signals – something that could be regarded as 2. Neural Implant Operation thought communication? On March 14, 2002, an array of one All of these questions present an exciting hundred silicon electrode needles was new frontier for research linking humans and surgically implanted into the median machines closer together. As a result, in the nerve fibres of my left arm, at the 1990’s various scientists speculated on a Radcliffe Infirmary, Oxford, UK. Each future in which implant technology became a one of the electrodes was 1.5 mm in norm for all [6]. In one example Peter length, the total array measuring 4 mm Cochrane, who was then Head of British x 4 mm. With the entire median nerve Telecom’s Research Laboratories wrote [7]; fascicle estimated to have a maximum ‘Just a small piece of silicon under the skin is diameter of 4mm, this meant that each all it would take to enjoy the freedom of no of the electrodes penetrated well into cards, passports or keys. Put your hand out the fascicle. to the car door, computer terminal, the food During the two-hour operation, a you wish to purchase and you would be first incision was made centrally over dealt with efficiently. Think about it: total the median nerve for a length of just freedom; no more plastic’. over 4 cm, directly up to the wrist. A However, apart from heart pacemakers second incision was then made, and the like to overcome a problem, no one proximally to the first, 16 cm up the had actually experimented with implants to inside arm towards the elbow. This provide extra abilities. Until that is, 24 second incision was 2 cm in length. August 1998 when, as reported in [8], a Following a tunnelling procedure to silicon chip transponder was surgically connect the two incisions together, a implanted in my upper left arm. With this in piece of open tubing was run between place, the door to my laboratory opened the incisions, creating a clear passage. when I approached, the corridor light came The array, with its connecting wires, on automatically and a voice box in the was then passed down the tubing from entrance foyer welcomed me with “Hello, the incision nearest the elbow to that Professor Warwick” when I entered the nearest the wrist. building. Once the array had been But the identifying signals my 1998 successfully passed down the tubing, implant transmitted were not affected by the tubing was removed from the wrist what was going on in my body and signals end, leaving the array in position over transmitted to the implant from the computer the exposed median nerve fascicle by did not affect my body in any way. For that, the wrist. Wires from the array travelled

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up the inner arm, exiting at the second characteristic was being exerted by the incision where they were attached to an nervous system in response to the electrical terminal pad. The array was current. The current was in fact being pneumatically inserted into the radial side of applied as a bi-phasic signal with 100 the median nerve fascicle under microscopic usec inter signal break periods. It control. Once the array was successfully in could be said, in fact, that this signal position, both incisions were closed. waveform, which was the most successful tried, closely emulated the 3. Input/Output Signals first harmonic of motor signals With the array acting as a direct electrical recorded. connection into the human nervous system, The array allowed motor neural it was found to be eminently possible to signals to be detected from the small transmit neural signals directly from the collection of axons around each peripheral nervous system to a computer. electrode. Because the majority of These neural signals could be readily signals of interest occurred at generated by simple finger movements. frequencies of below 3.5 KHz, low The signals were transmitted to a computer, pass filters were employed to ensure either by a straightforward hard wire from that higher frequency effects, including the terminal pad via an interface unit, or those due to noise, were either though a radio transmitter attached to the removed from the procedure or, at pad. least, significantly reduced. In this way, It was, however, also possible to stimulate it was relatively easy to generate the nervous system, via the array, useful motor neural signals simply by transmitting current signals from the making controlled finger movements. computer to bring about sensations. In In the cybernetic experiments carried experiments to investigate appropriate out, these motor neural signals were current signals to be input, it was found that transmitted directly to the computer, currents of less than 80 uA in magnitude had where they could be made use of to little perceivable effect at that value, though operate a variety of networked certain of the electrodes produced a technological implements [9]. recognisable effect, the associated applied Whilst motor neural signals could be voltage being 40 to 50 volts. The exact generated and employed from the first voltage applied depended on the input day of experimentation onwards, in the resistance being encountered on each first stimulation tests, whilst wearing a particular electrode. Due to the variability of blindfold, a mean correct identification the human nervous system this resistance rate of 70% was achieved. What this was though, not identically the same on a means is that without prior warning, on day-to-day basis. average, seven times out of ten I could Stimulation currents above 100uA had successfully detect when a current little extra effect on nerve stimulation, stimulation had occurred and when it indicating that a non-linear thresholding had not. Further details on this are

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given in [10]. These stimulation tests did not using motor neural signals to control commence until six weeks after the implant technology and thus bring about a operation, and it took approximately two considerable lifestyle improvement. weeks of continued testing to arrive at The long term goal would therefore suitable current types to obtain this be, where necessary, to direct brain detection rate. implants to allow an individual who is An important feature of obtaining suitable paralysed to control their local current signals, recognisable on the nervous environment by neural signals – in system, was, effectively training of the brain popular terminology, to switch on lights to decipher the signals. In a sense, or perhaps drive their car just by therefore it was a mutually convergent thinking about it. In this sense, our exercise with, over a period of weeks, more experiment was useful in assessing the recognisable signals being inserted with, at present state of technology. the same time, the brain learning about the signals patterns and what they meant. This learning continued in the further weeks of 4. Application Studies the experiment. In order to demonstrate the sort Towards the end of the entire experiment, of applications possible, thereby which concluded with the implant being indicating the range of potential use extracted on 18th June 2002, over three for implant technology of this type, a months after the original implantation, a variety of applications were performed. mean perception rate of stimulation of over The first implementation was to 95% was being achieved. To all intents and make use of the neural signals being purposes though, because of several factors transmitted to control an articulated apparent in the method of experimentation hand. The aim of the hand, referred to [10], realistically this figure should be seen, in as the SNAVE hand, is to mimic the a practical sense, to be as near to 100% as operation of, in particular the control could be achieved. mechanisms inherent in, the human Before discussing the cybernetic hand. Effectively, neural signals applications actually carried out with the responsible for moving fingers in my implant in place, it is important to realise that own left hand were also used to the whole project was conducted in operate the articulated hand. association with the National Spinal Injuries Sensors in the fingertips of the hand Centre at Stoke Mandeville Hospital, allow for the grip shape to be adapted Aylesbury, UK. One aim of the project was as well as the applied force being therefore to assess the practicability of modified as necessary. Hence employing the same type of implant to help appropriate tension can be applied via those with a spinal injury. The aim was not the hand in order to avoid object so much one of attempting to restore slippage. In tests, whilst wearing a movement to otherwise motionless limbs, blindfold, sensory data from the but rather to consider the possibilities of fingertips was fed back down on to my

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nervous system. As more force was applied Due to the chair mobility, a short- to an object, so the amount of neural range digital radio link was brought stimulation was increased. At the same time, about between the implant and the the hand’s movements were being wheelchair driver control mechanism. controlled from my own nervous system. The radio transmitter/receiver unit was Over a two week period of regular worn as a gauntlet arrangement on my experimentation I learnt to judge, to very fine lower left arm. After about one hour of detail, within + 5%, a force just sufficient to learning time, quite reasonable control grip an object. of the wheelchair was achieved. As a follow on from the articulated hand Subsequently, considerable success investigation, on 20th May 2002 a team at was achieved in driving the wheelchair Columbia University, New York City, teamed around a cluttered, external up to bring about an internet link. With environment. myself in the Internet real-time labs in the One further experiment was to Computer Science Department of Columbia investigate the possibility of extra University, the implant was put on-line onto sensory input to the human nervous the Internet. The articulated hand system. To this end, ultrasonic sensors experiment was then repeated, although this were positioned on a baseball cap. time, signals from the neural implant were The output from these sensors was fed transmitted via the Internet to directly control down on to the radio transmitter/ the articulated hand back in the Cybernetics receiver gauntlet to provide neural Labs at Reading University in the UK. As stimulation via the implant. When an well as this, feedback information was object was in the vicinity of the transmitted from the hand’s fingers in the UK sensors, the stimulation rate was high, to stimulate my nervous system in New York. whereas as the distance increased, the A 100% success rate in signal recognition stimulation rate decreased. With no was achieved in this one off trial and the object present, no stimulation articulated hand was controlled adequately occurred. despite the delay in signal transmission due Tests were carried out in a normal mainly to the distance involved. (untidy!) laboratory environment. Whilst Neural signals were also employed to wearing a blindfold, I was able to control the directional movements of an readily navigate around objects in the electric wheelchair. For this purpose a laboratory by means of, what turned sequential state machine provided a simple out to be, a highly accurate ultrasonic solution, the machine being halted, by neural sense of distance. Obviously, drawing signals, to select the desired travel direction universal conclusions from a one off – forward, backwards, left, right. experience would be wrong, however Experiments were also carried out to what can be reported is that my brain selectively process signals from several of adapted very quickly, within minutes, to the implant electrodes over time in order to its new sensory input. realise fine control. Importantly, the stimulation pulses

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being received were linked directly with the ultrasonic detection, in terms of an indication of how far away any objects were. The 5. Conclusions So Far pulses were not witnessed as one of the The practical implant study carried out normal five human senses. When an object gives rise to a host of implications [11]. was brought rapidly into my ultrasonic ‘line of Firstly, by positioning such arrays in the sight’, a reactive, automatic recoil occurred motor neural area in the brain, this to, what felt like, a dangerous situation. should bring about a variety of he final experiment carried out involved technological control systems my wife, Irena, who had two electrodes operated merely by the individual inserted in her median nerve through thinking about moving. In essence, just microneurography, in roughly the same about any technical device that can be location to my own implant. controlled should be operable in this By means of one of the electrodes in way, domestic implements providing particular, strong motor neural signals could the obvious immediate application be obtained when she moved her fingers. field. The output from this electrode was linked For those people who are directly to a computer and was connected paralysed, implant technology should such that my own nervous system was therefore open up a whole new world. stimulated each time Irena moved her Whilst we should not be fingers. The process was also linked up in overenthusiastic in claiming that it will the reverse direction, with Irena’s nervous all happen today or indeed tomorrow, system being stimulated when I moved my at least we can say that a number of fingers. So when Irena moved her fingers things appear to be technically quite three times, I felt three pulses on my nervous possible. Directly from the results of system, and vice versa. our experiments, it should be possible What we had brought about was a direct for a paralysed person to switch on electrical connection between the nervous lights, make the coffee and even drive systems of two individuals. Through this their, suitably modified, car. connection, motor neural signals were In the tests carried out, a wheelchair transmitted from person to person to was driven around under the control of successfully achieve a simple my neural signals. The same should radiotelegraphy signalling system. be possible for someone who is It is apparent that with implants fitted not paralysed. Also an articulated hand in the peripheral nervous system, but rather was controlled from my nervous directly in the motor neural area of the brain, system. The same should be possible the same type of signalling between two for someone who has had their hand individuals could be considered to be the amputated. Further, I benefited from an first, albeit rudimentary, steps in thought extra (ultrasonic) sense. The same communication. should be possible for someone who is blind – not to repair their blindness

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in any way, but to allow them an alternative The programme of research presents sense. quite an ethical dilemma. Very few One part of the study was the people would argue against the investigation of infection and rejection as use of implant technology, as long regards the interaction between my body as it has been shown to be safe, to and the implant. The run of wires up the help those with a disability of some inside of my arm was an attempt to reduce kind. However the use of the same the effects of infection. In fact, no indication technological base in order to upgrade of infection was witnessed during the trial humans raises some serious questions. period, the two operation sites on my left Who gets an implant and who doesn’t? arm being monitored closely over that time. Will it be left purely to commercial As for rejection, results were far more enterprises to push the technology on encouraging than could have been or is it something for which some key imagined. Firstly, mentally my brain had political decisions need to be made? tuned in more and more to the signals used Our own research is now clearly for stimulation. Secondly, when the focussed on motor neural brain extraction operation took place it was found implants as the next step. Many that scar tissue had grown round the implant, research questions arise though, pulling it tightly into the median nerve fibres. in terms of number and positioning When the scar tissue was removed, it was of implants. Also the extent and discovered that the implant had neither lifted range of signals to be bi-directionally nor tilted from the nerve fibres – it was transmitted is of major concern. Of exactly where it had been positioned over the tests to be carried out, thought three months earlier. communication ranks as something of On the negative side, where the wires a priority. However this will mean that exited from my arm they were subject to more than one person will need to quite severe mechanical bending stresses be implanted for scientific, rather than and this resulted in gradual breakage of the medical, purposes – which could be wires [12]. In fact by the end of the difficult from an ethical standpoint experiment only three wires (therefore three Giving humans extra abilities by electrode connections) were still operative. technologically upgrading them (into Clearly the mechanical strength of the wires Cyborgs!) [11] now appears to be will need to be improved if long-term becoming possible. Shouldn’t humans implants are to be considered. However, if a be allowed to simply get on with it – device were to be completely implanted, as has (largely) been the case with then perhaps this would not be a problem. previous technical improvements – A complete implant, of this type though, and become superhuman? Humans would need a light/compact power supply are now in a position whereby we have and aerial. the potential to evolve our own destiny. Perhaps issues affecting such a move 6. Implications for the Future are now as much social and ethical as

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they are technical. Communication, Berlin, pp 265-270, Sept. 2002. References [10] Warwick, K: “A Study in Cyborgs”, [1] Chapin, J; Moxon, K, Markowitz, R and Royal Society of Edinburgh 2003 Joint Nicolelis, M., “Real-time control of a robot Lecture, ISBN 0 902198688, March arm using simultaneously recorded neurons 2003. in the motor cortex’, Nature Neuroscience, Vol.2, pp 664-670, 1999. [11] Warwick, K., “I, Cyborg”, Century, 2002. [2] Talwar, S; Xu, S; Hawley, E; Weiss, S, Moxon, K and Chapin, J; ‘Rat navigation [12] Warwick, K; Gasson, M; Hutt, B; guided by remote control’, Nature, Vol. 417, Goodhew. I; Kyberd, P, Andrews, B; pp 37-38, May 2002. Teddy, P and Shad, A: ‘The Application of implant Technology for Cybernetic [3] Nicolelis, M, “Actions from Thoughts”, Systems’, Archives of Neurology, to Nature, Vol. 409, pp 403-407, 2001. appear, 2003.

[4] Kennedy, P; Bakay, R; Moore, M, Adams, K and Goldwaithe, J; ‘Direct control of a computer from the human central nervous system’, IEEE Trans. On Rehabilitation Engineering, Vol. 8, No. 2, pp 198-202, 2000.

[5] Warwick, K; ‘QI: The Quest for Intelligence’, Piatkus, 2001.

[6] Kurzweil, R: ‘The Age of Spiritual Machines’, Viking, New York, 1999.

[7] Cochrane, P, ‘Tips for the Time Traveller’, Orion Business Books, 1997.

[8] Bushko, R. (ed), ‘Future of Health Technology’, IOS Press, 2000.

[9] Gasson, M; Hutt, B; Goodhew, I; Kyberd, P and Warwick, K: ‘Bi-directional Human Machine Interface via Direct Neural Connection’, Proc. IEEE International Workshop on Robot and Human Interactive

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Alex (Sandy) Chapter 48: Healthwear: Medical As part of this change in the way Pentland / in Technology Becomes Wearable we use computers, my research group World Health Strategy” Alex (Sandy) Pentland, Ph.D. at the MIT Media Lab (http://hd.media. eBook, www. Professor of Media Arts and Sciences & mit.edu) has been developing Futureofhealth. Director, Human Dynamics Research Group healthwear, wearable systems with org (Ed.) MIT Media Laboratory, Cambridge, MA, US sensors that can continuously monitor Renata G. Bushko, FHTI, the user’s vital signs, motor activity, 2016. From: Abstract social Interactions, sleep patterns, and Intelligent and idespread adoption of sensors that other health indicators. The system’s Extelligent monitor the wearer’s vital signs software can use the data from these Health Environment Wand other indicators promises to sensors to build a personalized profile (Ed.) Renata G. improve care for the aged and chronically of the user’s physical performance and Bushko, IOS ill while amassing a database that can nervous system activation throughout Press 2005 enhance treatment and reduce medical the entire day—providing a truly costs. personal medical record that can, we believe, revolutionize healthcare. 1. Introduction The concept of computing is rapidly 2. Healthwear Overview expanding from simply using a desktop Until recently, researchers have had PC, where people sit and type for a small little success in extending healthcare part of the day. Every day, more than into the home environment, yet there one billion people carry around portable clearly is a huge demand for this computation devices that have sensors and service. Americans currently spend Internetcapable connections—but we call $27 billion on healthcare outside them cell phones rather than computers. the formal medical establishment The most recent cell phones go far because they find it difficult to access, beyond telephony: They are truly wearable expensive, and painful (www.rwjf.org). computers. These location-aware devices A clear demand for better integrating have sensors for detecting sounds, images, the home into the healthcare body motion, and ambient light level, have environment exists. Not only that, but a secure Internet connection, and can a dramatic shift in the composition of download and upload programs as well as the US population makes it absolutely audio and image files. They also can serve necessary to develop such distributed as a situation aware intelligent assistant, systems. whether as personal agents that use the digital equivalent of 3M’s 2.1 Caregiver Shortage Post-it notes to augment reality or as a Although the US had 25 caregivers means of forming tight-knit intellectual for each disabled person in 1970, the collectives in which people can supercharge success of our healthcare system will their social networks. lower the ratio of caregivers to at- home disabled to 6 to 1 by 2030 (www.

agingstats.gov). How will those six people healthcare costs, this data can provide care for a disabled person? Certainly, a powerful epidemiological information centralized system of visiting nurses is not for use in improving our knowledge an option for providing this care—such a about keeping society healthy. For system would leave too few individuals example, today because the huge working at other jobs in the economy to expense of clinical trials limits the support it. size and sensitivity of drug testing, Thus, a more highly distributed system is harmful interactions are often detected not only desirable, but absolutely necessary. only months or years after a drug is These statistics provide the driving force introduced to the general populace. behind the development of healthwear. Continuous, quantitative behavior This concept offers an unobtrusive method logging has the potential to generate for acquiring in-depth knowledge about enough data so that researchers could the body that could help manage chronic discover these interactions more medical conditions such as cancer, diabetes, quickly. degenerative disorders of the nervous Another application that is system, or chronic pain. Perhaps just as potentially even more important is importantly, the deployment of continuous the early detection of epidemics like monitoring devices provides an excellent SARS or biological weapons attacks. opportunity to fully inform medical providers Today, reports of the treatment of about a patient’s condition, thus helping the an unusual number of patients with patient obtain the best treatment possible. similar symptomatology at a medical Already, health-conscious individuals facility often provide the first warning are wearing small digital pedometers and of a potential epidemic. Widespread exercise monitors. Indeed, some companies continuous monitoring could detect such as Nissan in Japan give such devices such outbreaks much sooner by to employees to heighten health awareness noticing when unusual numbers of and decrease medical insurance costs. In people are behaving lethargically or the future, people who dress for success staying home from work. may also wear a healthwear personal trainer However, creating such an that helps keep them active, knowledgeable, information architecture requires and involved. safeguards to maintain individual privacy. Indeed, we believe that this 2.2 Opportunities and Concerns issue demands immediate, thoughtful As new sensor, computing, and attention and public debate, perhaps communication technology becomes beginning with the current concern available, healthcare professionals will be about using cell phone signals to able to organize huge medical databases track people. The current forces for for use in tracking every test taken and creating huge databases and big medicine prescribed over an individual’s medicine are powerful and all too lifetime. In addition to helping drive down successful. The potential solution is

to place control and ownership of as much 3.1 Hardware Components personal information as possible in the Figure 1 shows the MIThril system. hands of the individual user, sharing only Designed for use with either a information cleansed of identifying features. modern programmable cell phone or This power-to-the-people approach favors a wireless personal digital assistant using wearable sensing devices rather than (PDA), MIThril offers input, output, and sensors in the surrounding environment general computation functions and can because the information starts out in the support a wide range of physiological control of the individual, and the legal measurements.1,2 The MIThril tradition in the US is that individuals own the hardware architecture is designed to data collected from their bodies. be modular and easily configurable so that it can handle a variety of sensors 3. MIThril and tasks. The software architecture In J.R.R. Tolkien’s Middle Earth stories, mithril supports using the ad hoc, on-the-fly is a precious metal used to craft armor combination of sensor signals from with properties that protect its wearer from multiple users to control signaling and evil. The term thus seems an apt name outputs. for the technology that provides the basis A sensor hub interfaces with the for healthwear. Highly flexible, the MIThril MIThril body bus, which combines architecture provides a modular system tied the Philips I2C multiple device serial together by wireless networking protocols protocol and power lines. The sensor and a unified multiwired-protocol power and hub provides a bridge to the sensor data bus for sensors and peripherals [1]. data, enabling data acquisition, buffering, and sequencing, and it can be used as a stand-alone data-acquisition system [2]. This is particularly useful for large-group applications that do not require real-time processing, wireless communication between users, or complex user interaction and thus do not require a cell phone or wireless PDA to be part of the system Currently supported devices include accelerometers for motion detection, IR active-tag readers for Figure 1. MIThril system. Plugging the biosensor hub location and proximity detection, audio into a cell phone or wireless PDA provides a system that offers input, output, and general computation input and output devices, battery functions and can support a wide range of monitors, GPS, analog two-channel physiological measurements. EKG/EMG, two-channel galvanic skin response sensors, and skin-

temperature sensors. MIThril uses an RS- Intended to act as a streaming 232 interface to communicate with a wide database, the Enchantment range of commercially available sensors for Whiteboard captures the current monitoring pulse oximetry, respiration, blood state of some system, person, or pressure, EEG, blood sugar, and CO2 levels. group. On modest embedded hardware, the board can support many 3.2 Software Architecture simultaneous clients distributed across The core MIThril software components a network while making hundreds include the Enchantment Whiteboard, of updates a second. We have used the Enchantment Signal system, and the Enchantment Whiteboard with the MIThril Real-Time Context Engine. the Enchantment Signal system for These tools provide the foundation for bandwidth-intensive voice-over-IP-style developing modular, distributed, context- audio communications between teams aware wearable and ubiquitous computing of up to 50 users. applications. The Enchantment Whiteboard implements an interprocess communications 4. Life Patterns system suitable for distributed, lightweight, The MIThril system provides a modular embedded applications. Unlike traditional framework for real-time understanding interprocess communications systems such of sensor data. The results of this as RMI and Unix/BSD sockets—which are process can be used locally for based on point-to-point communications— reminders and wearer feedback, or the Enchantment Whiteboard uses a client- they can be broadcast to other users server model in which clients post and read to enable smart-group communications structured information on a whiteboard and increased awareness of other server. members’ health and activity levels. This architecture lets any client exchange Pattern recognition techniques are the information with any other client without basis for modeling and interpreting the the attendant complexity in negotiating output of the wearable sensors. The direct client-to-client communication. These standard pattern-recognition approach exchanges can take place without the client breaks this process into four stages: knowing anything at all about the other • Sensing. A digital sensing device clients. Clients can subscribe to portions of measures something in the real the Enchantment Whiteboard, automatically world, resulting in a digital signal receiving updates when changes occur. of sampled values. For example, Further, clients can lock a portion of the a microphone sensor converts whiteboard so that only the locking client continuous fluctuations in air can post updates. It also supports symbolic pressure—sound—into discrete links across servers, letting whiteboards sampled values with a specified transparently refer to other whiteboards resolution, encoding, and sampling across a network. rate.

recognition accuracy greater than • Feature extraction. A raw sensor signal 95 percent. We have also applied is transformed into a feature signal more this same basic approach to audio suitable for a particular modeling task. and video to accurately identify the For example, the feature extraction stage setting in which conversations take for a speaker-identification-classification place—in a restaurant, in a vehicle, task might involve converting a sound and so on—and even to classify signal into a power-spectrum feature the type of conversations a user signal. engages in during the day [4,5]. Once we model the behavior • Modeling. A generative or discriminative and situation, we can classify statistical model—such as a Gaussian incoming sensor data to build mixture a model of the user’s normal model, Support Vector Machine behavior. We can then use hyperplane classifier, or hidden Markov this model to monitor health, model—classifies a feature signal in trigger reminders, or even notify real time. For example, a Gaussian caregivers. Information about mixture model could be used to classify the wearer’s social interactions accelerometer spectral features as is particularly interesting. walking, running, sitting, and so on. Understanding face-to-face encounters is critical to developing • Inference. The results of the modeling interfaces that respect and support stage, possibly combined with other the wearer’s social life. Social information, are fed into a Bayesian interactions are also very sensitive inference system for complex indicators of mental health. Thus, interpretation and decision making. an important challenge for our We use machine-learning techniques behavior modeling technology is to to record raw sensor measurements build computational models that we and create statistical models of users’ can use to predict the dynamics of behavior and the surrounding context. individuals and their interactions. Most commonly, we use hidden Markov The number of parameters is models —which are also the basis a significant factor in a model’s of speech recognition systems—for learnability and interpretability. behavior modeling. We have used this The requirement for minimal approach to build systems that use parameterization motivated our sensor measurements of hand motions development of coupled hidden to perform real-time recognition of Markov models (CHMM) to describe American Sign Language and even interactions between two people, to teach simple T’ai Chi movements where the interaction parameters [3]. Typically, these systems have are limited to the inner products vocabularies of 25 to 50 gestures and a of the individual Markov chains

[6]. As a practical matter, a CHMM is 5.1 Medical monitoring and limited to the interactions between two Feedback people. We have therefore begun using Healthwear promises to be especially a generalization effective for monitoring medical of this idea, called the “influence model,” treatments. Currently, doctors which describes the connections prescribe medications based on between many population averages rather than Markov chains as a network of convex individual characteristics, and they combinations of the chains [7]. This check the appropriateness of the allows a simple parameterization in medication levels only occasionally— terms of the “influence” each chain and expensively. With such a data- has on the others, and we can use it to poor system, it is not surprising that analyze complex phenomena involving medication doses are frequently interactions between large numbers of over- or underestimated and that chains. unforeseen drug interactions occur. To apply the influence model to Stratifying the population into human networks, we have extended the phenotypes using genetic typing can original formulation to include hidden improve the problem, but only to a states and to develop a mechanism degree. Continuous monitoring of for learning the model’s parameters motor activity, metabolism, and so on from observations [8]. Modeling human can be extremely effective in tailoring behavior this way allows a simple medications to the individual. parameterization of group dynamics in For example, consider Parkinson’s terms of the influence each person has patients. For them to function at on the others, and we have found that it their best, their medications must provides a sensitive measure of social be optimally adjusted to the diurnal interactions. variation of symptoms. For this to occur, the managing clinician must have an accurate picture of how the 5. Healthwear Application patient’s combined lack of normal Several ongoing projects hint at the movement (hypokinesia) and disruptive capabilities healthwear will offer. These movements (dyskinesia) fluctuates applications include medical monitoring and throughout a typical day’s activities. To feedback systems for those with chronic achieve this, we combined the MIThril medical conditions, monitoring social system’s wearable accelerometers networking to reinforce healthy behavior, with standard statistical algorithms and mental monitoring to detect the to classify the movement states of symptoms of depression or dementia. Parkinson’s patients and provide a timeline of how those movements fluctuate throughout the day.

Two pilot studies were performed, reminder requests but which cannot consisting of seven patients, with the goal of know the user’s context. assessing the ability to classify hypokinesia, Perhaps the major obstacle to dyskinesia, and bradykinesia (slow this vision is that people resist being movement) based on accelerometer data, reminded to exercise, take their clinical observation, and videotaping. Using medicine, or skip that extra helping the patient’s diary as the gold standard, the of dessert. Subliminal memory aids— result was highly accurate identification of visual and audio reminders that lie bradykinesia and hypokinesia. In addition, just below the user’s threshold of the studies classified the two most important perception—may offer one way around clinical problems—predicting when the this problem. Our research shows that patient “feels off” or is about to experience under the right conditions, subliminal troublesome dyskinesia—perfectly [9]. text or audio cues can jog the memory much like overt cues even though 5.2 Memory Glasses the person receiving the cues is not Regardless of age, we’ve all had our aware of them. In one experiment, for moments of forgetfulness. We accept such example, subliminal text cues improved memory lapses as human fallibility, but performance on a name-recall task by we would be grateful if researchers could 50 percent compared to the uncued find a way to cue our natural memory and control [11]. Perhaps more important help us overcome these lapses. Perhaps than this positive effect, our research such a device also could, for example, suggests that incorrect or misleading help improve an elderly person’s memory subliminal cues do not interfere with or provide critical cues for emergency memory recall. This contrasts starkly medical technicians, doctors, or firefighters with the effect of overt miscues, which in a nondistracting way. Toward this end, have a significant misleading effect. we are developing memory glasses that might someday help people with challenges ranging from complex memory loss to simple absent-mindedness. Figure 2 shows a prototype of this wearable, proactive, context-aware memory aid based on the MIThril platform and wearable sensors [10]. Memory glasses function like a reliable human assistant, storing reminder requests and delivering them under appropriate circumstances. Such Figure 2. Memory glasses. A wearable, proactive, a system differs qualitatively from a passive context aware memory aid, the memory glasses reminder system such as a paper organizer, system combines the MIThril platform with or a context-blind reminder system such as wearable sensors to provide a device that functions like a human assistant, storing reminder a modern PDA, which records and structures requests and delivering them under appropriate circumstances.

A practical system might use a Bluetooth consumption, socializing, or sleeping— connection between cell phones to healthwear increases the frequency obtain the names of nearby friends. Similarly, of these reminders. The system a combination of information about would not tell people something is location, proximity to others, time, and specifically wrong or describe why it surrounding sounds could assist in situation left a particular message, nor would recognition. The system could then use this it call the doctor except in extreme context information to trigger the appropriate circumstances, because doing so prompt, which would flash across the user’s could violate people’s privacy and glasses or be communicated through might actually interfere with proper an earpiece. If the system presented medical support. Instead, healthwear the prompt subliminally, users would not strengthens the social support network consciously process the reminder and so when the need is likely to be most would be unaware that the prompt was significant. jogging their memory. Thus, the subliminal prompts that the memory glasses provide 6.2 DiaBetNet would not interrupt a user’s daily routines. Children also need social support networks, and they tend to be 6. Social Networking extremely sensitive to social context. Reinforcing an individual’s social support We focused on this tendency when we system may be the most effective way to created DiaBetNet, a computer game encourage adopting more healthy behavior for young diabetics that uses belt-worn patterns. Thus, one aspect of healthwear’s motion sensors, a wireless Internet core functionality is interpersonal connection, and a standard PDA for communications supported by continuous an interface [13]. DiaBetNet capitalizes biomedical sensing [12]. on their passion for social games to encourage children with diabetes to 6.1 Embedded Social Networking keep track of their food intake, activity, Healthwear’s social networking capabilities and blood sugar level. answer broad and immediate needs. For A typical day in the life of a diabetic example, aging parents now commonly child using DiaBetNet would unfold live far away from their families. Healthwear as follows. In the morning, the child can help in such a situation by promoting clips his wireless accelerometer communication between family members and DiaBetNet case—with wireless when it senses a suspicious change in an Internet connection, PDA, glucose elder member’s behavior. In one version, meter, and wireless receiver for the healthwear occasionally but continuously accelerometer—onto his belt and goes leaves phone messages reminding grown off to school. Throughout the day, children to call their parents and vice the PDA records his activity from the versa. However, when a marked change in accelerometer, data from measuring behavior occurs—such as decreased food glucose and injecting insulin from the

glucose meter, and user-entered information over the four-week trial. Finally, more about food consumption. youth in the Game Group monitored At any time, the user can see a graph on their hemoglobin levels [14]. the PDA that summarizes the day’s activity, carbohydrate consumption, and glucose 6.3 Mental Monitoring data. From time to time, a wireless Internet Healthwear technology also can assist connection sends this data to a secure in the early detection of psychological central server. disorders such as depression. Even DiaBetNet is a group gaming environment though they are quite treatable, mental that requires guessing blood-sugar levels diseases rank among the top health problems worldwide in terms of cost based on information that wearable sensors to society. Major depression, for collect: The more accurate the answers, instance, is perhaps the leading cause the higher the score. For example, imagine of disability in established market that a user named Tom begins to play economies [15]. DiaBetNet with others on the wireless Researchers have long known that network. Transformed into his cherished speech activity can be affected in alias, Dr. T, Tom finds that his fellow players pathological states such as depression were all within 30 milligrams per deciliter of or mania. Thus, they have used guessing their blood sugar levels correctly, audio features such as fundamental but his guess was closer than anyone else’s. frequency, amplitude modulation, Tom challenges a DiaBetNet player called formant structure, and power Wizard and looks through Wizard’s data. distribution to distinguish between Although Wizard was euglycemic in the the speech of normal, depressed, morning, he ate a late lunch. Therefore, Tom and schizophrenic subjects [16]. decides that Wizard’s glucose level would Similarly, movement velocity, range, and frequency have been shown to be high and guesses 150 mg per dl. Wizard correlate with depressed mood [17]. guesses his glucose to be 180 mg per dl. In the past, performing such Tom wins again and grabs five more points. measurements outside the laboratory He shoots a brief conciliatory message to was difficult given the required his vanquished foe and signs off. In clinical equipment’s size and ambient noise. trials, 93 percent of DiaBetNet participants However, today even common cell successfully transmitted their data wirelessly phones have the computational to the server. The Game Group transmitted power needed to monitor these significantly more glucose values than the correlates of mental state. We also Control Group. The Game Group also had can use the same methodology for significantly less hyperglycemia—glucose more sophisticated inferences, such 250 mg per dl—than the Control Group. as the quantitative characterization of Youth in the Game Group displayed social interactions. The ability to use a significant increase in diabetes knowledge inexpensive, pervasive computational

platforms such as cell phones to monitor that these influence parameters are these sensitive indicators of psychological effective indicators of status within state offers the dramatic possibility of early a social network and the degree of detection of mental problems. coupling to the social network [20]. Perhaps the most sensitive measure of mental function is social interaction, which 7. Summary clearly reveals attitudes, emotions, and Judging from the adoption rates of cognitive function [18]. To investigate this advanced cell phones and wearable idea, we are using a MIThril-based device health tools such as pedometers, dubbed the sociometer to collect data about within this decade much of the US daily Interactions with family, friends, and population will likely have access to strangers such as: continuous, quantitative monitoring of • How frequent are the interactions? its behavioral health status, coupled with easily accessible biosignals. • Are the interactions energetic or How will this change our lives and our lethargic? society? An exciting possibility is that Are the interactions appropriate without with the widespread adoption of long gaps or frequent interruptions?Using healthwear, researchers could, for the these sociometers we collected almost first time, obtain enough data to really 1,700 hours of interaction data from 23 understand health at a societal level. subjects. Participants in this study also filled For example, correlating a continuous, out a daily survey that provided a list of their rich source of medication data from interactions with others. The sociometer and millions of people could make drug conversation-detection algorithms classified therapies more effective and help 87.5 percent of the conversations as medical professionals detect drug greater or equal to one minute, a far greater interactions more quickly. If correlated accuracy than achieved using the survey with medical conditions, the data method. could illuminate the etiology and The few conversations that the automatic preconditions of disease far more sociometer method missed typically took powerfully than is possible today and, place in high-nise,multiple-speaker situations further, serve as an early warning [19]. Once collected, researchers can use system for epidemic diseases like the influence model, a statistical framework SARS. that is a generalization of the hidden Comparing the medical data Markov models commonly used in speech with genomic and protonomic data recognition, to model the interaction data. from different population samples Modeling spoken behavior this way allows a could provide a powerful method for simple parameterization of group dynamics understanding complex gene and in terms of the influence each person has environment interactions. However, on the others. Our initial experiments show when considering the effects of

healthwear systems, we would be wise to [2] V. Gerasimov, Every Sign of Life, recall Marshall McLuhan’s dictum that “the doctoral dissertation, Dept. Media Arts medium is the message.” The way in which and Sciences, MIT, 2003. a new technology changes our lifestyle may [3] T. Starner, J. Weaver, and A. well be more important than the information Pentland, “Real-Time American Sign it conveys. Healthwear will likely be Language Recognition Using Desk considered more personal and intimate than and Wearable Computer-Based Video, traditional health tools because it will form a Hidden Markov Models, IEEE Trans. constant part of a user’s physical presence. Pattern Analysis and Machine Vision, Psychological studies have shown that Dec. 1998, pp. 1371-1375. clothes do indeed make the man. [4] A. Pentland, “Smart Rooms, Smart Thus, healthwear will not only be part Clothes,” Scientific Am., Apr. 1996, pp. of what the user wears but part of who 68-76. that user is. Body-worn technology will [5] S. Basu, Conversational Scene likely change our self-perception and Analysis, doctoral dissertation, Dept. of self-confidence in ways that are today Electrical Engineering and Computer unpredictable. While it could be more Science, MIT, 2002. effective at promoting healthy behavior than [6] N. Oliver, B. Rosario, and A. traditional approaches, healthwear also Pentland, “A Bayesian Computer could be more seriously abused. However, Vision System for Modeling Human with more than one billion cell phones Interactions,” IEEE Trans. Pattern already being worn every day, there is Analysis and Machine Intelligence, no escape from being absorbed into this Aug. 2000, pp. 831-843. far more intimately connected new world. [7] C. Asavathiratham, The Influence Our goal now should be to design this Model: A TractableRepresentation for technology to make that world a very human the Dynamics of Networked Markov place to live. Chains, doctoral dissertation, Dept. of Electrical Eng. and Computer Science, Acknolwedgements MIT, 2000. An earlier version of this article was [8] T. Choudhury et al., “Learning published in the May 2004 IEEE Computer Communities: Connectivity and magazine, and is reprinted here by Dynamics of Interactive Agents,’’ Proc. permission. Int’l Joint Conf. Neural Networks, Special Session References on Autonomus Mental Development, [1] R. DeVaul et al., “MIThril 2003: IEEE Press, 2003, pp. 2797-2802; Applications and Architecture,” Proc. 7th http://hd.media.mit.edu. Int’l Symp. Wearable Computers, IEEE Press, 2003, pp. 4-11; www.media.mit.edu/ wearables.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 442 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

[9] D. Klapper, Use of a Wearable Ambulatory [17] M.H. Teicher, “Actigraphy and Monitor in the Classification of Movement Motion Analysis: New Tools for States in Parkinson’s Disease, master’s Psychiatry,” Harvard Rev. Psychiatry, thesis, Harvard-MIT Health Sciences and 1995, vol. 3, pp. 18-35. Technology Program, 2003. [18] P. Franks, T.L. Campbell, and C.G. [10] R. DeVaul, Memory Glasses: Wearable Shields, “Social Relationships and Computing for Just-In-Time Memory Support, Health: The Relative Roles of Family doctoral dissertation, Dept. of Media Arts Functioning and Social Support,” Social and Sciences, MIT, 2004. Science [11] R. DeVaul, V. Corey, and A. Pentland, & Medicine, Apr. 1992, pp. 779-788. “The Memory Glasses: Subliminal vs. Overt [19] T. Choudhury and A. Pentland, Memory Support with Imperfect Information,’’ “Modeling Face-to-Face Proc. 7th Int’l Symp. Wearable Computers, Communication Using the Sociometer,” IEEE Press, 2003, pp. 146-153; www.media. W9 Workshop, Proc. Int’l Conf. mit.edu/wearables. Ubiquitous Computing, IEEE Press, [12] M. Sung and A. Pentland, “LiveNet: 2003, pp. 3-8; http://hd.media.mit.edu. Health and Lifestyle Networking through [20] T. Choudhury, Sensing and Distributed Mobile Devices,” tech. report TR Modeling Human Networks, doctoral 575, MIT Media Lab, 2003; http://hd.media. dissertation, Dept. of Media Arts and mit.edu. Sciences, MIT, 2003. [13] V. Kumar et al., “DiaBetNet: Learning and Predicting Blood Glucose Results to Optimize Glycemic Control,” poster exhibit, 4th Ann. Diabetes Technology Meeting, Atlanta, 2002; www. diabetestechnology.org. [14] V. Kumar, The Design and Testing of a Personal Health System to Motivate Adherence to Intensive Diabetes Management, master’s thesis, Harvard-MIT Health Sciences and Technology Program, 2004. [15] C.L.J. Murray and A.D. Lopez, The Global Burden of Disease, Harvard Univ. Press, 1996. [16] D.J. France et al., “Acoustical Properties of Speech as Indicators of Depression and Suicidal Risk,” IEEE Trans. Biomedical Eng., July 2000, pp. 829-837.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 443 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

David Andre, Chapter 49: Health. Care. Anywhere. improvements in wireless technology Astro Teller / Today. will manifest the future of health Health. Care. Anywhere. David Andre, Ph.D. and Astro Teller, Ph.D. care as personal, ubiquitous, and Today. in Director of Informatics and CEO, respectively, collaborative. World Health BodyMedia, Inc, Pittsburgh, PA, USA Strategy” 1. Introduction eBook, www. Futureofhealth. Abstract In 2005, the United States spent org (Ed.) hat if clinical quality medical approximately 1.8 trillion dollars on Renata G. equipment were available to healthcare. Of this, approximately 0.6 Bushko, every consumer in a form factor trillion can be attributed to diseases FHTI, 2016. W Intelligent and that was inexpensive, accurate, and easy or conditions caused by the genetic Extelligent to use? What if this equipment provided makeup of the patients. Approximately Health information that previously was un- 1.2 trillion is attributed to poor lifestyle Environment measurable or very difficult to measure? choices – people not taking care (Ed.) Renata G. Bushko, IOS What if the physiological state of individuals, of themselves. Despite this at most Press 2005 at resolutions measured in thousandths of 9 billion (0.5% of the total) dollars a second instead of in visits per year, could were spent on helping people better be measured easily, making it possible to manage their health. Why is this? ascertain caloric intake and expenditure, Certainly, convincing people to change patterns of sleep, contextual activities such their behaviors is difficult, but a large as working-out and driving, even parameters part of the problem is that you can't of mental state and health. What aspect of manage what you can't measure. You healthcare wouldn't change? We present a wouldn't try to fly an airplane without system that is available today that enables instruments, but most people try to this vision. This award-wining multi- navigate their lives without a channel wearable physiological monitor dashboard for their bodies. Most has enabled the collection of more than 90 traditional devices for measuring million minutes of data in natural settings physiological signals are large, bulky, from thousands of subjects engaged in and expensive. Polysomnography diverse activities. Data modeling efforts machines [1] measure how well a are resulting in applications that present patient sleeps, but require a (probably meaningful and actionable information in restless) night in a sleep clinic with real-time to users and their designated many wires and electrodes glued to collaborators (physicians, family members, their bodies. Measuring energy counselors, coaches, etc.) We describe expenditure requires an indirect the SenseWear system, its design, and calorimetry machine [2], and although a summary of validation studies, current some are becoming more portable, commercial applications, and ongoing they require breathing into a tube and research. This discussion will show how carting around heavy equipment for the convergence of design for wearability, the analysis. advances in machine learning, and Surely, however, the advances in

miniaturization and electronics can provide story about data and data analysis, as medical devices and computers that are much as it will be a story about form smaller, cheaper, more sophisticated, and factors and size reduction. The more personalized [3, 4, 5]. On the physical monitors are conduits to these computing side, this push has culminated distilled facts about our bodies, not the today in the explosion of handhelds (mobile value in and of themselves, just as phones, iPods, gameboys, digital cameras, mobile phones are the conduits for PDAs, etc.) as the new computing platform— wireless spoken communication cheaper and more sophisticated enabling between people. But even more than smaller and more personal interactions. On portability for mobile phones, the medical side, similar advances have wearability is a requirement for been made. Watches with ambient physiological sensors. If you can’t temperature sensors and glucose monitors, stand wearing it, you won’t wear it. And heart straps for joggers, pedometers for that means that the constraints of dieters, etc. [6, 7, 8, 9]. There are clinical wearability in the most physical and body monitors your doctor can prescribe practical sense, the constraints of and your nurse can administer such as where sensors can gather useful holter monitors and ambulatory blood information on the human body, and pressure cuffs. These devices are becoming the constraints of wearability, sociology wireless and less dependent on and fashion all need be attended to for professionals for their application. More and this vision to be realized. more they are providing the means to Fundamentally that means that the transmit information back to caregivers lines between design (industrial, quickly and seamlessly. So is that all that is mechanical, product, communication) required? No. The killer applications are just and traditional engineering (e.g. starting to emerge; applications from weight electrical engineering, software management to fitness to disease engineering, biomedical sensing, and management. But the critical element in all data modeling) will continue to blur as of these areas is the interpretation and the ubiquitous, pervasive, and presentation of the data. collaborative computing revolutions Wearable body monitoring goes from manifest a future of computing and delivering potentially interesting data to healthcare that is wearable, personal, delivering life altering information when it and sympathetic. does enough of the data analysis to provide This chapter will discuss the design, consumable, actionable nuggets of body current applications, and future of the knowledge automatically to wearers and SenseWear system. The first sections their overseers. This is the difference will describe the sensors, hardware, between the sheet music and the violin software and the design parameters concerto, the difference between the and capabilities that enable the haystack and the needle. In that sense the tracking of multiple channels of future of wearable body monitoring will be a physiology at resolutions up to 32 Hz,

in natural settings, for extended time acceptability. The design of a product periods, with high degrees of comfort. The that is to be in continuous contact with sociological challenges of introducing the human body twenty four hours a physiological devices and new models of day is to design for an extreme human health metrics to medical research environment. People carry all sorts of and to consumers will be discussed. This will devices around with them every day, be followed by an introduction to the data- such as PDAs, cell phones, wallets, mining prediction and classification that wrist watches, etc. BodyMedia first had underlie the utility of the SenseWear system, to ask what makes people comfortable along with a discussion of the value of and then design all the electronics, context for interpreting physiological sensors, and packaging around those measurements. Finally, a promising and human needs. Through the creation of diverse array of research findings and a multi-channel, ergonomic and ongoing initiatives will be summarized. durable sensor hub, individuals who would otherwise be tethered to 2. The SenseWear system. machines are being granted greater As mentioned in the introduction, a device freedom. For others, they opt to wear that can begin to transform health care must the device, though they would never meet two difficult criteria. It must provide have been suffered the annoyance medically accurate data about a person's life and cost of a lab device, because the but be designed well enough that it is device provides them benefits worth unobtrusive and easy to wear. The system the effort to wear it. In the must be simple enough for the consumer development of SenseWear, but provide information useful to the BodyMedia prototyped a number of healthcare professional. Although devices ranging from chest straps to BodyMedia, Inc has several wearable body smart rings. These prototypes and the monitoring products, this chapter focuses on development of the design criteria its SenseWear system, which includes a were informed by studies on wearable wearable armband that senses acceleration, computing and medical devices such heat flux, galvanic skin response, and as those used for sleep apnea temperature and records the data and research, actigraphy measurements, derived measures over that data for later the accuracy of accelerometers for presentation to the user. energy expenditure measurements, and on materials such as elastic straps 2.1. Designing a physiological computing [10, 11, 12, 13, 14, 15]. The criteria for the device for everyday use SenseWear Armband included that it The design of a wearable physiological had to: accurately work for up to two computing device is an effort in finding the weeks under continuous use (24/7); synergy among competing criteria ranging work during active athletic and work from physiological accuracy to comfort, and situations as well as during sleep; be mechanical engineering to social easy to manufacture and robust

enough to survive everyday use in low (0 ˚C) comfortable, very easy to use, something and high (45 ˚C) temperature environments; be that blends into your life so you forget it is small enough to keep the overall monitor height there. In a case study, a high school and footprint unobtrusive beneath clothing; be student wearing the monitor for two weeks non-invasive and non-irritating to the skin and said, “You kind of get used to it and don’t hypoallergenic; have extremely low power even know you’re wearing it.” [16]. consumption; and be cost effective. To meet these objectives the area of the body where the device would be worn had to be: similar in size and shape on men and women between the 5 and 95% size range; relatively large in surface area (at least 2 in. by 3 in.) to accommodate the required components, including batteries and electronics; low in mobility (non-bending or stretching even during high activity); and have a continuous circumference for easy attachment and detachment. Fig. 1 shows how the upper arm meets many of these criteria. It is unoccupied ‘real estate’, gender-neutral, least obtrusive and Figure 1.Wearability maps for heat flow, GSR, low in the number of collisions, a relatively soft acceleration, heart rate, and temperature. area where a device can be worn comfortably, and is generally concealed by clothing. On the 2.2. The SenseWear Pro2 wearable upper arm it is also the case that device weight body monitor in this area does not induce fatigue and an The SenseWear Pro2 Armband is a adjustable strap accommodates a one size fits sensor hub worn on the back of the all design. upper right arm (tricep area, Fig. 2) [17]. Many of the objectives were met through It enables continuous collection of low- engineering novel design features. The level physiological vital sign streams symmetrical flexible wings (shown in Figure 2) and derives from those accurate stabilize the device, accommodate diverse arm statements of human body states sizes, and create sufficient pressure for the and behaviors. The device contains sensors to function. A proprietary hypoallergenic five different sensors. A two-axis and non-latex elastic strap was developed for accelerometer tracks the movement appropriate tension and repeatable attachment. of the upper arm and provides Iterative user testing was conducted with information about body position. A hospital patients, football players, factory proprietary heat-flux sensor measures workers, rescue workers, firefighters, and the the amount of heat being dissipated general public. The goal in making this by the body by measuring the heat wearable device was actually to make it as loss along a thermally conductive invisible to the user as possible. Very path between the skin and a vent on

the side of the armband. Skin temperature The raw data values can be retained and near-armband temperature are also (reducing the recording time, of course) measured by sensitive thermistors. The through a simple software switch. armband also measures galvanic skin Enclosed in a shock and splash response (GSR – the conductivity of the proof thermoplastic housing, the wearer’s skin) which varies due to sweating monitor straps to the user’s right upper and emotional stimuli. The unit also contains arm. At 0.8 in. tall by 3.4 in. long and a wireless chip and can communicate 2.1 in. wide, the housing squeezes wirelessly with scales, blood pressure under all but the tightest shirtsleeves cuffs, and other medical systems. It can with barely a bulge. As it is wearable transmit collected sensor data with 916 MHz and unobtrusive, the Armband ‘sees’ wireless body-LAN connectivity to a wireless people in the context of their natural communicator unit with <1 mW power daily activities rather than from the output. The armband is made of flexible constrained viewpoint of a laboratory. ABS, attaches with an elastic Velcro strap (custom designed to have stretch, air/water 2.3. What SenseWear senses is not permeability, and hypoallergenic properties what it reports so as to mimic the skin to the greatest extent Having multiple sensors is very possible), weighs less than 3 oz., stores important to the success of the 14 days of continuous body data and has armband and its ability to accurately enough power for 14 days of continuous monitor the physiological states of the wear from a single AAA battery. Using a wearers. Multiple sensors allow for 4MHz MSP chip from Texas Instruments it the disambiguation of contexts that transforms the raw physiological data such might confuse a single sensor. For as movement, heat flux, skin temperature, example, if a wearer’s motion is high, it near-body temperature, and galvanic skin might be due to exercising or to being response into snapshots of the user’s life. in a moving vehicle. However, the Each sensor is monitored 32 times signatures of temperature, sweat, and per second, and data is tracked over heat flux are typically quite different a period of time (typically a minute but for exercise and being in a car. The this can be adjusted through software). algorithms in BodyMedia’s software Currently, 41 different features of this multi- utilize the physiologic signals from all dimensional raw data stream are gathered the sensors to first detect the wearer’s as separate channels. For example, the context and then apply an appropriate variance of the heat flux is a channel, as is formula to estimate energy expenditure the average of the heat flux values. Some from the sensor values. The armband channels are fairly standard features (e.g. can recognize many basic activities standard deviation) and others are complex such as weight-lifting, walking, running, proprietary algorithms. Then typically, these biking, resting, and riding in a car, bus, summary features for the epoch are stored or train. Other activities are classified and the raw data discarded to save memory. into combinations of these basic

activities; for example, baseball could be developed for energy expenditure, broken down into a combination of mostly sleep, physical activity, and the set of near-restful activity and running. Key to activities mentioned above: weight- the armband’s utility is that it can be worn lifting, walking, running, biking, resting, comfortably during a person’s normal and riding in a car, bus, or train. life, and does not require any time in the laboratory for uncomfortable measurements. 2.4. Wireless technology The SenseWear system includes a 916 Mhz wireless technology that allows the armband to communicate securely and wirelessly with other devices including computing devices (PCs, PDAs), display devices (watches, kiosks), and other medical devices (blood glucose meters, weight scales, blood pressure cuffs, pulse oximetry meters). BodyMedia has enabled these devices with the SenseWear Fig. 2. SenseWear Armband front with time stamp Transceiver (Figure 3), allowing them to button, back showing sensor interface, and shown communicate with the armband. Users on arm. can take their measurements on these The algorithms are all created using a other devices, press the button on proprietary algorithm development process the armband, and the measurements that utilizes a data-driven machine learning are stored in the armband along with approach. Data is first collected at clinical the data it records itself. All of the sites with laboratory equipment such as recorded data can then be transmitted metabolic carts or metabolic chambers. to a PC via a wireless communicator Next, compressed channels are created (Figure 4) that connects to USB port from this raw data that can stored on the on the PC. Alternatively, the data can armband that are useful for determining both be uploaded to a web-server via a the wearer’s activity as well as measures wireless gateway (Figure 5) which such as energy expenditure or sleep state. contains either a standard or cellular After this, context detectors are developed modem, depending on the application. that classify the wearer’s context. Finally, for each context, a specific algorithm is created using automated machine learning techniques to predict the measure of interest (such as energy expenditure). Section 5 describes the algorithm development process in more detail. At this point, accurate algorithms have been

