For StanleyFalkow, alegacy ofmentorship By KristaConger vidual’s genome sequence. privacy and potential discrimination based onan indi- university, amelioratesmany concernsaboutgenomic at the ologists, computer scientists and cryptographers with the inquiry, Stanford researchers say. vealing any genetic information not directly associated for thepresence ofdisease-associatedgeneswithoutre - and withhisenergyofcourse people withhisideasandtime tus, Falkow “isoneofthemostgenerous Professor in Cancer Research, Emeri- bridge basic science and medicine. and inbig,connect-the-dotsideasthat impact ofmicrobes onhumanhealth, ogy, inresearch thatunderscores the eral ways:intheteachingofmicrobiol- deepening hislegacyatStanford insev- any credit, thesefacultymembersare faculty careers at Stanford. ogy and immunology — have made their professor of medicine and of microbiol- immunology; and , MD, PhD, professor ofmicrobiology and ogy andimmunology;Denise Monack, professor ofpediatricsandmicrobiol- Manuel Amieva, MD,PhD, associate scholars inhislab. Three ofthem— graduate studentsandpostdoctoral in science. young toforgecareers researchers trying erosity and inspiration as an adviser to Medicine, becameknown forhisgen- ogy andimmunologyattheSchoolof PhD, aprofessor emeritus ofmicrobiol- microbial pathogenesis.” ship thatcreated thefieldofmolecular nificant, legacy:“hisinspiringmentor- lesser-known, albeitperhapsequallysig- the effectsofantibiotics,” but also for a how microbes causediseaseandresist contributions toward understanding lauded not only for “his monumental Volume 9, No.15Volume 9, without compromisingscience participants for genetic-study Technique enhancesprivacy W By KathyZonana This “genome cloaking” technique,devisedby bi- It is now possible to scour complete human genomes The Robert W. and Vivian K.Cahill Although Falkow is quick to deflect He has mentored more than 100 Over the course ofhis career, Falkow, year atthe White House, hewas a National Medal ofSciencelast hen was awarded INSIDE STANFORD MEDICINE August 28, 2017 28, August SCIENCE PHOTO /SHUTTERSTOCK.COM PHOTO SCIENCE See PRIVACY Stanley Falkow hired DeniseMonack asalabtechnician in1984.Now, she’s aprofessoratStanford. a wonderful job,a wonderful sothatyou can’t help sharing interesting ideas and having such of being a generous person, but the joy of evidence ofjoy. Andit’s not justthejoy giving withanythingotherthanobvious man said.“He never hasdone any ofthat all ofhisotherresources aswell,” Rel- , page7 PublishedbytheOfficeofCommunication&PublicAffairs unsuitable for stem cell studies, researchers find researchersunsuitable forstemcellstudies, Popular mouse model of humanimmunesystem By KristaConger them. response totransplanted stemcellsorderived from model is not suitable for studying the human immune The researchers conclude that the humanized mouse thatpatientswilllikelyrequiredrugs aftertransplant. sult, they can’t beused to study the immunosuppressive of genetically mismatched human stem cells. As a re- mice are unabletorobustly reject thetransplantation what wouldoccurinahumanpatient,thehumanized for diabetes and skin grafts for burn victims. response tothe transplantationofpancreatic isletcells for decadestostudy, amongotherthings,theimmune mune system. Researchers have relied upon the animals engineered tohave ahuman,ratherthanmurine,im- humans. and whentobeginwide-scalestemcelltransplantsin animal modelbefore makingdecisionsaboutwhether Medicine. according toastudyby researchers attheSchoolof cells does not reflect what is likely to occur in patients, man immune system responds to transplanted stem A typeof However, theStanford researchers found that,unlike Known as “humanized” mice, the animals have been The researchers optimizationofthis urgefurther mouse widely usedto assess how thehu- people and try to do useful things.”people and try ing questionsandwork withsuchgreat lucky to get to think about these interest but leave hisroom feelinglikewe are so But first,how Falkow’s journeytobecomingamas- not tomentor TIMOTHY ARCHIBALD stem celltransplants. model doesn’t reflect what is likely to occur in humans who receive Joseph Wu andhiscollaborators found thatawidelyusedmouse animals.” could inhibitthisrejection. We can’t dothatwiththese work that bestinpatients,ortoscreen drugs fornew ety ofimmunosuppressive tolearn whichmight drugs medicine andofradiology. “We couldthentestavari- diovascular Institute and professor of cardiovascular said Joseph Wu, MD,PhD, director ofStanford’s Car- reject foreign stemcellsjustasahumanpatientwould,” “In anidealsituation,thesehumanized micewould - you think through things.” doing it.It’s atechniqueheusestomake what hemeantandspendthewholeday tofigure outable. Iwouldleave trying eva said. “It wasalmost likesome par- that couldhave several meanings,” Ami- and thenhewouldmakesomeinsight about hisresearch. “He wouldjustlisten fice asapostdoctoralscholartotalk wise.”they usually thought I was very what theysaidwantedtodo. And dents said, and then Itold them to do carefullyI listened very to what my stu said. “And intheyears whenIlistened, the bestthingtodowasjustlisten,” he tion thatmight notbe theirs. “Idecided tive, orpushsomeonetoward anaspira- enjoy it.’” becauseIcan’tlife isruined gohomeand experiments andgohome,now my day,to do was go into the lab every do was stunned. Andhesaid,‘All Iwanted and notforme,’” Falkow remembered. “I you’re satisfied,because thisisforyou into my office and said, ‘Falkow, I hope just earned a PhD in a colleague’s lab. had, attheurgingofFalkow andothers, Walter Reed ArmyInstitute ofResearch University, andaformerco-worker from in hisfirstfacultyjob, atGeorgetown ter mentorbeganwithamistake.He was Stanley Falkow. he said.“And thenItookaclassfrom aboutthelackofinspiration,”bit angry these facts,andIremember beingalittle andaboutall school; theywere dry very disappointed with the classes in medical during . “I was a little bit On thesideofmicrobes Amieva recalled visitingFalkow’s of- Falkow wouldnever againbesodirec- day he got his degree, he walked “The Amieva wasfirstinspired by Falkow See See Page 5 study found. seasonally, a Tanzania varies gatherers in of hunter- a population diversity of microbe The gut- FALKOW MOUSE, page7 STEVE FISCH , page6

- Statewide, race of infants influences quality of their hospital care By Erin Digitale pregnancy), those who died before 12 with “other” ethnicity had lower Baby- The next step, Profit said, is to help hours of age and those with severe con- MONITOR scores than white infants, California’s NICUs identify ways in Infants’ racial and ethnic identities in- genital abnormalities. while black and Asian infants did not which they can each make progress in fluence the quality of medical care they Profit and his colleagues used an in- have significantly different treating all infants more receive in California’s neonatal intensive dex they had previously developed and scores than whites. However, equitably. “Our goal is to care units, a study from the School of validated to measure NICU care. To use across the state, white infants develop a dashboard of dis- Medicine has found. the index, called Baby-MONITOR, scored higher on measures parity measures for NICUs The study, which examined medi- each infant’s medical records are evalu- of whether standard medi- throughout California so cal care of more than 18,000 of the ated and scored on nine yes-or-no ques- cal practices were being fol- that each can see how they’re state’s smallest babies at 134 Califor- tions, all of which have been shown lowed. For instance, 89 performing for infants of nia hospitals, was published Aug. 28 in in prior research to reflect the quality percent of white infants and different races and ethnici- Pediatrics. of medical care. Some questions as- 88 percent or Asian infants ties in comparison to their The disparities were not uniform: At sess whether patients received aspects in the study received steroids peers,” he said. The feedback some California hospitals, infants from of NICU care that are in keeping with before birth to mature their Jochen Profit will become part of the work vulnerable populations received worse standard medical practices for premature lungs, while 87 percent of of the California Perinatal care than white infants, while at others, babies, such as being examined for an Hispanic infants and 85 percent of black Quality Care Collaborative, which has they received better care than whites. In eye disease called retinopathy of prema- infants got the same treatment. The dif- organized successful quality-improve- general, however, the hospitals with the turity, or receiving steroids before birth ference remained statistically significant ment initiatives to help NICUs across best outcomes for their patients also de- to