Figure 3. The SenseWear BioTransceiver that Figure 5. A platform for immediate and remote allows medical devices to communicate with the body monitoring armband. 3. Current Applications of the SenseWear system The thing that is really going to change society with respect to health care, wellness and fitness is the ability for people to start to learn about Figure 4. The SenseWear Wireless Communicator themselves. BodyMedia’s design (left) and Wireless Gateway (right) allow mantra is, ‘make it fun and meaningful communication with a PC or a web-server. to see how you feel.’ The BodyMedia platform creates a feedback loop: This ability to communicate with different people want to manage their own devices allows the user to receive health but until now, trying to do it feedback anywhere – whether on the go, was like dieting without a scale. The at their home, or in their doctor’s office. feedback loop is the presentation of Furthermore, their trusted health advisors actionable information that is otherwise (e.g. friends, nurses, nutritionists, coaches, unavailable to them (e.g. sleep/awake physicians) can look at the information on states each night down to a per minute a printed report given to them by the user, basis if desired). This information online, or on their own PC. Figure 10 shows allows people to assess progress a representation of the entire system, with toward their health goals. There are the armband serving as a hub for information numerous applications that can be that is reported to the web, to a PC, to a supported once data is being tracked. custom remote device (such as a baby People could track elements of their monitor), to a cellular phone, or to a watch health as closely as they track their display. financial portfolios. Having baseline data from an aggregate population and

from individuals themselves, it is becoming summaries, and detailed information possible to flag individual anomalies and about the sensor values that were detect potential health problems. recorded. Figure 6 shows a report, The armband interface is highly with one screen showing totals, daily customizable. It can be programmed to totals of energy expenditure, steps beep or vibrate when calorie-burn targets taken, amount of sleep, amount of are met or as a reminder to take medicine. lying down, and amount of physical It is a communications ‘hub’ collecting and activity. For example, you can see transmitting data from multiple devices that David played soccer on Monday worn on the body, all toward the goal of and went snowboarding on Friday keeping the wearer alert to danger signals from these graphs. The lower part of and mindful of health necessities. This the figure shows the software’s ability system provides comprehensive, actionable to display detailed information. You feedback about a person’s body and can see at the top of this part of the lifestyle that can be shared with researchers, figure an auto-journaling of Friday and physicians, dieticians and personal trainers Saturday, showing when David was via the Internet (Fig. 7). Internet applications physically active, was motoring (in a can allow consumers to enter additional moving vehicle), sleeping, sedentary, data such as calories consumed and body and lying down. The bottom of the fat measurements to add further meaning graph shows a minute by minute plot to the body data gathered from their of energy expenditure, heat flux, and armbands. BodyMedia’s goal is to help skin temperature. The sensor values people become more aware of themselves shown in the report are configurable in in ways they have never done before and the software. have a fun and engaging time doing that. The Innerview Research Software One opportunity that has significant benefits has been used at thousands of sites for is to employ a human relationship such as a variety of purposes. Some of these that with a physical fitness trainer. Similarly include to analyze exercise physiology Debra Tate showed that the combination data, serve as a measure for tracking of online information and regular feedback medical conditions such as pain or from a coach along with the ability to self- physical activity during recovery from monitor diet and calorie estimates resulted surgery, examine skin temperature in preliminary successes [18]. in soldiers, build emotion-detecting The SenseWear system has been algorithms from the data collected by deployed in several applications to date. the armband [19], analyze a person’s The first application was a research software reactions to architectural spaces package called the Innerview Research [20], and as a variable in longitudinal Software that was designed for researchers studies of disease causation. Other and clinicians to use. This piece of applications have included the study software offers the ability to customize the of sleep behaviors, competitive sailing, armband’s recording rates as well as reports, human computer interactions, and

stress response in car and tank drivers. a subject with Sydenham’s Chorea. Groups studied range from professional Sydenham’s Chorea is a childhood athletes to the elderly to children. The disease that causes rapid and frequent products have survived intact in extreme involuntary movements but is benign in environments such as Mt Everest, the North that spontaneous recovery will occur Pole, the South Pole, the highest lake in the in a few weeks. This subject was world, the Pittsburgh Steelers training camp, treated with antibiotics, steroids, and and National Guard live firefighter training antiepileptic therapy. At the outset, sessions inside burning planes. the subject was burning 1910 kcals/ day as measured by the armband, with frequent involuntary muscle movements. In the following few days, the subject burned fewer and fewer calories per day as measured by the armband and additionally scored lower on several indicies (TAS, flogosis) of the progression of the disease. After six days, the subject was nearly back to normal, with only minimal choreic movements in the limbs. Blood tests revealed normal TAS and flogosis levels and the armband showed only 1400 kcals/day expenditure. At day 10, energy expenditure as measured by the armband increased in conjunction with some reappearance of symptoms. The SenseWear system with the Innerview Research Software is being increasingly used in clinical situations in Europe. In addition to the Innerview Research software, the SenseWear Figure 6. Reports from the Innerview Research Software system is utilized by several commercial web applications to A case study such as the following can address issues of wellness, weight- help to illuminate the power of this kind loss, and fitness. Apex Fitness and of free-living body information. Using the BodyMedia launched bodybugg (a Innerview Research Software, Perini et al private labeling of the BodyMedia [21] investigated the relationship between technology) to the general public physical activity estimates and energy in the US at the start of 2005. On expenditure estimates with the recovery of a daily basis, the bodybugg weight

management system (the left side of Figure 7) monitors and calculates a patient’s caloric intake and expenditure and returns to both the patients and their care providers the difference between the two as the patient’s day-by-day caloric balance. In providing this information, bodybugg is a weight management system that uses the continuous monitoring and collecting of physiological data to show the effect that lifestyle has on weight loss. Depicting calories burned, calories consumed, activity duration, and steps per day, the product strives to increase personal awareness of health and parameters of weight Figure 7. The bodybugg web application. management. The ability for a third-party to view the data (in this case, the personal trainer or Fitness Professional) provides the user with a greater sense of integration and allows the third-party to give significantly better feedback. The bodybugg program (www.bodybugg.com) has thousands of users and is growing quickly. Other variants of weight-management software have also been developed. One such system, designed for clinical weight management and diabetes management, has been piloted since 2003 with great results, with many subjects losing weight Figure 7a. The Wellness Project web application. – even as much as 80 pounds. Another related application is The Wellness Project. One question many have when first This variant focuses on meeting calorie encountering the armband is whether burn, step, and physical activity duration people will actually wear the armband goals in the context of an online community over long periods of time. Fig. 3 setting. Groups can compete amongst illustrates the amount of time users of their members or among different groups. the device actually wore it. That 83% The right side of Figure 7 shows this web of users wear it for more than 7 hours application. a day is a testament to the wearabilty

of the device. To the extent that industry But the ability to put very small and commercial review is an indicator of high performance computers on the reaching the goals for appropriate design, human body in natural environments the SenseWear system has won both the over long periods of time has opened Industrial Design Excellence Award and the a new avenue. That avenue is the Medical Device Excellence Award [22, 23]. modeling of human health through the In fact, it is interesting that BodyMedia is the modeling of the data given-off by the only company in the world ever to win top human body, often without any initial honors in both of these awards for the same deep understanding of why that data is product platform. what it is. In Section 6, evidence will be presented that this method is accurate in powerful, valuable, and broad ways. But first, asks the skeptic, “Is this even good science?” “Should this even be allowed to count as a model of human health?” Science is the making of models of the world and the testing of those models to show their predictive value. A model is nothing other than a simplification of the world, ideally reducing non-essential aspects of the world and retaining just those elements that are ‘useful’ (that are required for accurate predictions to be made). The ‘models’ or algorithms that BodyMedia constructs are 4. The sociological context of the modeling of human mathematic simplifications of large health amounts of raw data gathered with its

devices, gathered in the presence of 4. The sociological context of the medical gold-standard lab equipment modeling of human health (such as metabolic carts (Fig. 8) or Traditionally, models of human health have polysomnography machines) [2, 1]. been models of how the human body works. Ideally, these algorithms have captured That the previous sentence sounds like a the underlying trends in the data so tautology exposes how deep the bias goes that when worn by a person not in the that you cannot model human health without presence of medical gold-standard modeling how the human body works. equipment, the result a BodyMedia This bias is understandable since until device returns accurately predicts very recently there did not seem to be any what the medical gold-standard lab alternative. equipment would have returned in

the same situation. So these are models real-time or long-term body monitoring of human health. They just happen to be in natural environments involves tens models of what the body is doing rather than of thousands of times as much data as why it is doing it. These models are tested the current models of human health against the very same yardstick as classic are built upon (periodic readings of models of human health: their ability to blood pressure, cholesterol, bone accurately predict what is happening to the density, etc.). Kuhn [24] describes the body in question. institutional adoption of new paradigms as a 25-year process; and it took the medical community the better part of a century to build a set of models of human health around this data. So waiting for a community, even one as smart and as dedicated as todayâ€™s medical community, to build this next generation of models as we move, metaphorically, from physiologic snap shots to physiologic movies, is not realistic. The second issue is that statistical mathematical models are built by trying to minimize some error function with respect to the predictions that connect the dependent axes (the Fig. 8. Metabolic cart in a lab setting. inputs, which are in BodyMedia’s case the raw data measured many The next natural question, once the times per second by the SenseWear legitimacy of the method has been satisfied, Armband) to the independent axis (the is the real value of the method. There is a output, the predicted value, in this case prevalent assumption, in both the medical BodyMedia derived values such as industry and the general public, that any sleep state, calories burned in the past model built or â€˜learnedâ€™ by a machine day, body position, etc.). Assuming that (as all statistical mathematical models are the data has been properly collected to some degree) could not possibly be as (an assumption that is necessary accurate, or as useful as a model built by a for verification in all model building person. More specifically, there is often an exercises) the people and situations unarticulated assumption that when these on which these mathematical models models are wrong they will be wrong in are built and tested represent the much larger or much more problematic ways conditions that happen the most often than equivalent models built by a person. or are the most important to predict The first response to these concerns is that correctly. Models such as the ones

built by BodyMedia are constructed explicitly commonly called supervised machine to minimize these errors when applied to learning in the computer science unseen subjects. This cannot honestly be community. said for more traditional models of human The process of supervised machine health because they have, as an additional learning is the building of a model in constraint, that the model is understandable some chosen representation (such as to the researcher building the model. The an artificial neural network, a decision case can be made that special cases not tree, or a probabilistic network). Input seen during the training and testing phase signals are collected in the presence of a statistical mathematical model may be of the labels to be predicted by the predicted incorrectly in the real world. Of model being learned. This set of input course, when these same special cases are signals and labels is often referred withheld from human researchers building to as the training set. These labels more classic models of human health, the are usually either classifications (e.g. same risk for a model that miss-predicts in ‘Astro was jogging between 2 and 3 these same situations exists. pm’) or regression values (e.g. ‘Astro’s level of energy expended in the 5. Data modeling, data mining and sensor past minute was 5.65 kcals’). These fusion from multi-sensor streams labels are treated as ground truth ‘Bioinformatics,’ is the intersection of though in practice there is almost life science and computer science. The always some error in them. Statistical SenseWear system allows for the gathering machine learning techniques (e.g. and interpreting of multiple streams of vital back propagation in the case of an sign data which is then used to derive artificial neural network) are then used statements about the human body, such as to create, train, or ‘learn’ a model such calories burned, sleep, and activity type. The that the model accurately relates the fundamental insight for BodyMedia is this— inputs to the known outputs (labels). instead of monitoring individual parameters These techniques often search (symptoms) that healthcare institutions through possible model frameworks are used to looking at—blood pressure, to find the best one. The models are pulse oximetry, cholesterol level and so compared using methods such as on—BodyMedia monitors lower level vital statistical bootstrapping and cross- signs many times a second, and then builds validation, which measure the ability mathematical models of the data collected. of the model to generalize to unseen These models are built in the context of the data. After the best model is selected, ‘right answers’ from medical gold standard it is evaluated on a completely unseen equipment such as metabolic carts for set of data. energy expenditure or polysomnography There is considerable science for sleep states. This process of building in picking from existing model mathematical models goes by several representations or making a new names in different disciplines, but is most representation when going through

this supervised machine learning process. (the inputs in our discussion above), In addition, it is often the case (as it is with around 10 million min of that data have BodyMedia) that the predictions are not been explicitly labeled as to their made by single classification or regression classification (e.g. ‘lying in bed’) or their models, but by hierarchical or networked level (e.g. stage 2 sleep according groups of these models. For example, for to the polysomnography machine). a stream of vital sign signals collected by These 10 million min of streaming the SenseWear Armband, a first model physiological data have been accrued might attempt to classify the kind of activity from over 500 subjects with over 120 represented by these signals (e.g. jogging, different labeled activity types. biking, resting, sleeping, etc.). Then, for each Figure 9 shows the rate at which of these particular activities, a specialized this data stream is increasing. The model has been built that is particularly advantage of receiving all of this good at rating some prediction problem data is that even where the data is (e.g. energy expended per minute) for not annotated or explicitly labeled, that particular kind of activity (e.g. biking). the data can be used to improve BodyMedia approaches the data modeling the algorithms – both by helping in process through a variety of statistical testing the algorithms but also through methods including symbolic modeling where semi-supervised learning techniques. expert knowledge exists (e.g. Decision Exactly because this data improves the Trees, Production Systems,etc), numeric algorithms, users have some impetus modeling to fill in gaps in expert knowledge to provide data, which can improve the (e.g. Neural Networks, Bayesian Networks), information they themselves receive state modeling for body states such as sleep from the system. This creates a states that shift in predictable ways (e.g. virtuous data cycle that encourages the Hidden Markov Models, Partially Observable use of the system and the contribution Markov Models), and clustering when all else of data toward the general good. fails or when labels are not available. The bottom line, however, is that for real world problems, what generally makes the most difference is the quantity and quality of the training data available to the models being learned. To date the combined time that users, researchers, subjects, and customers have worn SenseWear Armbands amounts to over 300 million min over the past 5 years. Data from approximately 100 million minutes, from over 3000 individuals, have been collected by BodyMedia to form a corpus of physiological data. Of those 100 million minutes of physiological data

are ambiguous when seen from the perspective of a single sensor. By choosing sensors carefully, a higher dimensional space of streaming vital signs can disambiguate these human body states, dramatically increasing what a wearable device can determine; and increase the accuracy of any indirect measurements derived from the lower-level vital signs. Fig. 10 shows a simplistic example of how multi-sensors can disambiguate human body states that would appear ambiguous to any single sensor. In this example, the challenge is to identify the type of state the human Figure 9. Hours of data uploaded to BodyMedia, by body is currently in. The use of day. multiple sensors can also help to more accurately capture the correct level from a particular category. For example in Fig. 11, a model that could see only the motion of a person would credit the person with a higher level of energy expended per minute during the ‘walk around the block’ activities rather than during the ‘climbing stair’ activities. This is, it turns out, generally false. And that can be seen by the model built by BodyMedia through the use of multiple sensors. Again in Fig. 11, we see that the rate the person is Fig. 10. Activity and condition map: sedentary, producing and releasing heat is higher vehicle, aerobic, resistance vs. fever characterized during the stair climbing activities and by heat, motion and heart rate. the models can take advantage of this additional information to more closely The next question many ask is approximate what a metabolic cart (one reasonably, ‘Are all these different of the medical gold standards on the parameters really necessary?’ The subject of energy expenditure) would challenge in real world (i.e. out-of-the- say under these same circumstances. hospital) body monitoring is that there In practice, these examples do not are a lot of states of the human body that capture the complexities the models

must address. For example, it is possible that if during a period sensor A is increasing and sensor B is decreasing, or vice versa, then the output should be judged to be increasing, but if both or neither of the sensors is increasing, then the output should be judged to be decreasing. This sort of relationship cannot be captured by any first order statistical models as the correlations between A, B, and the output are all zero. This conceptual example highlights the Fig. 12. Longitudinal and transverse demands on the models being learned to accelerometer data from the armband for capture arbitrarily complex relationships biking, running, driving, and office conditions in the data, not just linear trends. As an (in micrograms per millisecond).

example of this, in Fig. 12, examples from What does all this amount to in the four classes of human activity are shown. end? These learned models allows In all four cases, the two axes represent BodyMedia, with very high accuracy, two orthogonal dimensions of motion and to say to a new user who puts on a the points represent a trace in that two SenseWear Armband statements such dimensional space over two seconds. What as, “You burned 400 calories over the we see here are patterns that might be past hour” or “You were in bed for 8 thought of as ‘strange attractors’ that help hours last night, but you only slept for 5 to identify and differentiate these different hours and with frequent interruptions.” activities. These patterns are not just a The following table shows our current matter of the amount of motion per minute, accuracies for a set of new vital signs but the kinds or patterns of motion that occur we derive from the raw data. in sequences over short (or even over long) periods of time. Algorithm Accuracy Algorithm Accuracy Energy Error < 10% Lying Error < 1% Expenditure down duration Exercise Error < 3% Sleep Error < 3 Duration onset minutes Exercise Error < 5% Wake Error < 3 type Time minutes recognition Step count Error < 2% Sleep Error < 5% Duration Fig. 11. Sensor data from accelerometery and heat flux comparing flat walking and stair climbing. Sedentary Error < 3% Motoring Error < 5% duration Duration

Independent researchers have written many the beginning of a similar revolution as validation papers about the SenseWear a natural outcome of pulling additional system, especially with respect to comparing meaning from the long-term, detailed, energy expenditure measurements from objective and accurate views of the the system to estimates from gold-standard physical states of large numbers of laboratory equipment. These include tests people and transforming these into on normal individuals from 18 to 75 on a meaningful, desirable, and actionable variety of exercise equipment comparing applications. We envision utilizing this against indirect calorimetry, such as Jakicic data scientifically for data mining and et al [25], Fruin and Rankin [26], Wadsworth commercially as a resource for creating et al [27], and McClain et al [28], all showing and improving algorithms. It will be significant correlations. Several researchers possible to compare a user's data have examined disease-specific populations, with similar users, creating empirical such as cardiac patients [29] and patients definitions of what is the norm and with chronic obstructive pulmonary disease what is abnormal. These data mining [30], finding good results as well. In a very challenges and opportunities on large interesting preliminary study, Mignault et al collections of group data are in their [31] compare the armband to doubly labeled infancy, but an active area of effort for water over a ten day period. The subjects BodyMedia. were diabetics examined as part of a larger study. In these patients, the researchers 6. Research and development noticed no significant differences between directions the doubly labeled water technique and While there are many exciting on- the estimates from the armband. The going applications discussed above, correlations were extremely high (0.9696), BodyMedia is engaging in continued with a technical error of measurement of refinements to the platform and the only 104 kcal/day (less than 5%). The authors development of new body monitoring conclude: "... preliminary analyses suggest capabilities. These including the that the […] Armband is an acceptable device integration of new sensors and the to accurately measure total daily energy ongoing development of data models expenditure in type 2 diabetic patients over to extract new physiological features a 10-day period". and contextual activities. Some of Human body data, when aggregated, the areas that BodyMedia is focusing also has tremendous value beyond the on include: fine-grained sleep detail value of the individual statements to (e.g. Rapid Eye Movement); personal individual users. The revolution in the duress; fatigue, alertness, drowsiness; financial services industry over the past mental stress, anxiety; hydration, 30 years came as a direct result of the perfusion, homeostasis; surrogates access to and real-time analysis of the for glucose level; calories consumed world’s minute-to-minute financial vital signs. (when, and approximate quantity); Wearable physiological computing is just at biometric identification (‘finger printing’

based on personal biometrics); heart that ECG can only be observed using information taken solely on the upper arm; electrodes spaced on “either side” of and core body temperature prediction. the heart. Al-Ahmad, Homer, and Wang Efforts to make the device more unobtrusive [32] have presented preliminary results are also underway. of validating these prototypes, showing that the armband measures heart rate and beat-to-beat variability comparably to a Holter monitor. Preliminary results in incorporating heart rate information into the equations for energy expenditure are supporting McClain et al’s [28] finding that the incorporation of heart rate can reduce the error of the algorithms for certain activities. Fig. 13 shows a prototype of a new version of Fig. 13. A prototype version of a future BodyMedia platform for ambient computing. the device that incorporates heart-rate electrodes in a patch version of the For all of these areas, BodyMedia has armband. collected some anecdotal data and To accomplish many of these discovered, in many cases, compelling signs research goals for additional body that significant opportunities for armband- state prediction, further additional based monitoring exist. For example, in the sensors may need to be added case of measuring heart signals from the to versions of the body monitors upper arm, BodyMedia has discovered a made by BodyMedia. BodyMedia new, patent-pending, method of obtaining is experimenting with acoustic electrical signals from the heart solely from sensors; optical sensors, pressure electrodes placed on the upper left arm and barometric sensors; GPS digital continuously, and for extended periods of compass, and gyroscopic elements; time. This latest BodyMedia innovation ambulatory blood pressure; micro- can record ECG data from the upper arm, needles for the administration of as well as other locations on the human medication and sample collection; body previously considered impractical ambulatory pulse oximetry; by conventional standards, without wires, bioimpedance [33], and near-body adhesives, or other equipment. BodyMedia ambient air and environmental has integrated the technology into prototype sensors. The potential to increase the versions of the armband using one non- understanding of human physiology adhesive electrode and one adhesive in natural settings and humans’ electrode. Production of a non-adhesive physiological interactions with their system is underway. Their invention is environment is substantial particularly noteworthy because it challenges conventional wisdom in electro-cardiology .

7. Conclusions “how can we get accurate information As many pundits have commented, the from the body in a way users will current state of healthcare is problematic. love?” Given that users won’t wear Costs are skyrocketing and the current twenty different devices, we work to institutions are breaking under the load. build a single system that delivers Consumers are getting saddled with more value on multiple fronts from the same of the financial responsibility of their own piece of effort. Finally, we recognize healthcare. Dissatisfied with their options that continuous body monitoring and their care, many patients fail to comply is providing data that science and with the treatments and programs that can medicine haven’t seen before. We best help them. Patients and caregivers are working to build systems that alike have a hard time managing that which take advantage of these increasingly they can’t see – and it is exactly those things large data streams both to better help that go unmeasured that are costing us the the consumer and to increase our most – 1.2 trillion dollars last year alone. knowledge of health, physiology, and In attempting to address these problems, human behavior. we must take into account several factors. The SenseWear system and its First, healthcare will increasingly come to applications are a first step toward a be ruled by consumers due to the power of vision of the future of healthcare that the market. Second, consumers will need enables users to manage their health personal health care tools to help them and care for their bodies anywhere manage their health and wellness through they choose to do so. The future of helping them manage the root causes of healthcare is happening today. their health and wellness – their choices and behaviors. Nearly all of the tools that Acknowledgements consumers end up using will require as The authors would like to thank inputs physiological information about their the many, many researchers who bodies. This will require wearable body incorporate our products into their monitoring that is simultaneously medical- research and share their assessments grade and consumer-desirable. with the world. We’d also like to BodyMedia is today addressing this acknowledge everyone at Bodymedia need by following a few simple principles. who created the products, systems, We strive to find the new vital signs that and concepts that make it all possible. resonate with consumers and the behaviors Special thanks to Jong-Lin Yu, they wish to manage. In addition to Chris Pacione, Max Crossley, Jonny incorporating our increasing knowledge Farringdon, Quang Tang for their of the human body, we also directly model assistance in creating this chapter. the relationship between these new vital signs and the physiological signals we can References measure from the body. A fundamental [1] Van Bemmel, J.H., Musen, M.A. (Eds.), 1997. Handbook of Medical Informatics. Springer, New question for us is York.

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Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 465 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 466 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 467 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 468 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 469 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 470 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 471 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 472 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 473 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 474 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 475 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Renata G. Chapter 50: How Can We Avoid Bushko / How Individual and Inter-generational Medical Definition 1: Individual Error Can We Avoid Individual Errors? Error occurs when we could have and Inter- Renata G. Bushko, M.S. had a positive impact on person’s generational Director, Future of Health Technology life assuming current state of medical Medical Errors? Institute, Hopkinton, MA, USA science, knowledge and resources but in World Health we fail to do so. Strategy” eBook, www. Abstract Definition 2: Inter-generational Error Futureofhealth. rrorless, invisible, continuous and Error occurs if we could have had infrastructure-free healthcare should org (Ed.) positive impact on populations’ health Renata G. become our goal. In order to achieve Bushko, FHTI, E but we failed to that goal, we need to rapidly move from 2016. From: current episodic and emergency-driven achieve that because of inappropriate Intelligent and “healthcare delivery system” to an intelligent allocation of resources. Extelligent E.g. If we invested in nonomedicine Health and extelligent health environment. Environment That requires introduction of distributed the day that Dr. Eric Drexler described (Ed.) Renata G. affective Intelligent Caring Creatures (ICCs) it, we could be saving lives with Bushko, IOS consisting of healthons. Healthons are much more advanced nanorobots Press 2005 tools combining prevention with diagnosis today. If we, as a society, decide

and treatment based on continuous to delay research on postponing monitoring and analyzing of vital signs and aging or common sense knowledge biochemistry. Unlike humans, who posses representation, only two or three dimensions of thinking, we may create an inter-generational healthons can assure errorless health error that costs us millions of lives. because of their adaptability, flexibility, and It is not enough to set a goal to multidimensional reasoning capability. ICCs reduce the number of medical errors, can do “the right thing” based on (1) state- of-art medical knowledge, (2) data about which is what happens with many emotional, physiological, and genetic state improvements programs. These of a consumer and (3) moral values of a medical errors must be eliminated. We consumer. The transition to the intelligent strive for errorless space missions. The health environment based on ICCs requires same should happen in health care. the solutions to many currently unsolved The life of an astronaut is equally healthcare problems. This paper lists important as the life of any other the unsolved problems (by analogy to person. mathematical unsolved problems list) and The invisible feature of new explains why errorless healthcare with bionic healthcare means that it is handled in hugs and no need for quality control is an unobtrusive way that does not possible. disturb the normal lifestyle of the consumer. 1. Errorless, Invisible, Continuous and Infrastructure-free and continuous Infrastructure-free Healthcare healthcare means that it goes on A concept of errorless healthcare is based anywhere and all the time. Healthcare on the broad definition of an error:

How Can We Avoid Individual and Inter-generational Medical Errors? 476 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

becomes life-care. (glutamate is a neurotransmitter secreted by nerve cells that influences 2. Intelligent Caring Creatures and sensory perception, learning and Healthons memory). Affective Intelligent Caring Creatures (ICCs) A Robopet jumping on its elderly are needed to achieve errorless, invisible, owners lap to remind him/her about continuous and infrastructure-free his/her medication or exercise healthcare, something that is impossible schedule, an artificial nose extension within the current organization of the sensing allergents before they cause healthcare system. ICCs consist of negative reaction, or Professor “healthons” that consumers carry in their Shioyama’s electronic eye translating bodies, on their bodies (intelligent health the visual input into instructions of how environment) and that are embedded in their to cross the street for the blind, or a homes, offices, cars, plains, furniture and second skin (E.g. BodyMedia’s robo-pet assistants (extelligent heath bodybugg™ or continuous environment). Healthons are tools combining thermometer) suggesting diet change prevention with diagnosis and treatment are also good examples. Artificial red based on continuous monitoring and cells that can help us stay underwater analyzing of our vital signs and biochemistry for two hours without an oxygen tank of the body. Healthons in 2050 will be like or the relational agent that explains the vitamins or tooth brushes in 2005 – broadly work of other healthons in a virtual available and used by everyone. There will medical visit via Nomad-like glasses be one difference, however, because they and realistic OLED display are yet will be able to talk to each other and, if additional examples. desired by the consumer, they will be able to The best example of a healthon that explain what is happening with consumer’s combines diagnosis, therapy and health at any moment. It is very important treatment is “surgical injection” that the designers of ICCs include the developed by Philips Medical Systems: “explain on human level” feature in the an injectable chemical agent (Apomate) products they produce. Otherwise, we will identifies the portion of the heart be left out by the omnipotent machines. experiencing the heart attack, and the same agent delivers VasoEndothelial 2.1 Examples of Healthons Growth Factor to the region of the Memory glasses are a good example of a heart attack to cause new blood healthon: a consumer wears them and his/ vessels to grow thus repairing the her recognition of people increases 50% heart non-invasively. Cellular without any conscious effort by the healthons are possible because of fast consumer. Another example is a nanooptical progress in nanotechnology. One of sensor placed in the brain that can monitor the examples is nanomolecular tagging glutamate and that allows for feedback on technology – molecular bar-coding sys the progress in the learning in children invented by Krasen Dimitri that allows

How Can We Avoid Individual and Inter-generational Medical Errors? 477 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

tagging, identifying, and counting individual and to make sure that we can take molecules. advantage of all newly available 2.2 Adaptiveness – The Key to Errorless hardware. Healthmaticians and Healthcare NURSES must remember to include the The key attribute that guarantees an “explain on human level” feature in all errorless health maintenance process is ICCs – even those who can program adaptability, which could be achieved by themselves based on the experience common sense knowledge representation they have had. These learning ICCs with analogical reasoning engine. Adaptive can self correct, and some of them can biomechatronic and nono-biomechatronic set their own goals. Because of that, ICCs, non-brittle and non-human, will have a healthmaticians developed an better chance of avoiding errors than “Emotion in Motion” engine that can humans. Investment in the creation of non- indirectly influence ICCs to set brittle ICCs with common sense will humanitarian goals. generate extensive benefits in healthcare where the compartmentalization and the 4. Deriving Dynamics from Medical enormous size of new medical research is Data - the Key to Errorless prohibiting a single un-aided human mind Healthcare from being effective. We cannot currently derive the dynamics of the system from data 3. Big Need for Software about our body and genes. There is a In the ICCs era, there will be no need for better chance that machines can do healthcare quality control, but instead a that before we – mere humans – can. great need for software quality control. This is what medical science is trying to Everything from nonomolecular devices in do “manually,” using previous our bodies to relational agents explaining to experience, isolated data points, and a us nanorobot’s actions will contain software lot of guessing. It is like trying to find an programs. Intelligent Caring Centers ant in a 5000 square-foot house. (equivalent to current hospitals but without What if we have all possible data patients because of infrastructure-free about the way our body functions healthcare organization) will reprogram and gathered by wearable or implantable upgrade Intelligent Caring Creatures. devices? Does it change much? Yes – Intelligent Caring Centers will be run by but only if we can reason on the data healthmaticians (mathematicians that serve and derive dynamics of the human health) and NURSES (New Unified phenomena that manifested itself by Resource Systems Engineers) who also take that data care of healthon allocation according to the Intelligent Caring Creatures and medical needs and the ethical convictions of healthmaticians have a better chance the population. Significant investment in of inferring the dynamics that need to software development methodologies is be understood than human physicians. needed to conquer the software bottleneck Humans can only process comfortably

How Can We Avoid Individual and Inter-generational Medical Errors? 478 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

in three dimensions while computers can see an infinite number of dimensions. We will need to trust the distributed network of 6. Bionic Hugs – Unlimited Supply of Intelligent Caring Creatures and NURSES Care – Remote Presence who built the medical intelligence into our Errorless, infrastructure-free healthcare external environment. The time that it takes t could be possible with an army of accept the fact that machines decide about bionic helpers – a type of specialized the healthcare process will determine the Intelligent Caring Creatures who time that it takes to achieve errorless replace current nursing and are made healthcare. available in any amount to all who need physical or emotional help. From 5. Talking to Our Cells – a simple handshake to a sophisticated Nanocommunication dialog, bionic intelligent caring What if we had a digital model of a human creatures will be able to help. including the functioning of each and every Bionic pets will play an important cell? What if a wearable computing paradigm role too. The human need for affection applied to each and every cell? Cells would and friendship will be fulfilled even for be making a decision to “wear” the those who cannot care for a real pet. nanomonitor or not; to undergo nanosurgery Robo-pets will also serve medical roles or not; to die or not. Cells would be – gathering data about the consumer reporting to organs and to their owners (us) and reminding about healthy behaviors about the probability of a mutation that may and disease management routine in cause a problem (e.g. cancer) later on. Or chronic conditions. With robotic-pets should we forget about reporting all together encouraging an active lifestyle, – why waste the time doing that – let’s give childhood obesity will be a long our cells the power to fix themselves and to forgotten history. communicate only with other cells that perform related functions. This would mean 7. Extelligent Adaptable Environment invisible healthcare – similar to the invisible Most of us will still have a chance to disease creation process. Real-time live in an extelligent environment that electrical detection of single viruses is will change depending on the already possible – we are moving in the emotional and physical state of the right direction. We are also moving rapidly consumer. With the use of OLED wall- from the era of robotic surgery to sized programmable displays nanosurgery. A high-speed ultrasensitive wirelessly communicating with body bar-coding system for identifying individual sensors, it will soon be possible to molecules by NanoString Technologies gets design healing environments that are us closer to knowing ourselves on a cellular so much underutilized. For example, a level and talking to our cells. patient who loves outdoors but has to stay immobile for some time could program his room as a tent with

How Can We Avoid Individual and Inter-generational Medical Errors? 479 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

windows showing pine forest and wind beings is to make sure that it will moving the branches and an occasional happen – that new brave human/ blue bird’s call. The walls could also be self- machine systems will be able and will programmable based on diaries from the be willing to share their findings with us past describing most positive energizing human beings. experiences. Objects that we use in every day life will 9. Getting There – Example of talk to each other, to the walls, cabinets, our Turning Existing Infrastructure into second skin and nanorobots inside our HealthStructure bodies. They will be working together to Before we all wear body monitors in create the most favorable living environment the form of second skin, we would all for each of us. be healthier if we could get a quick medical checkup while pumping 8. Remote Presence and Trust in Invisible gasoline at the gas station. Our Healthcare blood pressure at least should be Physical and virtual remote presence will measured every time we stop at the extend to unthinkable proportions. What if a gas station and we should also be new type of a human/machine doctor – checked for sleepiness and alcohol “doctoron” could care for 100 patients with level (breathalyzers) to determine if the similar disease at the same time? Of we should continue driving. Falling course, that would be needed only if asleep at the wheel causes a large consumer chooses to know each and every percentage of accidents. We could step of the care process. Most consumers imagine facilities for those who need to will choose to lead a normal, uninterrupted take a nap or rest (Sleeping chambers) life style instead of checking on the right at the gas stations. doctoron’s decisions. It will be more and more so within our capability to extend our 10. Unsolved Health Problems life spans indefinitely. There will be no need By analogy to mathematics where there to double-check our human/machine is always a list of unsolved problems doctorons or even use them. Most people to guide the young generation of will delegate control to their cells directly. mathematicians, Future of Health Just like computers are used in Technology Institute conducted an mathematical proofs (computer performs “unsolved health problems” survey in tasks that are not possible to be verified by 2003-5. The results are listed in the humans), they will be also used this way in table below. All survey participants were healthcare – without us understanding each also asked to state what will we gain if and every step of the reasoning and we solve that problem and what will we computation behind a decision. But we need lose if we do not solve it. Solving these to be in control – we need to understand problems will get us closer to errorless, qualitatively what is happening and our invisible healthcare with bionic hugs and biggest current responsibility as human no need for quality control.

How Can We Avoid Individual and Inter-generational Medical Errors? 480 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Table 1. Unsolved Health Problems – Based on HFTI’s Unsolved Problems Survey 2003-5

Unsolved Problem What will we gain if we solve What will we lose if we do not this problem? solve this problem? Lack of clean water in much of Reduced (especially child) Lives developing world. mortality rates. Lack of drugs resulting from Cures for previously Funding for genetic research human genome. untreatable, fatal illnesses. Really effective interfaces with Efficiency Usability human users. Significant (in magnitude) Enormous increase in efficacy/ Status quo replacement of human productivity and better "results"/ professionals by machines. outcomes. Translation from the Laboratory We may see more of these We will waste a lot of our to the Bedside: many projects make a difference in intellectual capital on projects innovations seem to never to clinical treatment. that don’t make it to the get past the bedside. “proof of concept demo” phase. Lack of tools to build causal If we are able to overcome We will continue to build models that integrate all the problems of how to an increasingly fragmented pieces of medical and process build, interpret and validate knowledge base and many information; information what will often be massively important discoveries will systems that can help us to underspecified models of not get translated into useful integrate all information into physiological systems, then we understanding. causal models, test the models will be able to accelerate the against available information, process of discovery. and help us do thought experiments to devise new hypothesis to test. Independent nanorobots with Stop disease before it Lives. smart software controls. develops. Anticipating human and system We will be better able to Medical errors will continue to failures so that processes can optimize the care we can give limit our ability to give the best be devised to prevent these with the clinical advances we care possible with the current failures. have in hand. clinical knowledge. Structured capture of clinical Increased formal encoding We will continue the present data (history, physical of phenotype information to process of having this examination, progress notes, enable research, clinical care, information unavailable. Some procedure reports, discharge decision support, etc. could be captured through summaries. natural language processing techniques, but structured data capture also encourages more discipline and thoroughness in recording, and provides more opportunity for timely decision support.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 481 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Personal longitudinal integrated This will foster improved We will continue the present health record. continuity of care, access to process of fragmented, relevant information to care incomplete, inefficient providers, better decision management of episodes of making, decreased errors care without ever having a (e.g., overlooking an allergy complete picture of the health or ordering of a medication status of a patient. conflicting with another), and the ability to track a patient's care over time, issue reminders, recommendations for improved health, etc. Comprehensive structured This will provide the ability to Continued current state of population health data bases. do analyses of screening tests, limited comparability and size genome-phenotype correlation, of datasets. outcomes analyses, technology assessments, and clinical prediction/prognosis. Application of cutting edge Decrease in incidence of Individual quality of life technologies for Primary chronic illness and money and economic stability in Prevention i.e. implanted spend for chronic illness, care health care costs as current calorie counter/blood sugar and improved quality of life. population ages with chronic monitor with beeper or such illnesses due to behavior for weight loss, nicotine or factors. drug aversion implants etc to give ongoing feedback and stimulus for behavior change. The simple low cost pedometer is a good example, but perhaps taken to a higher level or personalized monitoring. Cost benefit ratio analysis of Truly beneficial and cost Increasing personal and 3rd health technologies. effective health technology party costs for marginal efficacy applications. - "technology for technology sake". Inadequate distribution of Equity in world health. Continued Inequitable current technologies, based on distribution which may geography, income etc. eventually be the death of us all i.e. SARS AIDS etc. spreading world wide without available monitoring and prevention measure

How Can We Avoid Individual and Inter-generational Medical Errors? 482 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Lack of coordination. A specific example of positive If we do not attack the problem This problem crosses all coordination among medical of coordination, we risk applications of technology, systems includes the sharing additional sources of error, loss whether business, aerospace, of patient information among of our ability to track errors, or medical. In medicine, the pharmaceutical and patient and loss of time, not to mention cost of mistakes is already too records so that errors in increases in medical error and high. prescriptions, both in hospital possible law suits. and out of hospital are reduced, if not eliminated. But also that same mechanism of sharing, can provide a uniform source of information across many platforms, many software systems, so that validation and cross checking among the different systems may be simplified and when errors are detected, more easily tracked. Lack of recognition that not Reduce patient load, empower Continuing on the path we are all medical problems can be patients, create first steps in on is no longer an option. solved with "more technology"... the cultural shift to one where Health insurance costs are sometimes, "LO TECH", is a patients begin to take an not going down. Not only are more cost effective and patient ACTIVE rather than PASSIVE Americans uninsured they are friendly. E.g., providing access role in their own health. also underinsured. to meditation classes can reduce the cost of medication for chronic medical conditions such as high blood pressure and pain management. Effective use of media such It will take time to help We will continue to see the as TV and the internet to consumers reach for self care deterioration of health status. raise awareness and engage in their medicine cabinets The cost of insurance, and the the average consumer into rather than pills, but eventually cost of Hi-tech healthcare need healthcare. Make being we can hope to see an to be offset by low tech, such healthy "trendy"; make it improvement in the overall as dietary habits, practice of "attractive". This requires health of human race reducing meditation, and so on. administrators to make this a the costs of chronic conditions line item in the budgets, and the incidence of health a non-technical issue, but problems. implementation is technical. Regenerative Medicine: ability Find cures for millions that Billions of dollars spent on to apply stem cells to address suffer and sometimes die unpromising therapy as well as regenerative medicine. prematurely from degenerative incalculable human misery. illnesses. Background noise in biological Ability to rapidly detect Millions of lives lost to agent detection system. pathogens to isolate infectious disease epidemics populations from further that may be able to be curbed exposure. with early detection.

Future of Brain’s Health: Prevention of Neural Inflammation with Traditional Chinese Herbal Medicine 483 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Growing new Telomeres from Potentially slow down the aging Immortality stem cells. process. 100% Electronic infrastructure Greater portability of data, Privacy lapses, consumer for medical records. greater collation of data for apprehension. research, longitudinal tracking of health information, and potential reduction in medical errors. Wide-spread mobile computing Instant access to reference Application in well-funded in medical care. and clinical information, greater vs. poorly-funded settings; evidence-based healthcare. physician resistance and lack of acceptance of new computing technology. Personal understanding of Lower heath costs and better Unbounded cost of health care. preventative health lifestyles. quality of life. Adequate pricing of health care Reduction of serious ethical Lost market pressure for problems in health care pricing. improved health care costs with monies being extracted for drugs and procedures no care and health. Inpatient medical error as the Eliminate of a substantial 220,000 unnecessary third leading cause of death. portion of 220,000 inpatients deaths and millions Medication error is the largest unnecessary inpatient of outpatient deaths and subcomponent and by itself deaths per year and millions disabilities. About is the fourth leading cause of of persons maimed or $500 Billion in unnecessary death. 60% of medication error incapacitated in some way. healthcare costs. is caused by physician ordering Elimination of a portion and 30% is caused by nurse of about 1M unnecessary administration. outpatient deaths. Elimination of about half of patient visits and hospitalization by proper disease management. Outpatient medical error Human Lives See Above (even higher than inpatient error, perhaps by an order of magnitude) Disease management errors - Human Lives See Above the iceberg of which medical error is the visible tip. E.g., many unnecessary amputations on diabetics performed every year in the U.S., caused by improper follow-up. Bringing the bio-med Fast progress and better Slow progress hypothesis builders and penetration of innovations into the tech developers closer practice. (educational challenge).

How Can We Avoid Individual and Inter-generational Medical Errors? 484 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

A reliable protein/proteomics Human Lives – Reduction in Lack of individualized database for NORMAL human unnecessary anxiety about biochemistry understanding serum. (Surprisingly, from the “symptoms” that are part of and treatment. many decades doctors have normal variation not a sign of looked for signs of disease disease. in the blood, the normal constituents--proteins-in blood are very poorly known, both qualitatively and quantitatively. Before we can exploit nanotech & high throughput methods, we really must get a handle on what the range of normal proteins is in peripheral blood). Expediting tech transfer from Reduction in suffering. Wasted human effort. lab to clinic (administrative, governmental challenge). Finding the genetic basis of We'll be able to control We will fail to give people the telomerase-independent telomerase-independent longer healthy life spans and telomere extension seen in cancers (including half of all reverse aging in order to about 10% of human cancers. sarcomas, for example) by reverse aging comprehensively gene therapy in the same way enough to keep people alive that we will be able to control and healthy for a few decades telomerase-dependent cancers more than now, which will be by gene therapy against the enough to let us improve the telomerase genes. therapies further and keep us alive indefinitely. Making the 13 protein-coding We'll be able to ignore the We will fail to give people mitochondrial genes work accumulation of mitochondrial longer healthy life spans. when placed in the nucleus. mutations during aging, See Above because they will be harmless -- the proteins that are made from the mitochondrial DNA will be made from nuclear copies of the genes so the mitochondria will still work. Finding microbial enzymes to We'll be able to treat all major We will fail to give people break down the cholesterol diseases that are caused longer healthy life spans. analogues that cause by the accumulation of See Above. atherosclerosis and maybe garbage inside cells. That Alzheimer's disease. includes atherosclerosis, macular degeneration and probably most types of neurodegeneration. Lack of machines with common Well cared for population. Worldwide healthcare crisis sense that could take care of Increased health status of the due to lack of care givers. us population. Unnecessary suffering.