help mature their lungs. Other ques- after adjusting for possible confounding the state improve the medical care they livered better care to white infants. In tions assess specific medical outcomes, factors. deliver. The researchers are also working addition, the study found that black and such as experiencing a hospital-acquired Black infants had lower rates than with the Vermont Oxford Network, a Hispanic infants were more likely than infection or growing at a healthy rate. white infants of receiving any human sister organization that monitors NICUs white infants to receive care in poor- All questions are worded such that better milk at discharge — an indicator of across the country to provide similar worse outcomes — but also had better feedback to hospitals nationwide. MAESSE PHOTOGRAPHY / SHUTTERSTOCK.COM outcomes in some areas, including faster “We need to continue to identify vul- growth rates and lower rates of chronic nerable populations, make sure they get lung disease and collapsed lung. His- their needs met and find better ways to panic infants did worse than whites on engage all families in our care,” Profit all components of the score except col- said. lapsed-lung rates. Hospital care during the newborn Across NICUs, those that provided period is not the largest contributor to the poorest quality of care tended to health disparities that minority infants have the smallest disparities between experience, Profit noted, estimating that ethnicities; in some, blacks fared better socioeconomic and biological differences than white infants. As quality scores rose likely make a larger contribution. Nev- across hospitals, white infants tended to ertheless, that does not mean disparities do better. in medical care should be ignored, he The researchers also found that al- added. though racial and ethnic differences in “For many of these infants, their time NICU care were fairly small when exam- in the NICU sets them on track for their ined across California as a whole, some entire life,” Profit said. “If we can get individual hospitals had large gaps in things right early on, that could have a how they cared for infants from different huge long-term effect.” racial and ethnic backgrounds. Other Stanford collaborators on the Individualizing care research are Jeffrey Gould, MD, profes- sor of pediatrics; biostatistician Mihoko Disparities exist in how babies of different racial and ethnic origins are treated in California’s neonatal Addressing the disparities will require Bennett, PhD; Ciaran Phibbs, PhD, intensive care units, according to a new study. a nuanced approach, Profit said. “It’s re- associate professor of pediatrics; and ally important for NICUs to individu- Henry Lee, MD, associate professor of alize care to the pediatrics. Profit, quality NICUs. outcomes produce higher scores. patient population Gould and Lee “There’s a long history of disparity The analysis then adjusts scores to they see,” he said. “There’s a long history of are members of in health care delivery, and our study account for the length of the mother’s For instance, Stanford’s Child shows that the NICU is really no dif- pregnancy, whether the mother received Hispanic families disparity in health care Health Research ferent,” said the study’s senior author, prenatal care, whether the baby was from who are primarily delivery.” Institute. Jochen Profit, MD, associate professor a single or multiple birth, the baby’s Spanish-speaking Researchers at of pediatrics. “Unconscious social biases 5-minute Apgar score (a quick assess- may be experienc- Duke University that we all have can make their way into ment of the infant’s physical health at ing language barriers that make it harder School of Medicine and the University the NICU. We would like to encourage birth) and whether delivery was by ce- for parents to ask questions and act as of California-Santa Cruz also contrib- NICU caregivers to think about how sarean section. advocates for their infants. “For them, uted to the work. these disparities play out in their own Scores were also statistically adjusted having access to translation and person- The study was supported by grants units and how they can be reduced.” to reflect the fact that some hospitals nel who speak Spanish is really criti- from the Eunice Kennedy Shriver Na- The smallest babies cared for sicker babies, on average, than cal,” he said. Hospitals