How Can We Avoid Individual and Inter-generational Medical Errors? 485 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Lack of comprehensive Faster progress towards Slow progress towards working easy to use framework errorless healthcare. errorless healthcare. for performance evaluation of adaptive complex systems. Maintaining long-term Increased speed of No good communication engagement between users acceptance of caring machines. between people and caring and health dialog systems machines. (caring machines), especially crucial for chronic disease management systems in which we need people to use the system regularly for the rest of their lives. Encoding of behavioral Exponential growth of the use Limited use of caring machines. medicine concepts and and utilization of the caring theories into shareable machines. computational ontologies, to support information sharing and re-use.

9. Conclusions errorless, invisible, infrastructure-free Utilizing Intelligent Caring Creatures (ICCs) and continuous sooner – to enter a to achieve errorless healthcare requires healthon era. The Worldwide Marathon departure from thinking that the only entity for Health: Healthon Initiative initiated that can justify a medical action is an un- by FHTI will start that process. aided human being. Once we are ready to delegate management of our health to ICCs Acknowledgements we need to make sure that they are able The author gratefully acknowledges and willing to explain their multidimensional participants of Future of Health reasoning. Compiling a list of “unsolved Technology Summits 1996-2005 – problems” helps moving towards errorless especially those who responded to healthcare. It would be useful to have FHTI Unsolved Problems Survey. awards system for solving currently unsolved healthcare problems to make healthcare

How Can We Avoid Individual and Inter-generational Medical Errors? 486 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Kevin Warwick/ Chapter 51: Thought to Computer with machines, far more intelligent than Thought to Computer Communication ourselves, becoming the dominant ‘life’ Communication Kevin Warwick form on earth? An alternative is for in World Health Professor of Cybernetics, Department of humans to e-volve, to technically Strategy” Cybernetics, University of Reading, UK eBook, www. upgrade the human form by linking Futureofhealth. much more closely humans with org (Ed.) Abstract technology. In science fiction terms Renata G. Bushko, FHTI, his paper describes some of the this means we will become Cyborgs – 2016. Original implant experimentation presently part human, part machine. Chapter underway. The basic approach taken But what sort of an upgrade are we from Future T of Health is introduced and general techniques are looking at for humans? It may be that Technology explained. Achievements already attained spare arms and legs become the order (Ed.) Renata G. are summarized and short term plans are of the day, but unless we are all going Bushko 2002, IOS Press expanded. Potential results, as they could to become Inspector Gadget look impact on healthcare and related issues, are alikes, with corkscrew fingers and thrown into the arena. The author propeller heads, it is difficult to see speculates ‘a little’ on what might be where this will get us. No, clearly it is achieved in the future with implant not a physical upgrade where the technology. rewards are greatest, it is a mental one. In fact healthcare problem number one 1. Introduction in this new technological world, in that Let’s start with a few basics. Humans are, for most physical aspects of the human the most part, successful at being humans. body are rapidly becoming redundant. As Homo Sapiens we have though been Some people, as a result, become around for only 100,000 years or so, which is obese, whilst others take regular, a very brief time span in comparison with enforced, exercise. What is to be done many other creatures. Just as Big Macs with physical bodies that are no longer relate to gourmet food so humans relate to required to perform as they used to, life on earth. But the moving hand of yet are living much longer is indeed a evolution points to the future. Some pertinent question. But I will not creatures adapt, surviving or even becoming attempt to answer it here. more successful, those that don’t will, almost Even though humans have been in surely, die out. Even the Big Mac, as we their way, fairly successful on earth, we know it now, will not last for ever. are extremely limited in what we can It is possible that humans will slowly do and how we perform. Clearly we change, to utilize more effectively the have physical limitations. In the last technical world we are creating. The few centuries in particular we have consequences of not adapting at all are employed technology to improve our potentially horrific. Could we really end up capabilities. So we can lift heavy

loads, dig tunnels, accurately and rapidly ultrasonic signals, and comprehends it repeat a mundane task, communicate in 8-dimensions? Surely this would instantly around the world and fly. completely change our understanding of the world; what we believe to be Even though humans have been in their possible and what not. way, fairly successful on earth, we are extremely limited in what we can do and how we perform. Clearly we have physical 2. Self-Experimentation limitations. In the last few centuries in In the fall of 1998 I had a silicon chip particular we have employed technology to transponder surgically implanted in my improve our capabilities. So we can lift left arm, with this in position the main heavy loads, dig tunnels, accurately and computer in the Cybernetics building at rapidly repeat a mundane task, communicate the University of Reading was able to instantly around the world and fly. monitor my movements. Essentially at But what are the possibilities for humans various doorways large coils of wire to be upgraded to cyborgs to take on board within the door frame provided a low some of these abilities? Could it be possible power radio frequency signal which for ourselves, in cyborg form, to understand energized the small coil within the the world in many dimensions, by linking our transponder. This in turn provided an human brain directly with a computer brain? electric current enabling the Could we then directly tap into the transponder’s silicon chips to transmit a phenomenal math and memory performance unique signal to the computer, of the computer. What’s the use of the identifying me. human brain remembering things or learning Signals were, in this way, transmitted math when the computer brain can do those to/from the computer and inside my tasks much better? Whilst human brains will, body. To demonstrate some of the on their own, evolve relatively slowly, capabilities, a voice box by the perhaps by gradually expanding over entrance welcomed my arrival each generations; could it be possible for us to morning with “Hello Professor bring about a form of designer evolution by Warwick”, the door to my lab opened connecting computer brains, with near- as I approached and the computer was infinite potential, to our own. aware of what time I entered a room Our senses also might be directly and when I left. It switched on lights for upgraded. Is it possible, for example, for us me, automatically, as appropriate. The to take on board x-ray, infrared and experiment having been a success, 9 ultrasonic signals? Could these be fed days after its insertion, the implant was directly to our brains? What then would the removed. world feel and look like to a cyborg who Since that time we have been senses it also in terms of ultra violet and working on the next step of our

research program, a new implant. The investigate a nervous system implant if, operation to put it in position is tentatively as a scientist, you are not yet ready to scheduled for September 2001, almost have one positioned in your brain. exactly 3 years after the previous Apart from a direct connection onto experiment. Once again the target area is the nervous fibers, the implant will my left arm, just above the elbow. This time contain a transmitter, a receiver and however a direct connection will be made some local signal processing and with the nerve fibers running up the center conditioning. The implant will merely of my arm. Electronic signals on the nerve be providing an interface between the fibers will be picked up and transmitted to a nervous fibers and the computer, it will computer, rather like tapping into a not be carrying out any signal telephone conversation. Signals will though understanding itself. also be received from the computer, and We wish to look at a range of played down onto the nervous fibers. signals. Firstly a series of movement The nerve fibers in the upper arm link the experiments will be conducted. The brain to the hand and they carry a variety of signals which cause particular fingers signals. In one direction signals from the to move will be recorded in the brain cause movement and dexterity in the computer and then played back again hand, whilst in the opposite direction in an attempt to recreate the sensory data from touch or pressure is movement as closely as possible. passed. Also apparent are a number of Secondly signals from an ultrasonic body state signals concerned with sensor will be directly played down temperature, blood flow and the like, along onto the fibers and I will visually learn with physical emotional signals such as when objects are close by and when anger, shock and excitement. Signals not, thereby relating visually to the relating to pain are also sent via this route. signals on my nervous system. We will So at any instant in time the nerve fibers see if I can directly sense objects close carry a very mixed collection. Some people by. Hopefully the movement might regard many signals as noise, but this experiments will contribute to research is not really the case at all, as every signal is in that area whilst extrasensory signals important. This said, if you are investigating could be immediately useful as an movement then signals relating to anger or alternative sense for people who are pain could be deemed to be noise as they blind. do not directly relate to the study at hand. Then come experiments more into One thing is apparent however and that is, in the unknown. Pain, anger and shock the upper arm the nerve fibers are rather signals will all be stimulated as much as like a Freeway in that most of them directly possible and recorded on the link the brain and hand, with very few turn computer, even excitement. The offs. It is therefore a good place to relevant signals will then be played

back down again onto the nervous fibers. feelings, to an extent at least. I am Will my brain indicate any of the original scared of being high up in a building. feelings? This is what we wish to find out. Can we arrange for one of us to be in Could it be possible to initiate the feeling of the UK and the other in the USA – pain electronically? If so perhaps we can perhaps I can be in the Empire State send in equalizing signals instead, to Building. What will Irena feel when counteract the effects of pain in an signals from my own nervous system in individual. Can we electronically cause that situation appear on hers, as she is excitement, happiness and so on? If so we sitting quietly? are looking at the potential world of Clearly these experiments are only e-medicine. a start of person to person 3. Communication communication by means of direct As long as the experiments go well with my nervous system signaling. At this stage implant in place, my wife Irena will join me by we have very little idea as to how far having her own implant. What we wish to we will be able to take it. Could it be look at then is communication from one possible in the future, with implants person’s nervous system to the other. directly positioned in the brain to Potentially across the internet. So the communicate in the same sort of way. signals from my own nervous system will be Could we send our thoughts to a played down onto Irena’s nervous system computer? Could we think to each and nice versa. Both implants will be other? Could we communicate by positioned at roughly the same point in our thought signals alone? Obviously we upper left arms. will not be able to go that far with our Obviously movement signals will be of own next experiment. It will be merely interest. When I move my left index finger a step on the way. and the electronic signals that achieve that are played down onto Irena’s nervous 4. Medicine system, will it achieve anything like the same It is worth remembering that the human movement in her hand? When she feels brain is an electrochemical entity. In pain in one finger, due perhaps to excessive the western world we have, till now, pressure, will I feel the same sort of pain? largely concerned ourselves with the Indeed is it roughly the same in men and chemical aspects of the brain. women? If she gets excited (as in the Chemicals are employed for a number presence of an attractive young man), what of reasons – to ease a headache, to will I feel when the associated signals prevent pregnancy, to help get to appear on my nervous system? sleep or, in the case of coffee, to help We hope to have time to look at phobias wake us up and perform better in and fears. Irena is extremely frightened of examinations. Could anything like the spiders. I would like to experience those same sort of effects be realized, fairly

easily, electronically? If so the potential for signals, when transmitted to the e-medicine is enormous. Perhaps electronic computer, were enough to cause the signals could be used to provide a viable treat to be electronically released. alternative to cigarettes, without some of the Interestingly the rats soon learned that side effects. Indeed electronic signals have they didn’t have to actually pull the already been successfully used to combat lever, merely thinking about it was the effects of both Parkinson’s disease and sufficient. As far as humans are Alzheimer’s disease. concerned, several groups are We must however remain rather wary in experimenting with computers linked opening up this field. Just as electronic to the nervous system. Ross Davis’ signals might potentially be used for their team at the Neural Engineering Clinic positive medicinal effects, they might in Augusta, Maine have been similarly be used for individuals to get high developing technology to attempt to on a daily, electronic pick-me-up? The field treat patients whose central nervous of cybernetics is perhaps just around the system has been damaged by an corner. accident or a disease such as multiple sclerosis. They have obtained 5. Supporting Cases excellent results in regaining muscle Much research work is being carried out control by means of computer presently by various research groups around generated (as opposed to brain the world which directly supports and generated) signals. influences our own work. For example as Perhaps the most stunning research recently as 1997 a group at the University of so far though is that carried out by Tokyo attracted a microprocessor directly to Philip Kennedy and his team at Emory the motor neurons of a cockroach, which University in Atlanta. There they have carried the computing power around as a implanted an electrode directly into the back pack. Signals from the microprocessor brain of a paralyzed war veteran, were then used to drive the cockroach Johnny Ray. He is paralyzed from the around in a planned route. No matter what neck down and hence cannot control the cockroach might have itself wanted. or move any part of his body below Meanwhile in 1999 it was reported that that point. A functional MRI scan was John Chapin at the MCP Hahnemann School used to detect brain activity when of Medicine in Philadelphia and Miguel Johnny was asked to think about Nicolelis at Duke University had implanted moving his arms and hands. The electrodes into rats’ brains. Initially the rats implant was positioned in an area of were taught to pull a lever in order to get a the brain seen to be active under such ratty treat. However the implants were circumstance. positioned such that the rats merely had to With the implant in place Johnny think about pulling the lever and these was able to move a cursor around on a

computer screen thereby spelling out words The range of capabilities of, and and constructing sentences, merely by intelligence associated with, humans is thinking about it. The electronic signals in dependent on our brain cells and the his brain which relate to thoughts, about way they are connected together. certain movements, are transmitted to the However if we enable implants to link computer by a radio signal in a similar way to our brain directly with a computer then our own implants. What is incredible though anything that computer can connect to is that not only can Johnny, in this way, could potentially operate for us. Not communicate by means of his thoughts only could doors open and lights alone but also that his working brain has switch on automatically, as they did actually readjusted to its newly found power. even for my first implant, but we might His own neurons have grown into, and be able to drive a car or fly a plane strengthened the link with, the implant. merely by thinking about it. I feel that once some rudimentary trials have 6. Cybernetics been carried out we would rapidly All of this research is very much at the heart learn how to expand our abilities and of what cybernetics (a term originated by operate the whole system more Norbert Wiener of MIT) is all about: humans effectively. and technology acting together as an overall But communicating from brain to system. One key element of this is computer and ultimately from human consideration of the human brain as just brain to human brain, in terms of another, albeit extremely important, physical thought signals alone opens up new organ in the human body. The human brain questions. Why would we need to has no magical properties over and above speak? Will language and the culture its physical working. A brain’s as we now know it, disappear consciousness is merely a function of its completely or will it still have a small operation, it is not some remote entity that role to play, perhaps in the exists elsewhere in the ether. Thoughts are development of babies. As humans merely as a result of particular states of the evolve to this new level so telephones brain, dependant on a set of electrochemical become obsolete. If we communicate signals in the brain at that time. by thoughts perhaps we will become On average a human brain has, less open and learn to control our something like, 100 billion individual cells. It feelings and emotions more. Indeed a is a complex network, each cell connecting simple evolutionary step would with thousands of others to produce its own suggest that those who could better operation. It is extremely difficult, at the control their feelings might be more present time, to unravel and hope to fully likely to succeed in the new world. understand its actual operation. It is certainly not a parallel processing device however. 7. Immediate Uses

Implant technology does though offer some hence it was linked to me. We were more immediate potential uses. Dependent not separate, yet complemented each on the position of an implant, certain body other. When the implant was removed, states can be measured, or inferred, e.g. on the one hand I felt relieved that any blood pressure, temperature and pulse. potential medical problems, such as The relevant values can then be transmitted infection, were behind me, however I to a computer which gives an overall also felt that I had lost a friend, in that conditional indicator. Whilst this could be myself and the computer were not useful for athletes and other sports people, longer an item! it would have a direct impact in patients With the new implant including undergoing constant monitoring. In these a nervous system connection, such cases electrodes repeatedly placed on feelings of affinity can only get the skin surface can cause deep sores and stronger. When brain links are involved much bleeding after a while. The implant they will be stronger still. As a cyborg alternative is, I feel, worthy of investigation. would you have the same morals and But the real potential appears when ethics as those of a human? I would brain implants are considered. Computer think not. Sure the cyborg started in based machines are rapidly becoming more human form and hence human values intelligent, perhaps in a complementary way probably play a part, however I would to humans. Linking a human brain to such guess that as a cyborg it would be technology, creating a cyborg seems to cyborg morals and ethics that would be a natural way ahead, simply upgrading be in evidence. the human form. In most cases though the computer brain would not be operating 8. The Future in stand alone, but rather would be part We must be careful as we investigate of a network, with mixed intelligence and further into the use of implants. Until capabilities. The question then needs to now they have been mainly for helping be asked as to how the human fits into out something in the human body that. In that way a cyborg would not be an that is not functioning correctly, as is individual but would themselves be a node the case with a heart pacemaker or a on the network. Away from the network cochlea implant. However implants your capabilities are limited to the poor in general open up the possibility of performance of humans, connected into giving humans extra capabilities. In the the network and you are merely part of a short term this may mean we can think considerably greater whole. about repairing, to a certain extent at With my first implant it did not take long least, a nervous system break, and before I mentally considered the implant to hence get people moving again. be part of my body, part of me. However Possibly we’ll also be able to bring the computer was linked to the implant, about extra senses and apply complex

electronic signals to help both physical and mental illnesses. References and further reading When we link human brains and [1]S. Greenfield, ‘The Private Life of the computer brains together though, we are Brain’ Penguin 2000 going a stage further. By creating such mental cyborgs we are doing something [2]S. Griffiths (ed)., ‘Predictions’. Oxford more. We will change the basic nature of University Press, 1999 ourselves. We will give ourselves much more powerful means of communication, [3]A.Scammell (ed.)., ‘I in the Sky’, Aslib and the ability to think about problems in Press, 1999 many dimensions. Those without an implant, i.e. those that remain as mere humans, [4]K. Warwick, ‘In the Mind of the will become very sorry individuals unable Machine’, Arrow, 1998 to compete. They will, roughly speaking, occupy the position that chimpanzees are in [5]K. Warwick, ‘Cybernetic Organisms – today. Our Future?’, Proc. IEEE, Vol. 87, No. 2, If you were to ask me whether I would pp 387-389, 1999. wish myself to go for the unknown and unchartered cyborg future, I do not have [6] K. Warwick, ‘Cyborg 1.0’, Wired, Vol. to think twice to answer. No way, under 8, No. 2, pp. 144-151, Feb. 2000 any circumstances do I want to belong to a chimpanzee-like sub species. It’s a cyborg [7]K. Warwick, ‘QI: The Quest for life for me. Intelligence’, Piatkus, 2000.

Acknowledgement [8]N. Wiener, ‘God and Golem The author wishes to thank Nortel Networks Incorporated’ Chapman & Hall, 1964 and Computer Associates for their financial assistance. He also wishes to thank the staff of Stoke Mandeville Hospital, Aylesbury, UK – it is only through their expertise that this is becoming a reality.

I would also like to acknowledge the input of the team at Reading, in particular Brian Andrews, William Harwin and Mark Gasson. Finally my sincere thanks go to Ali Jamous from Stoke Mandeville Hospital for his medical expertise.

Kevin Warwick Chapter 52: Of Mice and Men: Brain brain is a complex computational / Of Mice and platform. Studying how the brain Men: Brain Cultured in the Laboratory Linked to a Cultured in the Physical Robot Body processes and encodes information in Laboratory Kevin Warwick living animals [4] can be technically Linked to a Professor of Cybernetics, School of Systems problematic as access is limited by the Physical Robot Engineering, University of Reading, UK skin, skull and the sheer number of Body in “World neurons present in the brain. Moreover, Health Abstract whole animal approaches capable of Strategy” n this chapter we consider a distinct recording the activity of individual eBook, (Ed.) neurons or small populations thereof Renata G. example of the link between biology and Bushko, Itechnology, with particular reference to are limited by the invasive nature of FHTI, 2016. the brain. We look at the example of a brain such techniques. For these reasons Futureofhealth. cultured in the laboratory which is then laboratory cultured neurons grown on org a planar array of non-invasive From Strategy linked to a physical robot body. The overall for the Future entity therefore consists of a physical robot electrodes provide an attractive of Health (Ed.) body controlled by a purely biological brain. alternative possibility. It rapidly Renata G. The entire system provides a wonderful processes a plethora of information, is Bushko, IOS adaptable to noise and is tolerant to Press 2009 base for the study of the fundamental features of diseases such as strokes and faults. Recently, progress has been Alzheimer’s disease, as well as allowing for made towards the integration of a basic investigation into the mechanisms for biological components (such as neural signal transfer. neurons) and electronic components. These technologies are beginning to 1. Introduction blur the distinction between the The intelligent controlling mechanism of a synthetic and the organic. Reger et.al. typical mobile robot is usually a computer [1] demonstrated that it was possible to system. Research is however now ongoing use the brain of a lamprey in order to in which biological neuronal networks are control the trajectory of a robot whilst being cultured and trained to act as the others are beginning to control brain of a real world robot – either replacing creatures such as cockroaches [2] and or operating with a computer system. rats [3] as if they were robots. Studying Studying such neuronal systems can give an how the brain processes and encodes insight into biological neural structures and information in living animals [4] can be has immediate medical implications. The technically problematic as access is principal aim of the research described here limited by the skin, skull and the sheer is to assess the learning capacity of number of neurons present in the dissociated cultured neuronal networks. This brain. Moreover, whole animal has been approached by the creation of a approaches capable of recording the hybrid system incorporating closed loop activity of individual neurons or small control of a mobile robot solely by a populations thereof are limited by the dissociated culture of neurons. The human invasive nature of such techniques. For

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 495 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

these reasons laboratory cultured neurons neurons, or small groups, from a single grown on a planar array of non-invasive electrode. With multiple electrodes a electrodes provide an attractive alternative picture of the global neuronal activity possibility. of the entire culture can be pieced Recent research has focussed on together. It is also possible to culturing networks of some tens of electrically stimulate any of the multiple thousands of brain cells grown in vitro [5]. electrodes in order to induce neural These cultures are created by dissociating activity. The multi-electrode array the neurons found in cortical tissue using therefore forms a functional and non- enzymes and then culturing them in a destructive bi-directional interface with specialised chamber by providing suitable the cultured neurons. environmental conditions and nutrients. The The objective of the project base of the chamber itself is composed of described here is to investigate the an array of multiple electrodes (a multi use of cultured neurons for the control electrode array – MEA) providing an of mobile robots and as a result to electrical interface to the neuronal culture investigate some fundamental aspects [6,7,8,9]. The neurons in such cultures of brain activity – especially those spontaneously begin to grow and branch associated with memory. out and, even without external stimulation, For the purpose of this research, it begin to re-connect with nearby neurons is necessary that the disembodied cell and commence both chemical and electrical culture is provided with embodiment, communication. This propensity to since a dissociated cell culture growing spontaneously connect and communicate in isolation and receiving no sensory demonstrates an innate tendency to input is unlikely to develop much useful network; studies of neural cultures of this operation since sensory input type suggest that they mature in around a significantly affects neuronal month [10,11]. The neuronal cultures connectivity and is involved in the themselves form a monolayer over the development of meaningful electrode array on the base of the chamber relationships necessary for useful making them extremely amenable to optical processing. In particular, the use of microscopy and accessible to both physical rodent primary dissociated cultured and chemical manipulation [9]. neuronal networks for the control of The multi-electrode array enables the mobile robots is a novel approach to voltages to be recorded from each discovering the computational electrode, allowing the detection of the capabilities of biological networks [13]. action potential firing of neurons near to Typically, in vitro neuronal cultures each electrode as voltage spikes consist of many thousands of neurons. representative of charge transfer within the As a result signals generated by them electrode’s recording horizon. Using spike are highly variable and multi- sorting algorithms [12] it is then possible to dimensional. In order to extract from separate the firing of multiple individual such data components the features of

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 496 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

interest which are representative of the distance from it [15]. It is important to network’s overall state, appropriate pre- stress here that inherent firing actions processing and dimensionality reduction of the culture were sent to a computer techniques must be applied. The signal which then made a decision (in a processing involved can be broken down binary sense) as to what action the into two discrete areas: ‘culture to robot’, an Koala should take. The culture itself output machine learning procedure was not directly controlling the Koala processing recorded neuronal activity and through a feedback loop and no ‘robot to culture’, an input mapping process, learning action was reportedly from sensor to stimulus. exploited. Although this research Several schemes reported in the stands as a landmark, it is these literature have thus far been constructed in features that are both critical in the order to investigate the capacity of hybrid study described here. systems. Notably, Shkolnik created a very In a well publicized experiment, interesting control scheme for a simulated DeMarse and Dockendorf investigated robot [14]. Two channels of a Multi Electrode the computational capacity of cultured Array (MEA) were selected for stimulation networks by introducing the idea of and a signal consisting of a +/-600mV, implementing the results in a “real-life” 400μs biphasic pulse was delivered at problem, in this case that of controlling varying intervals. The concept of information a simulated aircraft’s flight path (e.g. coding was formed by testing the effect of altitude and roll adjustments) [17]. electrically inducing neuronal excitation with Meanwhile recent developments have a given time delay called the Inter-Probe focused on the application of learning Interval (IPI) between two stimulus probes. techniques in neuronal cultures. This technique gives rise to a characteristic Shahaf and Marom [18] were one of the response curve which forms the basis for first groups to achieve desired discrete deciding the robot’s direction of movement output computations by applying a using simple commands (forward, backward, simple form of supervised learning to left and right). randomly connected neuronal cultures. Other groups meanwhile used a More recently, Bull & Uroukov [19] simulated rat [15] which moved inside a four- successfully applied a Learning wall environment including barrier objects, or Classifier System to manipulate cells physical robots such as ‘Koala’ and into responding in pre-defined ways to ‘Khepera’ robots [16]. The latter were electrical input signals. However, both employed in a sort of embodiment of these cases indicated successful experiment wherein one of the robots (the results in only about one third of their Koala) attempted to maintain a constant experiments, indicating the underlying distance from the other which moved under complexity and vulnerability of the random control. It was reported that the networks, along with apparent Koala robot managed to successfully difficulties in achieving repeatability. approach the Khepera and maintain a fixed Such work also highlights the

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 497 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

importance of understanding key functional these disassociated neurones is and effective connectivity features within the subsequently smoothed out onto a cultures. Clearly this will assist in attempting Multi Electrode Array which sits in a to perform learning schemes, but it should nutrient rich bath. Every couple of days not be seen as a prerequisite. The this bath needs to be refreshed in importance of experimentation through order to not only provide a food adaptive feedback control cannot be source for the culture but also to flush stressed more clearly. away any waste material. It is clear that even at such an early stage, Once they have been laid out on such embodiments (real or virtual) have a the array the neurones start to prevailing role in the study of biological reconnect – indeed even within the learning mechanisms. The physical and first 24 hours such new connections simulated robots proposed here provide the are clearly visible under the starting point for creating a proof-of-concept microscope. These can be regarded control loop around the neuronal culture and initially as mere projections forming a basic platform for future - more specific - into axons and dendrites, making reinforcement learning experiments. As the connections between neighbouring fundamental problem is the coupling of the neurones. By the time the culture is robot’s goals to the culture’s input output almost one week old electrical activity mapping, the design of the robot’s can be witnessed to appear relatively architecture discussed in this paper structured and pattern forming in what emphasises the need for flexibility and the is, by that time, a densely connected use of machine learning techniques in matrix of axons and dendrites. search of such coupling. ted matrix of axons and dendrites. The main point to stress here is that each Neuron firing can sometimes appear, cultured network, when embodied, acts as a from external inspection, to be neural experimental test bed. Hence, with initiated at random, resulting in signals such a foundation in place, it is possible to (action potentials) pulsing through the investigate effects on the culture of electrical network. In many cases a large bunch and chemical stimulation alongside external/ of neurones will fire spontaneously, environmental effects – this means that the something which is referred to as representation of memories and how the bursting. Exactly what these bursts culture deals with neural death in certain are is not completely known however regions can be investigated. some see them as being the result of sensory deprivation, to be quelled 2. Culture Preparation by the embodiment of the culture, In order to realise the cultured neural providing it with sensory input [24]. network, this firstly involves the removal of During its lifetime, which presently the neural cortex from the fetus of a rat. is typically up to a maximum of three Enzymes are then applied to disconnect the months, the culture must be housed neurons from each other. A thin layer of in an incubator which maintains a

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 498 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

constant body temperature under relatively sterile conditions. A smaller version of this is then employed as a temporary base for the culture when it is required for it to communicate bidirectionally with its robot body. Once a test run has been completed (typically taking an hour or so), then the culture is returned to its incubator home.

3. Closing the Loop The overall system is constructed with a closed-loop, modular architecture in mind. Figure 1, a) An MC200/30iR-gr MEA, showing Neuronal networks exhibit spatiotemporal the 30 µm electrodes which lead to the patterns with millisecond precision [16], the electrode column–row arrangement b) processing of which necessitates a very Electrode arrays in the centre of the MEA rapid response from neurophysiological seen under an optical microscope, c) x40 magnification, showing neuronal cells in close recording and robot control systems. The proximity with visible extensions and inter- software developed for this project runs on connections. Linux-based workstations communicating over the ethernet via fast server-client modules, thus providing the necessary speed and flexibility required when working with biological systems.. The study of cultured biological neurones has in recent years been greatly facilitated by commercially available Multi Electrode Array systems. These consist of a glass specimen chamber lined with an 8x8 array of electrodes as shown in Figure 1. A standard MEA measures 49 mm x 49 mm x 1 mm and its electrodes provide a bidirectional link between the culture and the rest of the system. The associated data acquisition hardware includes the head- stage (MEA connecting interface), a 60 channel amplifier (1200x gain; 10-3200Hz bandpass filter), a stimulus generator and a data acquisition card

Figure 2: MEA with culture close to Miabot robot.

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 499 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Thus far we have successfully created on-the-fly streaming of spike-detected a modular closed loop system between data is the preferred method when a (physical) mobile robotic platform investigating real-time closed-loop and a cultured neuronal network using learning techniques. Multi-Electrode Array (MEA), allowing for bidirectional communication between the culture and the robot. It is estimated that each culture employed consists of 50,000 to 100,000 neurones. The spontaneous electrochemical activity of which is used as input to the robot’s actuators (its wheels) and the robot’s (ultrasonic) sensor readings are (proportionally) converted into stimulation signals received by the culture, effectively closing the loop. Figure 3, Modular Layout of the Robot/MEA For the software-hardware/robotic System framework we have selected the Miabot (see Fig.2), a commercially available robotic 4. Experimentation platform exhibiting very accurate motor We firstly conducted experiments in encoder precision (~0.5 mm) and speed a successful closed loop test with (~3.5 m/s). Recording and stimulation a model cell, which is an electronic hardware is controlled via open-source test circuit equivalent to a passive MEABench software[23]. The Miabot is live culture, i.e. it is a simulation of wirelessly controlled via Bluetooth. the culture when acting in an “ideal” The overall closed loop system therefore way. We then conducted the same consists of several modules including the experiment with a live culture. In robot, the MEA and stimulating hardware, order to do so, initially, an appropriate a directly linked workstation for conducting neuronal pathway within the culture computationally expensive neuronal data was identified and a suitable stimulus- analyses and a separate machine running response electrode pair were chosen the robot control interface – a sort of prior to the run. The pair was chosen network manager routing signals directly based on the criteria that the response between the culture and the robot body. electrode shows minimal spontaneous The modular approach to the problem can activity but responds robustly to stimuli be seen in more detail in Figure 3. (a positive-first biphasic waveform; Client code performs text logging of all 600 mV; 100 μs each phase) delivered important information during an experiment via the stimulating electrode. The run, which can then be analysed offline. robot followed a forward path within As a sampling frequency of 25 kHz of the its confines until it reached a wall, culture activity recording demands large at which point the front sonar value network, processing and storage resources, dropped below a set threshold

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 500 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

value (approximately 30 cm), triggering An indication of the robot’s typical a stimulation as shown in Figure 4. If the activity during a simple wall-detection/ responding electrode registered activity right turn experiment is shown in following the pulse, the robot turned in order Figure 4. The sonar threshold is set at to avoid the wall. The robot also turned approx. 0.3 cm from a wall, meaning spontaneously if activity was registered on that a stimulation pulse was applied to the response electrode, however the main the culture, via its sensory input, each results of interest were the chain of events: time this threshold was breached – Wall Detection–Stimulation–Response. essentially when the robot approached The model cell experiment provided sufficiently closely to a wall. Yellow a realistic representation of the maximum vertical bars in Figure 4 indicate speed at which the closed loop could electrode firing events - that is signals respond, dependant subsequently on appearing as responses on the output the “thinking” delay in the response of electrodes from the culture. These the culture. Such a study opens up the events are deemed ‘meaningful’ only possibility of investigating response times of in the case where the time separation different cultures under different conditions between stimulation and response and how they might be affected by external is under 100 ms. In other words the influences such as electrical fields and event is a strong indicator that the chemical stimulants. electric stimulation on the sensory/ As a follow up closed loop experiment input electrode subsequently caused the robot’s individual (right and left a neural response on the motor/output separately) wheel speeds were controlled electrode [25]. via the frequency recorded from the two chosen motor/output electrodes. Meanwhile received sonar information is used to directly control (proportionally) the stimulating frequency of the two sensory/ input electrodes. The setup is reminiscent of a simple Braitenberg model [20], however in this case the direct sensor-to-speed control Figure 4: Sensory-Motor sequence data for the culture (typical of early life). is being decided solely by the cultured network within the overall feedback loop. In Figure 4 the green trace indicates For comparative purposes the experiment the front sonar value on the physical has been performed with both real and robot base, giving a direct indication simulated robots. Run-times have only been of the closeness of an object (perhaps executed for approximately 30 min., which the wall of the corral) to the robot is not typically enough to evoke Long Term body. The yellow bars indicate Potentiation (LTP) plasticity effects between motor responses of the culture. A the stimulating-recording electrode sites [21, ‘meaningful’ event chain would be 22]. for example at 1.95 seconds, where

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 501 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

the sonar value drops below the threshold period of time within the robot body value (0.3) and a stimulation-response in its corral area. This experimentation sequence occurs. can take place for an hour or two every day. Although learning has not, Results Model Cell Live Culture as yet, been an immediate focus of the Wall -> Stimulation 100% 100% research, what has been witnessed event is that neuronal structures that bring Stimulation -> 100% 67% about a satisfactory action tend to Response event strengthen purely through the habitual Total closed loop 75 ms 200-500 ms process being performed (referred to time as Hebbian learning). This is mainly Run time 4 mins 2 mins 40 secs an anecdotal observation at this time, Meaningful turns 41 22 Spontaneous turns which it is wished to formalise and 41 16 quantify through a detailed analysis

using several cultures. Table 1, Basic statistics from the right-turn experiment. ‘Closed loop time’ refers to the time between wall Following the completion of these detection and a response signal witnessed from the first phases of the infrastructure setup, culture. ‘Meaningful turns’ refer to the robot turning a significant research contribution, it is due to a wall detection->stimulation->response chain felt, lies in the investigation of electrical of events. and chemical effects on the neural Table 1 contains typical results from a trial structure and the signalling pathways. run, firstly with the ideal model cell and Already tests have been carried out secondly with a cultured neural network to inhibit neural activity by applying acting as the sole controlling decision maker restrictive chemicals to regions of for the robot body. If the live culture acted the overall structure. The response “perfectly”, making no mistakes, then the two of the remainder of the structure columns (Model Cell and Live Culture) would is then being witnessed as to the be identical. This experiment has ‘closed effectiveness with which the remaining the loop’ inclusive of the custom stimulation structure takes on board actions and protocols and has set the basis for the responses previously manifested in the following experiments which will focus on now dead tissue – how does it learn characterising the culture responses and tasks previously carried out by the now include Machine Learning techniques for inactive neural pathways. performing more complex robot control. But the main role that the network will perform is that of memory 5. Medical Research elicitation. The mobile platform can be Initially the inherent operating characteristics taken to various positions and it can of the cultured neural network have been be witnessed what happens within the taken as a start point to enable the physical neural pathways at certain instances. robot body to respond in an appropriate Over a period of time the emphasis will fashion. The culture then operates over a be on studying how these pathways

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alter and the possibilities of strengthening likely to provide great insight into the the pathways for longer term performance. workings of the neuronal network by This will be more pertinent as the cell looking at the culture’s performance structures age (presently 3 months is about over a time period in terms of the the extreme) – different schemes will be effects on its neural plasticity. attempted to retain memory elements for as long as possible. Acknowledgements This work is funded by the UK 6. Conclusions Engineering and Physical Sciences The culture preparation techniques Research Council (EPSRC) under grant employed are constantly being refined and No. EP/D080134/1. have lead to successful and stable cultures that exhibit both spontaneous and induced References spiking/bursting activity. 1. Reger, B., Fleming, K., Sanguineti, A stable robotic infrastructure has also V., Simon Alford, S., Mussa-Ivaldi, F. been set up, tested and is in place for future (2000). Connecting brains to robots: machine learning and culture behaviour An artificial body for studying the experiments [26]. computational properties of neural There are a number of ways in which tissues. Artificial Life 6:307-324. the current system will be expanded in the 2. Holzer, R., Shimoyama, I., Miura, H. future. It is anticipated that the Miabot may (1997). Locomotion control of a bio- be extended to include additional sensory robotic system via electric stimulation. devices such as extra sonar arrays, mobile In proceedings of International cameras and other range-finding hardware Conference on Intelligent Robots and such as an on-board infra red sensor. A Systems, Grenoble, France. considerable current limitation is however 3. Talwar, S., Xu, S., Hawley, E., Weiss, the battery power supply of an otherwise S., Moxon, K. and Chapin, J. (2002). Rat autonomous robot. navigation guided by remote control. A main future consideration is therefore Nature, 417:37-38. the inclusion of a powered-floor for the 4. Chapin, J., Moxon, K., Markowitz, robot’s corral, to provide the robot with R. and Nicolelis, M. (1999). Real- relative autonomy for a longer period of time control of a robot arm using time. Future work will adapt a Miabot to simultaneously recorded neurons operate on an in-house powered floor, so in the motor cortex. Nature the robot can be provided with a constant Neuroscience, 2:664-670. power supply; this feature is necessary since culture behaviour tests will be carried out for many hours at a time. Progression of the project will require benchmarking the results obtained from the culture. This behavioural evaluation is

Of Mice and Men: Brain Cultured in the Laboratory Linked to a Physical Robot Body 503 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

5. Bakkum, D., Shkolnik, A., Ben-Ary, G., 12. Lewicki, M. (1998). A review Gamblen, P., DeMarse, T. and Potter, of methods for spike sorting: the S. (2003). Removing Some ‘A’ from detection and classification of AI: Embodied Cultured Networks. In neural action potentials. Network: Proceedings of the Dagstuhl Conference on Computation in Neural Systems. 9(4): Embodied Artificial Intelligence, pp. 130-145. R53-R78. 6. Thomas, C., Springer, P., Loeb, G., 13. Chiappalone, M, Vato, A, L Berwald-Netter, Y. and Okun, L. (1972). Berdondini, Milena Koudelka-Hep, Aminiature microelectrode array to monitor Sergio Martinoia (2007), Network the bioelectric activity of cultured cells. Exp. Dynamics and Synchronous Activity in Cell Res., 74:61-66. cultured Cortical Neurons, International 7. Gross, G. (1979). Simultaneous single Journal of Neural Systems, Vol.17, unit recording in vitro with a photoetched Issue.2, pp. 87-103. laser deinsulated gold multimicroelectrode 14. Shkolnik, A.C. (2003), Neurally surface. IEEE Transactions on Biomedical controlled simulated robot: applying Engineering, 26:273-279. cultured neurons to handle an 8. Pine, J. (1980). Recording action potentials approach / avoidance task in real time, from cultured neurons with extracellular and a framework for studying learning microcircuit electrodes. Journal of in vitro, Masters Thesis, Department of Neuroscience Methods, 2:19-31. Computer Science, Emory University, 9. Potter, S., Lukina, N., Longmuir, K. and Wu, Georgia. Y. (2001). Multi-site two-photon imaging of 15. DeMarse, T.B., Wagenaar, D.A., neurons on multi-electrode arrays. In SPIE Blau, A.W. and Potter S.M.. (2001), The Proceedings, 4262:104-110. Neurally Controlled Animat: Biological 10. Gross, G., Rhoades, B. and Kowalski, Brains Acting with Simulated Bodies. J. (1993). Dynamics of burst patterns AUTONOMOUS ROBOTS, Vol.11, generated by monolayer networks in Issue.3, pp. 305-310. culture. Neuronbionics: An Interdisciplinary 16. Rolston, J.D., D.A. Wagenaar, and Approach to Substitute Impaired Functions S.M. Potter. (2007), Precisely Timed of the Human Nervous Systems, H. Bothe, Spatiotemporal Patterns of Neural M. Samii and R. Eckmiller (Eds.), Amsterdam: Activity in Dissociated Cortical Cultures. North-Holland, pp. 89-121. Neuroscience, Vol.148, p. 294–303. 11. Kamioka, H., Maeda, E., Jimbo, Y. 17. DeMarse, T.B. and K.P. Dockendorf. Robinson, H. and Kawana, A. (1996). (2005), Adaptive flight control Spontaneous periodic synchronized with living neuronal networks on bursting during the formation of mature microelectrode arrays. Proceedings. patterns of connections in cortical neurons. 2005 IEEE International Joint Neuroscience Letters, 206:109-112. Conference on Neural Networks, Montreal, pp.1549-1551.

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18. Shahaf, G. and S. Marom. (2001), Learning 25. D.Xydas, D.J.Norcott, K.Warwick, in networks of cortical neurons. Journal B.Whalley, S.J.Nasuto, V.Becerra, Neuroscience, Vol.21, Issue.22, pp. 8782– M.Hammond and 8788. J. Downes, Architecture for Living 19. Bull, L and I. Uruokov. (2007), Initial results Neuronal Cell Control of a Mobile from the use of learning classifier systems to Robot, Proc. European Robotics control in vitro neuronal networks, in Symposium EUROS08, pp. 23-31, Proceedings of the 9th annual conference Prague, 2008 on Genetic and evolutionary computation. 26. D.Xydas, K.Warwick, S.J.Nasuto, (GECCO), pp.369-376, London, England. V.Becerra, M.Hammond, J.Downes, 20. B.Hutt, K.Warwick and I.Goodhew, S.Marshall and (2005), Emergent Behaviour in Autonomous B. Whalley, Living Neuronal Network Robots, Chapter 14 in “Information Transfer in Control of a Mobile Robot, International Biological Systems” (Design in Nature Series, Journal of Adaptive Contol and Signal Vol. 2), Bryant, J., Atherton, M. and Collins, M. Processing, to appear, 2009. (eds.), WIT Press. 21. L. Cozzi, P.D.A., M. Chiappalone, A.N. Ide, A. Novellino, S. Martinoia and V. Sanguineti,(2005)Coding and decoding of information in a bi-directional neural interface Neurocomputing, 65-66 (Computational Neuroscience: Trends in Research 2005): p. 783-792. 22. A. Novellino, P.D.A., L. Cozzi, M. Chiappalone, V. Sanguineti and S. Martinoia, (2007) Connecting Neurons to a Mobile Robot: An In Vitro Bidirectional Neural Interface. Computational Intelligence and Neuroscience, p. 13. 23. Wagenaar, D.A.D., T.B.; Potter, S.M., (2005) MEABench: A Toolset for Multi- electrode Data Acquisition and On-line Analysis. Proc. 2nd Int. IEEE EMBS Conf. Neural Eng.,: pp. 518–521. 24. Marks, P. (2008), Rat-Brained Robots Take Their First Steps, New Scientist, Vol.199, No.2669, pp.22-23.

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Rosalind Chapter 53: Affective Medicine: related to stress. We’ve been doing E. Picard / Affective Technology with Emotional Intelligence experiments in our lab where we Medicine: Rosalind W. Picard, Ph.D. bring in people, give them a task on Technology Director, Affective Computing Research the computer that mildly or strongly with Emotional Group, Massachusetts Institute of frustrates them, and measure how Intelligence in Technology Media Laboratory, Cambridge, “World Health they behave. Our aim is to try to MA, US Strategy” teach the computer how to recognize eBook, (Ed.) when the user is frustrated, irritated, Renata.G. Abstract Bushko annoyed, stressed or otherwise in or a long time people have kept FHTI, 2016. some significant emotional state, and Futureofhealth. emotions out of the deliberate tools org, From of medicine and science; scientists, then to equip the computer so that it Future of F can do a better job of serving people, physicians, and patients have often felt Health ideally not causing them so much Technology and sometimes expressed emotion, but no (Ed.) Renata G. tools could sense, measure, and respond stress. It’s recently become a joke in Bushko, IOS to their affective information. A series of the lab when some piece of equipment Press 2002 recent studies indicates that emotions, fails or causes aggravation – “is this particularly stress, anger, and depression, one of Picard’s affective computing are important factors with serious and experiments designed to irritate me?” significant implications for health. This What could technology do if it could paper highlights research at the MIT sense that the user is frustrated or Media Lab aimed at giving computers the otherwise in some unusual emotional ability to comfortably sense, recognize, state? Could the system change or be and respond to certain aspects of human changed, so as to reduce frustration emotion, especially affective states such as in the future, or could it help the user frustration, confusion, interest, stress, anger, then and there to feel less stress? and joy. Examples of recently developed systems are shown, including computer Our research has focused on both systems that are wearable and computers approaches: identifying components that respond to people with a kind of active of computer interfaces that could listening, empathy, and sympathy. Results be improved by designers, as well are reported for computer recognition of as having the computer help users emotion, for teaching affective skills to manage strong negative emotions autistics, and for having computers help better. This is all part of our effort in users manage emotions such as frustration. “affective computing,” computing that relates to, arises from, or deliberately 1. Introduction: Frustration, Irritation, influences emotion [18]. This article Stress and Health will focus the topic further -- on some Perhaps the most common emotions people recent findings about emotion and feel in interacting with today’s technology medicine -- together with examples are frustration, irritation and other feelings of new affective technology we are

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developing that has potentially interesting down with a cold or upper- and important implications for health." respiratory infection. Stress is increasingly recognized as a Depression: In work cited by medical problem. A recent Blue Cross Blue James Strain, where 100 patients Shield survey in New England cited the received bone marrow transplants, number one health concern of members in a follow-up study was conducted this part of the United States to be stress of the 13 who had been depressed – rated above cancer, AIDS, high blood vs. the other 87. Of the 13 who had pressure, and other medical conditions. depression, only 1 was alive a year Dan Goleman, in Chapter 11 of his book later; of the other 87, 34 were still Emotional Intelligence [7], cites a number of alive two years later. Another study, studies pointing to important roles in health and medicine for emotions – particularly by Howard Burton et al., associated states of stress, anxiety, chronic anger, and early death of dialysis patients with depression. Following are just a few of the depression: depression was found examples that he includes: to be a stronger predictor of death Stress/distress: Studies of the physical than any medical sign. Similarly, manifestations of stress reveal many heightened risk of death from measurable changes caused by stress heart disease has been correlated in the human body, influencing not only with an ongoing sense of despair immune system functioning but also and hopelessness. The effect heart rate variability, blood pressure, and of depression on heart attack other important bodily functions. Several survivors is as great as that of major studies have been conducted examining medical risks such as left ventricular the impact of stress on immunity. For dysfunction or a history of previous example, Sheldon Cohen, a psychologist heart attacks.Anger: Dr. Redford at Carnegie-Mellon University exposed Williams at Duke University found people to a cold virus after assessing how much stress they were experiencing that physicians who scored highest in their lives. Of course, a robust immune on tests of hostility while they were system usually resists a virus, so mere in medical school were seven times exposure doesn’t mean you will get sick. as likely to have died by the age of Cohen found that 27% of the low-stress fifty as those who scored low on the subjects came down with a cold while hostility tests – their tendency to get 47% of the high-stress people came angry was found to be a stronger down with the cold. In another study of predictor of early death than were married couples who kept daily logs of factors such as high blood pressure, hassles and upsetting events, a strong high cholesterol, and smoking. pattern emerged: three or four days after Findings by Dr. John Barefoot at the an especially intense marital fight or other University of North Carolina show upset, they came that scores on a test of hostility

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correlate with the extent and severity of desktop, laptop, and palmtop, coronary artery disease in heart patients technology is now embedded into undergoing angiography. appliances, clothing, jewelry, implants, The studies above are but a few of the many and even pills we can swallow. With that reveal emotion to be a measurably all these new forms, technology has important health factor. Note that none of the the opportunity to detect physical studies show that emotions cause medical and physiological expressions of illness – rather they contribute to decreases many human emotional states. With in immune system functioning and to other additional sensing and processing, the physical factors that may significantly expressions of emotional state can be prolong or exacerbate an illness. It is fool associated with other events – such hink that “positive thinking” or “making as what the person is doing when yourself happy” can prevent all illness; they get angry or stressed, what else it is also foolish to continue to think that is happening in their body concurrent emotions have no significant effect on health with episodes of depression, (perhaps – the truth appears to lie somewhere in the related to their heart functioning or middle, with emotions playing not the only their physical activity level) or what the role, but an important measurable role that interface (if the person is interacting has typically been ignored. with one) may have just done [19]. In the Affective Computing group at The rest of this paper is divided MIT, we are particularly interested in the into four areas: (1) Sensors that enable intelligent handling of affective states the user to communicate information commonly expressed around computer related to emotion in a way that systems: frustration, confusion, disliking, is physically and psychologically liking, interest, boredom, fear, distress, comfortable; (2) Progress in computer and joy. Computers and other forms of recognition of emotion; (3) Tools for technology are interacting with people in helping people learn affective skills, more ways than ever before – beyond including a system for autistic kids;

Figure 1. Stress is a significant factor in health; it arises in many forms when interacting with technology.

Affective Medicine: Technology with Emotional Intelligence 508 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

(4) Respectfully handling emotions, such as possibilities for those who want to reducing user frustration. communicate and better understand affective information. The tools 2. Comfortable Sensing of Signals include new hardware and software Emotions often involve both thinking and that we have developed to enable feeling – both cognitively experienced certain machines not only to receive events and physical changes in the body. emotional expression, but also to Although there is no technology that can recognize meaningful patterns of truly read your thoughts, there are a growing emotional expression. In particular, we number of sensors that can capture various have integrated several physiological physical manifestations of emotion -- video sensors into clothing and jewelry – a recordings of facial expressions and posture blood volume pressure sensor in an or gesture changes, microphone recordings earring, skin conductivity in a shoe of vocal inflection changes, skin-surface and a glove, respiration in a sports bra, sensing of muscle tension, heart-rate and more [19] (See some examples in variability, skin conductivity, blood-glucose Figure 2). These sensors communicate levels, and other bodily changes, and (if with new wearable computers that can invasiveness is allowed), swallow-able or control peripherals such as a wearable implant-able sensors or means of capturing music player/DJ [8] or a wearable bodily fluids for analysis. These are just a camera [10]. For example, the wearable few of a growing number of possibilities. camera system we built saves video Our research efforts include building based on your arousal response tools to facilitate multiple forms of emotion tagging the data not just with the usual sensing, not to force this on anyone, but to time stamp, but also with information allow for a larger space of about whether or not it was exciting

Figure 2. Emotion influences many changes in the body. These patterns of change can be sensed by various new wear-able or swallow-able technologies.

Affective Medicine: Technology with Emotional Intelligence 509 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

to you, as indicated by patterns it detects in can increase significantly with physical your skin conductivity [10]. The same system exertion or with sneezing, as well as could potentially be modified to detect and with anger and other affective states. communicate health-related variables to you Inferring the source of a change is and your physician, perhaps for monitoring easier if you can independently detect and analyzing patterns of stress, anger, or the change – such as via context depression. sensors that indicate the person’s With any wearable system there are movement or activity. design issues regarding not only what is to One of the physiological sensing be sensed, but also how the sensing system systems we built that is robust to can be made comfortable and robust to motion artifacts is the “Conductor’s noise that arises from activity unrelated to Jacket,” one version of which is shown the signal being measured. The key source in Figure 3. This highly expressive of noise when measuring emotion from wearable system, created by Teresa ambulatory patients is artifacts that arise from Marrin, associates patterns of muscle physical activity. Heart rate, for example, tension and breathing with expressive

Figure 3. The “Conductor’s Jacket” used both for gathering physiological changes related to expression and for controlling MIDI output.

Figure 4. Wearable systems can be increasingly hidden in ordinary clothing; their form factor can be modified to not impair social interaction.

Affective Medicine: Technology with Emotional Intelligence 510 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

gestures that the conductor uses to shape almost everything hidden under the the music. Seven electromyogram (EMG) tuxedo, and he asked us to redo it and one respiration sensor are included “in red, with the wires in silver on the in the version shown here. The EMG’s are outside for all to see.”) We found that attached with custom-fit elastics sewn into when we integrated sensors with the the shirt, so that they remain snug without “lizzy” wearable (Figure 4, at right) that strong adhesives, and yet do not move the private eye output display was an as the arms are moved. This wearable impediment to social interaction, and system was designed first to measure the input device (chording keyboard) how professional and student conductors took too long for subjects to learn. naturally communicate expressive Consequently we modified a Palm information to an orchestra. After analyzing Pilot to serve as an input/output real conducting data from six subjects, device to the wearable, allowing the Marrin found around thirty significant Palm to display physiological signals expressive features (largely related to and receive annotations for them. muscle tension changes that signaled Although a palm device is not hands- interesting musical events) [16]. She has free like a heads-up display, it is more subsequently developed a version of the comfortable for many people in social jacket that transforms natural expressive settings. gestures of the wearer into real-time Emotions modulate not only the expressive shaping of MIDI music [17]. A modes shown in Figure 2, but also professional conductor, Marrin is currently many others, including hormone and using the jacket both for live performance neurotransmitter levels. The latter are and for helping educate student conductors, currently not easy to sense without providing precise feedback on timing, drawing saliva or blood or using tension, and other important aspects of other invasive procedures. Presently, expressive technique. none of these procedures provides In addition to the goal of making instantaneous wireless access to wearable sensing devices robust and the changing levels. However, physically comfortable, we have been new implant-able and swallow-able concerned about the psychological sensors are being developed by factor – how do these sensors feel from many researchers, exploiting strides a personal comfort standpoint and within in nanoscale technology, and giving a social setting? We do not believe there access to internal bodily signals is a one-size-fits-all answer, but rather we previously unavailable in real time find that people like to exercise choices; in (e.g., Figure 5, courtesy of Prof. many cases, these choices include hiding Scott Manalis at MIT) Sometimes, the sensors, so that they are not visible social-psychological concerns (although a notable exception was one of such as privacy make one form of the professional conductors we worked sensing preferable to another. For with – we took him a sensor jacket with example, although one person might

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be comfortable communicating facial for each emotion, this was not always expressions to a computer using a video the case; in general, the variations camera, another might be concerned within the same emotion from day to about the identifying information that the day exceeded the variations in camera would see. In distance learning different emotions on the same day. and in intelligent tutoring systems, there is Using a variety of methods of pattern an opportunity for the student to transmit recognition and baselining, we have signals such as confusion or interest in obtained recent results of 81% real-time, without having to stop and click recognition accuracy in selecting which on anything that interrupts their attention of eight emotions was expressed by [22], and without giving away their identity. an actress, given 30 days of data, eight One means of accomplishing this is via a emotions per day, and features of the wearable sensing system designed and built four signals: respiration, blood volume by research assistant Jocelyn Scheirer, the pressure, skin conductivity, and muscle “expression glasses” described in the next tension. (See Healey and Picard (1998) section. and Vyzas and Picard (1999) for details of the data collection and the recognition algorithms [9], [25].) The eight emotions investigated were: neutral, hatred, anger, romantic love, platonic love, joy, and reverence. These are the best known results to date for emotion recognition from physiology, and they lie between machine recognition results of affect from speech and of affect from facial expressions. Figure 5. New forms of sensing enable real-time It should be noted that these results wireless readout of internal bodily signals such as are for a single user, and they are temperature or pH. obtained by a forced selection of one 3. Computer Recognition of Emotional Expression of the eight categories; hence, these One of the wearable-computing platforms results are comparable to recognition we built includes a small A-to-D with eight results in the early days of speech channels for physiological sensing. We have recognition, when the system was re- developed algorithms that run on the trained for each speaker, and it knew wearable system, extract features from the that the person was speaking one of physiological signals, and relate these to a eight words, although there could be deliberately expressed emotion. Short variation in how the person spoke the segments of four physiological signals for words from day to day. Much more two emotions are shown in Figure 6. work remains to be done to Although the segments here look different understand individual differences as

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well as differences that depend on context patterns detected by our Hidden- – whether developmental, social, or cultural. Markov-Model based approach were I expect that, like research in speech able to significantly discriminate these recognition, this work will gradually expand two kinds of episodes [5]. However, to be able to handle speakers from different the recognition results were still far cultures, of different ages, speaking (or from perfect, indicating that although expressing) continuously, in a variety of this information is helpful, it must be environments. combined with other signals for a more Figure 6 (right) shows a computer task confident decision. and data-gathering system we designed that Stress is sometimes a by-product of was intended to induce negative stress and feelings such as confusion, which a collect data synchronized with the stress- person may choose to communicate eliciting events [21]. We gave the user a goal by furrowing his or her brow. The with incentive: race through the task as furrowing of the muscle can be quickly as possible, obtain the best score (a detected by a camera if lighting and mix of accuracy and efficiency) and win a head position is carefully restricted $100 prize. Along the way, we had the (otherwise current computer vision system freeze up as if the mouse was not techniques are inadequate) but these working, delaying their progress. We restrictions, coupled with the recording continuously measured two physiological of identity, can make some subjects signals—skin conductivity and blood volume uncomfortable. An alternative sensor pressure—then compared patterns in these to a camera is a pair of wearable signals when all was going smoothly vs. “expression glasses” (Figure 7) that during the episodes of unexpected delays. senses changes in facial muscles [22]. Although we cannot determine whether These glasses have a small point of these episodes corresponded to true contact with the brow, but otherwise feelings of frustration or non-frustration, we are considered by some users to be did find that in 21 out of 24 subjects, the less obtrusive than a camera in that the

Figure 6. Examples of four physiological signals sensed during different emotional

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glasses offer privacy, robustness to lighting communication that humans use changes, and the ability to move around concurrently while engaged in freely without having to stay in a fixed conversation, learning, and other position relative to a camera. The activities. drivers trying to do more than expression glasses can be used while concentrating on a task – the wearer does not have to stop and think about how to communicate a facial expression. The glasses can be activated either unconsciously or consciously. People are Figure 7. Expression glasses sense facial free to make false expressions, or to have a muscle changes and detect furrowing “poker face” to mask true confusion if they of the brow, a signal sometimes used to do not want to communicate their true communicate confusion. feelings, but if they want to communicate drive. We have conducted them, the glasses offer a virtually effortless experiments measuring the impact of way to do so. low and high cognitive load tasks on Why wear expression glasses, instead of drivers talking over a telephone raising your hand or pushing a button to say headset while driving in a simulator. We you’re interested or confused, as was placed drivers under different load implemented decades earlier [23] by conditions (fast or moderate speed, Sheridan and his colleagues? The answer and fast or slow questioning with is not that there should be one or the other; simple arithmetic problems like “12 + both kinds of feedback offer advantages. 14”) while otherwise keeping the driving Sometimes people miss the subtlety of this task the same. The drivers were point: affect is continuously communicated occasionally exposed to signs labeled while you are doing just about anything. “brake” or “continue” and were When you pick up a pen, you tend to do so instructed to brake as soon as they very differently when you are angry vs. when saw the brake message. Most drivers you are joyful. When you watch somebody, braked within 0.7-1.4 seconds after the your eyes behave differently if you are message; however, there were a interested than if you are bored. As you number of incidents where braking listen to a conversation or a lecture, your took place 1.5-3.5 seconds after the expression gives the speaker feedback, brake message, or not at all. In almost unless, of course, you put on a poker face. all of the latter cases, the subject was In contrast, if you have to think about talking on the phone. On average, the pushing a button to communicate your drivers talking on the phone had feelings, or to raise your hand to say you’re reaction times to brake messages that confused, then you have to interrupt your were 10% slower than when they were concentration to take such an action. Self- not on the phone; more importantly, report is important, but it is no substitute for the variance in their braking times was the natural channels of largely non-verbal four times higher – suggesting that

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although delayed reactions were infrequent, Our research is developing means when delays happened they could be very of recognition of physiological patterns large and potentially dangerous. The fact related to stress in many different that they didn’t happen often could natural environments. We have furthermore create a false sense of security. recently moved outside the world Although physiological data gathered in of simulators and equipped a car to these experiments was limited, our analysis examine driver behavior features joint indicated a potential for recognizing patterns with physiological information. One that might indicate whether or not a driver such sensor set-up is shown in Figure was likely to respond with a slowed reaction 8 (right). In a recent set of experiments or not [24]. we induced stress in a dozen drivers We are beginning to analyze affect in by having them drive around Boston speech, an area in which humans perform at under four stress-eliciting conditions only about 60% accuracy (on roughly eight while we recorded electrocardiogram, emotion categories, when the content of the skin conductivity, respiration, blood- speech is obscured). Our initial focus is on volume pressure, and electromyogram speech from drivers, taken from the signals, together with video and other experiment above, examining if the driver’s information about the driver’s behavior vocal characteristic under different load and context. Knowing how stressed conditions shows reliable indications of somebody truly became is hard to stress [6]. As manufacturers put more assess; therefore, we used three gadgets in cars, such as talking navigation different methods of assessment: self- systems and restaurant guides or grocery report of the driver, driving condition reminders triggered by GPS-sensed (rest, busy city, easy highway, tolls/ location, there is increased potential that the turn-around), and third-party coding of driver might be interrupted at a stressful time complexity level based on number of that could diminish safety. Another human events each minute during the driving passenger would be able to sense if the situation. Our analysis of patterns of timing was good or not and make a safer driver physiology, led to an average decision about interrupting the driver; stress recognition rate of from 89- however, the systems being put into cars are currently oblivious to these factors. If the driver is conversing with one of the car systems, he or she may be distracted at a bad time, compromising safety. We are trying to give the system the ability to sense stress pattern changes in the driver’s speech Figure 8. Stress was measured from vocal intonation and from driving behavior when (as well as responsiveness patterns in the drivers were given tasks over a phone driver’s behavior, per above) so that the car headset (left). We designed and integrated can be more sensitive to the safety factor. a physiological sensing system into a Volvo for measuring bodily signals related to stress among Boston drivers out on the road (right).

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96% accuracy depending on which of three For one student, the pattern changed methods was used for labeling the “true” very slowly, becoming stable red stress level of each subject [11]. when I started asking some research An increasing amount of human-human questions. I thought nothing of it, communication takes place through because he could have simply been machines. In many cases it would be helpful squeezing the phone more tightly by if the machine would simply facilitate the shifting his position. However, even transmission of affective cues. An example though he knew that I could not tell his of a system designed to expand human- feelings from the color, he expressed human communication capabilities via to me that he wasn’t trying to squeeze computer is the TouchPhone, developed it tighter at all and he thought it by Jocelyn Scheirer in our lab (Figure 5). was red because he was stressed The TouchPhone augments regular voice about a question I asked him. The communication with pressure information student was a non-expressive male indicating how tightly the speaker is holding engineer who had never revealed the phone. For example, if you routinely talk such signs of stress to me in the years to an elderly parent by phone, this would of conversations we had had prior to enable you to not only hear their voice, this TouchPhone conversation. The but also to see how they were holding the technology thus facilitated opening phone: Is it the same as most days? Or up a greater range of emotional today does their grip seem weaker, tense, or communication – by his choice – it more fidgety? The pressure is continuously did not impose this, but simply made it mapped to a color seen by the person on easier for him. The color did not give the other side – calibrated to blue if light away how any of the students was pressure is applied – and to red if strong truly feeling. However, the system pressure. The computer performs no provided a new channel of non-verbal interpretation of this signal; the color signal communication that, in turn, could and is simply transmitted to the conversational did sometimes open up a new line of partner as an additional low bit-rate channel verbal communication of information. I met with four of my students for four hours of TouchPhone conversations and the results, while anecdotal, were interesting and were consistent with experiences we have had with other emotion-communication technologies. I found that each of the Figure 9. System that senses how phone four students had a nearly unique color is being held (left.) Examples of intonation pressure pattern, which was distracting changes in annoyed and sad speech (right). until I moved the pattern into my periphery where it became ambient, adding a flavor of background rhythm to the conversation.

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and understanding the emotional expressions of people if given lots of examples to learn from and extensive training with these examples. We have developed a system— “ASQ: Affective Social Quotient”— Figure 10. The “ASQ” Computer system shows video aimed at helping young autistic clips to autistic kids and prompts them to choose the children learn to associate emotions stuffed dwarf that expresses the emotion appropriate with expressions and with situations. to the video scene. The system senses the child’s response and rewards accordingly. The system plays videos of both natural and animated situations giving 4. Helping Build Human Emotional Skills rise to emotions, and the child interacts Computers just “don’t get it” when it comes with the system by picking up one or to practicing many of the social-emotion more stuffed dwarfs that represent skills that most of us take for granted. the set of emotions under study, and Although autism is a complex disorder, and that wirelessly communicate with some of the comments here will not apply the computer. This effort, led by my to all autistics, there are nonetheless some student Kathi Blocher, has been tested intriguing characteristics that many autistics with autistic kids aged 3-7. Within share with computers. Both tend to have the computer environment, several difficulty with social-emotional cues. Both kids showed an improvement in their tend to be poor at generalizing what they ability to recognize emotion [1]. More learn, and learn best from having huge extensive evaluation is needed in numbers of examples, patiently provided. natural environments, but there are Both can be fabulous at certain pattern already encouraging signs that some recognition tasks. Autistics, like computers, of the training is carrying over, such also may have very good visual memories. as reports by parents that the kids Many autistics have indicated that they like asked more about emotions at home, interacting with computers, and some have and pointed out emotions in their indicated that communicating on the web interactions with others. Despite “levels the playing field” for them, since these successes, this work is only one emotion communication is limited on the small step; the difficulties in teaching web for everyone. an autistic to appropriately respond Because many of the issues we face to an emotional situation are vast, in giving computers skills of emotional and we will no doubt face similar intelligence are similar to those faced difficulties for a long time in trying to by therapists working with autistics, we teach computers how to respond have begun collaboration with these appropriately. experts. Current intervention techniques for autistic children suggest that many of them can make progress recognizing

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5. Respectfully Handling Emotions admitted to a 42% higher consumption Not only do many people feel frustration of alcohol when interviewed by and distress with technology, but also they computer than when interviewed for show it. A widely publicized 1999 study by the same information by psychiatrists Concord Communications in the U.S. found [15]. that 84% of help-desk managers surveyed Suppose that a computer could said that users admitted to engaging in detect patient stress or frustration “violent and abusive” behavior toward with high confidence, or that a computers. A survey by Mori of 1250 people person directly reports frustration to who work with computers in the UK reported the machine so that some kind of that four out of five of them have seen response by the machine might be colleagues hurling abuse at their PC’s, while appropriate. How should the computer a quarter of users under age 25 admitted respond? to having kicked their computer. It seems Goal: that no matter how hard researchers work Reduce user frustration once it has on perfecting the machine and interface occurred design, frustration still occurs. In fact, even Strategy: if computers were as smart as people, they 1. Recognize (with high probability) would still sometimes frustrate people; the that the situation may be same is true in human-human interaction: frustrating, or that the user is even the most intelligent people sometimes showing signs of frustration likely frustrate others. Hence, there is a need to due to the system address frustration at run-time – detecting it, 2. Is user willing to talk? If so, then Practice active listening, with and responding to it. empathy and sympathy, e.g., This need is particularly important in “Good to hear it wasn’t terribly light of the impact of stress on health, frustrating” and the important role of computers in “Sorry to hear your experience increasing interacting with patients. In some wasn’t better” cases, patients prefer giving information “It sounds like you felt fairly to a computer instead of to a doctor, even frustrated playing this game. when they know the doctor will see the Is that about right?” information: computers can go more slowly Allow for repair, in case computer if the patient wishes, asking questions at the has “misunderstood” In extreme patient’s individual speed, not rushing, not cases, the computer may even appearing arrogant, offering reassurance apologize: and information, while allowing the physician “This computer apologizes to you more time to focus on other aspects of for its part in ..” human interaction [3] [2]. Also, in some 3. Polite social closure cases, patients have reported more accurate information to computers; those referred for assessment of alcohol-related illnesses

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game to freeze, thereby thwarting their attempt to show their intelligence or win a prize). Afterward, subjects would interact with the agent, which was designed to help them reduce their frustration. Finally, they would have to return to the source of their frustration and engage again with the game, at Figure 11: The 2x3 experimental design, comparing which point we measured how long the emotion-support agent and two control they continued to interact with it. Our conditions in both a low-frustration condition and a high-frustration condition. prediction was based on human- human interaction: if somebody In developing this system, we avoided frustrates you, and you are still highly language where the computer might refer to frustrated when you have to go back itself as “I” or otherwise give any misleading and interact with them, then you will implications of having a “self.” The system minimize that interaction; however, if assesses frustration and interacts with the you are no longer feeling frustrated, user through a text dialogue box (with no then you are likely to interact with them face, voice, fancy animation or other devices longer. The 2x3 experimental design is that might provoke anthropomorphism.) The shown in Figure 6, where thirty-four only aspect of the interaction that evokes users played the game in a low- another person is the use of language, frustration condition, while thirty-six which although cleansed of references to played the same game with simulated self, nonetheless was made deliberately delays. friendly in tone across all control and test We ran three cases for each of the conditions, so that friendliness would not be low and high frustration conditions. a factor in this study. The first two cases were controls, text- The emotion support agent was tested based friendly interactions having with 70 users who experienced various essentially the same length as the levels of frustration upon interacting with a emotion-support agent. The first simulated network game [14]. We wanted to control (ignore) just asked about the measure a strong behavioral indication of game, ignoring emotions, and the frustration, since self-report is notoriously second control (vent) asked about the unreliable. Thus we constructed a situation game, but then asked questions about where people were encouraged to do their the person’s emotional state and gave best while test-playing an easy and boring them room to vent, with no active game, both to show their intelligence, and to listening, empathy or sympathy. After win one of two monetary prizes. Half of the interacting with one of the three subjects were exposed to an especially (ignore, vent, or emotion-support), each frustrating situation while they played player was required to return to the (simulated network delays, which caused the game, and to play for three minutes,

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after which the quit button appeared and significant medical factors, even when they could quit or play up to 20 minutes the patient might not mention them. more. Compared to people in the ignore Although our findings of a computer’s and vent control groups, subjects who ability to reduce stress were only interacted with the emotion-support agent based on one kind of stress-provoking played significantly longer, behavior situation, the strong behavioral effect indicative of a decrease in frustration. we obtained in just a few minutes of People in the ignore and vent cases both addressing the emotion, suggests that left quickly, and there was no significant perhaps something significant can be difference between their times of play. We done by physicians to address also analyzed the data to see if there were emotions related to health, even within any significant effects with respect to the limits of a brief office encounter. If gender, trait arousability, and prior game a computer in a few minutes can playing experience; none of these factors produce a significant behavioral effect, were significant. (For more details regarding how much more effect could a truly this system, experiment, and findings, see sensitive and caring emotion-savvy Klein (1998) [13]). person have in the same amount of These results suggest that today’s time? machines can begin to help reduce frustration, even when they are not yet smart 6. Concluding Remarks enough to identify or fix the cause of the This paper has highlighted several frustration. Our findings further indicate that it research projects in the MIT Media takes very little time to help the user reduce Lab’s Affective Computing Research stress – the emotion savvy agent took no group. The selected projects are more time than the two controls, and all of believed to be relevant for future the interactions took around 4-6 minutes. health because they advance the state This time included not only addressing the of the art in physiological sensing, in person’s feelings, but also asking several recognition of emotional signals, in questions about the game. In other words, development of emotional skills, and in less than a few minutes of addressing the use of computers to help people emotion were sufficient to provide a manage emotions. Based on the significant behavioral change in the user. growing number of studies showing Today, physicians usually have so little that emotions such as anger, anxiety, time with patients that they feel it is depression and stress are significant impossible to build rapport and medical factors, helping people better communicate about anything except the manage these emotions becomes a most obviously significant medical issues. key form of preventive medicine. As However, given findings such as those computers assist in gathering highlighted at the start of this paper, information from patients, in helping emotional factors such as stress, anxiety, medical patients communicate with depression, and anger can be highly one another and with care-providers,

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and in disseminating information to patients, disease prevention. I do not wish to the need grows for affective intelligence in see the scale tilted the other way, the computer interface. Patients who have where machines twitch at every their feelings properly addressed are more emotional expression, or where likely to leave satisfied, are less likely to physicians treat emotion and not the return as often, and are less likely to incur accompanying medical problems. legal cost [7]. These effects translate into What is needed is a reasonable dollars saved, so that respecting and balance. The aim of new affective responding to patients’ emotions is good technologies for medicine should be to medicine and good business. help medical care givers attend to Research into the development of patients’ full health needs – both affective technologies is relatively new, and emotional and non-emotional–in a many other labs have recently started similar balanced, respectful and intelligent projects, so that it would take a much longer way. paper to overview all the research in this area. There are also many exciting findings References relating affect and cognition, such as those [1] Blocher, K., “Affective Social Quotient of Isen and colleagues showing a significant (ASQ): Teaching Emotion Recognition impact of a mild positive state on medical with Interactive Media & Wireless decision making – facilitating efficiency and Expressive Toys,” MIT SM Thesis, May thoroughness in medical diagnostic 1999. reasoning [4], with a number of other [2] Card, W. I. and Lucas, R. W., “Computer interrogation in medical benefits [12]. Readers who are interested in practice,” Int. J. Man-Machine related work are encouraged to visit the Studies,14, 49-57, 1981. references of the papers cited at the end of [3] Dove, G. A. W., Wigg, P., Clarke, this document, which contain over a J.H.C., Constantinidou, Maria, Royappa, hundred pointers to related research B. A., Evans, C. R., Milne, J., Goss, C., conducted beyond our lab. Gordon, M. and de Wardener, H. E., Over the years, scientists have aimed to “The therapeutic effect of taking a make machines and technologies that are patient’s history by computer,” J. of the intelligent and that help people be Royal College of General Practitioners, intelligent. However, they have almost 27, 477-481, 1977. completely neglected the role of emotion in [4] Estrada, C. A., Isen, A. M., and intelligent interaction, leading to an Young, M. J. “Positive affect facilitates imbalance where emotions are typically integration of information and ignored. Similarly, emotions have been decreases anchoring in reasoning among physicians.” Organizational largely ignored in the general medical Behavioral and Human Decision community, with the exception of many Processes, 72, 117-135, 1997. recent investigations that have measured [5] Fernandez, R. and Picard, R. W., “Signal their impact and found emotion to be a Processing for Recognition of Human Frustration,” significant factor in health recovery and in Proc. IEEE ICASSP ’98, Seattle, WA, 1997.

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[6] Fernandez, R. and Picard, R. W., [17] Marrin, T., “Inside the Conductor’s “Modeling Drivers’ Speech under Stress,” Jacket: Analysis, Interpretation, and Proc. ISCA Workshop on Speech and Musical Synthesis of Expressive Emotions, Belfast, Sep 2000. Gesture,” MIT PhD. Thesis, Media Arts [7] Goleman, D. , Emotional Intelligence, and Sciences, 1999. Bantam Books, New York, 1995. [18] Picard, R. W., Affective Computing, [8] Healey, J., Dabek, F. and Picard, R. W., MIT Press, Cambridge, MA, 1997. A New Affect-Perceiving Interface and its [19] Picard, R. W, and Healey, J., Application to Personalized Music Selection, Affective Wearables, Personal Proc. 1998 Workshop on Perceptual User Technologies 1, No. 4 , 231-240, 1997. Interfaces, San Francisco, CA, 1998. [20] Reeves B. and Nass, C. (1996). [9] Healey, J. and Picard, R.W. , “Digital The Media Equation, Cambridge Processing of Affective Signals,” Proc. Int. University Press; Center for the Study Conf. on Acoustics, Speech, and Signal of Language and Information. Processing, Seattle, WA, May 1998. [21] Riseberg, J., Klein, J., Fernandez, [10] Healey, J. and Picard, R. W. , StartleCam: R. and Picard, R.W., “Frustrating the A Cybernetic Wearable Camera, Proc. Intl. User on Purpose: Using Biosignals Symp. on Wearable Computing, Pittsburgh, in a Pilot Study to Detect the User’s PA, 1998. Emotional State,” CHI ’98 Short Papers, [11] Healey, J. A. “Wearable and Automotive Los Angeles, CA. A longer version Systems for Affect Recognition from of this paper has been accepted Physiology,” Ph.D. Thesis, Dept. of Electrical for publication in Interaction with Engineering and Computer Science, May Computers, 1998. 2000, MIT. [22] Scheirer, J., Fernandez, R. and [12] Isen, A. M., Positive Affect and Decision Picard, R.W., “Expression Glasses: A Making, in Handbook of Emotions, Eds. M. Wearable Device for Facial Expression Lewis and J. Haviland, Guilford Press, NY, Recognition,” CHI ’99 Short Papers, 2000. Pittsburgh, PA, 1999. [13] Klein, J., “Computer Response to User [23] Sheridan, T. B., “Community Dialog Frustration,” MIT SM Thesis, Media Arts and Technology”, Proc. of the IEEE, 63, No. Sciences, June 1998. 3, March 1975. [14] Klein, J., Moon, Y, and Picard, R. W., “This [24] Vyzas, E. “Recognition of Computer Responds to User Frustration.” Emotional and Cognitive States Using CHI 99 Short Papers, Pittsburgh, PA. A Physiological Data,” Mechanical longer version has been accepted for Engineer Thesis, June 1999, MIT. publication in Interaction with Computers. [25] Vyzas, E., and Picard, R. W. , [15] Lucas, R. W., Mullin, P. J., Luna, C. B. “Online and Offline Recognition of X., and McInroy, D. C., “Psychiatrists and a Emotion Expression from Physiological Computer as Interrogators of Patients with Data,” Workshop on Emotion-Based Alcohol-Related Illnesses: A Comparison,” Agent Architectures at the Int. Conf. on Brit. J. Psychiat., 131, 160-7, 1977. Autonomous Agents, Seattle, WA, 1999. [16] Marrin, T. and Picard, R. W. , “Analysis of Affective Musical Expression with the Conductor’s Jacket,” Proc XII Col. Musical Informatics, Gorizia, Italy, 1998.

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Timothy Chapter 54: Future of Caring Machines those who are surrounded by people Bickmore, may not always get the comfort, caring Rosalind W. Timothy Bickmore, Ph.D. Picard/ Future Assistant Professor, College of Computer and attention they need to thrive. of Caring and Information Science, Northeastern These unmet emotional needs are not Machines in University, Boston, MA, USA just frivolous desires whose neglect is World Health inconsequential; a significant body of Strategy” Rosalind W. Picard, Sc.D. eBook, www. Director, Affective Computing Research research now indicates that addressing Futureofhealth. Group, MIT Media Laboratory, Cambridge, an individual’s needs for emotional org (Ed.) MA, USA care-taking is essential for maximizing Renata G. their health and well-being. Bushko, FHTI, 2016. Abstract Over the last decade, researchers Intelligent and eeling cared for has profound effects in affective computing—that which Extelligent on physiology, cognition and emotional relates to, arises from, or deliberately Health state, and has significant health influences emotions [1]—and related Environment F (Ed.) Renata G. ramifications whether the source of this disciplines have developed a number Bushko, IOS feeling is an intimate other, friend or health of technologies and performed a wide Press 2005 provider. Unfortunately, not everyone has range of experiments that demonstrate access to social networks populated with that an individual’s need for caring caring individuals or has health providers could be met (at least partially) by who are patient, empathic and reliably computational artifacts ranging from available when emotional support is computer agents to wearable needed. Over the last decade, a range of computers to robots. computational artifacts and technologies In this chapter, we first review the have been developed that could help fill this literature on human-human and animal- unmet need in many peoples’ lives. Caring human caring and their known effects machines are technologies that interact with on health. We then review the research an individual to accomplish a goal while also that has been conducted over the last behaving in ways that give the individual the decade on technology development feeling of being cared for. This chapter and experiments that serve to work presents evidence that these machines can towards the goal of building machines begin to lead to significant health benefits, that people feel care about them. We such as increased adherence to prescribed close with some observations and health behavior change and medication visions about the possible futures of regimens. caring machines

1. Introduction 2. Human-Human Caring and Health People cannot always get the support that Implications they need. As families become more Feeling cared for has profound effects geographically dispersed and as the on physiology, cognition and emotional population ages, social isolation is becoming state in humans. It plays an especially more and more prevalent. In addition, even crucial role in the helping and medical

professions. According to Levinson, et al, “A recipient’s reports are always the most growing body of literature suggests that strongly correlated with the positive outcomes of care are optimal when effects. physicians address patients’ emotional and Studies have consistently found a personal concerns in addition to their relationship between social isolation biomedical problems. Patient satisfaction, and mortality, and this effect is most patient adherence, and biological outcomes profound for those individuals who are can be improved with a patient-centered the most isolated. One study found that model of care that demonstrates respect older women who lived alone and did and caring for patients” [2]. not have contact with family or friends Social support is the name given to those had mortality levels three times greater behaviors that take place within the context than those who lived with others or of a personal relationship, and that serve to had more frequent contact with family provide aid and assistance. This group of and friends [7]. behaviors has been broken down into Note that while social support can several subtypes of support including: involve attempts at persuasion (e.g., via emotional support (expressions of empathy, informational support), it is trust, esteem, reassurance of worth, fundamentally different from other affection, attachment, intimacy); instrumental types of social influence in that it is support (material assistance); informational always provided in a context of caring, support trust and respect [4], and thus the (giving advice and information); appraisal technologies that may be involved in support (information that is useful for self- artificial caring need to be concerned evaluation); and social network support (e.g., with a much richer and deeper set of providing introductions to other people) [3, issues than those involved in 4]. Of these, emotional support is the most argumentation or strongly and consistently associated with “captology” [8]. health and well-being. For example, a number of studies have demonstrated that 2.1. Caring by Health Professionals emotional support, provided in the context There is also a known association of intimate relationships, increases survival between patients’ perception of caring rates among people with severe by health professionals and patient cardiovascular conditions [5]. The effects of satisfaction, treatment regimen all kinds of social support are primarily a adherence and outcomes, across a function of the perception of support by the wide range of health disciplines. The one receiving it, rather than the perceptions, most significant empirical support of intentions or actual behavior of the person this phenomenon is in the field of providing it [6]. For example, in studies in psychotherapy, in which measures of which both the provider and the recipient of “working alliance” social support were asked about the kinds –the trust and belief that the therapist of support provided in a relationship, the and patient have in each other as

team-members in achieving a desired and future together, continuity outcome—show consistently high behaviors (appropriate greetings and correlations with successful outcomes [9]. farewells and talk about the time spent Even in physician-patient interactions, apart), and reference to mutual physician empathy for a patient plays a knowledge, as well as explicit significant role in prescription compliance, messages of esteem (see [13] for a and a physician’s lack of empathy for a summary). patient is the single most frequent source of There are also nonverbal behaviors complaints [10]. indicative of caring such as facial However, health professionals cannot expressiveness (including displays of provide an individual’s primary source of concern), head nodding, and tone and social support. Professionals are rarely timing of speech. Nonverbal available to provide support over long "immediacy" behaviors—including periods of time, and the power differential in close conversational distance, direct the provider-patient relationship may hamper body and facial orientation, forward empathic understanding [4]. Additionally, lean, increased and direct gaze, professionals are under significant demands frequent gesturing and postural to reduce costs and to see more patients in openness—have been found to project less time. Time spent with a machine costs liking for the other and engagement in significantly less than time with a health the interaction, and to be indicative of professional. As the time that patients caring [14]. interact with machines increases, it is prudent to consider how that interaction can 3. Animal-Human Caring and Health be designed to contribute to helping the Implications patient feel cared for. Pets can also provide a sense of caring and emotional support, and have been 2.2. Caring Behavior found to be correlated with several There are several human communicative kinds of beneficial health-related behaviors that are known to elicit the effects, although the specific perception of feeling cared for by a person. mechanisms of these effects have not Although providing any kind of social been determined [15]. Candidate support can indicate caring, demonstrations mechanisms for the health-related of empathy and comforting behavior are benefits of pet ownership include: the perhaps the quintessential examples, and opportunity for people to provide are widely cited in the helping literature as nurturance, since it can increase their being key in achieving desired outcomes [11, self esteem; the ability of pets to 12]. Other behaviors that can contribute to an provide network support through their impression of caring include social dialogue, role as social catalysts; and their ability self-disclosure, emphasizing commonalities, to instill a perception of social support meta-relational communication (particularly in their owners, given that they are emotional aspects) talking about the past always available and reliable,

nonjudgmental, perceived as caring about be feeling. While there is no and needing their owners, and can provide instrument that can directly read an tactile comfort and recreational distraction individual’s feelings, there are a variety from worries. of ways that people communicate their feelings to each other (often 4. Progress Towards Caring Machines imperfectly), and these modes of Although the literature cited above communication are becoming describes the significant positive health increasingly accessible to machines. effects of perceived caring by humans and These ways range from dialogue and pets, these sources of support also have verbal expressions to non-verbal cues many drawbacks associated with them. First, such as facial expressions, postural other people may not be consistently shifts, gestures, and more. available or reliable to provide support when Machine conversational agents are needed. Human helpers may react computer characters designed to carry negatively if their help is rejected [4]. For on a dialogue with a person, and this older adults, the problem of physical and dialogue can help the machine to mental abuse by those who are otherwise sense emotional information. While supportive is also a real problem [16]. Finally, machines remain very limited in their many individuals may simply not have a ability to understand most of language, network of friends available, or may live in a they can already engage successfully location in which pets are not allowed. For in quasi-scripted dialogues about all these reasons, computer agents that feelings [17-19]. There are times when provide people with the perception of it is appropriate to overtly ask how feeling cared for may be able to help fill this somebody is doing, which can lead to emotional void in the lives of many disclosure of feelings, e.g., individuals. “How’s it going?” Before a machine can provide effective “Not so great.” emotional support or caring, it is first helpful “Oh dear. Sorry to hear. Anything I for the machine to have some idea of what can do to help?” “I don’t know, I just kind of emotions an individual is expressing: feel terrible about …” Is he upset? Is he pleased? In the following Sometimes feelings are not sections we first review the state of the art in communicated through what is sensing human emotional state, then move said as much as how it is said, e.g. on to a review of technologies designed to “Good Morning!” can be spoken with intervene at the appropriate time. genuinely cheery enthusiasm or with annoyance, disdain, and other kinds 4.1 Technologies for Sensing Human of inflection that may very clearly Emotional State contrast the words used. Dialogue In order to respond in a caring way to systems have a chance to sense people’s feelings, it is important first to have the words selected by a person and a reasonable assessment of what they might reason about the associated affect

[20-22], and also have the opportunity to it has been shown that an agent’s listen to para-linguistic aspects of speech for empathetic responses can influence indications of a person’s feelings [23, 24]. skin conductance in a way that is Clearly if there is no dialogue, then associated with decreased stress [27]. speech won’t work, and other modes of Stress and anxiety are increasingly sensing will be needed. In many medical being recognized as common in situations, it is natural to sense aspects medical interactions and are also of a person’s physiology. Physiological linked to a number of significant health information has been shown to carry problems; hence, the new ability information that can be used to classify of empathetic technologies to help an individual’s affective state. Picard, et reduce stress has many implications al, built a recognition system using four for health care. Other forms of affect physiological signals, which learned patterns sensing technologies have been for an individual over time, and achieved developed for specific environments. 81% recognition accuracy classifying one Physiological sensors have been put of eight states (anger, joy, sadness, hatred, into computer mice [28] and sensors platonic love, romantic love, reverence, and have been put into a chair to sense neutral) that an individual was having [25]. postural changes related to levels of (The person was seated, and deliberately high or low interest in young learners focusing on having each of the eight working with educational software on emotions.) a computer [29]. There is also lots of research on automated recognition of facial expression and on head gestures to discern states such as “concentrating,” “disagreement,” “thinking,” “unsure,” and “interested,” [30] all of which could also be helpful to a machine trying to appear more caring by adjusting its responses to those of the person with whom it is interacting. Stronger results can be obtained by combining multiple channels, e.g. face with voice [31] or face with chair, mouse and task Figure 1. Klein et al. used simple dialogue boxes to convey the impression of active listening, empathy, [32]. Different kinds of sensing may be and sympathy to frustrated computer users. more or less natural in different kinds of environments, and confidence that Signals such as skin conductance and the computer has properly recognized heart rate variability have also been shown the person’s affective state tends to to be indicators of stress in natural situations, increase with more than one mode of e.g., driving in Boston [26], and recently sensing.

4.2 Technologies for Influencing the 4.2.2 Computers As Social Actors Perception of Being Cared For In their seminal series of studies Once a computer agent has detected that and resulting book—The Media a user is in need of caring, it may engage Equation—Cliff Nass and Byron Reeves in some caring behaviors even without at Stanford have demonstrated that detecting the person’s state, although when computers produce social cues knowing more about their state enhances that people respond in fundamentally chances of success. There are a wide range social ways, even though this reaction of comforting behaviors a computer could is entirely unconscious [37]. In their use to intervene (as outlined in Section 2.2), book, they describe studies that with the quintessential example being the demonstrated the following relational expression of empathy. Here, we review effects: some of the systems and studies in which • Computers that use flattery, or a computer used empathy and other caring which praise rather than criticize behaviors in its interaction with users. their users are better liked. Additional examples include the work • Computers that praise other of Lisetti, et al [33], Paiva, et al [34], and computers are better liked than Prendinger, et al [27, 35]. computers that praise themselves, and computers that criticize other 4.2.1 CASPER computers are liked less than One of the earliest empathic agents was computers that criticize themselves. the CASPER affect-management system • Users prefer computers that match developed by Klein et al. [17, 36], which them in personality over those that was demonstrated to provide relief to do not (the “similarity attraction” users experiencing frustration. The system principle). presented a frustrated user with a series of • Users prefer computers that menus (e.g., see three examples in Figure become more like them over 1) that prompted the user to describe his or time over those which maintain a her affective state, provided paraphrased consistent level of similarity, even feedback, allowed users to repair the when the resultant similarity is the computer’s assessment and provided same. empathetic and sympathetic feedback. This • Users who are “teamed” with agent was found to be significantly better a computer think better of the than a venting-only agent (to which users computer and cooperate more could simply describe how they felt in an with it than those who are not open-ended manner without feedback), teamed (the “in-group membership” or an agent that ignored their emotions effect, which can be achieved by completely, in relieving frustration, as simply signifying that the user and measured by the length of time users were computer are part of a team). willing to continue working with a computer Since the Media Equation was after a frustrating experience. published, Reeves and Nass and

their students have continued doing reported about their stress and how studies within this “Computers As Social interruptible they were [19]. The device Actors” paradigm. Morkes, Kernal and would interrupt people on average a Nass demonstrated that computer agents dozen times a day, in order to query for that use humor are rated as more likable, their stress levels and acquire a better competent and cooperative than those understanding of whether or not it was that do not [38]. Moon demonstrated that a a good time to interrupt. Two versions computer that uses a strategy of reciprocal, of the system were built, one designed deepening self-disclosure in its (text-based) to be empathetic and one not, and conversation with the user will cause the both of which were friendly and user to rate it as more attractive, divulge polite, and engaged in brief text-only more intimate information, and become dialogues with the user, for example: more likely to buy a product from the computer [39]. System: Morning, Jane! Do you have In one of their most recent, and relevant, a minute? studies in this paradigm, Brave, Nass and Jane: Yes Hutchinson compared the use of empathic System: You know the drill – feeling facial displays and text messages by an stressed? embodied computer agent (using images Jane: It’s there – but not the worst. of a person’s face with different emotional System: Wish it was better. Hope displays) with self-oriented emotional things start looking up. displays and messages [40]. They found System: Thanks so much for all your that the empathic agent was given more input. positive ratings, including likeability and trustworthiness, as well as greater perceived The above dialogue differed in only caring and felt support, compared to either one respect in the two conditions: In an agent that used self-oriented displays the empathetic condition all six of the and messages or an agent that performed above lines were exchanged. In the no emotion-oriented behavior. non-empathetic condition, the next to last line was omitted by the system. 4.2.3 Mobile System for Sensing and Thus, the empathetic condition took Responding to Stress an extra second or two to respond Can machine empathy make a positive to the user’s feelings before thanking difference in people’s acceptance of a the user, while the non-empathetic highly interruptive device designed to condition only gave the last line, a collect information related to stress? Liu polite thank you, in response to the and Picard modified a handheld device (HP user’s statement of her feelings. The IPAQ) to receive signals wirelessly from a set presence of an extra empathetic line of FitSense sensors for monitoring the heart, happened in each interruption during foot acceleration, and location context, all the days a user interacted with the and to associate this data with what users empathetic system.

The empathetic system also used a exercise advisor designed to help slightly different algorithm to trigger when subjects through a behavior change the interruptions would occur; however, this program, which was designed to inadvertently led to the system interrupting increase their physical activity levels. people significantly more. Each subject was The agent appeared as an embodied given each system to use for four days, in conversational agent [43], whose counter-balanced order. (Half the subjects speech and nonverbal behavior used “A” then “B”, without us indicating (including hand gestures, eye gaze anything about any differences in the two behavior, posture shifts, head nods, systems, while the other half used “B” then proximity and facial expressions) were “A”.) After the eight days, users chose which controlled using the BEAT text-to- one – A or B – that they wanted to use for embodied speech engine [44] (see the next four days. Seven out of ten chose Figure 1). Subjects conducted a 5 the empathetic system over the control. minute interaction with Laura daily on When asked at the end of each of the first their home computers for one month, eight days, “about how many times does during which Laura provided feedback it seem like the system interrupted you on their exercise behavior, helped today?” the users significantly underreported them overcome obstacles to exercise, the number when using the empathetic provided educational content related system, and not when using the control. to exercise, and obtained and followed Also, at the end of the eight days, those in up on commitments to exercise. the group currently using the empathetic A RELATIONAL version of the system reported a significantly higher desire agent used all of the caring behaviors to continue in the study. While the group of described above. For example, if subjects was small, these findings support a subject indicated they were not our intuition that introducing even a single feeling well (and thus unable to line of empathetic response could have a exercise), Laura provide appropriate measurable impact on people’s perception empathetic feedback while exhibiting of how interruptive a technology is, and a concerned facial expression (as on people’s desire to keep using the in Figure 1). A NON-RELATIONAL technology. version of the agent delivered identical health content but had all caring and 4.2.4 FitTrack relational behaviors removed. Evidence that computers can instill a Thirty-three subjects completed sense of caring comes from a recently the month of interactions with the completed study on the longitudinal effects RELATIONAL subjects with the agent. of relationship-enhancing behaviors used from the (69%) female agent and by a computer agent (a “Relational Agent”) twenty-seven completed interactions on measures of user-computer relationship NON-RELATIONAL Subjects were quality [18, 41, 42]. In this study the agent— recruited MIT campus, were mostly students and were 60% (balanced named Laura—played the role of an across the two conditions).

than the NON-RELATIONAL group, t(57)=2.43, p=.009. This measure is of particular importance since continuing with a treatment program is related to outcome, and desire to continue Treatment is likely to facilitate that result as well. One behavioral measure related to caring was evaluated. In the closing session, subjects were given a choice of farewell greetings to say goodbye to the agent. Significantly more subjects Figure 2. Exercise Advisor Agent in the RELATIONAL group (69%) chose the most sentimental farewell (“Take Quantitative Results care Laura, I’ll miss you.” vs. “Bye.”) than In this chapter we only describe results that in the NON-RELATIONAL condition are particularly relevant to the notion of (35%), t(54)=2.80, p=.004. caring; for a full description see [13]. These results include the following items from Qualitative Feedback the bond subscale of the Working Alliance After the experiment we asked Inventory, evaluated after four weeks of daily subjects about their experiences with interaction. Subjects in the RELATIONAL Laura. When asked whether they liked condition indicated significantly greater the overall concept of conversing with agreement (on 7-point Likert scales) with the and relating to an animated character, following items, compared with subjects in subjects reported strong opinions on NON-RELATIONAL: both sides of the issue. Representative • “I feel that Laura cares about me in her responses included: own unique way, even when I do things • “It was a really, really great idea that she does not approve of.” t(60)=2.39, to have some kind of animated p<.05 character because it makes you • “I feel that Laura, in her own unique feel like you’re actually talking to a way, is genuinely concerned about my person rather than having words on the computer screen.” welfare.” t(60)=2.19, p<.05 • “Personally I detested Laura.” • “I feel that Laura, in her own unique way, • “I like talking to Laura, especially likes me.” t(60)=2.56, p<.05 those little conversations about • “Laura and I trust one another.” school, weather, interests, etc. t(60)=2.05, p<.05 She’s very caring. Toward the end, When asked at the end of the month if I found myself looking forward to they would like to continue working with these fresh chats that pop up every Laura, subjects in the RELATIONAL condition now and then. They make Laura so also responded much more favorably much more like a real person.”