serving a larger tional Institute of Child Health and Hu- others. The final score for each hospital, proportion of African-American infants man Development. The study used data from the Califor- and for each group of patients within a may have different issues they need to Stanford’s Department of Pediatrics nia Perinatal Quality Care Collaborative, hospital, reflects whether the hospital address. also supported the work. ISM which has collected information on 95 did the same, better or worse than would percent of premature births in the state. be expected in addressing their patients’ The study included 18,616 babies whose medical problems. Scores were calculated birth weights were less than 3.3 pounds, separately for white, black, Hispanic, a category known as very low birth Asian and “other” infants and referenced weight, and who were born between the for each subgroup against whites. Cardiovascular symposium will bring beginning of 2010 and the end 2014. When researchers analyzed the popu- The research excluded infants born ex- lation of very low birth weight infants in tremely premature (before 24 weeks of their study, Hispanic infants and those together experts from Stanford, China

By Tracie White said Joseph Wu, MD, PhD, director of Inside Stanford Medicine is the Stanford Cardiovascular Institute, published monthly in July and The Stanford-China Cardiovascu- which is organizing the event. STANFORD December and semi-monthly lar Research Symposium will take place “This conference draws cardiovascu-

INSIDE the rest of the year. Sept. 21-22 at the medical school’s lar experts from many of China’s most MEDICINE Li Ka Shing Center for Learning and esteemed hospitals and universities, pro- is produced by Paul Costello Knowledge. viding a valuable opportunity to share Office of Communication & Public Affairs Chief communications officer The two-day conference, which is knowledge with Stanford and U.S. ex- Susan Ipaktchian free and open to the public, will bring perts that will improve international col- School of Medicine Director of print & 3172 Porter Drive Web communications together a variety of experts in cardiovas- laboration on cardiovascular research and Palo Alto, CA 94304 John Sanford cular medicine from the United States clinical care,” Wu said. Mail code 5471 Editor and China to share knowledge that can One of the keynote speakers is Vic- (650) 723-6911 Robin Weiss advance heart health. The conference tor Dzau, MD, president of the National http://med.stanford.edu/news/ Graphic designer aims to foster communication between Academy of Medicine and a professor of students, postdoctoral scholars, clinicians medicine at the Duke University School Send letters, comments and story ideas to John and researchers to share expertise in order of Medicine. Sanford at 723-8309 or at [email protected]. to facilitate future collaborations between Topics to be discussed include: Ad- Please also contact him to receive an e-mail version of Inside Stanford Medicine. China’s leading cardiovascular treatment vances in cardiac surgery, vascular and research institutions and Stanford, surgery, pe- See SYMPOSIUM, page 3 2 AUGUST 28, 2017 INSIDE STANFORD MEDICINE Study on what leads to chronic migraines seeks participants

By Bruce Goldman a doctor will see,” said the trial’s principal and get daily exercise — don’t just sit investigator, Robert Cowan, MD, professor around.” Researchers at the School of Medicine are recruit- of neurology and neurological sciences. Better understanding sought ing participants for a clinical trial aimed at finding out “Everyone knows at least someone who why some people who suffer occasional migraine head- suffers with migraine,” said Cowan, who Why some people are susceptible to aches progress to a chronic stage of frequently occur- holds the Betty Higgins Family Foundation migraines and why some — but not oth- ring migraines. Professorship in Headache Medicine and is ers — who do get them become more sus- The trial, underway for about two years now, has the director of Stanford’s Headache and Fa- ceptible over time isn’t well understood, recruited more than 200 participants, and investigators cial Pain Center. Cowan said. are seeking another 300. Candidates must be 18 years Of the 60 million people in the United Robert Cowan “The basic question we’re addressing is: or older. The researchers want to enroll not just people States who get headaches, he said, 37 mil- Why do some people get occasional head- lion of them get migraines aches while others get headaches with in- ALLIANCE / SHUTTERSTOCK.COM — intense throbbing headaches often creasing severity and disability? Are chronic migraines accompanied by nausea and/or hyper- just episodic migraines that occur more often? We sus- sensitivity to sound and light. Among a pect not,” he said. substantial fraction of migraine sufferers, The investigators will conduct rigorous analyses of this painful experience is preceded by a trial participants’ blood, brain function and cerebral characteristic premonitory, often visual, spinal fluid in an effort to find factors that correlate disturbance known as an aura. with migraine susceptibility, severity and frequency. Costly condition Participants will be asked to fill out medical ques- tionnaires and report to the Stanford campus for a Cowan experienced his first migraine minimum of two or three roughly one- to two-hour at age 5. More typically, though, mi- medical visits. (Free parking will be provided.) The graines hit people hardest during their investigators will draw participants’ blood and record most productive years. There’s an uptick their brain activity using functional magnetic resonance of migraine incidence in the teen years imaging and perform lumbar punctures, also known as and early adulthood, when people are spinal taps. Participants who agree to undergo fMRI getting their educations, starting families or lumbar punctures will receive compensation of $50 and building careers. apiece for each procedure. For as-yet unknown reasons, women “If we can find risk factors that predispose some Of the 37 million Americans who suffer from migraines, a few million progress to a are three times as likely as men to suffer migraine patients’ progression from an episodic to a chronic stage of having them more often than not. Investigators hope to find out why. from migraines. chronic condition, and use these to identify at-risk pa- The bulk of the estimated $15 billion tients, it may provide insight into personalized treat- to $30 billion annual cost of headaches to ments to prevent episodic headaches from becoming who experience migraines or other headache types, but the U.S. economy is accounted for by loss of work pro- chronic,” said Cowan. also people who don’t have headaches at all to serve as ductivity, said Cowan. These people, who experience Prospective participants who want to learn more control subjects. symptoms more days than not, number in the millions. about the trial or about their potential eligibility for “Our understanding of headaches lags well behind For the majority of patients with migraines, the it are encouraged to contact trial coordinator Bharati that for many other neurological conditions, which is most effective prescriptions are lifestyle recommenda- Sanjanwala at [email protected]. sad since it’s the most common neurologic complaint tions, he said. “Don’t skip meals, keep regular hours The trial is funded by the Sun Star Foundation. ISM

Latest Intermountain, KRIS NEWBY Stanford seed grant recipients announced The recipients of five new seed grants have been announced by Stanford Medicine and Intermountain Healthcare. In 2016, the two organizations began collaborating on joint clinical, research and education projects. Inter- mountain Healthcare is a not-for-profit health system based in Utah. The one-year seed grants of up to $75,000 are being awarded to projects jointly led by principal investigators from Stanford and Intermountain. The grants will take effect Sept. 1. Following are the names of the grant recipients and their project titles: • Alex Sox-Harris, PhD, associate professor of re- search at Stanford, and Stephen Warner, MD, Inter- mountain — Setting a foundation for collaborative surgical health services research at Stanford Health Care, Intermountain Healthcare and the Veterans Health Administration. • Ian Brown, MD, clinical assistant professor of emergency medicine at Stanford, and Joseph Bledsoe, MD, Intermountain — Electronic decision support for the diagnosis and treatment of acute pulmonary embo- lism in the emergency department. • Alan Schroeder, MD, clinical associate professor of pediatrics at Stanford, and Eric Coon, MD, Inter- Moon upstages sun mountain — Optimizing value in bronchiolitis: The A crowd gathered outside