When asked “Do you feel that she when the caring behaviors were really cared about you?“, many subjects included. responded affirmatively but qualified their responses with comments such as: 4.2.5. FitTrack for Older Adults • Yes, as much as a computer can care.” Relational agents may provide an • “Yea, I think there was an illusion there accessible user interface for much that she did.” of the older adult population, and an • “As much as it mattered to ... I never especially effective channel for health forgot that it was a computer program, communication and behavior change but you’ll notice that I find myself interventions. To test this hypothesis, calling her by feminine pronouns rather a pilot study was recently conducted than calling her an ‘it’. So, I definitely to evaluate the acceptance, usability remembered that she was a computer and efficacy of a version of the FitTrack program, but I did feel like it was a more system used by patients from the personal interaction than that.” Geriatric Ambulatory Practice (GAP) Other subjects responded with uncertainty at Boston Medical Center, the primary about the concept of Laura “caring”: safety net hospital in the Boston area • “I find ‘care’ to be a funny term to use [45, 46]. with a computer character. I felt like it was Several modifications were made helpful to have positive reinforcement, to the FitTrack system for older adults even if it was from a computer character.” including: use of large fonts, a touch- • “She’s a computer character. I don’t know screen interface, and modifications to if she cared about me. I don’t know if she the dialog content (see Figure 2). A feels. She’s a character and has a role, randomized trial compared subjects but I don’t know if she has feelings. But, it who interacted with the relational worked for me and I’m happy.” agent daily in their homes for two Finally, there was a group of subjects who months (RELATIONAL) with a standard answered negatively, emphasizing Laura of care control group who were only was a machine. given pedometers and print materials • “No, not really, because I plugged in a on the benefits of walking for exercise number and she had a script.” (CONTROL). The subjects were • “No. I felt like I was talking to a robot, to a twenty-two participants recruited into machine.” the study based on referrals from the These responses illustrate a range of GAP clinic. Participants ranged in age user feedback about a system that might from 62 to 84, were 86% female, and evoke feelings of caring – from liking to 73% were African American. Seventeen disliking, from acceptance of the effects (77%) were overweight or obese, and to denial of any effects. While clearly the nineteen (86%) had low reading literacy technology did not lead to strong [47]. Eight (36%) never used a computer reports of caring in everyone, nonetheless before and six (27%) reported having the effect was significant across the group used one only “a few times”.

When asked if they liked Laura, RELATIONAL subjects scored this 6.3 on a scale of 1 (not at all) to 7 (very much), and scored their relationship with her a 5.6 on a scale of 1 (complete stranger) to 7 (close friend). When asked if they felt that Laura cared about them, they gave this an average score of 5.9 on a scale of 1 (not at all) to 7 (very much). “By the way that she sound, she sound like she like me.” Figure 3. FitTrack for Older Adults “I remember one weekend I went to Wareham... You know, I began to feel bad Comparisons between the RELATIONAL about Laura, stuck in that box.” and CONTROL groups on daily recorded pedometer steps were based on 4.2.5 Caring Robots generalized estimating equations (GEE) Several recent efforts in academia regression models for longitudinal data and industry have focused on creating for increases in mean steps walked per robotic pets for older adults in order week for each subject. The estimated to achieve the same beneficial effects slope (increase per week in mean weekly found in animal-assisted therapy, steps walked) for the CONTROL group was namely to decrease stress, anxiety estimated as 83.9, while the slope for the and loneliness and improve mood, RELATIONAL group was estimated as 411.1. e.g. [48]. The “mental commit” robots The difference in slopes is significant (p = take the form of cute stuffed animals 0.004). The slope in the control group was such as a cat or a harp seal pup, and not significantly different from 0 (p = 0.295), are designed to foster an attachment while the slope in the RELATIONAL group with users. One study compared the showed significant increase in steps over effects of these robots on older adults time (p = 0.001). in a nursing home with the effects of an When asked if they liked Laura, identical robot that had a much simpler RELATIONAL subjects scored this 6.3 on behavioral repertoire, however no a scale of 1 (not at all) to 7 (very much), and significant differences were found scored their relationship with her a 5.6 on [49]. Although the robot was used in a scale of 1 (complete stranger) to 7 (close group sessions by the same individuals friend). When asked if they felt that Laura four days per week for three weeks, cared about them, they gave this an average and has long-term memory and a score of 5.9 on a scale of 1 (not at all) to 7 reinforcement learning mechanism, (very much). it is not possible for it to model a relationship with any particular user

given that it does not have the ability to Caring machines can certainly make discriminate between users. Another study use of more sophisticated techniques compared the use of a Sony AIBO robotic in how they address our problems. dog with a stuffed toy dog and a “clothed” For example, rather than just offering AIBO by a group of older adults with severe canned empathetic messages or dementia. This study found that patients messages indexed to degree of actually interacted more with the stuffed toy emotional upset (as in [17, 18, 40]), they than either of the AIBOs, but the differences can offer comforting messages that were not significant [50]. are indexed or formulated according There is also an emerging commercial to a much more fine-grained set of market for robotic dolls targeted at the older emotional criteria, such as: extent to adult caretaking market, particularly in Japan. which a user’s feelings are explicitly Bandai launched the Primopuel doll in 1999, acknowledged, elaborated and which is designed to resemble a five-year- legitimized; extent to which the old boy who continually asks to be hugged messages are centered on the and entertained. Dream Supply released user’s emotions (vs. the computer’s the Snuggling Ifbot in 2004, intended to feelings or the causes of the upset); be a speech-based conversational partner and whether the empathic messages for the elderly. Tomy recently announced also contain a cognitively-oriented the release of the Yumel doll, which also explanation of the user’s emotions or converses with older adults using speech, not [52]. These cognitive explanations and assists users in maintaining healthy can also help users re-examine the behaviors such as good sleep hygiene [51]. events that gave rise to their negative None of these systems have been reported emotions in the first place so that they on as being formally evaluated. can better cope with the situation. Of course making people 5. The Future emotionally dependent on their Our machines will undoubtedly continue to machines has many ethical improve in their ability to calm, comfort and implications. In addition to the possible soothe us, to gain our trust and attachment, malicious use of these machines for and—consequently—to help us in times of manipulation of their users (e.g., see sickness and crisis. They may even surpass [53]), computer crashes, repairs and the ability of many humans to do so, given upgrades—commonplace events that they are always available and reliably in our current world of computers— consistent. In addition, since they can be a suddenly become potentially traumatic persistent part of our lives over many years events for their users. or even decades, they can have perfect Another ethical issue is that this memories of our past history, personal kind of technology may serve to needs, values and aspirations (in human further socially isolate users from other relationships, long-standing intimates are the people, even though the potential best source of social support [4]). exists to use the technology to help

bring people together. For example, in is happening to them during hospital the FitTrack study involving older adults, or emergency room visits or about one subject involved her friends in her proper self care when they return discussions with Laura, and her friends home. Caring agents could provide would often ask her about her ongoing a persistent comforting presence interactions with the character [46]: throughout a hospital stay, answering “I brought my friends up here a couple questions, giving advice and preparing of times to listen to her. My girlfriend she a patient emotionally for diagnoses, came upstairs with me and I show it. She procedures, and home care. say ‘what’s that?’ and I say ‘let me show you.’ So I talk to her. So every time she References talk to me she say ‘Did you talk to Laura [1] Picard R. Affective Computing last night?.’” Cambridge, MA: MIT Press; 1997. In addition, computer agents can serve [2] Levinson W, Gorawara-Bhat R, in the capacity of match-makers, introducing Lambs J. A Study of Patient Clues people to others with similar interests, and Physician Responses in Primary contacting friends when it thinks someone Care and Surgical Settings. JAMA. could use some human social support, and 2000;284(8):1021-1027. even pro-actively helping someone maintain [3] Berscheid E, Reis H. Attraction and their social network by reminding them to Close Relationships. In: Gilbert D, Fiske contact their friends periodically and helping S, Lindzey G, eds. The Handbook of them work through relational problems. Social Psychology. New York: McGraw- These caring agents will not only reside Hill; 1998:193-281. on our computers, but in our home robots, [4] Glanz K, Lewis F, Rimer B. Health our mobile devices and in our health care Behavior and Health Education: facilities. Caring home health care robots Theory, Research, and Practice San could be used to help users through Francisco, CA: Jossey-Bass; 1997. physical rehabilitation regimens or to bring [5] Berkman L, Glass T. Social them their medication, with the warmth and Integration, Social Networks, Social gentle coercion used by a skilled nurse who Support, and Health. In: Berkman L, needs to motivate her patient to take care of Kawachi I, eds. Social Epidemiology. themselves. Mobile devices, such as smart New York: Oxford Press; 2000. phones or PDAs, provide a platform in which [6] Wethington E, Kessler R. Perceived caring health interventions can be delivered Support, Received Support, and anytime, anywhere, such as smoking Adjustment to Stressful Life Events. cessation messages at the instant a user Journal of Health and Social Behavior. gets a craving, or when someone is walking 1986;27:78-89. by the stairs on their way to the elevator. Finally, caring machines have obvious uses in our health care facilities, where patients are often ill informed about what

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Alexander Chapter 55: Cyber-anthropology: A New of Psychological Culture is viewed Libin, Elena as an essential part of Cyber- Libin / Cyber- Study on Human and Technological Co- anthropology: evolution anthropology while concentrating A New Study Alexander Libin, Ph.D. on the following core issues: (1) on Human and Cyber-Anthropology Research, Inc., ethical questions, such as whether Technological Georgetown University, Washington, D.C., or not technological tools can be Co-evolution in “World USA employed to solve human problems; Health Elena Libin, Ph.D. (2) moral consequences of bringing Strategy” Cyber-Anthropology Research, Inc., cutting edge technology into our eBook, (Ed.) Georgetown University, Washington, D.C., every day life; (3) studies of individual Renata G. Bushko, USA differences regarding psychological FHTI, 2016. competence of technology users Futureofhealth. Abstract through effective vs. ineffective, org - From independent vs. addictive, and active Intelligent and or the first time cyber-anthropology Extelligent is defined as a concept and a new vs. passive dichotomies. Psychological Health field of study aimed at the analysis Culture is defined as the study of a Environments F of person’s reciprocal relations with the person's competence associated with (Ed.) Renata G. the use of modern technology and Bushko, IOS computer-generated (CG) world evolved Press 2005 as a result of technological progress. In the individual acceptability of technological cyber-era, simulated reality has come to innovations. Several crucial dilemmas the point of becoming a force that has the arise when a human being is engaged potential to transform the human race. Digital in a simulated environment, and beings such as virtual and embodied agents, artificial agents inhabit a human world. although not a part of the natural human The ultimate goal of Psychological habitat, have become necessary elements of Culture is to provide people with the people’s surroundings and life conditions. As knowledge necessary for adequate a theoretical construct, Cyber-anthropology recognition of scientific innovations to is concerned with the merger of natural overcome obstacles in the process of and artificial worlds mediated by the human implementing technology to enhance imagination, as well as compatibility between human well being. people and digital life they have created. As an empirical study, Cyber-anthropology 1. Computer-generated reality: a deals with the psychophysiology and personal touch psychophysics, semantic and semiotics Since ancient times people employed of human engagement with computer- their imaginations to model fictitious generated reality that is viewed as a realities filled with bizarre creatures Complex Interactive System. Personal and strange life forms capable of competence as a crucial element of any acting beyond human possibilities. cyber-system underlines the importance When all the other necessary survival of psychological culture in artificial world tools were exhausted, people used exploration. A newly developed concept the power of their minds to gain

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the strength of the spirit when fighting acknowledged the beginning of a unknown diseases or trying to understand science that focused on studying unpredictable chains of events. Sometimes, physical, psychological, and cultural the thin line between the real and imaginary trends in human development. The worlds would became blurry or even aims of anthropology include the disappear. The degree of self-immersion whole range of analyses from cultural into one’s own fantasy combined with artifacts (i.e., archeological method) people’s ability to keep up with their actual and diversity of customs and beliefs life requirements would result either in total (i.e., ethnographical method) to the mal-adaptation or in the re-construction of study of human kind’s similarity to the existing realities. Modern technological and divergence from the animal tools have enriched human abilities not only kingdom (i.e., methods of physical in exploration, but in altering our inner and anthropology and sociobiology). The outer worlds. With the development of digital body of knowledge about human vehicles for information technologies, we life phenomenology was greatly entered a realm never experienced before expanded by the explorations of by the human mind or senses. How do philosophical, structural, psychological these new experiences fit into the existing and semiotic anthropology (see Table methodology of human studies? What 1). However, regardless of the scientific are the conceptual frames for analyzing paradigm underlying the investigation and interpreting a person – cyber-world of a particular aspect of human – world interaction? Is it possible to predict the interactions, anthropological analysis outcome of those interactions? Below are strived to search for the answers to defined some primary coordinates of the the two inter-related questions posed emerging field of Cyber-anthropology – a by our very existence: How do human theoretical and practical study of human- beings transcend themselves in their centered, digitally-based technological own experience?, and: How do people systems, their structure, development, and actually behave? functioning. [3]. Over the last twenty centuries, 1.1. On the crossroad of Anthropology and the systematic study of Homo Cybernetics sapiens, specifically their physical, A clashing charisma of anthropological psychological, and socio-cultural studies attracted materialists and idealists, functioning, went through numerous empiricists and methodologists, naturalists transformations. The recent one is and humanitarians. The term associated with the rise of highly ‘anthropology’ (from Greeks ‘anthro-’ – a technological systems based upon man, and ‘logos’ – a study) was coined electronic “brains” and digitally by Aristotle more than 2000 years ago [1], originated behaviors. In such hybrids, and the new discipline of anthropology a person appears as a human agent was formulated by Kant in 18th century [2] who performs a peripheral or –

Cyber-anthropology: A New Study on Human and Technological Co-evolution 539 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

sometimes – a central role in the complex of Cyber-anthropology. Its dual nature system functioning. A concentrated view is an adequate systematic method for on the essence of relationships between studying this hybrid phenomenon – the artificial and living systems was formulated cyber world. by Norbert Wiener in 1948 in a concept named cybernetics (from Greek kybernet(es) 1.2 Cyber-anthropology: Human or steer(-s) man) [4]. Cybernetics is viewed world through the prism of as a science of control processes in technology organic, and technological, mechanical and The definition of the new phenomenon electronic systems. Cybernetic principles is unavoidably multi-semantic, for it are employed by psychology for exploring has to account for the methodology the phenomena of artificial intelligence and and the epistemology of the variety of emotion-like behaviors, by social sciences analyzed experiences, as well as their for studying effective management, and by theoretical and practical implications. engineering for analyzing the optimizing Bearing this in mind, we would like possibilities of technology-based processes. to present a unified framework that Both worlds – human and artificial – came combines various meanings – or, to existence as a result of evolution: socio– rather, dimensions for the analysis – biological or technological respectively. of the emerging field named Cyber- The development of two independent anthropology (see Table 1): subjects of study – anthropological and technological – brought to life a new field

Table 1. Definitive classification of Cyber-anthropology

Anthropological Cyber-anthropology elements models of man Focus of the Subject of Related cyber- computer-mediated Cyber-anthropology phenomena analysis study Physical Reconstruction Archeological Digital anthropology/ of human and evolutionary reconstruction Cognitive beings via virtual aspects of of human’s anthropology representations human physical predecessors, representations their behavior, and through the associated artifacts historical and geographic prospective Ethnographical Analysis of Social manifestation Virtual heritage and anthropology Social computer-mediated of interactions Internet culture. anthropology social interactions between humans and virtual agents

Cyber-anthropology: A New Study on Human and Technological Co-evolution 540 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Philosophical Methodological Reflection on Sense of immersion anthropology analysis of human existence and presence computer- into digital world produced generated by person’s phenomena such engagement as presence and in virtual reality immersion or virtual communications Structural Structural analysis Functioning of Imaginary, virtual, anthropology/ of semantic and digital symbols and embodied Semiotic semiotic of digital personages; digital anthropology artifacts folklore; myths of computer era Psychological Study of Psycho- Digital self and anthropology compatibility physiological, virtual identity; between human psychological, cyborg-dilemma; and technology and social effects psychological produced by aspects of people- human – computer robot co-existence interactions

Cyber-anthropology for the first time engagement with computer-generated is defined as a concept and a new field reality viewed as a Complex Interactive of study aimed at the analysis of human System [5]. reciprocal relations with the computer- generated (CG) world which have evolved 2. Cyber-anthropology as a science as a result of technological progress. In of differentiation between living and the cyber-era, simulated reality has come artificial complex interactive systems to the point of becoming a force that has The importance of the notion that the potential to transform the human race. speaks to distinctions in origin, Digital beings such as virtual and embodied structure and ultimate goals of living agents, although not a part of the natural and non-living, inanimate, artificial human habitat, have become necessary systems has been emphasized elements of people’s surroundings and by many authors. The founder of life conditions. As a theoretical construct, differential psychology and inventor Cyber-anthropology is concerned with of the IQ (Intelligence Quotient) the merger of natural and artificial worlds hypothesis, William Stern, pointed mediated by human imagination, as well out that the biggest methodological as the compatibility between people and mistake is to apply mechanistic the virtual and embodied forms of digital interpretation to the analysis life they have created. As an empirical of ‘a person’, which transforms study, Cyber-anthropology deals with the it into ‘a thing’ by eliminating a psychophysiology and psychophysics, certain psychological component semantic and semiotics of human from the epistemological and

Cyber-anthropology: A New Study on Human and Technological Co-evolution 541 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

phenomenological analysis [6][7]. A differing as a main element in person–cyber- criteria, based upon the ‘closed vs. open’ world interactions emphasizes the dichotomy, was offered by von Bertalanffy, a key role of psychological knowledge creator of the modern systematic approach, in understanding the character of to distinguish between non-living, closed cyber-anthropological models. In and living, open complex systems [8]. 1930, Vygotsky rightfully suggested A study of the principles of mental that a study of psychological systems representation revealed the fundamental focuses rather on the analyses of role of tactile-kinesthetic gestalts in forming relations between different functions a hierarchical structure not only of sensory- and modifications of these relations motor, but emotional and cognitive mental over time, than on changes within each phenomena [9]. Only the neuronal core of function and their structure [12]. an open living system is able to produce It is notable that a concept tactile-kinesthetic sensation unavailable in of complexity brings two vitally the artificial systems. The latter is based significant components into the exclusively upon information exchange cyber-anthropological approach – in the form of electric impulses, which lie the non-linear nature of examining at the foundation of electronic-originated phenomena and its interactive phenomenology. No matter how complex nature. Perhaps because interactivity the system is and how high the level of the is a main characteristic of the brain system’s internal or external interactivity is, [10], mental functioning [9] and the ability of living beings to transform non- human development in general transitive physical properties of an object [11], an interactive nature of cyber- into the internal sensation through the applications makes them natural tactile-kinesthetic mechanism [9], remains - like part of our physical and social a major criteria that differentiates between environment. On the other hand, natural and artificial phenomena, mental having human personality as a main and virtual representations, real and unreal element in person–cyber-world experiences. interactions emphasizes the key It is notable that a concept of complexity role of psychological knowledge brings two vitally significant components in understanding the character of into the cyber-anthropological approach cyber-anthropological models. In – the non-linear nature of examining 1930, Vygotsky rightfully suggested phenomena and its interactive nature. that a study of psychological systems Perhaps because interactivity is a main focuses rather on the analyses of characteristic of the brain [10], mental relations between different functions functioning [9] and human development in and modifications of these relations general [11], an interactive nature of cyber- over time, than on changes within each applications makes them natural - like part function and their structure [12]. of our physical and social environment. On the other hand, having human personality

Cyber-anthropology: A New Study on Human and Technological Co-evolution 542 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

3. Practical applications of Cyber- as a transitional class combining both anthropology virtual and embodied elements, and, The artifacts produced by digital finally, the last group (E) presents a technologies form the subject for newly emerged class of embodied experimental and applied Cyber- agents – a materialized form of anthropology research. Primary classification digital activity. Cyber-anthropological of computer-generated phenomena sheds studies of person – robot interactions some light on the practical agenda of are carryied out in two modes Cyber-anthropology,, which includes an recognized as Robotic Psychology examination of: and Robotherapy. Robotic psychology A. Cyber-space, including: 1) computer- focuses on the compatibility between mediated communication such as Internet, humans and robots [13], while Email, Chat groups, Virtual communities, Robotherapy concentrates on using 2) World Wide Web as a mediated form of interactive robots as therapeutic immediate social contacts, 3) cyber-culture agents for people with psychological B. Virtual environments as part of 1) problems or limited physical, cognitive, VR-based application (i.e., database or emotional resources [14][15]. representations, cyber-therapy products), 2) video games, and 3) virtual projection of 4. First research priorities from the digital structures Cyber-anthropologist’s point of view C. Digital representation or reconstruction Although traditional approach has of real experiences associated with 1) proved the effectiveness of the living beings such as humans – ancient in formula ‘All’s well that ends well’, a case of traditional physical anthropology more important rule at the beginning and archeology, or modern in case of new ventures (ought to sound like) of virtual medicine, and 2) material sound like: “It’s better to start well. ”. objects (i.e., virtual heritage or modern Presented below is a brief schema architecture) for the Cyber-anthropology research D. Human-computer interactions as necessary to establish a systematic constellation of psychological and techno-knowledge [16] about the field: ergonomic factors including multi-modal • Emotional experiences triggered by interfaces both virtual and embodied digital E. Embodied agents in the form of interactions; interactive robotic creatures with artificial • Criteria of differentiation between intelligence and sensory feedback, e.g., real and imaginary worlds lifelike robots imitating living beings, • Symbolic meaning of computer- humanoids, etc. mediated interactions and digitally- generated experiences The first three sub-groups (A- • Stereotypes and myths about the C) are organized in a class of virtual origins and functioning of cyber- phenomena, the fourth group is structured reality

Cyber-anthropology: A New Study on Human and Technological Co-evolution 543 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

• Psychological and psycho-physiological to psychological competence of effects produced by person interactions technology users through effective vs. with virtual and embodied agents ineffective, independent vs. addictive, • The nature of presence and immersion active vs. passive dichotomies. Classification of cyber-phenomena based Among the main topics that catch on tactile-kinesthetic and visio-geometrical the attention of psychological culture gestalts and related studies on multi-modal researchers are such questions as interfaces `Why does one person maintain a Finally, the concept of Psychological lifestyle independent from modern Culture deserves a special attention in technologies while others develop Cyber-anthropology study program. technology (TV, computer, internet etc.) addictions?`, `What are the 5. Psychological Culture as a subject for psychological parameters that Cyber-anthropology studies can predict effective or ineffective • Exploring advantages and disadvantages technology usage? `, and `How of human-cyberworld co-existence; technology can help people cope with • Understanding the psychological their problems without putting an extra specifics of interactions between burden on them?` persons and their artificial partner (i.e., In sum, Psychological Culture virtual or embodied agent) on all levels: studies the extensive range of sensory-motor, emotional, cognitive, psychological aspects of technology– behavioral and social; mediated communication that arise • Studying how the rich diversity of our on the merge of artificial and human personalities justifies a broad variety of worlds. environments and agents; • Searching for possible solutions of 6. Technology–mediated solutions moral dilemmas stemming from human- for human problems technology interactions; In recent decades, the merger of • Providing people with knowledge artificial and human worlds has shown required for the further virtual space its promising results. Many researchers, expansion and effective person–artificial engineers, and practitioners have agent collaboration. already proven the productivity of First of all, Psychological Culture technological applications in such concentrates on ethical questions such as areas as health, education, therapy and whether or not technological tools can be entertainment. In particular, exploration employed to solve human problems. The of virtual reality advantages known as next important issue relates to the study `immersion` and `sense of presence` of the moral consequences of bringing promoted a creation of original VR- cutting edge technology into our every based methods of psychological day life. The third core question involves a therapy. A new approach named study of individual differences with relation Cybertherapy [17] showed

Cyber-anthropology: A New Study on Human and Technological Co-evolution 544 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

effectiveness of VR-applications employed companions, the effectiveness of for treating psychological disorders including people’s communication with their phobias (i.e., fear of flying, agoraphobia, etc.), artificial partners depends on their social anxiety, different kinds of addiction compatibility. Therefore, the robot’s (i.e., gambling, tobacco addiction), and design should take into an account a cognitive and emotional deficits (i.e., autism, whole range of both psychological and attention deficit hyperactivity disorder, ergonomic parameters. This means sensory disintegration, etc.). Computer- performing a comprehensive analysis generated reality has proven to be a of human differences that underlie useful therapeutic tool for a wide variety preferences in communication mode of populations such as children and the or intensity of interactions, degree of elderly, persons with physical and mental emotional or tactile stimulation, and disabilities, and people who live both in the specifics of personal needs that home environment and clinical settings. are essential for maintaining effective Success of early VR-based therapeutic person–robot compatibility. interventions has inspired designers to tive person–robot compatibility. further investigate the potential of artificial Obviously, the broad diversity of tools to provide real-life benefits. This is a people’s personalities justifies the vivid example of mutually advantageous creation of a wide variety of virtual collaboration between technology and and embodied agents. Since a person psychology. is the central part of technology- Another promising technological mediated communication, human application concerns the development factors define the adequacy and of embodied digital agents or interactive effectiveness of the process’ robots. The contemporary world of robotics organization per se. An outcome is inhabited by a broad variety of artificial of computer-mediated interactions creatures designed for the purpose of depends on two inter-related issues: helping people with special needs to • whether or not the person’s overcome their limitations and enrich their individuality matches the specifics quality of life. Nowadays, robotic creatures of artificial environment or agent; are used as mediators in the treatment of • the level of the person’s mood disorders, loneliness and depression, psychological culture based upon and as rehabilitation aids. The concept of an understanding of the role and an artificial partner [5] places person-robot place technology takes in human interactions into a psychological, rather than life. a technological, context. Beneficial features of robots as human companions lie at the 7. Moral dilemmas of human foundation of a new field of study named engagement with the artificial world Robotic psychology and Robotherapy Without doubt, exciting virtual reality [13], [14]. Even so, interactive robots serve (VR) and robotics’ applications have as therapeutic agents or stimulating enriched science and engineering,

Cyber-anthropology: A New Study on Human and Technological Co-evolution 545 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

industry and public service, medicine and culture aims at studying the nature of entertainment, psychology and psychiatry, simulated illusions and elaborating education and therapy. Technological agents criteria for experiencing the sense of positively influence the quality of human presence without side effects. life by bringing accessibility and comfort, inspiration and enjoyment. Computerized 7.2. Coping With Difficulties vs. tools have greatly expanded the human Escaping From Life capability to visualize desires, materialize Technological applications provide images, and observe the hidden processes. people with new tools for coping with However, several crucial dilemmas arise life’s difficulties. when a human being is engaged in the The level of individual psychological simulated environment, and artificial agents culture or psychological competence inhabit the human world. depends on understanding the meaning of technological progress for 7.1. Virtual Presence vs. Reality Absence one’s own life. If used appropriately, Cyber-phenomenon known as ‘presence’ artificial reality expands human is a subjective sense of being in a virtual possibilities and enhances quality of environment. Sheridan defines presence as life. However, there is much evidence ‘sensory information generated only by and of using technological innovations within a computer...a feeling of being present as an excuse to escape from real in an environment other than the one that life problems into an illusory world. person is actually in’ [18]. Visual, auditory Psychological Culture is aimed at and haptic sensations produced by virtual studying the criteria of differentiation reality applications are a part of an artificially between technology–mediated simulated environment, otherwise known coping and defensive strategies. as artificially simulated illusions, which allow Coping strategies are defined as persons to experience ‘presence’. Artificially cognitive, emotional, and behavioral triggered senses of presence may create effortsdirected toward resolving an positive, though illusory, experiences (i.e., experiencing difficulty. Defensive VR-based treatment of phobias), or create strategies are cognitive, emotional and false experiences resulting in a new chain of behavioral effortsdirected away from real problems (i.e., MUD-addiction based on actual problem solving [19]. false identity). One of the main psychological problems and moral dilemmas associated 7.3. Assistance vs. Substitute with the phenomena of presence stems The next main task of Psychological from the person’s inability to distinguish Culture is to bring awareness to between real and artificial words. Individual an individual as well as social inability to understand that those two worlds consciousness about the value of both are not identical, but different, creates a technology–mediated assistance and barrier for implementing the achievements human support. Neither artificial reality of engineering science. Psychological nor any of its superlative products

Cyber-anthropology: A New Study on Human and Technological Co-evolution 546 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

may serve as a replacement for genuine intervention of any kind is based upon human relationships. Lack of psychological conscious preference of technological competence necessary for the adequate means viewed as a way to improve use of technical innovations in our daily human assistance while providing life leads to various side effects, such as compassionate professional treatment computer dependence, mixed identities [22]. resulting from rejection of real self in favor Thus, a concept of Psychological to the virtual persona, replacing human Culture based upon an idea that communications with electronic message human engagement with an artificial exchanges and interpersonal relationships world is not an escape from reality and with person–machine interactions. an excuse to avoid life’s challenges, In particular, the moral dilemma of but an opportunity to expand coping ‘assistance vs. substitute’ stressed in the resources. use of robotic creatures for therapeutic purposes. The most important concern 8. Conclusion. many researchers and practitioners pose is Cyber-anthropology can be defined as that robots would become a substitute for a study of how humans are influenced human caregivers [20], [21]. This is true for by the artificial world produced by the any kind of robotic assistance. For instance, technological evolution. In a broad the use of robotic pets poses a question: sense, Cyber-anthropology is the ‘Are robotic pets designed with the intention science of investigating physiological, of replacing our favorite cats and dogs?’ psychological, and socio-cultural This dilemma requires special attention from phenomena that occur as a result of psychological culture research. When a interactions between human mind– robotic creature is employed in therapeutic body systems and artificial computer– practice, it is necessary for a therapist generated reality. to keep in mind that any state-of-the-art To gain benefits from cyberspace robot is only a technological tool. The use exploration, as well as from interactions of technological innovations establishes with virtual and embodied agents, special requirements for psychological one needs to employ a systematic culture of the therapist or professional analysis of psychophysiology and caregiver. It is especially important to psychophysics, semantic and semiotics not delegate a therapist’s function to a of human–artificial world co–existence. robot. Humanistic robotherapy considers Cyber-anthropology, while studying innovative technological tools as an a complexity of person–machine additional resource essential to human care, interactions, employs principles of but not the other way around. Robotherapy Psychological Culture. The ultimate cannot be interpreted as an excuse goal of the new approach is to provide for a therapist to avoid responsibility or people with the knowledge necessary deprive caretakers from human assistance. for adequate recognition of scientific Effective technology–mediated health innovations to overcome obstacles in

Cyber-anthropology: A New Study on Human and Technological Co-evolution 547 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

the process of implementing technology to [8] von Bertalanffy, Robots, Men and enhance human well–being. Minds. Psychology in a modern world. George Braziller, New York,1967. Acknowledgments Authors would like to thank the Faculty [9] L. Vekker, and A. Libin, The at the Department of Psychology at the Nature of Mind: Principles of Mental Georgetown University, and especially our Representation, unpublished dearest friend and colleague Professor manuscript. Monographs of the James T. Lamiell, and Professor Lee Ross at Complex Interactive Systems Research the Department of Psychology at Stanford University for their continuing support of Inc., 2002. our projects and for their enthusiasm so [10] K, Pribram, Languages of the Brain, necessary at the beginning of any new New York, 1971. venture. [11] M, Bornstein, and J. Bruner (eds), Interaction in Human Development. References Lawrence Erlbaum Associates, [1] Encyclopedia of Philosophy, volume 1, Publisher, Hillsdale, New Jersey, 1989 Nauka, Moscow, 1960, p. 79 (in Russian). [12] L, Vygotsky, On Psychological [2] E. Kant, Anthropology from a Pragmatic Systems. In: Selected work, volume 1, Point of View. Leipzig, 1797/1926 (in German). Pedagogic, Moscow, 1989, pp.109-131 [3] E. Kant, Critique of Pure Reason. (in Russian). St.Martin’s Press, New York, 1781/1965. [13] A, Libin and E. Libin, Robotic [4] N. Wiener, Cybernetics, Wiley, New York, Psychology. In: Encyclopedia of 1948. Applied Psychology, Academic Press, [5] A, Libin, Virtual Reality as a Complex San Francisco (in print; expected in Interactive System: A multidimensional 2004). model of person-artificial partner co- [14] E, Libin and A. Libin, Robotherapy. relations. In: H. Thwaites, & L. Addison (eds.), In: Encyclopedia of Applied Proceedings of the Seventh International Psychology, Academic Press, San Conference on Virtual Systems and Francisco (in print; expected in 2004). Multimedia. IEEE Computer Society, Los [15] E, Libin and A. Libin, A New Alamitos, CA, 2001, pp. 652-657. Tool for Robotic Psychology and [6] W. Stern, Person und Sache. System des Robtherapy Studies, Cyber-Psychology Kritischen Personalismus. Leipzig, 1923 (in and Behavior, volume 6, 4, Media German). Institute, San Francisco, 2003, pp. 124- [7] J. Lamiell, Critical Personalism, Sage, San 131. Francisco, 2003.

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[16] E, Schraube, The Politics of [22] Libin, A., Libin, E. (2004). TechnoKnowledge: An Experimental Person – Robot Interactions From Moment in Psychology. In: N. Stephenson, the Robopsychologists Point of R. Jorna, L. Radtke and H. Stam (eds.), View: The Robotic Psychology and Theoretical Issues in Psychology. Captus Robotherapy Approach. In: Person – University Publication, Toronto, 2003. Robot Interactions for Psychological [17] Wiederhold, B.& Wiederhold, Enrichment, IEEE Special Issue K.(1998). A Review of Virtual Reality as (expected in 2004). Psychotherapeutic Tool, CyberPsychology & Behavior: The impact of the Internet, Multimedia and Virtual reality on Behavior and Society, 1(1), 45-52. [18] Sheridan, T.(2002). Defining our terms. Presence 1(2):272-274. [19] Libin, E. (2003). Individual differences in coping-defense strategies related to solving life difficulties. Ph.D.Thesis, Institute of Psychology at the Russian Academy of Education (in Russian). [20] Libin, A., Libin, E., Ojika, T., Nishimoto, Y., Takeuchi, T., Matsuda, Y., Takahashi, Y. (2002). On Person – Robot Interactions: Cat NeCoRo Communicating In Two Cultures (Phase 1. USA – Japanese study). Proceedings of the 8th International Conference on Virtual Systems and Multimedia, Creative Digital Culture, VSMM Society, Seoul, pp. 899 – 905. [21] Libin, A., Cohen-Mansfield, J. (2004). Therapeutic robocat for nursing home residents with dementia: Preliminary inquiry, pp.111-117. American Journal of Alzheimer’s Disease and Other Dementias, 19 (2).

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Marina U. Bers, Chapter 56: Potential of Using Computer also present design recommendations Joseph Gonzalez- Heydrich, David Technology to Support and Augment for future interventions of this kind. R. DeMaso/ Psychotherapeutic Interventions in Potential of Hospitals, Communities and Homes 1. Introduction Using Computer Marina U. Bers, Ph.D.* Advances in medical care have greatly Technology to Support Assistant Professor, Eliot-Pearson increased the life expectancy of and Augment Department of Child Development, children and adolescents Psychotherapeutic Tufts University, Medford, MA, US suffering from a myriad of physical Interventions Joseph Gonzalez-Heydrich, M.D. illnesses. Despite these advances, in Hospitals, Communities and Assistant Professor of Psychiatry, Harvard many youngsters Homes in World Medical School & must continue to contend with a Health Strategy” Medical Director, Outpatient Psychiatry chronic physical illness and ongoing eBook, www. Programs, Children's Hospital, Boston, MA, treatment [1, 2]. It has been recognized Futureofhealth. org (Ed.) Renata US that enhancing adaptive coping G. Bushko, FHTI, David Ray DeMaso, M.D. strategies improves health outcomes 2016. Original Associate Professor of Psychiatry, and resiliency in many patients. Chapter from Harvard Medical School & Associate Interventions that provide information, Future of Health Technology (Ed.) Psychiatrist-in-Chief, Children’s Hospital, facilitate expression of feelings, and Renata G. Bushko Boston, MA, US allow mutual support are important 2002, IOS Press components of psychoeducational Abstract interventions that have been found his chapter explores the potential of to be useful. In addition there is using computer technology to support an emerging recognition that both Tand augment psychotherapeutic emotional and physical benefit can interventions in hospitals, communities and be gained through the development, homes. We describe two applications piloted expression, and understanding of at Children’s Hospital Boston. The first an individual’s personal narrative or pilot explored how patients with pediatric “story” of a physical illness [3]. Personal heart disease used the Storytelling Agent narratives often include how a physical Generation Environment (SAGE) computer illness has changed or not changed program to create interactive storytellers who they are, their relationships and and share their personal stories. The second life choices, and “what it means to involved youngsters on hemodialysis for end them.” stage renal disease using the Zora graphical Parallel to these psychotherapeutic multi-user environment to create a virtual city developments in the support of and form a therapeutic virtual community. physically ill patients, computer In this chapter we show how computer technologies have evolved that technology can be used to help patients facilitate mutual support networks, explore their identity, cope with their illness the exploration of the self, and the and provide mutual support and interaction. development of personal narratives. We The recent increase of home pages,

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 550 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

chat-spaces, virtual worlds, multi-user Media Laboratory in Cambridge, environments and Internet-based role- Massachusetts to help children “play playing games are “real world” examples out” what is happening in their lives of these technologies. Turkle [4] suggests by telling and listening to stories. In that the “Internet has become a significant order to encourage child’s emotional social laboratory for experimenting with the engagement, the wise storyteller’s constructions and re-constructions of self assistant was embodied in an that characterize postmodern life.” Despite interactive stuffed animal (rabbit) — a these technologic advances the challenge soft interface. With SAGE, children remains of how to design environments that became the designers as well as leverage the characteristic of the computer users of their creations. Thus, SAGE to purposefully support explorations about supported two modes of interaction. identity that can lead to therapeutic personal In the first mode, children share their narratives and better mutual support. personal stories with a wise sage, and Identity construction environments [5] his rabbit assistant, who “listen” and can serve this purpose. They are designed then offer a relevant tale in response. following the philosophy of constructionism In the second mode, children can [6] that asserts that people learn best when add to the collection of wise sages engaged in creating meaningful projects by designing their own storyteller for that they can reflect upon and share with themselves and others to interact with. others. Therefore identity construction They then write stories for their sage to environments enable children to design tell [7]. their meaningful computational projects to In order to support children in explore their sense of self. In this chapter creating their own characters, a we present two examples of identity visual programming language was construction environments, SAGE and Zora. developed to design and program: SAGE enables children to design interactive (1) the scripts that are used by the storytellers, while Zora provides them with storyteller, (2) the conversational tools to create a virtual city. This chapter structure or flow of the interaction, (3) describes the use of these two identity the body behaviors of the interactive construction environments in Children’s toy, which behaves as the pet Hospital Boston. assistant of the storyteller, and (4) the database of tales that are offered in response by the character. SAGE also 2. SAGE: Telling Stories With An has multimedia capabilities allowing Interactive Soft Rabbit children to record their own stories and SAGE (Storytelling Agent Generation to draw their own characters. SAGE Environment) is an identity construction was designed to focus on creating environment that supports the creation of stories and storytellers that invite individualized “wise or sage storytellers” reflection about the child’s inner world. by children. It was developed at the MIT

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 551 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

SAGE seeks cognitive and emotional as part of a larger project by the engagement. Hence, the decision to authors to understand and promote embed the assistant of the sage storytellers family coping with cardiac illness, in a programmable interactive stuffed hospitalizations, and invasive medical animal (see figure 1). The stuffed animal is procedures. The aim of this project capable of some of the types of nonverbal was to explore the feasibility of behaviors that humans use to indicate physically ill children to use SAGE as engagement and which are commonly well as its usefulness and safety in the found in conversational narratives between hospital setting. people (i.e., the rabbit moves as the To engage hospitalized youngsters children converse with it). In design mode, in the project, we created special children are able to decide on the toy’s characters for SAGE that could communicative behaviors as well as the tell stories relevant to the medical different personalities it might have. environment. This began with “Mrs. Needle” who was a cartoon-type character that engaged children around the common child fears of “needles or pokes.” This character used humor as a way to “break the ice” with these children. These characters proved quite successful as evidence by the creation of new hospital characters, e.g., “Mr. Tape”, by the children themselves. Interestingly hospital professionals even created their own characters, e.g., “Mr. Squeeze”. The following are two examples of how two patients used the system to write stories of their medical experiences. • Lisa created a character (herself) called "Sadly Alone." The character Figure 1: Interactive programmable stuffed rabbit asks the user, “Are you feeling sad?” and then told Lisa a story. In 3. Stories From The Heart response, Lisa worked on her own Patients admitted on the hospital’s story with a close family member. cardiology ward (ages 7 to 16) were asked Lisa was gravely ill when working to use the SAGE to tell their stories and with SAGE wrote the following. to create interactive characters. Informed “My name is Lisa, and I have a problem. consent was obtained from all families I’m 16 years old and I have a real bad heart problem and I am getting ready

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 552 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

to have a heart transplant really soon but the had with different storytellers (some hardest thing is my mother [is very sick] And already existing and others created by I have a little brother, so it’s so hard to leave them alone so I just stay strong and do what the patient). Interaction between the I have to do and if you ever have this kind of patient (CHILD) and SAGE happens problem just stay strong for your family and through the keyboard (i.e., typing input think of me.” and text-to-speech or recorded output. • Samuel is a 13-year-old boy who had had • This is a log of an interaction a successful heart transplant. He wrote between Damian and the rabbit, three stories about this experience and best friend of “Mrs. Needle.” put them together into a trilogy called CHILD: I guess yes “The heart transplant dictionary”. SAGE: Well, Mrs. SAGE: Hi, what is your “At first I felt very sick and I had to go into the name? Emergency room. First I had an IV which I never CHILD: Damian had before which I was pretty scared about SAGE: Welcome, Damian. I am Bunny, and then I had a blood test on my arm and I the best friend of Mrs. Needle. She hides never had one of those either which I was very in the computer because she is a little scared about too but the IV was much scarier shy. She thinks that all the kids hate her. because I didn’t know how much it was going So she asked me to talk on her behalf. Is to hurt. And another scary part was a lot of that OK with you? different doctors coming in all the time and that CHILD: yes made me nervous because it made me think SAGE: Wonderful, wonderful, Damian! that there was something very wrong with me Mrs. Needle is worried because kids [...] but then I got better and I got to go home scream when they see her. But, have you and I thought that everything will be OK but met Mrs. Needle before? then I got sick again and I had to go back to Needle is my best friend and she hides the hospital and then they realized that I had to in the computer. Tell me, Damian, how have a heart transplant. old are you? CHILD: 16 After my heart transplant I was very sick SAGE: Damian, you are older than me. I because my body was rejecting my heart and wonder if you are you scared of needles it made me feel very sick and I had to go in as I am ? I hate them, all except my friend for medicine and get biopsies twice a week Mrs. Needle. What about you? where they go through a vein in your neck with CHILD: They are all right a needle and they thread a catheter through SAGE: As I was telling you, Damian, I am and then they scrape a little piece of the Mrs. Needle’s best friend and she asked heart tissue to see if you have any rejection. me to find out why children hate her so Rejection is when your white blood cells do not much. She thinks that it is because she recognize your heart and think it is some bad stings, but she is not sure. What do you virus or disease because it is not your original think? heart and your white blood cells try to attack CHILD: yes no kid is excited to get any your heart. So I kept having rejection [...] so needles they sent me to [another hospital] to go on a SAGE: I see Damian ... what else can you experimental drug [...] and felt better and the tell me about this? new drug is working very well and now I have CHILD: the kids are afraid of it because no heart rejection at all [...] it hurts and they don’t like it to hurt and I guess that is it The following example is from actual SAGE SAGE: Well, Damian, let me see if I understand. I am sure that Mrs. Needle is logs of interactions that a 16-year-old patient very happy to hear what you have to say.

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 553 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Yes no kid is excited to get any needles the lot of children don’t like tape because kids am afraid of it because it hurts and they when you have to take it off it hurts. don’t like it to hurt and you guess that is it. Am Some kids like me to put me anywhere, I right? like the face, hands, just for fun. Do you CHILD: yes like tape? SAGE: Guess what, Damian? Mrs. Needle has CHILD: no a story for you. She is shy but she loves to tell SAGE: I am sorry, why don’t you like me. stories. She always says that they have power... Does it hurt you? Listen to her... CHILD: sometimes, yes Ms. Needle’s Story: They built me to sting, but SAGE: Well, I am good for taping things that is not all I do. If you were a flower I could up that are broken and I come in water you without hurting you. But you are not, different kinds. I try to do the best I can and I am not a water pot. My nose is like a hose with making things back to normal. So, or like a straw and my belly has goodies than Damian, how old are you? can help you to heal. When my belly is empty, CHILD: 16 the goodies are yours and you can feel better. SAGE: You are lucky to be able to live But sometimes it is the other way around. that long. My life expectancy is only two My belly starts completely empty, and then it to three years. Some people use me up becomes full with your goodies. You can think fast and sometimes I am forgotten in the of me as a someone that only stings, but I also junk drawer. I get pretty lonely in there. do good. The problem is that this is not always Would you like to hear my story? immediately obvious. CHILD: yes SAGE: I loved Mrs. Needle’s story, but how SAGE: When I am used as medical tape about you? Does it somehow relate to what you I am the number 1 user for nurses and told me before, Damian? doctors. I go on IVs and wrap things up. I CHILD: yes it does am good to write on for the nurses to put SAGE: I see, Damian, please explain me the on IV medication. You can use me just connection. I don’t get it. about everything in the hospital but I am CHILD: The children don’t realize that the stuff not very sticky for heavier objects. I could can help them, the medicine. SAGE: I see, be colored on and used for decorations Damian, you got the power of the story. I am for kids that are very bored. Some sure my friend Mrs. Needle will be very happy. people just throw me around and drop I wish that you will always have the courage to me which hurts my feelings, I can’t pick keep telling and listening to stories. I hope to them up and drop them, but I thank them see you soon....Bye ! for using me as their number one choice. Well it was nice talking to you, maybe • After playing with “Mrs. Needle”, Damian you will talk to me again and listen to my story. Bye decided to create his own character called “Mr. Tape.” He created the As shown in these examples (as well conversational structure, the scripts that as many others) youngsters with “Mr. Tape” says, and also the stories pediatric heart disease were able that he tells. After, he interacted with the to readily use the SAGE to express character and invited other people in the significant fears and feelings. SAGE Cardiac Unit to play with him. This is a proved feasible, safe, and useful. saved log of Damian’s interaction. It enabled children to adaptively SAGE: Hi my name is Mr. Tape. What is yours? express emotions through the creation CHILD: Damian SAGE: Well hello, Damian, my name is Mr. Tape. of stories and narratives along with I am very sticky, as you probably may know, a the development of innovative and

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 554 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

interactive characters with whom they could city and populate it by designing converse. Nevertheless the SAGE did not spaces, objects and interactive engage children in sharing their stories with characters that can be programmed to others in a community. When an individual engage in interactions with other users. is facing adversity it can be helpful to share The environment also has a story one’s personal narrative and becoming writing capacity. The name Zora was part of a social network that shares similar inspired by one of the cities that Italo concerns. Recognition of SAGE’s limitation in Calvino describes in his book Invisible developing a supportive community led to Cities, “This city is like a honeycomb in the next prototype, Zora. whose cells each of us can place the things we want to remember...So the 4. ZORA: Designing And Inhabiting A world’s most wise people are those Virtual City who know Zora.” [9]. Zora is a 3D graphical multi-user Users are graphically represented environment designed at the MIT Media by avatars with the owners’ image. Laboratory [8]. Users build virtual rooms and Children can visit each other’s homes populate them with objects and characters and can communicate in real-time representing aspects of themselves, through their avatars via text or program them with storytelling behaviors, gestures. Avatars can gather in the and converse with others in real-time “City Hall” to decide the laws of the through an avatar. Young patients used Zora virtual city as well as to discuss cases in the hospital’s dialysis unit. These patients related to community self-government form a community because they share a and current controversial news. Users common medical condition and treatment cannot only navigate around the 3D in their end stage renal disease. Yet, at virtual city, but also construct the city’s the same time there is little opportunity for private and public spaces: personal social interaction with each other as they homes, community centers and are confined to a single bedspace where temples. Temples are shared public they are attached to a dialysis machine for spaces that represent cultural traditions several of hours three times each week. or interests. Both personal homes and The aim of this project was to explore the temples are spatial representations potential of the Zora identity construction of identity composed by artifacts environment to facilitate mutual patient symbolizing intangible aspects of the support. In order to investigate this potential, self. the study examined the feasibility and safety Zora is an object-oriented of using the Zora virtual environment in a environment, meaning that users hospital setting. can make new objects by cloning Zora is a 3D graphical multi-user existing ones and inheriting its environment designed to support the attributes. Objects have the exploration of identity through storytelling following attributes: 1) presentation and programming. Users can create a virtual attributes, graphical appearance

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 555 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

and motion; 2) administration attributes, Laboratory staff created 3 spaces ownership, which determines who owns including the Restaurant. Patients the object and therefore can edit it, and designed personal homes as well as permissions, which set if the object can be several common spaces including cloned; and 3) narrative-based attributes, the Music Room and the Renal Rap textual description, stories, values and (described by the patients as a virtual conversations. Zora is implemented using space for dialysis patients to get the Microsoft’s Virtual Worlds platform, a together do fun things). development kit for building distributed multi-user environments [10].

5. A Virtual City in the Hemodialysis Unit During a five months pilot study in the hospital’s hemodialysis unit patients had access to a networked computer at their bedside and used it to create their own virtual city (see figure 1). The unit staff was also involved in participating in the study. Informed consent was obtained from all Figure 2: The Temple of Feeling Better participants.

Participants made a total of 94 objects ranging from pictures of the hospital staff to favorite cartoon characters to video games. Overall, the patients created 14 characters generally cartoon characters that they called “heroes.” The values dictionary of the city had 13 values with their definitions, e.g., "friendship", "doing something positive to help myself or someone else" and "respect" with the definition Figure 1: the Zora computer and the dialysis machine "people should be aware of what they do to other people's things." During this study, participants designed a total of 16 virtual places (see figure 2). During the study, the patients created Interestingly the hospital staff created 3 5 “cases” which are special types spaces including the Nurse's Room and of objects representing events or the Temple of Feeling Better (described by circumstances to be discussed and the staff as a place to tell each other ways agreed upon. They require community to cope with hard things). The MIT Medial members to take action to resolve them. For example one case dealt

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 556 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

with setting up the social organization of the virtual city, e.g., "…someone changed the appearance of my door and I don't understand why…I would like to suggest as a rule that there is no tampering with other people's stuff…” Participants posted in the bulletin boards 17 messages e.g., "I really liked what you guys have done with the renal rap room". They engaged in interactions with each other more on Figure 3: Satisfaction of Using Zora an asynchronous way than on a real-time When designing this pilot study there way. This is not surprising since not all the were some doubts about how patients, participants were in the same dialysis shift who are usually tired or sleep during and not all of them felt healthy to use Zora at most part of their treatment, would the same time. engage with Zora and if they would

even use itat all. Zora was found not 6. Feasibility and safety only feasible to use with patients In order to assess the feasibility and safety undergoing hemodialysis treatment,but of using Zora in a hospital, in the midst of that was also an enjoyable and positive the hemodialysis treatment, participants experience (both patients and staff) were asked to Hospital staff rated the experience rate the application using a 7-point Likert very high (mean = 6.5; standard scale anchored at one end by "1=not at all" deviation =0.58) (see figure 3). For and at the other end by "7=a great deal". example, one staff member noted that Descriptive statistics were calculated for being involved with the project helped each of these rating scales. Participants her learn about the infinite potential of were also asked several open-ended computer applications designed with questions.Feasibility a structure that might support different The patients (n=7) reported that they forms of therapy. Nurses did not find were very satisfied with Zora (mean = that Zora interfering with the patient’s 5.3; standard deviation =1.3) and that they medical care. On the contrary, they enjoyed very much participating in the enjoyed seeing their patients using experience (mean = 5.7; standard deviation Zora. One of the nurses said: “I liked it =1.6) (see figure 3)."It was really nice to have a lot because I noticed that kids could something fun to do at the hospital that say things in the computer that could keep my mind off dialysis and that it they might not say face to face was not schoolwork, but entertaining", said a and this has a lot of potential. It is a 15-year-old patient. wonderful program for kids who are restricted and limited to the outside world.”

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 557 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Nurses also enjoyed being involved with an appropriate way to discuss their different logistical tasks, such as helping kids feelings. Rather than going out an move the computers around and connect to punching a wall they had an the Internet. At a personal level, the hospital opportunity to discuss things and to staff enjoyed the fact that Zora helped them learn and to ask anything in Zora.” learn new computer skills. They regretted Another staff member agreed but that they could not devote more time to pointed out the importance of participate in the experience and the lack of supervising what children were doing a dedicated computer and saying, in case that intervention from an adult was needed. In the five Safety months that the program was running, Overall, the seven patients reported that there was no need of intervention. Zora was safe (mean = 5.93; standard However, the community of users was deviation =1.84) and that participating in the small and they all belonged to the experience was not hurtful (mean = 1.43; same institution.” standard deviation =1.13). When asked about the safety of using Zora, a 17-year-old replied 7. Exploration of personal identity ”It might be unsafe if you put certain things identityWhen the study was designed it in your room that younger kids shouldn’t was hypothesized that patients would see. But that’s the whole point with having use Zora to explore their illness as a the [virtual] city hall, where we set the rules key component of their identity. We and laws for Zora. I don’t think it’s not safe imagined kids would build virtual for kids.” Safety was a significant concern rooms populated by kidneys, dialysis given the multi-user and open-ended nature machines and nurses. However, this of Zora and the fact that it runs on the did not happen. On the contrary, all of Internet where children could easily find the patients consciously avoided any inappropriate content. This patient’s mentioning of hemodialysis in their response shows the importance of having in virtual rooms. As a 15-year-old said: “I Zora as a space for community participation am already on dialysis and I don’t want and democratic decision-making. In his to put things in my [virtual] room that perspective it was the patients’ responsibility remind me of dialysis; I don’t want to to make Zora a safe space, and not just a go to other rooms that have that kind matter of obeying a code of behavior of stuff either.” It is not surprising that, imposed by outsiders. when asking kids if participating in Zora Hospital staff reported that using Zora helped them gain perspective about was safe (mean = 5.63; standard deviation their illness, most of them replied that it =1.49) and they all agreed that participating in did not (mean 2.43; standard deviation the experience was not hurtful at all (mean = =2.30). 1; standard deviation =0). One of the nurses Children used Zora as a way to said: ”Zora was a safe place and a safe way escape from the harshness of dialysis, for patients to get their feelings out. It was not to think about it. Patients escaped

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 558 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

in two different ways. First, they used their Since undergoing dialysis was a avatars to “move around” the Zora virtual common factor for all of the participants city, while being “tied down” to bed and none of them felt the need to make it hooked up to the hemodialysis machine. explicit in their rooms. Instead they Patients decided where to go and visit in the chose to represent other aspects of virtual city and were able to make decisions their identity. For example, Sharon regarding how long to stay in the different created an Elvis Presley room with places. This sense of autonomy and control animations of the singer performing in was one way of escaping the frustrations of the walls while Rina created a horse dialysis where there is no possibility to move haven, with stories and pictures of her around in a free way, neither to make many horse at home. In future studies it might choices. be worth looking at what happens if Second, patients escaped the harshness patients create a Zora city together of dialysis by using their rooms to represent with kids that do not share their aspects of their identity that are usually medical condition and treatment. Will underplayed during treatment. In general they want to highlight the fact that while undergoing hemodialysis, patients dialysis is part of their identity? Or will spend their time sleeping or watching TV. they prefer to ignore it? Another Their identity is represented by “passive” question is what would happen if kids activities. However, when outside the were using Zora at home instead of at hospital, like most people of their age, they the hospital. By being removed from participate in active endeavors, such as the machines, would they use the working, going to school or going out with opportunity to reflect about their friends. Their image of themselves is not the experiences? same inside and outside dialysis. Zora provided a way to bring back the self-image 8. Facilitating mutual patient support of patients as active agents. It offered a and interaction different venue of how to use their extensive In order to facilitate mutual patient time in dialysis in a creative and fun way by support and interaction, Zora provided engaging in the creation of a personally both synchronous and asynchronous meaningful project. When asked what she ways of communicating and sharing learned during the experience, a 14-year-old experiences. The patients talked with said: “I learned new things about computers, each other in real-time through their like how to work with pictures and design avatars and they also posted my room, but I guess that I also learned messages and wrote stories for their about myself because I realized the things objects and characters. that I really care about and what my Patients reported that using Zora interests are and how to talk to others about helped them make friends or get that. In my room in Zora I could put both support from other kids on dialysis in a computers and other things I like.” moderate way (mean = 3.86; standard deviation =2.41). At the same time, they

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 559 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

reported that it greatly helped them to feel video games, movies and activities more part of a group on dialysis (mean = done during the weekend. Most of the 4.43; standard deviation =1.62). “I think that I conversations were task-oriented such always was part of the dialysis group but as helping each other to resolve using Zora helped me to get to know the technical problems and use some of people better because I could talk with the Zora features. them and see their interests, what they like and do not like by going to their virtual Asynchronous Communication: A homes”, said a 13 years old patient. Hospital Space to Voice Opinions staff perceived that using Zora helped Patients used Zora to post messages patients a lot to make friends (mean = 4.50; in each other message boards and to standard deviation =1) and a little less in write stories for their objects and making them feel part of a group (mean = characters. This asynchronous way of 3.75; standard deviation =0.5) (see figure 4). communicating their feelings was, as one of the nurses noted, “a way to Synchronous Communication: A Private Way help patients that weren’t on the same to Talk in a Public Space shift together to get an understanding The hemodialysis unit is a public noisy of the other patients when visiting their space where patients are physically together rooms”. for long periods of time. However, since their Asynchronous communication beds are far apart from each other, they facilitated the creation of a social cannot communicate with each other in a network by providing a space for private way. Although the dialysis patients patients to voice their opinions, without have all the characteristics to form a the burdens of face-to-face and real- community, they lack the means to converse time conversation. For example, while undergoing treatment. Most of the 17-year-old Larry dropped a case in patients particularly liked the fact that Zora the “Temple of Feeling Better” in which provided a good way to communicate with he complained about the increase of each other in a private way, while his time on the dialysis machine: ““I undergoing the public event of dialysis. ”I believe that my time on dialysis is too really liked that I could use Zora to talk to long. Most of the patients are on for other kids who were at a distance. only three and half-hours. Maybe you Otherwise I would have to yell across the can pull some string and get it cut room. But using Zora was great because back. Thank you. Please reply in others could not eavesdrop on my Caza’s room. Leave a message on the conversation and I felt more comfortable bulletin board”. He attached the value discussing things. I particularly liked to talk “pity” to the case but did not define it. with others about our favorite nurses, At first Larry made his case very small without being heard”, said a 13-year-old and hid it behind other objects in the patient. On-line conversations were not virtual temple. Only a very skilled Zora about dialysis per se, but about favorite user could find it. Meanwhile, one of

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 560 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

the hospital staff noted that Larry was upset Zora participants such as involving and could not talk about what was bothering other dialysis units. Another him. When we pointed out to her the case possibilitywould be to extend the that he created in the virtual temple, she experience to a large community used it as a jumping board to engage in a by including renal transplantand/or conversation with Larry. Shortly after, Larry at home dialysis patients. made his case big and put it in the center of • Need of more intervention the temple, thus recognizing the legitimacy Another goal was to observe of his feelings. Later, Larry engaged with Dr. how patients would useZora on Joe (a physician) in an exchange by leaving their own and how they would messages in each other’s rooms and create a participatory community. expressed that he was very happy to be However, thispatient population able to voice his opinions and be heard. requires a lot of direct intervention and guidelines in order to 9. Zora Design Recommendations beengaged and motivated in any A crucial study outcome was to identify not activity for long periods of time. only the positive aspects of Zora, but also As the child life specialistnoted problems. This is important to the design of “after a point in time the kids get future interventions tailored to the particular bored with anything, they want needs of this complex real-world setting. bigger and betterto keep them • Need of a broader community. In each entertained, and a lot of them dialysis session only three patients just want to sleep… they don’t wereable to connect to Zora at the want to doanything because they same time. This was due, on the one are not feeling good.” In future hand, to the lack ofcomputers, and in experiences it would be helpful the other hand, to the lack of motivated todesignate a project coordinator participants in the required agerange that would propose a tailored and the difficulties of having a broad syllabus. The creation of asyllabus patient population feeling up to work is a big challenge because, due to at thesame time. Therefore the Zora their medical treatment, not all the community logged in on real-time was patients canengage in the same very small. “It iskind of lonely in there type of activities at the same time. [Zora] because when you get on there • The question about dialysis are not many people withyou and it is content. All of the patients agreed hard to talk with others”, said a 15-years- that they did notwant to encounter old girl. Other patients pointed outthat in the Zora virtual city any content they felt embarrassed to talk with kids related to dialysis. They wanted they see everyday about their feelings Zorato be a space to escape from towardsdialysis. They rather talked dialysis. However, all hospital staff anonymously. In the future it might be had exactly the opposite o pinion. important to increasethe number of They thought that Zora would be

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 561 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

an excellent medium to teach kids about The question is how to create spaces dialysis and to engage them in thinking that engage children in learning about the process. For example, one and talking about dialysis. These of the social workers suggested the spaces should go beyond displaying creation of a restaurant because food is information produced by professionals. a big issue for kids undergoing dialysis. Patients need to take an active role The MIT Media Laboratory staff set up in their creation. For example, they the virtual space and asked patients could be the ones who, working to create the menus. For our surprise, together with the professionals, design none of the created menus took in the virtual rooms to teach visitors consideration the particular dietary about dialysis. For this to succeed restrictions of this patient population. it is important that the activity be Following is an excerpt of a conversation authentic, namely real visitors should that happened in the virtual restaurant be invited to walk around these rooms Vitor says ‘Washu, do you have any and engage in conversations with the idea about what should we have in the patients. For example, visitors can be menu?’ kids recently diagnosed with end stage Washu says ‘shrugs’ || renal disease, medical staff, parents of Vitor says ‘What drinks do you think we patients, elementary and high school should have in the menu?’ students interested in medicine. Washu says ‘coffee, tea, ice water, • Visualizing data. Patients reported etc....’ that using Zora did not help them Vitor ‘Which ones do you like best? ‘ gainperspective or understanding Washu says ‘I like tea with cream and about their illness (mean = 1.86; sugar’ standard deviation =1.21).At the Vitor says ‘I’ve never tried that, what psychological level, children about desserts’ did not use Zora to talk about Washu says ‘ice cream and there is dialysis, but as anescape from it. a Chinese dessert that all the nurses At the physiological level, Zora did love’ not support patients to explore Vitor says ‘What kind of food do you whathappens in their bodies while like?’ undergoing dialysis. However, Washu says ‘I like Chinese food and Zora can support both typesof Italian foods…noodles and fried rice interventions in future experiences. spaghetti and meat balls’’ On the one hand, a mental health Marina says ‘I wonder if there should be professional cancoordinate virtual a special menu for people on dialysis... meetings in the same style than what do you think?’ therapeutic communities. On the Washu says ‘I guess that is helpful to otherhand, the Zora environment people but I don’t like to be reminded can support the collection that I need different food’ and display of physiological

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 562 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

dataprovided by the dialysis machines environments such as SAGE and and other medical charts. This data Zora can provide an important indicates progress inthe treatment as opportunity for patients and staff to well as the level of compliance between participate in the process of gaining visits. If patients were encouragedto self-understanding and shared pay with this data in a friendly, creative understanding, which are cornerstones and educational way they could explore to coping and resiliency [11]. “whatif” possibilities regarding their own health care. And it would allow Acknowledgements researchers toinvestigate correlations We thank Seymour Papert, Mitchel between engagement with Zora and Resnick and Sherry Turkle for successful medicalcompliance. their advising role, undergraduate research assistant Daniel Vlasic for 10. Discussion the implementation of Zora, Darcy More and more hospitals are acquiring the Raches for doing the interviews and means to connect to the Internet. However, Matt Pots for his work with patients. connectivity by itself is not enough. We We are grateful to Dr. William Harmon, should ask ourselves how can we use Kristen McGee, and Evelyn Corsini and the Internet to support therapeutic work the nurses and patients at the dialysis already going on in medical facilities. unit of Children’s Hospital Boston. We Identity construction environments, also thank Linda Stone, Lili Cheng and such as SAGE and Zora, open up new the Microsoft Virtual Worlds research possibilities for health care. As shown group. in this chapter, the use of well designed computer technologies to implement well * This work was done as part of Marina grounded psychotherapeutic interventions Ber’s doctoral work at the MIT Media is feasible, safe, and useful to patients and Lab. staff. Introducing a fun, self-exploratory and community-building computer activity can References provide patients with the opportunity to be [1] Brem AS, Brem FS, McGrath creative. It help them express themselves M, Spirito A. (1988) Psychosocial and explore aspects of their identity in ways characteristics and coping skills in that are generally underplayed and even children maintained on chronic dialysis. avoided in the medical setting. Pediatric Nephrology 2:460-465. A computer based application that promotes [2] Brownbridge G, Fielding DM. increased coping and resiliency in the face (1994) Psychosocial adjustment and of pediatric illness can make accessible adherence to dialysis treatment psychotherapeutic interventions that regimes. Pediatric Nephrology 8:744- otherwise is only available to those living 749. geographically close to a major pediatric medical center. Identity construction

Potential of Using Computer Technology to Support and Augment Psychotherapeutic Interventions in Hospitals, Communities and Homes 563 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

[3] Gonzalez-Heydrich J, Bromley D, [11] Focht L, & Beardslee WR (1996), Strohecker C, Marks J, DeMaso DR, “Speech after long silence”: The use Ackermann E, Gibson S, Shen C, Umaschi of narrative therapy in a preventive M. (1998) “Experience journals: Using intervention for children of parents computers to share personal stories about with affective disorder. Family Process illness and medical intervention.” MedInf’98, 35:407-422 9th World Congress on Medical Informatics. IOS Press. 1998, pp.1323-1327. [4]Turkle, S. (1995) Life on the screen: Identity in the Age of the Internet. NY: Simon & Schuster [5]Bers, M. (forthcoming) “ We Are What We Tell: Designing Narrative Environments for Children “ In Narrative Intelligence. Edited by P.Sengers & Mateas. Amsterdam: John Benjamins. [6]Papert S. (1980) Mindstorms: Children, Computers and Powerful Ideas. New York: Basic Books. [7] Bers, M.; Ackermann, E.; Cassell, J.; Donegan, B.; Gonzalez-Heydrich, J.; DeMaso, D.; Strohecker, C.; Lualdi,S.; Bromley, D.; Karlin, J. (1998) “Interactive Storytelling Environments: Coping with Cardiac Illness at Boston’s Children’s Hospital” In Proceedings of Computer-Human Interaction (CHI’98) ACM,pp.603-609. [8] Bers, M. (1999) “Zora: a Graphical Multi- user Environment to Share Stories about the Self.” In Proceedings of Computer Support for Collaborative Learning (CSCL’99), pp. 33- 40. 9.[9] Calvino, I (1972) Invisible Cities, NY: Harcourt Brace Jovanovich [10] Vellon, M. Marple, K. Mitchell, D. & Drucker, S. (1995) “The Architecture of a Distributed Virtual Worlds System”. Virtual Worlds Group. Microsoft Research. Formatted: Bullets and Numbering

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James Drane, Chapter 57: Therapeutic Robotics for issues in the health (education and Charlotte rehabilitation), space, and defense Safos, Corina Children with Disabilities: A Case Study E. Lathan / James Drane; Charlotte Safos; and Corinna industries. AnthroTronix’ projects Therapeutic E. Lathan, PhD have been funded by a range of Robotics for AnthroTronix, Inc., Silver Spring, MD, US institutions, including the National Children with Institutes of Health (NIH), National Disabilities in World Health Abstract Science Foundation (NSF), Department Strategy” he advancement of technology is of Education (DoEd), NASA, and the US eBook, (Ed.) having a profound effect on enhancing Army. Renata G. the lives of children with disabilities. Since its founding, AnthroTronix Bushko, FHTI, T 2016. www. As advances in biomedical technology has worked with therapists, educators, Futureofhealth. allow research breakthroughs to continue parents, researchers, and children org From at a steady pace, more and more is being to develop a suite of alternative Strategy for technologies to help children with the Future of discovered about the nature of different Health (Ed.) disorders in children. At the same time, disabilities. These technologies Renata G. partly due to the continuing rapid rate of include CosmoBot, an interactive Bushko, IOS advancement (and societal acceptance) of therapy robot, and Mission Control, a Press 2009 robotics technology, researchers, educators, simple 4-button alternative computer and therapists are exploring the idea interface device. Combined with that robots might be used as an effective educational software and wearable therapeutic and educational tool. robotic interaction sensors, this suite, Over the past nine years, AnthroTronix known as Cosmo’s Learning Systems, has collaborated extensively with therapists, has been used by numerous children educators, researchers, parents, and with disabilities in research studies and children to uncover the therapeutic and classroom and home settings. educational benefits of including robotics as part of rehabilitation curriculum for 2. Challenges children. As a central part of this effort, the Throughout our years of working with company has worked with its colleagues to therapists and educators, we have develop and refine the CosmoBot system, encountered some who have been an interactive robotic toolkit designed to reluctant to accepting robotics as a enhance therapy, education, and play for useful tool for facilitating therapy or children with disabilities. educational activities. However, as the general public becomes more and 1. Introduction more comfortable with technology, AnthroTronix, Inc., a human factors robotics is being embraced as an engineering company founded in 1999, extremely effective medium for specializes in the development of interfaces communicating with children in ways that enhance human interaction with the that human therapists and educators technology around them. The company has cannot. developed interface technology to address

Therapeutic Robotics for Children with Disabilities: A Case Study 565 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

3. Background At the same time, there is a need 3.1 Autism Spectrum Disorder for more knowledge about how to Autism spectrum disorder (ASD) is relate specific child characteristics to characterized by impairments in from one components of a training package. to three aspects of behavior: reciprocal social interaction, communication, and 3.2 Cerebral Palsy, Brain Injury, and restrictive repetitive behavior. Reciprocal Stroke social interaction is the core impairment in Of children with physical disabilities, all variants and degrees of ASD [7], and may, many require ongoing PT/OT to of itself, be responsible for undermining the optimize their movement capabilities in child’s cognitive, social, and communicative order for them to participate in family, development [2, 3, 4]. The social deficits school, and recreational activities. The typically persist throughout the individual’s most common neurological disorders life. Basic sources of satisfaction, such as of the brain that impact the physical human relationships, fulfilling work, and ability of children are cerebral palsy, independence are beyond the majority brain injury, and stroke. of individuals with ASD, including many According to CerebralPalsyFacts. who are otherwise characterized as “high- com, “About two children out of functioning” with good verbal skills. every thousand born in this country Once considered a rare disorder, ASD is have some type of cerebral palsy. now recognized as a condition that occurs Studies have shown that at least with alarming frequency. A study published 5,000 infants and toddlers and 1,200 in 2003 by the Centers for Disease Control - 1,500 preschoolers are diagnosed and Prevention [5] reported a prevalence with cerebral palsy each year. In all, of 3.4/1,000 among children aged 3 to approximately 500,000 people in this 10. It has been estimated that over 40% of country have some degree of cerebral persons diagnosed with an ASD do not have palsy” [18]. The incidence of brain mental retardation [6]; effectively meaning injury among school-aged children that almost half of the population can be has been estimated by the Center considered “high-functioning.” for Disease Control (CDC) as 90 per The value of autism-specific, early 100,000, resulting in the addition of educational intervention has long been 60,000 children with new brain injuries considered incontrovertible [7, 8], particularly annually [19]. The incidence of stroke when delivered according to a structured, in neonatal children (<1 month of age) data-based procedure [9]. A number has been estimated by the CDC as of tightly controlled studies of specific 1 per 4,000 and for children from 2 intervention components, with small months to 18 years as 14.5 per 100,000 numbers of subjects, have contributed to a [20]. growing body of knowledge about useful Children with cerebral palsy, approaches and their potential benefits brain injury, and stroke have similar and limitations [10, 11, 12, 13, 14, 15, 16, 17]. physical impairments to movement,

Therapeutic Robotics for Children with Disabilities: A Case Study 566 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

although the sources or causes of the environment, exhibits social impairments differ. A common impairment behavior, and focuses its attention that requires PT and/or OT intervention is and communication on the user that of decreased amplitude and strength of in order to help the user achieve voluntary movement in the upper extremities specific goals [25, 26]. Feedback due to neurological involvement in the from therapists during the initial brain. These physical impairments can phase of our NIH-funded Gestural impact the child’s educational development Interfaces research study indicated by interfering with his/her ability to move that CosmoBot was effective in about and explore their environment, enabling children to reach not contribute to decreased social interaction only their traditional PT/OT goals and communication, and inhibit access to of strength and coordination for and interaction with computer or traditional example, but also improved the learning tools (e.g., manipulatives such as children’s attention to their tasks building blocks, books, writing tools, etc.). and allowed them to engage in pretend play - important for 4. Why Use a Robot? cognitive develop [27, 28]. There are significant advantages to using a 2) The flexibility and expandability of robot such as CosmoBot instead of software a robot: Children’s software for “play” for children’s therapy. These advantages is generally limited in content and can are elaborated below. Such data supports only engage a child’s attention for a the use of physical robots as adjuncts in limited time. For example, in a software therapeutic activities. maze, a child may be able to go from point A to point B a few times before 1) The ability of a robot to engage the they become familiar with the maze child: Children have been shown to and lose interest. Software has limited exhibit a high degree of interest in an options to make that maze more interactive robot [21, 22]. Researchers engaging to the child. With a robot in such as Dr. Cynthia Breazeal at the the real world, navigating from point A MIT Media Lab have demonstrated the to point B can be expandable to have differences between a robot and an different concrete goals (e.g., tagging animated character in terms of a person’s each person in the room, collecting engagement and perceptions of the ingredients for a sandwich, stacking robot and character. They found that blocks). CosmoBot, for example, a physical robot was more engaging allows exploration and is unlimited in and rated more highly on the scales of the ability to use it for creative play perceptions than an animated character therapy. Al Cook’s work with Lego [23, 24]. There are also researchers Mindstorms robots for unstructured who are looking at the advantages play [29] is a great example of the of a “socially assistive robot” such advantage of a robot over software. as CosmoBot that interacts with the Where Mindstorms falls short is in the

Therapeutic Robotics for Children with Disabilities: A Case Study 567 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

ability of the Lego robot (or a remote control • Degrees of freedom (DOF) – toy car) to engage the child in the way that a Although we do not know the socially assistive robot can. minimal number of DOF needed 3) Robot as an expandable platform: Finally, for a clinically appropriate robot, one can envision a robot system such as the based on our previous work [30], CosmoBot system as a platform, analogous we hypothesize that CosmoBot’s 9 to a desktop computer, where new content DOF will be sufficient. can be developed to address specific • Anthropomorphic – Appealing to therapy goals and to continually provide young children and can somewhat motivation for the children to interact with the mimic the child robot. For example, under our NIH Autism • Interface – Accessible to children Phase I SBIR grant, we developed Social with disabilities (e.g., alternative to Activity Modules for children with Autism that fine motor control operation) make use of the robot’s capability to attract • Expandable/Programmable – and sustain children’s attention and interest Needed for longevity and appeal to to foster key reciprocal social behaviors children of various ages including attending to others, imitation, • Embedded assessment/Data joint attention, and cooperative play. Our collection capabilities – Needed hypothesis is that the Social Activity Modules for therapeutic and educational constituted a novel, engaging, effective value mode of delivering social skills training to • Therapy value – Can target children with Autism Spectrum Disorder. a variety of PT/OT goals, and ultimately make the therapist’s job 5. The CosmoBot System easier 5.1 User-Centered Design of CosmoBot • Educational value – Activities target cognitive development System AnthroTronix has incorporated extensive input from a variety of therapists, researchers, educators, parents, and children during the design processes for the current CosmoBot and its two Figure 1. a) JesterBot; CosmoBot: b) version 1, predecessors: JesterBot and CosmoBot c) version 2, d) version 3 version 1 (pictured below in Figure 1). After considering this input, we defined functional The initial robot, JesterBot, whose requirements that the CosmoBot system name reflects a pun of “gestures” and should meet in order to be effective. These “robot,” was a simplistic robot with functional requirements and rationale can be limited degrees of freedom (DOF). Its summarized as follows: arms were able to move up and down • Target young children – Need for early and the robot could navigate a room intervention using two wheels.

Therapeutic Robotics for Children with Disabilities: A Case Study 568 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

The first version of CosmoBot became Control and Cosmo’s Play and a bit more complex, including a handheld Learn Software), which are pictured computer (iPaq) in its chest for onboard below. Cosmo’s Learning Systems processing. CosmoBot version 1 could was launched as a commercial also perform twice the arm movements as product in 2006 by AT KidSystems JesterBot in addition to moving its head. (an AnthroTronix subsidiary) targeting children developmentally aged 2-8.

Figure 3. The CosmoBot system: a) CosmoBot; b) Mission Control; c) Cosmo’s Play and Learn software

AnthroTronix has created gestural interface sensors (both wearable and stationary) that children can use to interact with CosmoBot. The array of sensors is shown in Figure 4 below (from left to right): an adapted standard 4-way joystick, wearable leg sensor, wearable arm sensor, wearable head sensor, wrist extension glove, and pronation-supination sensor with arm restraint brace. The head, arm, and Figure 2. Child controlling JesterBot using wearable wrist sensors leg sensors, for example, employ accelerometer technology to sense a After considerable aesthetic and functional child’s gestures. Threshold levels for all redesign, the current CosmoBot was born. of the sensors can be easily modified The “softer,” friendlier feel of this version in a software program. seemed to be well received by the children. Functionally, the onboard computer was removed and replaced by a Bluetooth link and an electronics board. Range of motion was also increased in CosmoBot’s head.

5.2 System Components The CosmoBot system as a whole primarily Figure 4. CosmoBot gestural interfaces consists of the CosmoBot robot and Cosmo’s Learning Systems (i.e., Mission

Therapeutic Robotics for Children with Disabilities: A Case Study 569 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

6. Pilot Studies with the CosmoBot System could become part of the explicit CosmoBot has been involved in six formal activity. Software development was research studies, with children with cerebral limited to the minimum necessary palsy, autism spectrum disorder (ASD), for running the study, with further Down’s syndrome, and speech-language development deferred to Phase 2, delays. The NIH, NSF, and DoEd have pending evaluation of the system. funded these studies. The most recent We evaluated the modified robot and study, funded by the NIH and conducted in prototype activities (Modules) with 2006 and 2007, explored the efficacy and young children diagnosed with an ASD, feasibility of using CosmoBot to improve the in order to assess usability and appeal. social skills of children with ASD. The Social CosmoBot study took place at the Neurodevelopmental 6.1 NIH Autism Study – Social CosmoBot Center for Young Children (NDCYC) in Crofton, MD, under the supervision 6.1.1 Study Description of the center’s director, Dr. Carole This “Social CosmoBot” research study Samango-Sprouse (Ed.D). Table 1 was a Phase 1 Small Business Innovation below briefly describes three of the Research (SBIR) study exploring the Modules that were tested in the study. feasibility of using CosmoBot to address Dr. Cheryl Trepagnier, an ASD expert different social skill discrepancies in children at the Catholic University of America, on the ASD spectrum. In this first phase, designed the Modules. AnthroTronix proposed to develop and test a system integrating a suite of prototype Table 1. Social Activity Modules description (1 Social Activity Modules and a modified example of 6) CosmoBot system. The Modules are Module 2 Look at that! engaging instructional activities directed at Goals addressed Joint attention fostering key reciprocal social behaviors that Activity Robot attempts to elicit are impaired in children with ASD. child’s attention to target to which he is The purpose of integrating the pointing Modules with the robot is to capitalize on Target Response Child follows robot’s CosmoBot’s demonstrated capability to point within 1 sec. attract and sustain children’s attention and Equipment Two closed boxes that can open under remote interest in social activities in which they control, each with a might not otherwise choose to participate. remotely controlled toy inside. Therapist Modifications to CosmoBot were proposed launches box opening in order to improve its utility as a tool and toy operation when sees that child is for instruction and practice in reciprocal looking where the robot social skills; modifications included indicates. installation of a camera in CosmoBot’s Procedure Therapist waits for child to be looking at robot nose, so that manipulating the robot's and inputs key stroke to direction of “gaze” to take in social cues initiate robot’s speech and point.

Therapeutic Robotics for Children with Disabilities: A Case Study 570 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

6.1.2 Research Tools Used • Parent Questionnaires •2 total; 1 pre-study, 1 post- study • 5-Minute Play Observation •Performed by Dr. Trepagnier • Videotaping • Observation Sheets •Completed by Dr. Trepagnier Figure 5. Module 2 – Look at That! focusing on joint attention and AnthroTronix staff • Software Log Files Dr. Samango-Sprouse recruited seven •CosmoBot control software children from among clients with an ASD recorded when, with which diagnosis. Each child was seen for 8 child, and during which sessions at the NDCYC. Characteristics module each CosmoBot of the child participants are listed below in action (verbal or movement) Table 2. Children’s scores are reported on occurred. the Leiter Brief IQ, an estimate of nonverbal IQ. Since children with ASD are language- 6.1.3 Outcomes impaired, with impairments ranging Tables 3 and 4 below summarize each from minimal to severe, nonverbal IQ is participant’s response to intervention. preferable to full-scale IQ tests. The baseline assessment and intervention approach is reported Table 2. Characteristics of children who participated in the feasibility study for each subject and the post data example highlights a specific outcome Subject Gender Chron. Age Leiter Brief observed. Code (months) as IQ of 5/1/07 SC01* M 77 123 SC02 M 82 131 SC03 M 59 85 SC04 M 46 NA** SC05 M 72 83 SC06*** M 73 82 SC07*** F 73 38

*SC01 was very distressed when he arrived for his first session and was withdrawn by his mother. **Leiter not available; WIPPSI-III performance IQ is 79 ***SC06 and SC07 are fraternal twins.

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Table 3. Highlights of participants’ responses to intervention Subj. Baseline Intervention Post Data Assessment Approach SC02 ASD. Highly Partnered with As sessions cooperative SC03 Therapist progressed, needed to find improved in ways to make the cooperating with Modules adequately partner to accomplish challenging for him Modules SC03 ASD, with mild Partnered with Improved attention cognitive delay SC02 Required to other’s behavior moderate support for (SC02) and positive participation affect sharing SC04 ASD with language Required Showed gains in delay. moderate support attending to faces for participation participation declined as sessions progressed SC05 ASD with rigidity Partnered with his Improved in and atypical sensory mother for all interpreting behaviors 8 sessions nonverbal Level of support communication, and needed for showed improved flexibility SC06 ASD with echolalia. Partnered with SC07 By last session, Notable for (fraternal successfully inattentiveness twin) produced and to instructions Required little interpreted despite high level of support to participate communication via functioning in Modules facial expression SC07 ASD with severe Partnered with SC06 Mother reported that communicative (fraternal child impairment and twin) complied with a unusual sensory Required high verbal request (for behaviors (mouthing level of support imitation) for the objects) to participate in first time. Showed Modules. improvement in performance of Modules over the 8 sessions. Also gained skill in operating joystick.

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Table 4. Summary of qualitative observational data (small “x” indicates some improvement, large “X” indicates marked improvement)

Subject SC02 SC03 SC04 SC05 SC06 SC07 FUNCTIONAL GOALS: 1.Gain experience in attending to other’s face x x x x x x 2.Improve joint attention N/A N/A X N/A x x 3.Increase interest in other’s activities N/A X x X x x 4.Demonstrate positive affect sharing X X x X X x 5.Gain experience in taking other’s X X x x X x perspective 6.Gain experience in communicating via x x x X X x gesture andfacial expression 7.Improve cooperation and attention to X X X X x X verbalinstructions Parent Questionnaire Social Skills Ratings 35 44 29.5 42 54 0 (Pre-) Parent Questionnaire Social Skills ratings 28 48 43 44 60 7 (Post-) Percent Change -7% 4% 13.5% 4% 6% 7%

Module 6, “Did we get a lot of points,” pictured below in Figure 6, focused on practicing nonverbal communication. This Module consisted of a card game in which one child (in front of CosmoBot’s nose camera) was shown either a high or low card. The therapist coached this child as to whether the card was “good” or “bad.” The Figure 6. Module 6 – Did we get a lot of child was then asked to convey to a second points? a) nonverbal facial card interpretation; child (watching CosmoBot’s nose camera b) nonverbal thumbs-up card interpretation (on video feed) video display)

Therapeutic Robotics for Children with Disabilities: A Case Study 573 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

6.1.4 Next Steps 6.2.1 Gestural Interfaces AnthroTronix intends to apply to continue this research study in order to expand on the Phase 1 research. The end goal of this research is to commercialize a suite of ASD- specific activity modules that help children and their therapists to more effectively achieve their therapy goals.

6.2 NIH Gestural Interfaces Study AnthroTronix engineers have developed innovative new ways for children with impairments (due to cerebral palsy, brain injury, or stroke) to interact, via Figure 7. Child interacting with CosmoBot via body gestures, with technology in their wearable sensor at Mt. Washington Pediatric Hospital environment (e.g., robots, software games). The end goal of this work is to enhance In Phase 1 of this project, we performed the PT/OT for these children through a technical feasibility study using allowing them to directly manipulate gestural interface technology and their environment. Development goals interactive robotics (the CosmoBot are twofold: 1) to create effective and system) to facilitate motor development intuitive gestural interfaces for children w/ and functional mobility of children with impairments and 2) to integrate CosmoBot a wide range of physical disabilities. with another therapeutic robotic device, Clinical testing of the CosmoBot Roamer-Too, to create a new robotic tool system was conducted with six that leverages the interaction capabilities of children at the Mount Washington both components. The gestural interfaces Pediatric Hospital in Cheverly, MD. are being designed to work with and Outcomes are summarized in Table 5 expand the capabilities of the CosmoBot below. system. In addition to developing these physical gestural interface devices, effort is being applied to developing specific content for the CosmoBot system to maximize its utility for PT/OT, specifically focusing on upper extremity movement (UEM) in these young children. These efforts are being conducted as part of an NIH-funded Phase 2 SBIR project entitled “Use of Gestural Interface and Robotics Technology to Facilitate Motor Development and Functional Mobility.”

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Table 5. Phase 1 Gestural interfaces study outcomes Efficacy Increased Improved Increased Improvement improved UE coordination in 3 attention to task in activities of strength in 4 children in 4 children daily living in 3 children children Motivation for Each child Each child No child claimed Other therapists Children engaged in asked for boredom or did in clinic used CB pretend play technology not want to use as reward for with CosmoBot during each CB in therapy many children (CB) in every during SLP & OT session over 4 months Therapist’s Ease Technology Technology CB gives Therapist saw of Use robust & easy to needed repair therapist high motivation use once over ability to keep when using CB 4-month period sessions new for each child, & fun during 4 leaving more months time for therapy & less coaxing child

Table 6. Additional Phase 1 study outcomes Name Child A Child B Child C Child D Child E Child F Age 10 5 5 4 6 8 Developmental 6 1/2 4 4 1/2 4 6 2 1/2 Age Diagnosis L hemi-plegia s. quadri- s diplegia & R s. quadri- s. R hemi- s. diplegia & all subjects plegia hemi-plegia plegia plegia ADHD diagnosed w/ CP; entry provides more details & other diagnoses Difficulty focusing N Y Y N Y Y attention on therapy tasks? FUNCTIONAL GOALS: Improve ADLs: x x tying shoes, fasten belts & buttons

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Improve ball skills x (throwing, catching) Increase ability to x walk farther than 20 steps using walker Increase ability x to independently dress & maintain hygiene Improve sitting x independently Sit in chair & lift arm x over head without falling over Control joystick on x power wheelchair Improve functional x x use of upper extremity STRENGTH/COORDINATION/RANGE OF MOTION (ROM) GOALS—to increase: supination ROM x x wrist ROM x x x bilateral x x coordination shoulder ROM x x x x Upper extremity x x x x x strength Elbow ROM x x SENSORS USED: (see Section 10 for details on sensors) Supination/ x x pronation brace Wrist extension x x x x x glove Wearable arm x sensors Wearable leg x x sensors Joystick x x x x Mission Control x x x x x x buttons

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The innovation research being undertaken 7 Conclusions in Phase 2 is to further develop and evaluate Clinical research studies using the use of gestural interface and interactive the CosmoBot system repeatedly robotics to treat young children with motor demonstrate the effectiveness of control and functional mobility impairments both using a robot (in general) and due to cerebral palsy, brain injury, or stroke. leveraging the CosmoBot character with children with disabilities. Phase 1 6.2.2 CosmoBot and Roamer-Too of our NIH Autism study demonstrated Through a partnership with Valiant that (1) children found the robot Technology, Ltd., whose team has motivating and engaging, (2) children developed an easy-to-program robotic participated in the instructional platform called the Roamer-Too, AnthroTronix activities, and (3) they demonstrated is working to create a new CosmoBot acquisition of the skills being taught. product that combines CosmoBot and Results from the initial phase of our NIH Roamer-Too (see Figure 8), implementing the Gestural Interfaces study (see Table Roamer-Too platform as CosmoBot’s base. 5 above) also suggest that CosmoBot Initial clinical testing of the prototype system is effective, both as (1) a therapeutic began in the fall of 2008. This CosmoBot intervention tool for targeting goals is also being used in our formal study with of increased strength, coordination, children with physical impairments at the and range of motion, with the ultimate Mayo Clinic in Rochester, MN. goal of improving function, and (2) a motivation for children to participate in therapy. Further research is currently underway (NIH Gestural Interfaces, Phase 2) to systematically and objectively evaluate these metrics in a controlled manner, over a considerable amount of time. However, further development will be needed to mold CosmoBot into a commercial version available to therapists everywhere. And while we look forward, the field of interactive robotics continues to grow and robotics technology continues to improve and become more available. Basic human-robot interaction is now easier and less expensive to achieve than ever before, with objective data collection included in the package! It Figure 8. CosmoBot version 3 (with integrated is therefore ever so critical that the Roamer-Too base)

Therapeutic Robotics for Children with Disabilities: A Case Study 577 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

disabilities community expand its leverage of [8] Harris, S.L., & Handleman, J. S., the incredible therapeutic potential of robots Age and IQ at intake as predictors like CosmoBot. of placement for young children with autism: a four- to six-year follow-up, References J Autism Dev Disord, 30 (2), 137-142, [1] American Psychiatric Association, 2000. Statistical Manual of Mental Disorders, [9] Eikeseth, S., Smith, T., Jahr, E., fourth edition, Text Revision (DSM IV-TR), Eldevik, S., Intensive behavioral Washington, DC: author, 2000. treatment at school for 4- to 7-year- [2] Trepagnier C., Infant social gaze in autism, old children with autism, A 1-year Proc 1995 National Conf on Autism, 453-7, comparison controlled study, Behav 1995. Modif., 26(1): 49-68, 2002. [3] Trepagnier C., A Possible Origin for the [10] McGee, G. G., Almeida, M. C., Social and Communicative Deficits of Autism, Sulzer-Azaroff, B., & Feldman, R. S., Focus on Autism and Other Developmental Promoting reciprocal interactions via Disabilities, 11(3):170-182, 1996. peer incidental teaching, Journal of [4] Dawson, G, Zanolli, K. Early intervention Applied Behavior Analysis, 25(1), 117- and brain plasticity in autism: Novartis Found 126, 1992. Symp., 251:266-74; discussion 274-80, 281- [11] McEachin, J. J., Smith, T., & 97, 2003. Lovaas, O. I., Long-term outcome for [5] Yeargin-Allsopp, M., Rice, C., Karapurkar, children with autism who received T., Doernberg, N., Boyle, C., Murphy, C., early intensive behavioral treatment, Prevalence of Autism in a US Metropolitan American Journal on Mental Area, JAMA, Jan 1;289(1), 49-55, 2003. Retardation, 97:359-372, 1993. [6] California Health and Human Services [12] Odom, S. L., McConnell, S. R., Agency: Department of Developmental McEvoy, M. A., Peterson, C., Ostrosky, Services, Changes in the population M., Chandler, L. K., Spicuzza, of persons with autism and pervasive R.J., Skellenger, A., Creighton, M., developmental disorders in California's & Favazza, P. C., Relative effects of developmental services system: 1987 interventions for supporting the social through 1998: a report to the Legislature, competence of young children with March 1, 1999, Sacramento, CA: California disabilities, Topics in Early Childhood Health and Human Services Agency, 1999. Special Education, 19, 75-92, 1999. [7] Freeman, B. J., Guidelines for evaluating [13] Rogers, S. J., Empirically supported intervention programs for children with comprehensive treatments for young autism, J Autism Dev Disord, 27(6): 641-51, children with autism, J. Clin. Child 1997. Psychol., 27(2): 168-79, 1998. [14] Rogers, S. J., Interventions that facilitate socialization in children with autism. J Autism Dev Disord. 30(5): 399, 2000.

Therapeutic Robotics for Children with Disabilities: A Case Study 578 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

[15] Bernard-Opitz, V., Sriram, N., Nakhoda- Institute of Technology, 2003. Sapuan, S., Enhancing social problem [24] Kidd, C.K. and Breazeal, C., “Effect solving in children with autism and normal of a robot on user perceptions,” children through computer-assisted In 2004 IEEE/RSJ International instruction, J. Autism Dev. Disord., 31(4): 377- Conference on Intelligent Robots and 84, 2001. Systems (IROS 2004), Sendai, Japan, [16] Bauminger, N., The facilitation of 2004 social-emotional understanding and social [25] Tapus, A. and Mataric, M.J. interaction in high-functioning children with "Towards Socially Assistive Robotics", autism: intervention outcomes. J. Autism Dev. International Journal of the Robotics Disord., 32(4): 283-98, 2002. Society of Japan, 24(5), July 2006. [17] Barry, T. D., Klinger, L. G., Lee, J. M., [26] Mataric, M.J., Eriksson, J. Feil- Palardy, N., Gilmore, T., Bodin, S. D., Seifer, D. and Winstein, C. "Socially Examining the effectiveness of an outpatient Assistive Robotics for Post-Stroke clinic-based social skills group for high- Rehabilitation", International Journal of functioning children with autism, J. Autism NeuroEngineering and Rehabilitation, Dev. Disord., 33(6): 685-701, 2003. Fall 2006. [18] CerebralPalsyFacts.com, “Cerebral Palsy [27] Singer, D.G. (Ed), Golinkoff, R.M. Statistics,” , March 28, 2005. = Learning: How play motivates and [19] “Rehabilitation of Persons With Traumatic enhances children's cognitive and Brain Injury,” NIH Consensus Statement social-emotional growth,” 2006. Online, 16(1): 1-41, Oct 26-28. [28] Schwebel, D.C., Rosen, C.S., [20] Lynch, J. K., Hirtz, D. G., DeVeber, G., and Singer, J.L., “Preschoolers' pretend Nelson, K. B. “Report of the National Institute play and theory of mind: The role of of Neurological Disorders and Stroke jointly constructed pretence,” British Workshop on Perinatal and Childhood Journal of Developmental Psychology, Stroke,” Pediatrics, 109; 116-123, 2002. 17(3): 333-348, 1999. [21] Dautenhahn K. & Werry I., “Towards [29] Schulmeister, J., Wiberg, C., interactive robots in autism therapy: Adams, K., Harbottle, N., and Cook, background, motivation and challenges,” A. “Robot Assisted Play for Children Pragmatics and Cognition, vol. 12, no.1, pp. with Disabilities” 29th Annual RESNA 1–35, 2004. Conference Proceedings, Atlanta, GA [22] Robins B., Dickerson P., Stribling P. 2006. & Dautenhahn K., “Robot-mediated joint [30] Plaisant, C., Druin, A., Lathan, C., attention in children with autism: A case Dakhane, K., Edwards, K., Vice, J. M., study in robot-human interaction,” Interaction and Montemayor, J., A Storytelling Studies, vol. 5, pp. 161–198, 2004. Robot for Pediatric Rehabilitation, [23] Kidd, C.K., “Sociable robots: The role Proceedings of ACM Conf. Of Assistive of presence and task in human-robot Technologies, ASSETS 2000, ACM interaction,” Masters thesis, Massachusetts Press, New York, pp. 50-55, 2000.

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Thomas R. Chapter 58: Future of Anti-addiction some chemical agonists. Technology Kosten / Future advances in manufacturing and of Ani-addiction Vaccines Vaccines in Thomas R. Kosten, M.D. delivery systems will improve future “World Health Professor of Psychiatry and Medicine, anti-addiction vaccines, but social Strategy” Yale University School of Medicine, New acceptance of anti-addiction vaccines eBook, (Ed.) Heaven, CT, US will depend on substance abuse Renata G. Bushko, program staff and the families of FHTI, 2016. Abstract substance abusers, who have some Futureofhealth. he medical rational for using anti-drug values that oppose medical solutions org - From to addictive diseases and view Intelligent and antibodies in the serum as a treatment Extelligent Tis to reduce drug levels in the brain addictions as moral problems. Health and to bind drug before it enters the brain. Environments Drugs of abuse are small molecules that 1. Introduction (Ed.) Renata G. Nearly 200 years ago Jenner first used Bushko, IOS can readily cross the blood brain barrier, Press 2005 while antibodies are larger molecules that vaccination (active immunization) for cannot get into the brain. Thus, any drug the prevention and treatment of human that is bound to antibody also cannot cross disease, and over these 200 years the blood brain barrier and cannot enter the only clean water may have provided brain. Active anti-drug vaccines stimulate a greater impact on worldwide public the body to makes its own antibodies, but health. By stimulating an immune the small size of abused drugs prevents response to disease-related organisms them from stimulating an immune response. vaccines have prevented illness Thus, individuals do not ordinarily produce or death in millions of individuals antibodies to abused drugs, and vaccines each year. Immunizations generate to stimulate antibodies are made by protective antibodies in the body fluids, chemically linking these abused drugs to which act as an early surveillance toxins such as cholera toxin. Alternatively, system to block or reduce the effects passive immunotherapy uses monoclonal of an invading organism or substance, antibodies that are generated in a laboratory such as a toxin. Antibodies are and then administered via intravenous continually produced and broken injection. Antibodies can be used to treat down (metabolized and inactivated) in drug overdose; to reduce drug use relapse; the body. The most common type of or to protect certain at risk populations who antibody (IgG) has a half-life in blood of have not yet become drug dependent. about 3 weeks [1]. That is, about half of The advantages of anti-addiction vaccines the antibody produced are that antibodies target the drug, not on day 1 is eliminated by day 21. Blood the drug’s sites of action in the brain and levels of antibody after vaccination are antibody binding inactivates the drug. maintained because new antibody is These vaccines can complement behavioral continually produced. After passive and other medical therapies with minimal immunization with monoclonal side effects and are not addictive like antibodies, a steady decline in

antibody level with a half-life of about while larger molecules such as 3 weeks is expected, so that repeated antibodies (molecular weights of about antibody doses every few months would 150,000 Daltons) cannot [3]. Thus probably be needed to maintain antibody any drug that is bound to antibody levels in blood. Recently, we have begun also cannot cross the blood brain to conceptualize abused drug as toxins that barrier and cannot enter the brain. In might also be treated and perhaps even animals, immunotherapy reduces drug prevented from developing into the disease distribution to brain within the first of addiction by using immunotherapy. few minutes after a single drug dose Several advances in immunotherapy by up to 80% [4, 5]. This is important allowed us to consider manufacturing because the rewarding effects of anti-addiction vaccines [2]. An early use drugs are also greatest in the first of immunotherapy involved polyclonal few minutes after a dose. Thus, the antibodies in the form of specific immune drug binds to the antibody, and the serum to treat infectious diseases. These rewarding or medically harmful effects antisera effectively treated pneumonia of the drug are reduced or blocked. and tetanus, but a serious adverse side Because these therapies target only effect was serum sickness, an allergic the drug, they are potentially safer reaction resulting from the administration than treatment with small molecule of animal antisera to humans. Thus, these medications, which bind directly to animal antisera could only be used as a important receptor systems in the brain last treatment option. Later, human donors and other organs. were immunized and human immune Immunotherapies for drug abuse globulin collected for treatment, and these can be either active or passive. Active are still used to treat hepatitis B, tetanus immunizations use drug vaccines to and Varicella zoster. We can now produce stimulate the body to makes its own monoclonal antibodies, which can be antibodies and to create a long-term produced by large scale manufacturing immunological memory for a more techniques, without the use of animals rapid future response to vaccine. or animal proteins and without the risk of An important consideration in this transmitting human infectious agents such as approach is that the small size of HIV and hepatitis viruses. abused drugs prevents them from stimulating an immune response. 2. What are anti-addiction vaccines? Thus, individuals do not ordinarily The medical rational for using anti-drug produce antibodies to abused drugs, antibodies in the serum as a treatment is and even after effective vaccination to reduce drug levels in the brain and to continued drug use does not make bind drug before it enters the brain. Many more antibodies. This lack of immune small molecules such as drugs of abuse stimulation by the abused drug alone (molecular weights of 200-300 Daltons) contrasts with infectious disease can readily cross the blood brain barrier vaccines where expose to the

infectious agent will itself trigger a strong surface antibody on B cells is required immunological response in a person who to stimulate antibody production, the has been vaccinated and markedly increase same drug hapten-protein vaccine the production of new antibodies. Like must be used for making more standard infectious disease vaccination, antibody, called boosting the immune antibodies are not produced until several response, when the antibody levels weeks after these active immunizations. fall to relatively low levels typically 4 to Passive immunotherapy uses monoclonal 6 months after the original vaccination antibodies that are generated in a laboratory series is completed. Periodic boosting and then administered via intravenous with the vaccine is required to keep injection. In this case more antibody can serum antibody levels high. The actual be administered and the protection can be serum level of antibody is affected by immediate, but it only lasts until the antibody the quality of the drug-protein vaccine, is cleared and there is no immunological the dose of the vaccine, the frequency memory against the abused drug. of vaccinations, the time interval between immunizations, and poorly 2.1 Active anti-addiction vaccination understood genetic variations among In active immunotherapy, the drug of abuse individuals. Based on results from (called a hapten) is chemically coupled to prior vaccine regimens it is anticipated an antigenic protein carrier like cholera that the immune response will not be toxin, and this combination is then used as a adequate for at least 3-6 weeks after vaccine. Vaccines are currently being tested the start of vaccination, and booster in humans for cocaine and nicotine [6, 7]. immunizations will be required every Because stimulation of an immune response 4-6 months to maintain a sufficient level requires multiple interactions on the surface of drug-specific antibodies. Improper of an antibody forming B lymphocyte, a timing of vaccinations could result single, small drug molecule (like cocaine or in a poor response or a significant nicotine) cannot produce cross-linking of reduction in the amount of circulating cell surface antibodies on a B cell to activate antibody. Thus, the timing and duration it to produce more antibodies. For this of vaccinations will need to be carefully reason, drug haptens must be irreversibly coordinated with patient needs and bound to their large protein carriers for use other medical interventions like as vaccines. The molecular orientation counseling or behavioral modification and spacing of the drug haptens on the programs protein surface are critical factors that scientists must control for an optimal immune 2.2 Passive monoclonal anti- response. Thus, the antibody response addiction immunotherapy will not increase if a vaccinated individual Passive immunotherapy does not uses the abused drug, itself, and only the vaccinate an individual to stimulate his/ circulating antibody at the time of drug use her antibody response, but administers will be protective. Because cross-linking of pre-formed anti-drug antibodies to the

person. This antibody medication could be abused substances with an early- polyclonal serum from an individual who has response system that can quickly been vaccinated against a drug of abuse. treat new addictive disorders and However, a monoclonal antibody could be potentially stop their epidemic spread. made with high affinity for a specific abused A similar rapid technology probably drug and be either a chimeric monoclonal can be developed for developing the comprised of 34% mouse protein and 66% much less expensive active vaccines, human protein, a humanized monoclonal since the initial development of both comprised of >90% human protein, or a cocaine and nicotine vaccines has fully human antibody. Currently, advanced suggested that several carrier proteins biotechnological techniques have produced derived from various bacterial toxins FDA-approved monoclonal antibodies can be effectively coupled to drugs of for ten therapeutic and one prophylactic abuse [7]. Extending this technology indication. For example, Synagis® is a to other currently abused substances monoclonal antibody approved for the such as marijuana, amphetamine or prevention of serious lower respiratory ecstasy, as well as to new generations disease caused by respiratory syncytial of “designer drugs” of abuse will be a virus (RSV) in pediatric patients at high risk of tremendous opportunity to have new RSV disease. This antibody is administered pharmacotherapies rapidly available before and then monthly throughout before experimental abuse of a new the RSV season to maintain protective substance develops into an epidemic. circulating antibody levels. Thus, passive immunotherapy with monoclonal is being 3. How might anti-addiction vaccines successfully applied in a variety of medical be used in the future? areas and is beginning to be applied in chemical addictions. 3.1 Three clinical applications of anti- Another technological development addiction immunotherapies for monoclonal therapy has been new Antibodies could potentially be used in ways to make specific immunotherapies in drug abuse treatment for three clinical relatively short periods of 12 to 18 months applications: to treat drug overdose; rather than the typical 15 years required to reduce drug use relapse; or to for bringing a new medication to market protect certain at risk populations who [8-13]. These immunotherapies can be have not yet become drug dependent genetically engineered as new abused [14]. Adolescent children of cocaine drugs are detected by emergency room dependent parents might illustrate this admissions of overdoses, by police seizures third application. If these adolescents from illicit drug dealers or by other early begin using cocaine, then preventative indicators of a new “designer drug” of vaccination might be considered abuse. Applying this technology to the to protect these adolescents from immunotherapy of addictions would allow becoming cocaine dependent with all us to match the rapid proliferation of newly its severe implications for psychosocial

as well as developmental complications. of rheumatoid arthritis. In summary, Other special populations such as fetuses flexible combinations of vaccination of drug abusing mothers might also warrant and monoclonal immunotherapies protective immunotherapy of the mother can address a range of therapeutic to prevent fetal exposure to the abused challenges in the addictions, and the drug. Vaccination could potentially be used models for using immunotherapies are in all of these situations, except for drug already being applied in other medical overdose, where only monoclonals will be disorders. suitable, because the effect of the therapy must be rapid and cannot be delayed for 3.2 Addressing current several weeks. Monoclonal therapy might immunotherapy limitations also be modified for special uses such as While current immunotherapies have overdose. For example, antibody fragments, potential limitations, most of them of a size that would be cleared by the can be addressed. Some of these kidney, could be used to treat overdose so limitations are technological, but others that not only would the antibody bind the are challenges from the systems of drug and lower the amount in the brain, but medical care delivery and from social also, the drug-antibody complexes would be consequences of these therapies. cleared quickly from the body. Depending Technological limitations differ for on the particular setting, a combination vaccines and monoclonals. One of vaccination and monoclonal antibody limitation for monoclonal antibodies therapy could be administered. In a drug involves their production, which is abuse protection or relapse setting, where time-consuming and expensive. one would like to have significant antibody Furthermore, the development of present over a long period of time, one a high affinity monoclonal anti-drug could envision administering a loading dose antibody is sometimes difficult to of a monoclonal antibody along with active achieve. This discovery process of immunization (vaccination) with periodic selecting an appropriate monoclonal repeat booster doses of vaccine to maintain antibody among the thousands that the desired serum antibody concentrations. can be produced will led itself to This combined approach of using active high throughput screening, which has (vaccination) and passive (monoclonal) been very effectively applied to many antibody therapy takes advantage of aspects of the drug discovery process the relatively low cost of vaccination for for small molecules such as antibiotics. long-term protection and the immediate The technological challenges for efficacy of more costly monoclonal therapy. vaccinations include the inadequate Monoclonal therapy can also be simply antibody response in some individuals. given repeatedly every couple of months. When an individual makes insufficient For example, Remicade® is given at 0, 2 antibodies, then the blockade of and 6 weeks as a loading dose and then the illicit drug will be ineffective or every 8 weeks thereafter for the treatment quite weak and easily overridden by

increasing the amount of drug used. While as infectious agents and large protein biotechnology advances may address many toxins. Improving vaccines by better biological reasons for such inadequate adjuvants than the alum ones currently antibody responses, adherence rates used, as well as by using concurrent for a wide range of treatment regimens cytokine treatments to enhance the have been far from perfect. For cocaine antibody response are other potential treatments lasting only 3 months dropout technological fixes to these challenges rates range from 15% to 79%, with an overall of individuals’ inadequate responses to rate of 48% [15]. Adherence may be a immune stimulation. Vaccinations also particular problem for completing a series may not produce antibodies in a timely of three to five initial vaccinations over 2 fashion for proper integration with to 3 months or for obtaining later booster other medical interventions (e.g., drug vaccinations in substance abusers. Insuring overdose). For overdoses, the obvious behavioral adherence will require other solution will be to develop monoclonal social strategies beyond this paper, but are antibodies for passive use. For other critical for the overall success of any anti- applications, where such a rapid addiction vaccine program. However, a response is not essential, concurrent more optimistic view is provided in a recent cytokine administration and sustained intervention targeting over a thousand release formulations may accelerate heroin addicts in Italy, 88% completed a full the antibody response. Oral or even six-month hepatitis B vaccine series [16]. So intranasal administration rather than high compliance is possible even in heavy injections of the vaccines may be drug-using populations. another technological improvement for Predicting who will develop adequate addictions like nicotine that sometimes responses will be improved substantially are viewed more as lifestyle issues as we develop better understanding of the rather than immediately life threatening genetic determinants of these responses. diseases. Individuals showing low antibody responses might then be treated more broadly for this 3.3 Unexpected social consequences relative immuno-deficiency by variations in of anti-addiction vaccines gene transplantation and perhaps infusions Because in some cases the drugs of of appropriate T and B type white blood abuse are closely related in structure cells to generate antibody responses, as to either neurochemicals or approved well as being given cytokines and other medications (e.g., nicotine replacement small proteins that enhance immune therapy for cigarette smoking), it is responses. The importance of such possible that the therapies could lead treatments for their immune system is not to unexpected adverse reactions simply to treat their inability to adequately or reduced effectiveness of other respond to these anti-addiction vaccines, but medications. This drug interaction is also their diminished ability to fight a broad easily tested, however, and extremely range of potential immune challenges such specific because of the specificity of

antibodies. Thus, this potential problem This enhanced craving due to partial will be easily detected and of a very limited blockade when a modest amount duration, since vaccines and monoclonals of drug is used coupled with the only maintain sufficiently high antibody levels diminished blockade of toxicities may to produce such effects for about 3 to 4 enhance accidental overdose risk. months without booster vaccination or re- The success of any blockade infusion of the monoclonal. The duration of strategy also assumes that the drug’s efficacy after an initial course of vaccination pharmacological effects primarily or active immunotherapy also raises drive drug use, but these effects are ethical considerations about stigmatization, not the sole motive for drug use. In because of the potential for long-lasting adolescents drug use may be a form immunologic memory to serve as a marker of defiant behavior and attenuating of past immunization for years or even a the primary reinforcing effects of an lifetime. Monoclonal antibodies, however, abused substance such as tobacco or have a finite life span and several months marijuana smoking may not deter the following treatment would no longer be substance use. Furthermore, some detectable. harm stems from behaviors associated Immunotherapies like all long-acting with drug use itself or from substances blockers also have special risks, because mixed in with the reinforcing drug that large amounts of drug could override is blocked [17]. Those potential harms the beneficial effects of immunotherapy. would be exacerbated if users sought Effectiveness of the blockade will also to override immunotherapies’ partial decrease over time, but not at a predictable blocking by taking more of the drug or rate in a particular individual. Blockades that taking it more frequently. For example, are completely effective either immediately the risk of lung cancer from cigarette from a monoclonal or progressively from smoke will be enhanced by greater a vaccine will both become progressively use. Even if a vaccine intercepts ineffective. As the level of blocking wanes the harmful effects of nicotine, tar over time following administration, there and other carcinogen exposures will is no obvious signal to the patient that the increase and damage the esophagus blocking effects have diminished after and lungs. weeks or months of sustained blockade. A related effect of relatively potent Toward the end of the â€œeffectiveâ€ risk reduction strategies is increased duration of blockade the patient may engagement in these risky activities. ingest a relatively large amount of drug that Existing data support this unfortunate previously had produced minimal effects, but effect of risk reduction strategies. now results in an overdose. Furthermore, Smokers compensate for filters and immunotherapies will not reduce drug low-tar tobacco by smoking more craving, and craving may increase as the cigarettes, inhaling more deeply, blockade becomes weaker and the drug or blocking the filter vents [18, 19]. abuser feels a partial or delayed drug effect. Similarly, Katz et al. [20] report that

the percentage of San Francisco men who specific for the drug and/or the drug report unprotected anal sex increased from class. 4. These immunotherapies can 24 percent to 45 percent between 1994 and complement conventional therapies 1999. The authors present correlations and (like behavioral modification) for a more anecdotal evidence linking this increase comprehensive medical approach. in risky sex to reduced fears of HIV since 5. The use of immunotherapy would the advent of HAART, which can effectively not necessarily preclude the use of treat AIDS. A survey reported by Ostrow chemical agonists or antagonists for et al. [21] also shows a correlation between the brain receptors or transporters unsafe sex and perceptions that HAART involved in the actions of the abused reduces the harmful consequences of HIV drug. An important exception is the infection. In both these cases, some of the combined use of a nicotine agonist safety gains brought about by a reduction therapy and anti-nicotine antibodies, in the probability of harm given unsafe although nicotine agonist therapy can conduct have been offset by increases in be used during active vaccination the probability of that conduct without interfering with antibody For illicit drugs, adverse consequences production. 6. Immunotherapy has a of attempting to override the vaccines different pattern and generally minimal could extend beyond the drug user to side effects compared to treatment other people, if immunotherapies increased with chemical agonists or antagonists. the demand for drugs from drug dealers 7. The antibodies are not addictive like and black markets [17]. For example, some chemical agonists. crime committed by users to get money to buy drugs and conflict related to drug 4. What technological advances transactions, (e.g., disputes among dealers might be made in immunotherapies? over drug money) account for more than 2/3 Technology advances in manufacturing of drug-related crime. If immunotherapies and delivery systems will improve increased market demand, they could yield future anti-addiction vaccines, as a net increase in drug-related crime and indicated above through several violence. examples. Perhaps the most important will be a marked increase in the 3.4 Summary of advantages for future speed for discovering and bringing anti-addiction vaccines new treatments to market for abused In spite of these various limitations, both substances, as new abused drugs active and passive immunotherapies have constantly evolve and are spread several major advantages over other among the youth of the world. Related approaches to treating drug dependence. advances will increase the stability 1. The antibodies target the drug, not the and longevity of antibody blood drug’s sites of action in the brain. 2. The levels and produce combination binding of drug to antibody inactivates vaccines and monoclonal antibodies the drug. 3. The antibody can be highly to simultaneously treat a variety

of abused drugs. Delivery systems for that support drug treatment vaccines can be improved. Current multiple may have unique rules and may injections can be converted to single not provide coverage for new injections in sustained release formulations therapies including medications; to improve peak antibody levels and sustain • Education and training – in many those levels more effectively. Injections programs training for staff relies also can be converted to oral and intranasal more heavily on an apprenticeship administration forms. As our understanding (experiential training) emphasizing of cytokines and other immune modulators traditional approaches rather improves, we will be able to add adjuvant than the more theoretical and agents to the basic vaccines that will cosmopolitan perspective found in graduate education; markedly reduce the time for antibody • Stigma – ignorance and prejudice production from several weeks to possibly about drug abuse contributes to several days. These adjuvants will also inadequate training in graduate increase the peak antibody response and programs and medical schools, prolong the duration of these responses inhibits the construction and thereby enabling less frequent boosters. location of facilities, and reduces Monoclonal antibodies will be produced in investments in technology more efficient plant-based systems rather development; than the significantly more expensive • Lack of knowledge about microbial incubator vats that now produce technology transfer – a lack these molecularly engineered proteins. of systematic research on the adoption of technology in drug 5. Facilitating adoption of technology in abuse treatment settings slows alcohol and drug treatment services the development of more effective Progress in the development of medications dissemination strategies; for the treatment of drug dependence will • Policy – local, state and federal lead to little application of these therapies, policies sometimes restrict the if drug abuse treatment practitioners and types of services available and programs are not ready, willing, and able the individuals who receive those to embrace medication technologies. Six services. broad sets of barriers to the diffusion and These six issues that slow diffusion adoption of emerging technologies in drug of any new medical therapy into abuse treatment settings were identified in substance abuse treatment may the Institute of Medicine’s [22] analysis of the be complicated due to several unintended behavioral consequences linkages between research and practice: of anti-addiction vaccines. These • Structure – small programs with limited consequences can be divided into resources may be unable to afford the four potentially negative scenarios. medical staff and training required to fully 1. Users can attempt to override the utilize medications; therapy with larger doses. 2. One drug • Financing – the multiple funding streams whose effects have not been blocked

can substitute for another drug whose References: effects have been blocked. For example, [1] T. A. Waldmann and W. Strober, amphetamine substituted for cocaine in a Metabolism of Immunoglobulins, stimulant abuser taking a cocaine vaccine. Progress in Allergy 13 (1969) 1-110. 3. There may be an increased incidence [2]T. R. Kosten and D. Biegel, and/or prevalence of drug use because Therapeutic Vaccines for Substance of a perception of less risk involved with Dependence, Expert Review of drug initiation. 4. Drug sellers losing sales Vaccines 1 (3) (2002) 363-371. may adopt aggressive actions in an attempt [3] M. W. Bradbury and S. L. Lightman, to move into new markets. All of these The Blood-Brain Interface, Eye 4 (Pt 2) scenarios emphasize how the intended (1990) 249-254. recipients of intelligent health environments [4] B. S. Fox, K. M. Kantak, M. can defeat the benefits of these new A. Edwards, et al., Efficacy of a technologies through unintended uses and Therapeutic Cocaine Vaccine in distortions of technologies and their goals. Rodent Models, Nature Medicine 2 (10) These six issues that slow diffusion of (1996) 1129-1132. any new medical therapy into substance [5] P. R. Pentel, D. H. Malin, S. Ennifar, abuse treatment may be complicated et al., A Nicotine Conjugate Vaccine due to several unintended behavioral Reduces Nicotine Distribution to consequences of anti-addiction vaccines. Brain and Attenuates Its Behavioral These consequences can be divided into and Cardiovascular Effects in Rats, four potentially negative scenarios. 1. Users Pharmacology, Biochemistry and can attempt to override the therapy with Behavior 65 (1) (2000) 191-198. larger doses. 2. One drug whose effects [6] T. R. Kosten, M. Rosen, J. Bond, have not been blocked can substitute for et al., Human Therapeutic Cocaine another drug whose effects have been Vaccine: Safety and Immunogenicity, blocked. For example, amphetamine Vaccine 20 (7-8) (2002) 1196-1204. substituted for cocaine in a stimulant abuser [7 M. Haney and T. R. Kosten, taking a cocaine vaccine. 3. There may be Therapeutic Vaccines for Substance an increased incidence and/or prevalence Dependence, Drug Discovery Today: of drug use because of a perception Therapeutic Strategies (in press). of less risk involved with drug initiation. [8] T. Turpen, T. I. Cameron, S. J. Reinl, 4. Drug sellers losing sales may adopt et al., Production of Recombinant aggressive actions in an attempt to move Proteins in Plants: Pharmaceutical into new markets. All of these scenarios Applications. The Soc. Exper. emphasize how the intended recipients of Biol., Canterbury, UK, Journal of intelligent health environments can defeat Experimental Botany the benefits of these new technologies 48(Suppl) (12) (1997). through unintended uses and distortions of technologies and their goals.

[9] G. P. Pogue, S. Garger, M. McCulloch, [17} R. J. MacCoun, P. Reuter Jr., C. Wolf, et al., From Dirt to Drugs: The Use of Viral (eds). Drug War Heresies: Learning Vectors to Make Pharmaceutical Grade from Other Vices, Times, and Places. Recombinant Proteins, Fifth International Cambridge University Press, New York, Symposium on Positive Strand RNA Viruses, 2001. 1998. [18] J. R. Hughes, Applying Harm [10] R. B. Holtz and S. Garger. Reduction to Smoking, Tobacco Commercialization of Recombinantly Control 4 (1995) S33-S38. Derived Therapeutics from Tobacco Plants [19 K. Stratton, P. Shetty, R. F. Wallace, in a cGMP Facility: Division of Biological S. Bondurant, Clearing the Smoke: Chemistry, American Chemical Society Assessing the Science Base for National Meeting, 1999. Tobacco Harm Reduction, Tobacco [11] R. B. Holtz. Purification Systems for Plant Control 10 (2) (2001) 189-195. Derived Biologics. Invited Paper. Plant [20] M. H. Katz, S. K. Schwarcz, T. Derived Biologics Seminar. Sponsored by A. Kellogg, et al., Impact of Highly FDA/CBER and USDA/APHIS. Ames, Iowa, Active Antiretroviral Treatment on HIV 2000. Seroincidence among Men Who Have [12] R. B. Holtz. Vaccine Production Using Sex with Men: San Francisco, American Plants as Bioreactors: Regulatory Issues and Journal of Public Health 92 (2002) Opportunities. Invited Paper. BIOPHEX. San 388-394. Jose, CA, 2002a. [21] D. E. Ostrow, K. J. Fox, J. S. Chmiel, [13]’ R. B. Holtz. Rapid Scale-up of Vaccine et al., Attitudes Towards Highly Active Production in Plants: Two Case Studies. Antiretroviral Therapy Are Associated Invited Speaker. World Vaccine Conference. with Sexual Risk Taking among HIV- Lyon, France, 2002b. Infected and Uninfected Homosexual [14] H. J. Harwood and T. G. Myers, (eds). Men, AIDS 16 New Treatments for Addiction: Behavioral, (2002) 775-780. Ethical, Legal and Social Questions. The [22] NIH Consensus Conference, National Academies Press, Amsterdam, Effective Medical Treatment of Opiate 2004. Committee on Immunotherapies and Addiction, JAMA 280 (1998) 1936-1943. Sustained-Release Formulations for Treating Drug Addiction. [15] M. Silva de Lima, G. Garcia de Oliveira Soares, A. Alves Pereira Reisser, M. Farrell, Pharmacological Treatment of Cocaine Dependence: A Systematic Review, Addiction 97 (8) (2002) 931-949. [16] G. Quaglio, G. Talamini, F. Lugoboni, et al., Compliance with Hepatitis B Vaccination in 1175 Heroin Users and Risk Factors Associated with Lack of Vaccine Response, Addiction 97 (8) (2002) 985-992.

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David H. Chapter 59: Future of Addiction this process, the panelists generated Gustafson, eight idea categories that visualized Tara E. Palesh, Treatment: Enhancing the Human Rosalind W. Experience and Creating a Fix for the future treatments for addiction using Picard, Paul E. Future technology. They were: (1) Integrated Plsek, Lynne David H. Gustafson, Ph.D. System and Record; (2) Monitoring/ Maher, Victor Research Professor of Industrial Treatment; (3) Virtual Experiences; A. Cappocia / Future of Engineering and Director of the Network (4) Treatment Access and “One Stop Addiction for Improvement of Addiction Treatment, Shop; (5) Networks; (6) Tailored Media Treatment in University of Wisconsin, Madison, WI, USA Campaigns; (7) Diagnostic Tools; and World Health (8) Help for Family. Two stories illustrate Strategy” Tara E. Palesh eBook, www. University of Wisconsin, Madison, WI, USA how these ideas could help a heroin Futureofhealth. Rosalind W. Picard, Sc.D. addict and an alcoholic. The sponsors org (Ed.) Renata Director, Affective Computing Research plan another meeting to bring these G. Bushko, Group, MIT Media Laboratory, visionary concepts closer to real FHTI, 2016. From: Intelligent Cambridge, MA, USA application. and Extelligent Paul E. Plsek Health Paul E. Plsek & Associates, Inc., USA 1. Introduction Environment It is the year 2020 in a large city. (Ed.) Renata G. Lynne Maher, RGN, BSc Hons, MBA Bushko, IOS Head of Innovation & Acting Director for Scattered along the city’s streets Press 2005 Improvement, NHS Modernisation Agency, are booths that resemble the old London, UK public telephone booths that have Victor A. Capoccia Ph.D. long disappeared from the urban Senior Program Officer The Robert Wood landscape. These booths cover a wide Johnson Foundation, Princeton, NJ, USA variety of health topics and people can talk to “virtual” counselors at the Abstract touch of a screen. Maria, a heroin he country’s system of providing addict, has passed these new public treatment for people struggling with health booths a few times—perhaps on Taddiction requires a fundamental her way to rendezvous with her drug overhaul. To address these daunting dealer. Today, she pauses for a closer problems, a group of experts from outside look. Maria’s boyfriend beat her up a the addiction field met in an intensive retreat few days before and she ended up in and envisioned a new future for addiction the emergency room. She is worried treatment that would use the latest available about her health. technology. Retreat leaders employed At the booth, Maria enters some creative techniques to help free up thinking information about her background beyond incremental improvement ideas. including telling the system that she is Current and former addicts or alcoholics in her 20s. Then the booth’s screen and family members also attended the filled with an image of a young woman retreat to provide the panelists with a real- about Maria’s age. The woman is world understanding of their lives. Through friendly and draws Maria in with her

Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 591 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

easy-going manner. The young woman, who Even so, it quickly became apparent is a “virtual” substance abuse counselor that improving the existing system named “Selene,” talks about the difficulty would not substantially improve of heroin addiction and says that she can addiction treatment. The current help Maria through the process of quitting system is not sustainable. Counselor drugs. In fact, Maria can get started towards salary levels are so low that it is difficult recovery today by stopping in any booth to to prevent counselors from leaving talk to her virtually. Selene will be waiting the field for jobs that offer higher pay. for her. Maria pauses to listen. This public Substantial increases in funding are health booth, where heroin addicts would be unlikely in the foreseeable future. Yet able to speak to a virtual substance abuse the demand for services is almost counselor, is just one way that technology certain to grow. The foundations may be able to provide critical support in of addiction treatment need to be some of the daunting problems facing this rethought to take full advantage of the country’s substance abuse treatment system. technology that is available today and While many effective drug and alcohol that will be available in the future. With treatment programs exist, they serve only a this in mind, RWJF funded a project small fraction of those in need. According to bring together creative thinkers in to the 2002 National Survey on Drug Use fields outside addiction to envision a and Health, only 15% of an estimated 22.8 new system that could effectively treat million addicts in the United States receive people struggling with addiction. The treatment. For every person who has been resulting ideas offer insights not only able to control this disease countless others into the future of substance abuse, but are far less successful. in how to tap into the creative process The Robert Wood Johnson Foundation to find solutions to some of the most (RWJF) supports research projects that daunting problems facing the health focus on treating people with addiction care system today. disease. Two of the authors (Gustafson and Palesh) served in the national program 2. The Creative Process office for the RWJF’s Paths to Recovery One of the difficulties in envisioning Program, a program with a sister relationship a new system of health care is that to a federal government program called people doing the envisioning are Strengthening Treatment, Access and often part of the system that is not Retention. The program was designed working. When people are steeped to improve administrative processes in a current structure, it is daunting that prevent addicts from accessing and to think creatively about a new way then staying in treatment. The program of providing services. To remedy this demonstrated substantial reductions in ongoing problem, staff at Paths to waiting time to receive treatment and Recovery looked for creative thinkers in numbers of clients dropping out of outside of the addiction field. The staff treatment. invited a small group of internationally

Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 592 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

respected experts in other fields to Members of the expert panel • Paul Plsek, author design an innovative and effective and developer of addiction treatment system. The Futurists DirectedCreativity experts represented fields such as • Timothy Baker-University • Victor Strecher– of Wisconsin, clinical University of Michigan, nanotechnology, robotics, biomedical psychology. communications science engineering, genetics, neurobiology, • Rena Bizios-Rennesselaer • Peter Szolovits– artificial intelligence, bio-informatics, Polytechnic Institute, Massachusetts Institute of social psychology, collaborative biomedical engineering. Technology, decision and • Patricia Brennan-University computer science. technologies and pharmacology. of Wisconsin, nursing • Sheila Wang – social Facilitators had a few key criteria for informatics. psychology. those they wanted to invite. They • Renata Bushko-healthcare needed people who: futurist. Addiction Experts • Noshir Contractor-University • Had a sound grasp of the of Illinois, communication • Bret Shaw– technology that will be ready for networks. communication science. use by 2020 • Juan de Pablo-University of • Maria Levis-Peralta– • Were not be encumbered by Wisconsin, nanotechnology. community activist. • BJ Fogg-tanford University, • Tom McLellan–addiction knowledge of the current system medical-informatics. services research. for treatment addiction • David Gustafson-University • Kristin Schubert– • Were creative, collaborative and of Wisconsin, medical Robert Wood Johnson communicative In addition to informatics/technology Foundation, genetics. innovation. • Elaine Cassidy– the outside experts, the group • Thomas Kosten-Yale Robert Wood Johnson included addiction experts and University, pharmacology. Foundation, evaluation. consumers of services (recovering • Dean Lea-organizational • Victor Capoccia– addicts and alcoholics and family development consultant. Robert Wood Johnson • Lynne Maher-British Foundation, addiction members) to provide a clear picture National Health Service, treatment of the treatment system today. The Modernisation Agency • Dwayne Proctor– consumers of addiction treatment • Jesper Olsson-Swedish Robert Wood services were vital to this project. Federation of County Johnson Foundation, Councils, medical- communications systems. They provided a first-hand, vivid informatics. • George, recovering portrait of their lives and their • Tara Palesh-University alcoholic needs. In all, 28 experts gathered of Wisconsin, systems • James, recovering heroin for an intense two-day retreat in engineering addict • Rosalind Picard- • Belle, mother of a current November 2004 to envision a new Massachusetts Institute heroin addict substance abuse treatment system of Technology, human for alcoholics and heroin addicts. computer interfaces

3. Logistics the participants. A poor location or any unexpected Coordinators paid close attention to travel inconvenience could have a severe impact on the details of the meeting’s location the creative thinking of the entire group. Planners and ambience to help make the chose a site that reflected the meeting’s goals. It was experience as positive as possible for a facility outside of Chicago in a location that was both

Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 593 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

relaxing and boasted the latest technology. counselors, more clinics and more The facility had ponds and streams with funding. paths for walking as well as an extensive While facilitators felt that it was exercise facility, good food and easily not important (and even counter accessible Internet connections throughout. productive) to understand the addiction Participants were provided with limousines treatment system of today, it was to the facility and a cell phone number of essential to understand how it feels to a meeting organizer should any problems be an addict and the family member arise. With these preliminary arrangements, of an addict. One of the facilitators even the small glitches that did occur were encouraged the development of a addressed quickly. All of the participants set of stories that described the life arrived feeling well taken care of and ready experiences of addicts and their family to work. members. Another facilitator who had To help the expert panel prepare for the personal experience with addiction retreat, facilitators developed a package treatment (she is the daughter of an for those who wanted more information on alcoholic) developed a prototype of a addiction prior to their arrival. Facilitators story. Instead of a story narrative, she sent a copy of Hooked: Five Addicts wrote a flowchart. It was a concise, Challenge Our Misguided Drug Rehab easy to follow format to present a large System by Lonny Shavelson to each panel amount of information quickly. More member. They also sent fact sheets about important, it was an innovative way addiction and its treatment and stories to break down the experience while of addicts and their families told in flow highlighting key events and aspects charts. However, the retreat did not hinge of the disease. The team used that on panelists having done any background approach to develop three other flow reading on addiction. Facilitators just asked charts that told the story of someone the panelists to bring their creativity to the affected by addiction. Facilitators meeting and arrive on time. identified a recovering heroin addict from an inner-city ghetto (James), a 4. Meeting recovering alcoholic CEO (George), The first day of the meeting, facilitators and the mother of a 21 year-old current gave participants their charge: to design heroin addict (Belle). an addiction treatment system that would involve no humans. They told participants 4.1 Day 1 that in the year 2020 all of the substance The morning of the first day of the abuse treatment professionals had been meeting, a facilitator presented each killed by a virus. Addicts and their families of the flow charts. The consumers would have to obtain help primarily through whose story was told in the flow technology. This charge freed up thinking charts were in the room. Provided beyond incremental improvement ideas with a rapid but detailed version of such as more training programs, more each consumer’s life, the panel asked

Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 594 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

consumers questions about anything they another’s ideas—a demonstration that did not understand or wanted more details the panel was becoming comfortable about. Panelists said they found it powerful with the notion of creative thinking and to have the four consumers depicted in were working well together as a group. the flow charts available to clarify any With that exercise as a start misconceptions and share more of their to future thinking the facilitators experiences. In fact, the question and randomly assigned panelists to one answer phase was so useful that it took of the four tables in the room. Each much longer than anticipated as panelists consumer joined a table so that they became deeply involved in the lives of could answer any questions that arose their new “customers.” The presentation of during idea generation. Facilitators the flow charts and the in depth discussion asked panel members to create as they fostered encompassed the entire many ideas as possible related to morning session rather than just a portion of the future treatment of addiction. it. However, during that time panelists were The four groups began with simply already placing ideas on post-it notes for throwing out ideas among themselves future use (which had not been planned until and then writing them all down. As the afternoon). expected, each of the four groups had After lunch, the panel transitioned into a different method to generate ideas. the idea generation phase. The planning The facilitators moved around the group had assembled a collection of room reading the ideas and marking creative thinking tools to prepare for the the ones that would need further meeting. The idea generation tools were explanation. In all the four groups based on the “directed creativity” concepts generated 268 ideas. Facilitators of attention, escape, and movement. compiled the ideas into an Excel sheet Innovative ideas are more likely to emerge for further analysis. By the end of the in a group when people focus attention on first day, participants had begun to something that they do not normally focus see a network of knowledge forming on, escape the current ways of thinking to focus on the future treatment of about the issue, and encourage free- addiction. wheeling mental movement to capture all ideas without censorship.1 2 3 For example, in the Future Tinkertoys™ tool, leaders 1 de Bono, E. Mechanism of Mind. London: helped generate escape and attention Penguin Books, 1969. by asking participants to identify attitudes, 2 technologies, and devices that they expect Plsek, PE. Innovative thinking for the improvement of medical systems. Annals of to be commonplace in the year 2020. Ideas Internal Medicine. came in such a torrent that facilitators wrote 131(6): 438-444. September 21, 1999. furiously just to try and keep up. Participants 3 Plsek PE. Creativity, Innovation and Quality. often built upon one Milwaukee, WI: ASQ Quality Press, 1997.

Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 595 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 596 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 597 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

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Future of Addiction Treatment: Enhancing the Human Experience and Creating a Fix for the Future 599 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

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Scott C. Chapter 60: The Future of Information these challenges, there are many Ratzan, Maria opportunities being created for I. Busquets / Technology for Health in Developing The Future of Countries international development agencies to Information Scott C. Ratzan, MD, MPA, MA increase their capacity for impact. Technology Senior Technical Advisor, Global Bureau for Health in at the U.S. Agency for International Developing 1. Introduction Countries Development During a visit to India in March 2000, in World & Editor, Journal of Health President Clinton watched a woman Health Strategy Communication,International Perspectives enter a village health center, call up a eBook, www. web page on the computer, and get Futureofhealth. Maria I. Busquets, MA org (Ed.) Renata Chief of the Communication, Management information on how to care for her G. Bushko, and Training Division in the Population, baby. This baby will live a longer life FHTI, 2016. Health than her mother, mostly because of Intelligent and and Nutrition Center at the U.S. Agency for 20th Century public health advances Extelligent Health International Development. and the new technological potential of Environment the 21st Century. (Ed.) Renata G. Abstract Unfortunately, it is a rare occurrence Bushko, IOS for a woman in a developing country Press 2005 hat is the future of communication technology for health in developing to have access to the Internet. The Wcountries? This chapter sets out hopes for progress in technologies to answer this question by first considering present ongoing challenges in access, the background and potential of information quality, and equity. In fact, over half of technology, identifying some of the the women in the world have never issues and trends in communication, and made a phone call. In Africa, which finally following with some challenges has a population of 700 million, fewer and opportunities of how communication than one million people had access technologies can make a difference to the Internet in 1998, and of this in health in developing countries. Past number 80 percent were in South research has shown that communication Africa. Among the other 20 percent can contribute to all aspects of population, the ratio of people who have access to health, and nutrition programs and is the Internet to those who do not is 1 to relevant in a number of contexts. Some of 5000, in the United States or Europe the trends in using information technology the ratio is 1 to 6.5. can be classified in the following categories: The woman in India in the example competition, cognitive-based presentations, above is an anomaly as many villages comprehensive translation, convergence, still lack a working telephone. The and culture. Challenges include finding a new information technologies way to include the South in the exchange potentials is concomitant with the of ideas and information. In addition, divide in the access to learning reaching a consensus on worldwide quality opportunities: 885 million people standards will not be easy. Yet, beyond in the world are illiterate, and two-

The Future of Information Technology for Health in Developing Countries 604 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

thirds of them are women. More than half technologies can make a difference in of these adults lives in India and China, health in developing countries. another one quarter in seven other nations While we read each day about HIV/ in Sub-Saharan Africa and South Asia. Yet, AIDS, cancer, and emerging diseases, information and communication technologies there has still been great progress in are often the hopeful solution to end these public health globally. Last century inequities, particularly among those who are in both developed and developing poor and isolated in developing countries. [1] countries, there has been a 25-year A search of PubMed in December 2000 increase in life expectancy, the most yielded 6,692 citations containing “Internet.” rapid improvement in history. Much of The number is growing by at least eight per the success is not due to better drugs, day. But of course, this is disproportionate surgery, and diagnosis. Almost all the with developing countries. Fewer than improvement has been the result of 0.1 percent of these articles are related public health: surveillance, sanitation, to developing countries, despite the fact nutrition, changing lifestyles, etc. that developing countries represent over Public health actually is a field 25 percent of the scientists in the world. that principally focuses on the transfer Similarly, a study of Medline looking back and exchange of information: data at 1992-96 showed the British Medical collection, surveillance, information Journal (BMJ) had only 0.4 percent of transmission, and communication. The the publications mentioning developing new communication technologies countries, the Lancet 0.6 percent, and the have great application in public health New England Journal of Medicine 0.05 practice. percent. When you look at content and language on the Internet, the statistics are 2. Background sobering—for example, only .02 percent Recent advances in information and of the Internet content comes from Sub- communication technology provide an Saharan Africa, and while content in several unprecedented means of overcoming languages has risen in recent years, English two of the root causes of extreme is still the predominant language used on poverty—ignorance and isolation. The the Internet. opportunity to communicate public With such a daunting challenge, we ought health information and expand the to answer the important question: What is flow of ideas and data coming from the future of communication technology for the South will allow for a horizontal health in developing countries? two-way dialogue that will contribute To answer this question, we will first to new opportunities to communicate describe the background and potential of public health information not available information technology (IT), some of the before. issues and trends in communication, and Effective use of communication follow with some ideas of challenges as technology can benefit personal well as opportunities of how communication and public health. Past research has

The Future of Information Technology for Health in Developing Countries 605 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

shown that communication can contribute into the communication experience. to all aspects of population, health, and Despite the potential of nutrition programs and is relevant in a communication technology, we must number of contexts, including (1) individual’s be mindful. While globalization has the exposure to, search for, and use of health potential to bring people together and information; (2) the collection, dissemination, to provide them with tools to advance and utilization of individual and population their social and economic well being health risk information (often termed risk and their health, it poses great risks. communication); (3) individual’s adherence There is a dark side to IT: the fact that to clinical recommendations and regimens; some can use it to create a “digital (4) the construction of public health policies, divide.” We must be particularly messages, and campaigns; (5) health concerned about Internet access provider-patient relations; (6) creation of for under-served populations and “health as we know it” through popular opportunities for girl’s and women’s culture and mass media transmission; and participation in the digital information. (7) the agenda-setting phenomenon of prioritizing public health and health care 3. Trends system developments. Most of the usage of We have five basic C’s that help communication technology has focussed on us describe the future trends in the first few areas using information technology in Most people today think of IT as development: electronic mail, Internet World Wide Web • Competition sites, and interactive CD-ROMs. These are • Cognitive-based presentations just a few of the many new communication • Comprehensive translation media that provide unprecedented global • Convergence access to people and information. • Culture The landmark ideals of Marshall McLuhan These areas are creating uncharted represent a challenge for those of us using territory as the new media evolves IT: McLuhan accurately predicted that “the Competition—The answer to the new electronic interdependence recreates question who’s knowledge and whose the world in an image of a global village.”[2] information will become more complex. Already, we have evolved communication While there are media conglomerates from broadcast to multicatch, but IT is more and publishers that have a monopoly than just the web. IT now includes the on communication of “knowledge” in ideas of demassification—narrowcasting our scientific and medical journals, this information to the end user, interactivity, a will change. Researchers and true exchange of information, asynchonicity, scientists have begun to bypass print the ability to communicate whenever journals and put research directly on with our “real time” interaction, and the web. mechanomorphism of multimedia to include Cognitive-based presentations— all the senses (except smell at this juncture) Powerful new cognitive formats will

The Future of Information Technology for Health in Developing Countries 606 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

evolve; as this happens, the traditional scientists, teachers, and Ministers of format of Abstract, Introduction, Methods, Health. A group of mid-level health Discussion, and Results could become professionals in Francophone Africa is, extinct. One new format may create a new for the first time ever, able to share language not just for computer information, compare experiences, and programmers, but consumers. A “Hypertext “speak” with other professionals with Comic Book” to teach children how to spot similar problems. landmines in Mozambique or a Nursing Electronic communication can also School Midwifery Curriculum in Kenya that be used for public health interventions enhances by iconic “cognitive” paradigms to persuade the general public or can allow a user to point and click to icons policy makers, such as through health for medical knowledge. For information or education, social marketing, or medical knowledge, the Uniform Medical advocacy. Because of the capacity to Language System may evolve into segment audiences, electronic cognitively based formats that maximize communication can be used to interactivity, hyperlinks, and memory. develop health education and Comprehension translation—Most books behavioral change materials for appear in only print format; one size fits all. specific populations (e.g., smokers, The IT future allows people to indicate their non-English speakers). backgrounds, education level, language Convergence will also bring preference, and interest with software to scientists to “push” new information individually tailor a translation to maximize into the world via Internet delivery. comprehension. These Intelligent Agents will Convergence will also take place as create a digital document for an the distinctions between the latest epidemiologist that will be different for a scientific findings, lectures, journals, physician in Canada or traditional healer in and books become blurred. Schools, Haiti. Translation software will evolve that books, and lessons will have can adapt for dialects, aphorisms, and other information days old, rather than years specific linguistic markers or decades old. Convergence—The convergence of Culture—There is a problem of media (computers, telephones, television, acculturating individuals to new radio, video, print, and audio) and the technologies. Repetition has induced emergence of the Internet create a nearly attitudinal change by familiarizing ubiquitous networked communication people with, in this case, technology infrastructure. The potential of this cannot through repeated exposure. Yet, the be underestimated. Networking can be used use of IT can in fact develop an for many purposes in public health, from information generation. This creating support groups of persons trying to generation can change governance quit smoking to “action alert” networks for and policymaking. One way processes advocacy purposes. We are already seeing and vertical organizations will be the creation of online communities amongst vestiges of the 20th Century. On the

The Future of Information Technology for Health in Developing Countries 607 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Internet, interactivity will prevail; policies and support health improvements. In the research may benefit from early feedback United States, the National Committee from users. A culture of passivity on the part on Vital and Health Statistics (NCVHS) of the users also may ensue. People may seeks to develop a system that links merely access and download information, surveillance systems, information treating the Internet as an online health sources, and establishes library. But as they spend more time on the communication linkages (on emerging Internet, gain access to different sites, and and reemerging diseases). notice consistencies and contradictions, The infrastructure makes it possible critical thinking ought to emerge as people for people not only to use health pose their own questions and apply their information designed by others, but own knowledge. Health policymakers and also to create resources to manage researchers should exploit such their own health and to influence the opportunities for interaction with users. health of their communities. For The health impact of interactivity, example, community groups could use customization, cultural diversity, and computers to gain access to survey enhanced multimedia is just beginning to be information, health indicators, disease explored. Yet, already, interactive health surveillance, and access about the communication technologies are being used quality of life in their neighborhoods to exchange information, facilitate informed and apply this information to create an decision-making, promote healthy behaviors, action plan to present to local elected enhance peer and emotional support, and public health officials. Information promote self-care, manage demand for is a critical element of informed health services, and support clinical care. participation and decision-making, and appropriate, quality information and 4. Current Initiatives support services for all are Through a U.S. Inter-Agency Agreement empowering and democratic. launched by President Clinton in late 1998, At the Millennium Assembly of the the Internet for Economic Development (IED) United Nations in September 2000, Initiative seeks to empower developing the right of universal access to countries to develop and use the Internet to information and communication boost their economies, gain access to services was discussed as a new knowledge and foster the free flow of ideas. component of the UN’s principles and Through this initiative, USAID Missions have conventions on human rights and supported the development of community development. When John Chambers of telecenters in Ghana, Guatemala, and Haiti; Cisco and Carly Fiorina of HP joined and the use of the Internet for Mayan- sixty-five other CEOs in June 2000, language education. they discussed how to make IT more Efforts are underway throughout the accessible to the world’s poor. When world to develop integrated national and the G8 held their meeting in Tokyo last global health information infrastructures to July, they focused on the crossroads of

The Future of Information Technology for Health in Developing Countries 608 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

development and IT, and in an and online) and others dedicated to unprecedented move, invited developing increasing the use of these country and civil society representatives to technologies in specific areas like join the Dot Force. When they meet again in health and agriculture. 2001 in Genoa, progress towards eliminating the digital divide will again be discussed. 5. Challenges President Bill Clinton recently held a panel Widespread availability and use of discussion on the Digital Divide in Health, interactive health communication and Education, and Technology. The common telehealth applications create several theme was the “the global divide giving way serious challenges. One is related to to a global connection.” the debate on whose information and Rhetoric has given way to action. For knowledge appears on the Internet or example, the United Nations has begun on a CD-ROM. Knowledge from the ``Health InterNetwork,â€ which is designed “North” will need to make space for the to improve public health around the globe ideas, experiences, and information by providing health information using stemming from other cultures and Internet technologies. It links scientists in experiences. Anyone that has tried to over 30 countries to the leading scientific cull through the clutter of the web will journals, databases and discussion groups. understand the challenge of creating Under the Leland Initiative, USAID is usable content, especially content implementing agreements with more than applicable to the health needs in the 20 Sub-Saharan African nations to enhance developing world. There are also Internet connectivity and use in a risks associated with consumers use of competitive policy environment. Now that poor quality health information to make through the efforts of many, African countries decisions. are connected to the Internet, the Leland Concerns are growing about the Initiative is supporting broadband Web making available large amounts connectivity to secondary cities and towns in of information that may be misleading, select countries such as Guinea and inaccurate, or inappropriate, which may Uganda. In addition, private and public put consumers at unnecessary risk. activities are beginning to provide access to Although many health professionals the Internet, especially through community agree that the Internet is a boon for access points, for the world’s population consumers because they have easier presently without such access by the end of access to much more information 2004. than before, these professionals are In Africa, there are hundreds of initiatives concerned that poor quality of a lot of developed by donor agencies—some information on the Web will undermine intended to increase access to these informed decision-making. These technologies in remote areas by establishing concerns are driving the development “waystations” (resource centers that provide of a quality standards agenda to help access to health information on CD Roms health professionals and consumers

The Future of Information Technology for Health in Developing Countries 609 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

find reliable Web sites and health information on the Internet. Recognizing the challenges we Reaching a consensus on worldwide face (outlined earlier), IT can still be quality standards will not be easy. The harnessed to empower individuals process will most certainly move us away and reinvent governments, promote from the more academic and traditional electronic commerce, and expand quality standards that were created by access to information. In the the North for the North. Finally, even if we development arena, IT has numerous were all connected with affordable access applications. and quality information, illiteracy and lack International Development of computer skills remain a considerable Agencies can use the new hurdle. technologies to reinforce and modify present forms of technical assistance. 6. Opportunities Interactive multimedia training The vision of new technologies cannot be courses are being used to provide underestimated. The power of technology opportunities for individual and group has been described as revolutionary, and interactions. CD-ROMs accommodate the Organization for Economic Cooperation a wide range of learning styles, and and Development has written of a new, their use seems to be increasing user’s knowledge-based economy. overall level of learning including Opportunities are many—the Internet is improved engagement and retention a one trillion dollar technical infrastructure of information. and, in theory, available to anyone; it’s Electronic training is becoming a global and borderless with new business reality—and big business. Hybrid CD- and development applications and models ROM/Web solutions are used when coming in from all directions; open when connectivity is a challenge. Start-up needed—24 hours a day—which means time costs often appear to make electronic zones are no longer a barrier; it’s changed delivery of training appear costly in the way we conduct work, recreation, and comparison to face-to-face training. even love!; and keeping it all together is However, given the large number of information—it’s the glue, the value-added— healthcare providers requiring training, that keeps us coming back for more. electronic training could be very cost The information revolution can be an effective. equalizer. Chat rooms around the world Virtual consultancy, where no one have recently been furiously debating what travels, is highly possible. Several is a false dichotomy of computers and pilot studies are already underway. technology on the one hand, and health, Collaborative research can take food, and basic services on the other. It’s place online, as can data analysis. It is not an either/or debate but a two-track possible to do online team planning approach to revolutionizing the way we do with members of the team at different business. points of the compass. Even real-time

The Future of Information Technology for Health in Developing Countries 610 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

epidemiology is possible online. agencies work with do not have Isolated communities can have access access to the Internet and most likely to online, accurate, up-to-date, quality never will. These populations receive health care information from local sources the benefits of ICT, but it is especially or the world’s largest medical library, the hard for the public to perceive. The National Library of Medicine at the National Famine Early Warning System[4] (FEWS) Institutes of Health. The MedlinePlus service in Africa was designed to utilize high provides access to extensive information technology means to provide advance about specific diseases and conditions, and warning of the development of famine has links to consumer health information, conditions. It was designed to allow dictionaries, lists of hospitals and physicians, acquisition and stockpiling of food in health information in other languages, and advance of market shortages. Thus clinical trials. the success of FEWS is marked by CD-ROMs and desktop publishing offer lower costs of food and fewer food university libraries advantages, and even shortages. Yet not only do most of the African University libraries are increasingly beneficiaries of FEWS not have direct connected to the Internet. Digital libraries personal access to its technology or are changing the work and, indeed, the idea any ICT technology, but they are not of the library. Increasingly, it appears that aware of the ICT benefits they receive. scientific publishing will be available online. [5] Additional applications include virtual The new technologies provide “toolkits” including communication strategic many potential ways through the planning software, international drug price above and many others to expand indicator guides, web courses on infection the opportunities of international prevention, Instant Messenger for real-time development agencies to maximize training, Cyber Cafés, community forum their impact on health concerns. message boards, multi-media idea bank on a. The technologies are built on condoms, Technology Assisted Learning interaction; Centers, and a database of free photos. b. They are inclusive—allowing There are numerous possibilities, almost the quick identification of a range all of which are presently ‘under-exploited’ of information on an issue and the in international health and development. choice of the information most relevant to the setting; And these possibilities will be much more c. The information and knowledge attractive and valuable with the acceleration can come from a range of of online interactive video technology. What perspectives and countries; has become clear to the authors is that d. They are flexible—when the waiting for technology stability is a losing information changes it can be tactic. updated very quickly; and An equally important concept to consider e. The new technologies operate at is the indirect impact of ICT. Many of the scale.[6] populations that international development Recent discussion of the future with

The Future of Information Technology for Health in Developing Countries 611 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

technology leaders in Silicon Valley and quickly and could result in better Virginia’s 270 Corridor found that no one efficiencies. can predict which of the new technologies • Data mining—the ability to sift (or the infinite number of upcoming through and manipulate (i.e., try developments) will go mainstream. Just to connect different variables as Napster [recently] and the world-wide and cross-reference topics) large web [5 years ago] were hugely surprising quantities of information in a vary in their rapid growth and use, the future is short time. This would really help also very difficult to foresee. Some of the information overload issues and possible areas mentioned by the experts lead to better, more targeted were: analysis. • Wireless—continued rapid expansion of wireless access and technology Finally, in the midst of this technology (e.g., Palm Pilot, RIM, information pager revolution, we must: networks, cell phones and WAP) • ensure women have equitable with the implication of being able access to the benefits of to access information and interact telecommunications and are not from potentially anywhere, at good disadvantaged by sector reform speed, and not restricted by land-line and industry changes; capacity. • design and provide • Personalization—automated telecommunications processes so that you ‘pull’ down the technologies and services which information that you want to see, not take into account women’s the information that the web sites are needs and requirements; and pushing at you, which provides rapid increase women’s information on the most recent trends, participation in all levels of the data, and experience relevant to telecommunications sector. [7] your work and restricts the necessity for long searches on many sites. 7. Conclusions Essentially, you take control. Even if the woman in the village at the • Video—will move ahead in leaps beginning of this chapter gets access and bounds. VBIC already offers a to the Internet, she will not necessarily guaranteed lip-synch online video be able to use the information to facility—training, conferences, one- improve her child’s health because as to-one calls, etc.—at U.S. $0.05 per it is often said, trying to get information minute. Virtual meetings could replace from the Internet is like drinking from some travel because quality and cost a firehose, you don’t even know what are getting that good. the source of water is. • Voice recognition--no typing: train The future will have more quality your computer to recognize your information provided by web sites but, voice. This software is developing very realistically, only a few branded, highly

The Future of Information Technology for Health in Developing Countries 612 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

credible sites will emerge (competition sense among people all over the world and convergence). Despite retrieving that they are entitled to participate accurate information, the woman in the openly in their government and village still has to decide if the information society. Greater mobility in using the is relevant to her situation. This hopefully technology will be made possible will become unnecessary as more data through the use of pocket sized would be generated and shared in a wireless devices such as Internet decentralized network linking knowledge enabled mobile phones. Extensive in the developing countries, creating a so- tailoring of the volume and style of called South to South dialogue. presentation of information can already Hopefully the future Medline will reference be done using hypertext and and share a number of journals from multimedia links. This can convert any developing countries. The Internet can material to accessible formats that converge with gateways to become a Global cater for different audiences. HealthLine. The problem is complex, and To ensure that the envisioned future possible explanations range from the does not remain merely commercial difficulties encountered by researchers in hype, a systematic effort should be developing countries in gaining funding for made to exploit the advances of research )only 10 percent of funding is spent information and communication studying problems relevant to developing technologies for use in developing countries) to the existence of “ethnocentrism countries. As has been described, at its worst” in biomedical publishing circles. many efforts are already being made But now, with the availability of publishing to bring these technologies to software that can be coupled with powerful developing countries. The long list of Internet search engines, it is possible for initiatives is impressive but how authors or local scientific societies to bypass successful have their efforts been to traditional avenues of scientific publishing. work synergistically? They can post their research directly on their In terms of health, attention would own web sites or, for example, on web sites be best directed to improving access that focus on international health or on to accurate and relevant information. general health and clinical research web Credible agencies or organizations sites like Pubmed Central or other electronic that provide evidence based health servers operated by biomedical journals. information can increase the speed Wireless is likely to be the principal with which users are able to download means to access the Internet. The second information by constructing mirror or billion people on the planet who access the replica sites in different geographical Internet will not access it through a personal areas. For example, the European computer, but rather through wireless Union funds the web site of Scientists devices. This is facilitated by the for Health and Research for development of less expensive technology Development (www.shared.de/ and ease of usage coupled with a rising sharedhome.html). This web site lists

The Future of Information Technology for Health in Developing Countries 613 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

potential donors, ongoing projects, and of Web Sites should also embrace resources available to researchers in change. It is critical to move from developing countries or their partners in the “talking at” to “listening to” and from developed world. Medical journals that have “brochure ware” to assessing and their own web sites can follow the lead of serving customer needs. Finally, the the BMJ and provide free access to their most often overlooked shift—the articles. movement towards changing what’s The relevance of information can be behind the web sites—the people, the improved partly by increasing the visibility of processes, and the corporate cultures. health research from developing countries. As the disparities between the Technical assistance in designing web sites information have and have-nots could be provided, preferably through the increase (not only between countries, creation of templates to be easily adapted but also within countries), so too do by different users. Alternatively, some inequities in health status. agencies might offer to host other Consequently, there is a great urgency organizations on their web sites, absorbing to act. The new global disease threats the costs of developing and maintaining the must be addressed not only with sites. For example, Kabissa (www.kabissa. medical means, they must be org/index.html) provides low cost domain complemented by efforts to enhance hosting for non-profit, non-governmental literacy, economic development, and organizations in Africa, including the the like—what Nobel Laureate Amartya Network on Equity in Health in Southern Sen has called “support led strategies”. Africa (www.equinet.org.zw), a network of Such strategies can include research, non-governmental, and health communication technologies to focus sector organizations seeking to influence on lengthening the factors that make health policy in southern Africa. economic development possible, of The development community is going which education, health, and the through the same struggle as many small empowerment of women are central private sector businesses. Many tend to components. take small steps, especially senior There are many success stories management. But major shifts are combining community effort and social warranted. It is absolutely critical to move mobilization to build on. Among the from viewing IT as a tool to viewing it as a most promising are programs for transformer. From the gigabytes and community-based literacy education, megahertz discussions of high end complemented by significant social computing to low end computing such as mobilization efforts using role models the $10 hand held device recently with high credibility from the local and developed by computer science students at national arenas, such as figures from MIT. From the Western perspective of the media and the entertainment desktop computers in every household to industry. wireless and satellites. The creation and use Ideally, education could evolve just

The Future of Information Technology for Health in Developing Countries 614 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

like this edited volume on the future of enough to individuals so that we health so that “virtual centers,” or develop health â€œnews you can collaboratories, where the expertise is use”? There are no longer drawn from many locations can be technological barriers to such ideas. integrated. These do not need to be from While many are optimistic that we the North or developed countries. Special will do the right thing and create a new consideration with new media technologies health as is “ought to be,” health as “we should address access issues for know it” today might prevail—a world underserved, minority, and disabled with disparities of income, health, and populations. Opportunities with new human rights, and environmental communication technologies can integrate justice. Humankind often advances new research methodologies and with market forces suggesting we have approaches to respond to the swift pace of the right to just do it, rather than just change inherent in the communication doing the right thing. While we have revolution. Ideally, a new connectivity can identified the latest frontier as foster relationships with other public health cyberspace, our ability to reach people agencies, advocacy groups, non- for profit supercedes promulgation as governmental and support organizations to a species. Perhaps, we are now at a the private sector. crossroads in the third millennium. Finally, there is an opportunity to advance Nearly fifty years ago, there was a a leadership position not only in publications different warning: “Science, which now and media channels along with the hospital, offers us a golden age with one hand, health care facility, and academic health offers at the same time with the other center, but also in using communication the doom we have built up inch by inch technology for health in the private and since the Stone Age and the dawn of public sector. Systematic agenda setting in any human annals. My faith is in the keeping appropriate health issues on the high progressive destiny of man.” political agenda in general could be of great While Winston Churchill warned of value. This is where highly credible the nuclear age, I also suggest a organizations, such as the World Health warning of the communication age. Organization, or professional organizations We must empower the individual to and governmental agencies could be most access information with appropriate powerful by providing accurate, trustworthy interactive health communication to data for public consumption. Developing enhance his/her decision-making. health leadership could be the most important communication advance. References Could there be a future when people [1] Tessa Tan-Torres Edejer, throughout the world can elicit accurate, up- Disseminating health information in to-date interpretation of study results that translates”health as we know“ into real-life developing countries: the role of the daily activities? Could we communicate well Internet BMJ 2000;321:797-800 ( 30

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September ).

[2] McLuhan, Marshall [8] Renata G. Bushko, Poland: Socio- technological Transformation – its Impact on Organizational, Process, [3] LaPorte 1997. Clinical and Service Quality of Health Care. In: W. Wieners (ed.), Global Healthcare Markets. [4] http://www.usaid.gov/fews/ Jossey-Bass Publishers, John Wiley & Sons, Inc. 2000, pp. 194-201.

[5] (John Daly paper for USAID) How development agencies are using information and communication technologies: examples from agriculture education, environment, and micro and small business. John Daly, InfoDev, World Bank.

[6] (Warren Feek paper for USAID) Real and Virtual - Technical Assistance - New technology opportunities for improved technical assistance by USAID Population Health Nutrition, January 2001.

[7] Engendering ICT Policy: Guidelines for Action. The Africa Information Society- Gender Working Group: Johannesburg, South Africa, 1999.

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Julia Royal Chapter 61: Strategies for Positive of a medical journal article in sub- / Strategies for Positive Outcomes: Can Information Technology Saharan Africa. Published in the New Outcomes: Can Make a Difference in Health in Africa England Journal of Medicine, the Information Julia Royall article concluded that “treatment with Technology Make a Chief, International Programs US National vitamin A reduces morbidity and Difference in Library of Medicine mortality in measles, and all children Health in Africa in World Health with severe measles should be given Strategy” Abstract vitamin A supplements.” [1] eBook, www. his chapter looks to the future through At the time, measles persisted Futureofhealth. org (Ed.) Renata the prism of pilot projects well in as a common killer of children in G. Bushko, FHTI, progress at the time of this writing: developing countries, and vitamin 2016. Strategy T use of a malaria electronic tutorial in Mifumi A was readily available almost for the Future of Health (Ed.) village, development of a mental health everywhere. Results of this research Renata G. electronic tutorial in northern Uganda, which had been carried out in Africa, Bushko, IOS and development of an electronic health however, had not reached African Press 2009 management system at Tororo Hospital. doctors who could have used it to Each demonstrates a strategy, rooted in save lives. The delivery of the medical African soil, whose ultimate objective is journal article in sub-Saharan Africa to improve health through IT and medical provided a symbolic gesture, bringing informatics. The projects connect users, home information that had belonged health professionals, and decision- there all along. When the antenna on makers, bringing together interdisciplinary the ground picked up the signal of teams. These projects all seek to address the satellite above, it officially brought the question: Can an information and down the article from the sky to the communication technology (ICT) intervention computer in the ground station in make a difference in morbidity and mortality Nairobi. in African settings? The findings indicate Mission accomplished, right? that not only can these interventions be Wrong! As difficult as it was to get all implemented but can be enhanced with the technology to work properly to community collaboration, making a positive accomplish this simple exchange, the outcome in terms of community adaptation challenge of access had just begun. more likely. Finally, this chapter proposes The article had been delivered into a a health informatics center, a Menlo Park void. The technology succeeded - for innovation and entrepreneurship in the first electronic delivery of a medical East Africa in which new ICT inventions journal article in sub-Saharan Africa - and interventions for better health can be but the transfer of bits, as yet, had no created from around the region. meaning [2]. This small but significant event 1. Background raises a major question regarding the In 1992, a small satellite in a low earth orbit challenges of using technology to quietly delivered the first electronic version achieve positive outcomes in health.

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 617 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Today, ubiquitous cell phones in African cities reach even remote areas. On a continent where infrastructures of transport and access to information remain often undependable or unreliable, the cell phone network acts as a superglue keeping people connected – with each other, with the price of coffee beans, or with relatives continents and oceans away.

2. Use of Electronic Tutorials Figure 1: Sister Gorretti in Health Center in Mifumi Village. (Photo: Julia Royall) 2.1 An electronic tutorial on malaria informs patients in Mifumi village. Oceans away, the National Library of From ivory tower to village health center Medicine (NLM) remains committed to and back: an interactive tutorial on malaria, reaching the consumer or end user, combining expertise from the U.S. National no matter what the location of the Library of Medicine’s MedlinePlus with user, through its popular and widely Makerere University Faculty of Medicine used database MedlinePlus [4]. In in Uganda to focus on tropical disease in 2005, NLM brought together the developing country contexts. [3] existing machine of MedlinePlus with Nurse Sister Gorretti is a seasoned medical school faculty and students professional who runs the Health Center at Makerere University Faculty in Mifumi village, about 45 minutes along of Medicine, which had recently a road through the bush outside of Tororo implemented a case-based curriculum. in Eastern Uganda. She drives to work on The challenge was to leverage the a motorcycle. Her approach is caring but delivery platform of MedlinePlus and no-nonsense, and beneath her unflappable to work tirelessly with two teams of demeanor, one can occasionally catch players from the US and Uganda to a glimpse of a warm smile. Gorretti is a reach a successful local outcome that remarkable blend of the fortitude and could be shared internationally. expertise required to run a Center which This project creates another layer treats large numbers of mostly women, of health care education in the field children, and babies, many with malaria. and in the medical school, connecting The surrounding area is highly malarious those two worlds in ways whereby with water standing in ditches and bogs. each can inform the other. The project Bednets have been distributed in the past leverages existing methodologies with no effect whatsoever on the morbidity such as MedlinePlus and the concept and mortality of this major killer of children of health information for consumers, under five. to create a new product for an African context, bringing together local health

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 618 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

and language experts and a respected university with the cultural context and artists who can reflect that particular context through their use of imagery.

Figure 4. Translation of Tutorial into Local Languages in Uganda.

Figure 2. “What is Malaria?” A page from Luganda version of NLM MedlinePlus Africa Tutorial on Malaria. (Artwork by Kenneth Nek) Figure 5. Instruction in the Preparation and Use of Bednets in Mifumi Village.(Photo: William Lubega) their yards which had previously been breeding grounds for mosquitoes. The testing, in turn, increased their desire for working in the field as “agents of change.” Students, health workers and staffs of clinics can now use the tutorials in both electronic, on computer, CD, or radio, and hard copy formats, Figure 3. Cultural Considerations in Image Creation: it is a common belief that mangoes cause malaria. as booklet and poster versions, to From NLM MedlinePlus Africa Tutorial on Malaria. educate the general public. Through (Artwork by Kenneth Nek) the Community Based Education and Service Program (COBES) at the As the medical students field tested the medical school, students have taken first tutorial they created on malaria, they the lead in the distribution of these witnessed tangible results of their success materials to district health offices, local through the integration of the messages health centers, youth centers, trading of the tutorial with the life of the village, centers, churches, NGOs, and schools for example villagers cleaning up areas of in twenty districts.

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 619 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Figure 8. Mifumi Health Worker Prepares to Use Booklets and Posters in the Field. (Photo: Figure 6. Students Nixon Niyonzima, Brian Julia Royall) Sseruyombya, and Ronald Kiweewa Take the “Information Intervention”on Malaria Prevention and Treatment to Mifumi Village. (Photo: William Lubega)

Figure 9. The Author with a Mother in Mufumi Health Center as She Uses the Electronic Version of the Tutorial. (Photo: Daniel Hama)

Figure 7. Artist Kenneth Nek with Malaria Tutorial Medical students from Makerere Posters on Wall of Mifumi Health Center. (Photo: Julia University, Moi University in Kenya, Royall) and visitors from Israel complete short residencies at the Mifumi Health Center. The project proves to be an innovative way of supporting the enthusiasm of medical students as well as engaging the interest of the people in the village. Makerere medical students have carried out a baseline survey of over 100 respondents on the community’s knowledge about malaria. This survey has been analyzed and will be critical in determining whether an information intervention in electronic Figure 10. Baseline Survey of Knowledge about and hard copy formats can make Malaria in Mifumi Village 2008. (Photo: Julia Royall) a difference in the morbidity and mortality of malaria in this community.

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 620 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Figure 12. Women with Malaria Posters in Mifumi Village. (Photo: William Lubega) Figure 11. Ronald Kiweewa, 4th Year Medical Student at Makerere University Talking with Children about Malaria Prevention in Mifumi Village. (Photo: William Lubega)

Figure 14. Bernard Guides a Patient through the Malaria Tutorial. (Photo: Daniel Hama)

not said from the CD, they request to know from us in detail. Yes…. Figure 13. Bernard, Using Tutorial Booklet, for “Once you see something, then you Educational Outreach at Mifumi Health Center. believe in it more than if you are told. (Photo: Julia Royall) When you physically see something really happening with your own eyes, “When we played Says Nurse Sister Gorretti: you learn from it more than when I tell the CD for them, after that we actually you. When you see something you stopped and asked them, have you got any really believe in it. And it is very close message from what you have just heard, because it really affects you. You they really say yes. And then when we ask really get it deep in you. It is very them some few questions that they say the possible that you can change behavior voodoo is not asking, or would not have from that….. asked. They say that it helps us to know “They (the patients) were proud that that they have understood and at the same they were learning to do something time they are practicing what they are and they actually listening to and then whatever was

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 621 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

were very happy with what was produced from the screen. A poster they also see and learn from, but from the screen as they were pressing (the arrows), they were also learning, and they felt that they were doing it themselves…. “It is possible that you can change a life. You can make that change to have a better healthy life.” [5]

2.2 Development of a Mental Health Figure 15. Sister Gorretti with Staff and Patients Electronic Tutorial in War Torn Northern at Mifumi Health Center. (Photo: Daniel Hama) Uganda. In the stunning first light in Gulu, the According to the New Vision, a epicenter of more than twenty years of national newspaper, a recent survey conflict in Northern Uganda, I imagine the conducted by a team of British and nightly pilgrimages made not so long ago by Uganda psychiatrists concluded that children, escaping the dangers in their the rate of PTSD was higher in northern villages. Death, rape, mutilation, destruction, Uganda than in most other places in and displacement. Their migration would the world. For example, out of 1,200 begin as a trickle in late afternoon then turn adults assessed by mental health into a human wave of thousands, sleeping doctors in Amuru and Gulu districts in in doorways, on mats, in streets. The kids 2006, 54% were suffering from PTSD. would carry a few possessions; at times, Researchers also found that 67% of the one could glimpse a small bluebook for respondents had depression. Health schoolwork. [6] workers report the preponderance of Here, at a new medical school, founded alcoholism with accompanying high in 2004, I meet with another team of levels of suicide, attempted suicide, enthusiastic medical students mentored by a and depression. Can the use of an dedicated faculty. The dean wants to create information intervention affect the an NLM MedlinePlus African tutorial on prevalence of mental illness? mental health with a focus on teens [7]. Information Intervention for Mental At the mental health unit of the Gulu Health in Northern Uganda is a district hospital, 9,600 cases of mental collaborative project of Gulu Medical illness were reported in 2006 and 2007, School, Saturday Vision and Rupiny with more than 4,400 cases reported in the newspapers, and the U.S. National past four months, according to officials. The Library of Medicine (NLM) to conditions include post-traumatic stress encourage community action in disorder or PTSD, depression, epilepsy, management and prevention of mental alcohol abuse, acute psychotic disorders, illness. and chronic psychosis.

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As a result of over two decades of war which can be prevented or managed. and massive displacement of people, the The medical students will translate the Gulu Medical School finds itself in the midst text into Luo, a local language, and will of a region plagued by serious issues of test it for clarity and accessibility as part mental health. Creating a tutorial provides a of their field work. “next step” intervention to follow a mental Using the text, Saturday Vision will health survey recently carried out in the meet with their marketing team and district by medical students. The mental then reach teachers, for briefing on the health problems emerging from the analysis project, and young people in these of the survey results will form the basis for two age brackets, for focus groups. At the text of the tutorial. Suicide and alcohol this point, there may be a need for abuse rates in the North of Uganda are high, Gulu Medical School to provide some and many students report difficulties at revisions, edits, or clarifications. home. Experiencing the effects of years of When the text is set, Saturday Vision war only recently turned to peace, and and Rupiny will advertise the contest in massive displacement of people, the Gulu the paper and accept entries from Medical School has decided to tackle the teens for artwork to illustrate the text. mental health problems of the region. On a weekly basis, entries will be Saturday Vision is well known for its selected for publication with the name successful outreach to young people, of the student, name of the teacher engaging them in dynamic interaction who most helped him or her, age, and through contests and work with teachers. the name and location of school. A Their process comprises working with the panel comprising a psychiatrist, a marketing and editorial team to create a pediatrician, and an artist, from the manual for schools, briefing teachers, North or well-versed in the issues of holding focus groups, advertising contests, the North, will choose the final sending contest guidelines to schools, selections of artwork for the tutorial. receiving entries, and publishing the weekly The winners will be announced and winners with a team of judges awarding final awarded prizes at a ceremony. The prizes in a formal ceremony. Rupiny is a complete tutorial, including winning regional weekly newspaper of New Vision entries and text, will be published as a whose reporters are committed to regular part of the Saturday Vision. coverage of health issues. The MedlinePlus African Tutorial on Gulu Medical School and the Saturday Mental Health will receive regional Vision will work together to create the distribution through Rupiny, national MedlinePlus African tutorial on mental health, distribution through the Saturday a unique educational tool with a focus on Vision, and electronic interactive teens ages 12-16 and 17-20. Gulu Medical international distribution online through School will provide the text of the tutorial, NLM’s MedlinePlus African Tutorials. An based on their recent survey analysis, easy to use booklet version of the setting forth four mental health conditions tutorial with a Teacher’s Guide will be

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published by New Vision as part of the department with its aim to provide project and distributed to teachers timely, available, and accurate throughout the North of Uganda. information. The latter has been a The evaluation component will be built problem. into the project from the beginning during NLM enabled the project to extend the initial briefing with teachers and focus to other parts of the hospital. Simon groups with students. Teachers and students makes sure that the project is not will be asked what they believe will be merely a technical exercise but a way successful outcomes. Based on these to use health systems to save lives. He responses, they will then assess whether or mentions that there will be many not these outcomes were achieved by the challenges – organizational, conclusion of the project. managerial, evaluative, social, and This project presents an excellent cultural. The second phase will focus opportunity for researchers at Gulu Medical on accuracy – capturing data correctly School to further their knowledge about and dealing with the ever present mental health in the region and develop challenges mentioned by the group -- innovative ways of prevention and power shortage and understaffing. To management. The project could eventually address the power shortage, Simon provide a model for use in other settings says they will work with management suffering the effects of war trauma. to stabilize power through a generator; for the understaffing issue, it may be 3. A prototype electronic health necessary to reanalyze the workflow management information system (eHMIS) and use volunteers. He also talks at Tororo Hospital. about the ability of the system to Radiating a youthful presence despite his accommodate flags, inter-messaging, experienced leadership, Simon Ndira stands and a PDA interface in which treatment in front of a group of staff at Tororo Hospital. can be entered in real time. He is not an outside expert but was born The hospital networks with a here and is now back, having spent ten computer at every critical point. Staff years in Europe working in Internet security trains on the eHMIS application as well in the private sector. His undergraduate as computer basics, and reports now degree came from the University of generate automatically, eliminating Heidelberg where he is currently completing paperwork as much as possible. his PhD. He is at Tororo Hospital to launch Soon, the system will be turned Phase 2 of the eHMIS project. It is the end over completely to the staff with Simon of the day for the weary hospital staff, but on standby if needed. This period they have stayed for the meeting. Simon marks the beginning of the research demonstrates impressive technical skills, phase, in which the impact of managerial knowledge, and vision. He monitoring, evaluation, and recounts the beginning of the project in improvement on technical and 2003 in the mother and child health nontechnical issues affecting the

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 624 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

application will be assessed. Simon and his 4.1 Can a health informatics center team will make corrections and measure for research and outreach, focusing accuracy. All staff will have access to the on innovation, incubation, and reporting module and will be able to make invention, support individual their own analyses. All will engage in the creativity and connect it with health research of what works, what does not, and and IT infrastructure? how to problem solve. The potential site for the Health Tororo Hospital will be the first hospital in Informatics Center for Research and Uganda and one of the first in the region Outreach in East Africa sits high on a with an eHMIS [8]. When everything is up hill, overlooking Lake Victoria. One and running, the question to be answered can easily envision the center as a will be whether or not the health system launch pad for new thinking, new ideas functions better electronically, without paper. and new ways to connect. The Center It is one thing to continue producing small may provide an African oriented interventions which are shown to make a engine for change, as it links medical difference. It is another to set up a students, health professionals, the arts mechanism which promotes development and humanities, business and and implementation of innovative solutions academic communities, with district on an ongoing basis, connecting human health offices. capital and infrastructure with extant The purpose of the Center is to agencies whose mission is to improve provide a base for research, training, health. development, demonstration, and dissemination of innovative uses of 4. A Menlo Park for 21st Century in East electronic information technology Africa: Promoting Innovation and resources to serve positive health Entrepreneurship in Health. outcomes in Uganda and in East Africa In Uganda as well as East Africa, there is no in general. An ICT incubator devoted link among medical students post- to health does not currently exist in graduation, their field experiences while in Uganda or East Africa. It will serve as school, and the district health offices and an extension of and an ongoing link Ministry of Health. In an effort to build on the among Ugandan medical schools and positive experiences of young people who schools of public health, including want to make a difference and engage Makerere, Mbarara, and Gulu, and the mentors from a variety of disciplines who communities of Uganda through the have much to offer, the concept for the Ministry of Health, District Health Center is a web which can draw together Offices, and the Uganda Council of creative minds of all ages to make a Science and Technology. This bridge difference in health in a district, a country, a does not currently exist in Uganda or region. East Africa. The Center’s approach brings together interdisciplinary teams to

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 625 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

address issues and challenges in the field of discussion, strategic information health. Team members come from the fields sharing, and planning to support of medicine, information technology, library interdisciplinary, systems oriented science, public health, agriculture, veterinary approaches. Work at the Center will science, computer science, social science, focus on developing innovations to anthropology, management, business, and enhance health care and disease the arts. These project teams and experts prevention in Uganda and East Africa. from a variety of disciplines engage in processes of innovation and implementation 4.2 Purpose of the Center of health solutions in Uganda with potential For students and medical schools, the solutions as straightforward as a planning Center will build on and extend the session for a month’s work in a village or as successful Problem-Based Learning complex as a design for cyberinfrastructure Curriculum and COBES Programs so to support health care delivery in country. that communities benefit directly over The Center will focus on how information the long term. The Center will provide technology resources can support and a link between the Faculties of inform each phase of the research cycle – Medicine and Public Health and the from the identification of an initial area of community on an ongoing basis interest, population and relationship of through involvement by students variables, to a study plan and research (COBES), doctors (COBES alumni), proposal, to actual implementation, researchers, and librarians. It will also reporting, publication, and presentation. provide positive, supported Beyond these traditional phases, the experiences in rural areas for students Center will go further in using IT to provide and young practitioners so that they interventions that can alter the morbidity and are encouraged to practice in those mortality in a particular village or district with areas. Finally, and most important, the the successful translation and Center will train future leadership in the implementation of this research in the field. medical and health community, and The research itself will be conducted in the build local capacity and leadership in rural communities at sites used for medicine, research, informatics and Community Based Education and Service public health for Uganda and East (COBES) programs of the medical schools in Africa. Uganda. The Center will serve as a nexus for the 4.3 Center Components and creation of culturally appropriate health Programs communication tools, which are community The Center’s objectives and activities based and created locally by physicians, would comprise four components: artists, health workers, and students – as in 1)To build local capacity in Health the case of MedlinePlus African tutorials [9]. Informatics by hosting intense one Away from the chaos of the city, the Center week hands-on Health Informatics will provide a restful and creative setting for Workshops. Entry to these

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 626 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

workshops would be competitive, and by medical schools, ministry, they could be taught by international districts, or outside organizations; experts in the field. Interested candidates to investigate Continuing Medical from the East African Region will be Education (CME) and Evidence- eligible to apply. based Medicine (EBM) development 2) To strengthen Community Based as well as use of Global Distance Education and Service programs by Learning Center (GDLN), to include encouraging student initiated outreach programs for nurses, clinical projects. These projects will require officers, paramedicals, and health modest funding and will be awarded management. competitively to projects from medical Each program will need to meet students at Makerere University in criteria as articulated in the Center’s Central and Southern Uganda, Mbarara purpose and approach. Each program Medical School in Western Uganda, Gulu will be evaluated by the program’s Medical School in Northern Uganda, organizational sponsors and directors and at Mifumi village outside of Tororo at its conclusion or at regular intervals. in Eastern Uganda. The projects will be Together with program collaborators, generated and implemented during the the Center will use these reports and medical students’ residencies in the field. evaluations to monitor the impact of They will focus on further research and the Center and carry out longitudinal implementation. As part of this program, tracking students will be mentored in all phases of project management [10]. 5. Conclusions 3) To provide infrastructure for ICT in Information Communication health by working with MTN and UTL, two Technology has come a long way large telecommunication service providers since those early days of low earth in Uganda. The Center could become a orbit satellites. Technological technical and programmatic focal point infrastructure can now carry the article for the expansion of broadband EASSy, on Vitamin A to the medical library or East African Submarine Cable System [11] to the researchers, clinicians, or health now under construction, so that it supports workers who compose the human demonstration ICT projects which may infrastructure. But despite significant have national or regional value. This advances, the challenge remains the infrastructure can provide underlying same: how can the media best carry support for online courses, telemedicine, the message in a way which results in and access to electronic health resources. behavior change for better health. The 4 To support continuous professional latter, of course, requires inspiration, development in rural districts by hosting perspiration, passion, invention, special seminars and courses in reinvention, and long term commitment training or idea/concept development: of those intermediaries working in the generated by the center or on request field.

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 627 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

This chapter offers examples [5] Interview with Nurse Sister Gorretti of imaginative problem-solving and at Mifumi Health Clinic, November 24, communication strategies as the human 2008. infrastructure seeks to engage Ugandans in taking charge of their health and [6] Source of information – becoming catalysts for change. The Health conversation with Prof. Nelson Informatics Center is a potential locus for Sewankambo, Dean, Faculty of internetworking the threads of human and Medicine, Makerere University. technical infrastructure with the needs of the surrounding society. In the words of an [7] B. Roberts, K.F. Ocaka, J. Browne, T. Ethiopian proverb, “When spider webs unite, Oyok, E. Sondorp, Factors associated they can tie up a lion.” with post-traumatic stress disorder and depression amongst internally Acknowledgments displaced persons in northern Uganda, The author gratefully acknowledges Donald BMC Psychiatry, 8:38 (May 19, 2008). A.B. Lindberg, MD, Director, National Library of Medicine, for his ongoing support and [8] See www.ehmis.net encouragement; Alison Oppenheim for her valuable assistance in preparing the draft [9] See www.nlm.nih.gov/medlineplus/ manuscript for publication; and colleagues in africa Uganda for their commitment to information technology, the creative process, and better [10] See http://www.nlm.nih.gov/ health. medlineplus/africa/index.html

References [11] See http://www.eassy.org/ [1] G. D. Hussey, M. Klein, A randomized, controlled trial of vitamin A in children with severe measles, New England Journal of Medicine, 323(3), (July 19, 1990) 160-164.

[2] J. Royall, SatelLife – linking information and people: the last ten centimeters, Development in Practice, 8(1) (February, 1998) 85-90.

[3] See www.nlm.nih.gov/medlineplus/africa

[4] See www.medlineplus.gov

Strategies for Positive Outcomes: Can Information Technology Make a Difference in Health in Africa 628 World Health Strategy For Happier, Longer Lives. Edited by: Renata G. Bushko - [email protected] © 2017, Future of Health Technology Institute.

Videos Big Questions in the Future of Health - Overview Consumer Empowerment Era - Self-care Big Data and Analytics in Health Future of Brain’s Health From Artificial Intelligence to Intelligent Health Future of Drugs and Pharmacology Future of Regenerative Medicine Future of Mental Health and Happiness Future of Pain Management Future of Medicine and Global Health Future of Computing Healing Plants and Modern Science Future of Surgery, Pathology and Medical Devices Future Health Challenges: Caring Emotional Machines and Avatars Investment in Health and Commercialization Future of NanoMedicine Fashion as Future of Health Technology Future of Healthy Cities and Transportation Connection Science – Mobile Social Networks Revolution Unite Science, Art, Technology and Medicine

Part II: World Health Strategy Lectures / Videos Big Questions in the Future of Health - Overview

46 Big Questions. New World Health Strategy: What fundamental changes and dramatic shifts do we need to prepare for? Renata Bushko

18 BIG Questions - Future of Medicine Renata Bushko

Report from FHTI by WBZ4- Robotic surgery, talking pill, doctor of the future, robotic therapy Mallika Marshall

Inspiration: Look at the Health from the Stars Jeffrey A. Hoffman

Consumer Empowerment Era - Self-care

How do we treat patients like valued customers? Sanjay Sarma

What is the future of massive consumerism in health and wellness? Eliza Moody

Future Patients - What do they want? Renata Bushko

How should we communicate to the public about health technology?* Shelagh Maloney

Mothers as Doctors: Mobile, Virtual, & Smart Health Assistants Renata Bushko

How can people become active participants in their care? CollaboRhythm John Moore

Big Data and Analytics in Health

Big Data and Health - how can it help you in work and life? Alex (Sandy) Pentland

Can terabytes of new data deepen our knowledge of the state of health care in the Commonwealth of Massachusetts? Sylvia Demetra Hobbs

How should we manage BIG Data for biomedical research? John Quackenbush

What are novel strategies for enhanced predictive modelling and deep learning in the biosciences? Tom Chittenden

How can Big Data make a big difference in the end-of-life care? Shari Heath

How can we reduce the economic burden of Type 2 Diabetes management through smartphone technology and Big Data? Ian Pentland and Todd Reid

Future of Brain’s Health

How to cure almost everything in brain disorder with light? Newton Howard

Brain. Future. Humanity. How to connect it all? Sebastian Seung

How can we identify and manipulate memory engrams? Susumu Tonegawa

What can we see with diamond cellular camera? Ronald Walsworth

Can we repair a broken brain with movement therapy approach? Hermano Igo Krebs

From Artificial Intelligence to Intelligent Health

World Health Strategy: What is the road from Artificial Intelligence to Intelligent Health? Renata Bushko

How should we honor and build upon Marvin Minsky’s work? Renata Bushko, Aubrey de Grey, Joshua Feast, Glenn Fields, Michael McDonald

Why Minsky’s Ideas are important for medicine? From Society of Mind to Society of Body Henry Lieberman

Remarks about Marvin Minsky Ray Kurzweil

Marvin thinks about thinking Marvin Minsky

How can we chart the future for digital health information systems? Gary Kreps

Future of Intelligent Software: Watson - The Jeopardy Challenge. What if we could have Watson-like Medical Personal Advisor? David Ferrucci

Future of Drugs and Pharmacology Health Design 101 Mike Dunkley

Drugs: What does the future hold? Lorraine Gudas

Future of Regenerative Medicine

What are seven secrets to staying young? Aubrey de Grey

Why do we age and what can we do about it? David Sinclair

What are microengineered biomaterials for regenerative medicine? Ali Khademhosseini

Future of Mental Health and Happiness

Can we forecast changes in mood and mental health, like we forecast a storm? Rosalind Picard

What is Happiness? Part I Part II Craig Feied

How can we form health habits? Alex (Sandy) Pentland

Future of Mental Health - Peace through RAGE Control: Rapidly Act Gain Emotional Control Joseph Gonzalez-Heydrich

Does your smartphone know more about your mental health than your doctor? Skyler Place

How does Akili’s neurogame work? “Project:EVO” Eddie Martucci

What is the future of depression prediction based on self-report diary via smartphone applications? Yoshihiko Suhara

How can we implement personalized positive psychology interventions in the form of interactive journaling? Sooyeon Jeong

Future of Corporate Health and Happiness Richard Bedrosian and Amy Bucher

Future of Pain Management

How can we reduce opioid misuse among chronic pain patients and what is the role of risk assessment and innovative technology?” Robert Jamison

What is the future of pain management? Navil Sethna

What is the future of pain management? Daniell Carr

What is best non-opioid pain management therapy? Darin Correll

Future of Medicine and Global Health

What is the future of medicine? Michael Gillam

Strategy for the Future = ITicine Renata Bushko

Future of Global Health Ramesh Raskar

Future of Public Health Chris Gibbons

Future of Healthcare in China Xing Jijun

Connected Health Joseph Kvedar

Importance of Language Interface Guergana Savova

Will healthcare be delivered by George Jetson in the future? Nick van Terheyden

How can we chart the future for digital health information systems? Gary Kreps

What is the future of Health Ecosystem? Renata Bushko

Future of Computing

Future. Computation. Health. Stephen Wolfram

What is the future of Computer Inerface? Randall Davies

What is Quantum Computing? Paola Cappellaro

What is the future of Mobile Video Programming? Dina Katabi

Using Deep Models of Medicine and Common Sense to Answer ad hoc Clinical Queries Douglas Lenat

What is common sense computing? Henry Lieberman

Healing Plants and Modern Science

Can Chinese herb-based medicines heal the immune system and cure allergies? Xiu-Min Li

How can we harness healing power from plants? Jing-Ke Weng

Can herbal flavonoids reduce inflammation? How does Arctigenin isolated from Arctium lappa L. inhibit IgE production? Renna Bushko

20th FHTI Award Ceremony Dr. Xiu-Min Li

Interview with Dr. Xiu-Min Li Xiu-Min Li, Renata Bushko

What is the healing story of Dr. Xiu-Min Li? Barbara Winston

Traditional Chinese Medicine, Western Science, and the Fight Against Allergic Disease. Henry Ehrlich

Can Food and Drug Allergies be Cured? Mariana Castells

Future of Surgery, Pathology and Medical Devices

What is the future of autonomous surgeons? David Gracias

What is the Future of Biopsy? Evin Gultepe

What is the future of pathology? Clinical Decision Support Systems Glenn Edwards

Anticipating Changes in Medical Device Industry Albert Di Rienzo

Future Health Challenges:

What are future healthcare challenges? Craig Feied

What are new innovative offerings to the consumer in the cancer treatment area? Lorraine Gudas

What would best catalyze 100% renewable energy distributed collectively through intelligent grids globally? Energy, Collective Intelligence, and Health Status Under Climate Change Michael McDonald

How can we detect disease before symptoms occur with immunosignaturing? Neal Woodbury

Is a hospital a place? The future of hospital care. Robert Teague

How should we change the treatment paradigm? Wellness and Anticipatory Care Glenn S Fields

Are exoskeletons a solution to physical disparity? Ernesto Rodriguez Leal

How can 3-D printing help with epithelial wound healing? Luis Alonso Pastor

Real-world Monitoring of Sleep Akane Sano

Caring Emotional Machines and Avatars

Q Sensor for PTSD, Sleep, Epilepsy, Anxiety, Autism, and Emotion Research Part I Part II Rosalind W. Picard

How can relational agents and avatars help patients? Timothy Bickmore

Automated Care - Future of Health Technology Award Lecture Joseph Kvedar

FHTI Product Award for Mobile Virtual Assistants & Human Emulation Technology Renata Bushko & Fred Brown

The Ultimate Patient Engagement Tool: Virtual Health Assistant, Ask Sara Fred Brown

Future of Behavior Monitoring Joshua Feast

Investment in Health and Commercialization

Health Investment Strategy David Steinberg

Health Investment Strategy: Hints on Investing in Health Eric Elenko

How can we accelerate formation and success of biotechnology startups? Albert Di Rienzo, Adam Greenspan, Eric Elenko

Future of NanoMedicine

What’s next in the Application of Nanotechnology-based Molecular Delivery Systems? Guillermo Ulises Ruiz Esparza

What is nanotechnology-based monitoring? Part I Part II Benjamin Miller

How can Google Glass remotely integrate with microfluidic biosensors and actuators? Yu Shrike Zhang

Implantable Nanocrystalline Diamond Neurosensors Heidi Martin

Fashion as Future of Health Technology

Is fashion the future of HealthTech? Mark Francis

Beauty Technology: When Technology meets Cosmetics Katia Vega with intro Renata Bushko

Real-world Monitoring of Sleep Akane Sano

Future of Healthy Cities and Transportation

Can you imagine cities that feel, understand, and take care of your wellbeing? Agnis Stibe

How can we build Persuasive Electric Vehicles (new healthy transportation)? Ryan C. Chin

How people connect up to the electronic nervous system that covers the planet - sensor browsers, tools as ‘prosthetics’, smart lighting and heating systems as extensions of your sense of comfort? Joseph Paradiso

Connection Science – Mobile Social Networks Revolution

How can network science be applied for an expanded understanding of large online network information structures and behaviors to modernize public health communication strategies for improved health outcomes? Brittany Seymour

Beginning a New Era in Healthcare: Mobile Social Networks Part I Part II Alex (Sandy) Pentland

Unite Science, Art, Technology and Medicine

How can Art and Science Unite? Renata Bushko, Wally Gilbert, Christopher MacDonald and Jehan Said

What is the the value of impermanence in design? Christopher Previte

Marvin thinks about music Marvin Minsky

Music and the Brain Peggy Codding

Performance by Maria Caruso’s Bodiography Contemporary Ballet

Strategy for the Future: Unite Science, Art, Technology and Medicine for Happier, Longer Lives Renata Bushko