the Clark Center on Aug. 21 to view the eclipse, which blocked out about 75 percent of the sun in the Bay bronchiolitis follow-up intervention trial. Area. The cloudy skies over campus cleared just in time that morning for viewers to glimpse the extraterrestrial phenomenon. The • Purvesh Khatri, PhD, assistant professor of medi- next time a solar eclipse will come to the United States will be April 8, 2024. But California won’t be in its path. cine and of biomedical data science at Stanford, and Patrick Carroll, MD, Intermountain — Early detec- tion of neonatal early onset sepsis using the Sepsis MetaScore: A genomic analysis of cord blood. • Marcy Winget, PhD, clinical associate professor Symposium eases,” and Haibo Zhang, MD, PhD, deputy director of medicine at Stanford, and Brenda Reiss-Brennan, continued from page 2 of cardiac surgery at Beijing Anzhen Hospital, Capital PhD, Intermountain — Pragmatic design for en- Medical University, who will speak on heart failure and hanced team-based primary care. ripheral arterial disease, interventional cardiology, ba- the heart-transplant program at his hospital. • Aruna Subramanian, MD, clinical associate pro- sic science and clinical trials. “Sharing complementary insights to advance car- fessor of medicine at Stanford, and Brandon Webb, Among the other speakers are Stanford’s Joseph diovascular health will benefit literally billions of peo- MD, Intermountain — Repurposing an old drug for Woo, MD, professor of cardiothoracic surgery, who ple worldwide, not just in the two countries,” Wu said. a new epidemic: Ursodeoxycholic acid and C. difficile will give a talk titled “The convergence of biologic and The conference is sponsored in part by the Chi-Li infection. ISM surgical reconstructive therapies for cardiovascular dis- Pao Foundation. ISM INSIDE STANFORD MEDICINE AUGUST 28, 2017 3 Students design small tools to tackle big scientific challenges

CAWA TRAN AND HEATHER CARTWRIGHT By Nathan Collins outcome of an experiment in the “de- Stanford’s Microfluidics Foundry, they mocratization” of a powerful set of tools jumped at the chance. Team Traptasia had a problem: The known as microfluidics. A non-smashing success tiny baby sea anemones they were trying Democratizing science to ensnare are, unlike their adult forms, Team Traptasia, Tran said, solved her surprisingly powerful swimmers. They Team Traptasia was part of a micro- problem “completely.” are also, as team member and chemi- fluidics course dreamed up by Polly After several rounds of design, trou- cal engineering graduate student Daniel Fordyce, PhD, an assistant professor of bleshooting and testing, Team Traptasia Hunt put it, “pretty squishy little de- genetics and of bioengineering and a built a microfluidic device that kept Aip- formable things.” Stanford ChEM-H faculty fellow. tasia alive and healthy long enough to Previous attempts to trap the anem- At the time, she was feeling a bit study. As a result, the researchers could ones, called Aiptasia, while keeping frustrated. A young Aiptasia sea anemone ejects algae actually watch the effects of rising wa- them alive long enough to study under “Microfluidics has the potential to (highlighted in blue-green) in response to ter temperature and pollution on living a microscope had ended in gruesome, if be this really awesome tool,” Fordyce changing water conditions. sea anemones and their symbiotic algae teensy, failure. said. That’s because microfluidic devices — something that has never been done

COURTESY OF POLLY FORDYCE shrink equipment that would normally Ultimately, researchers from four before. Tran, Cartwright and Team Trap- fill a chemistry or biology lab bench labs took part, including Tran, who was tasia will publish their findings soon, down to the size of a large wristwatch, working in the lab of John Pringle, PhD, Tran said. saving space and materials, not to men- a professor of genetics. Fordyce will be Other teams have helped labs design tion time and money. They also open up describing her experiences teaching that devices to study how the parasite that entirely new ways to conduct biological class in an upcoming paper, which she causes toxoplasmosis infects human research — trapping baby sea anemones hopes will provide a blueprint for people cells, to trap and study placental cells, and watching them under a microscope, eager to help others make use of micro- and to isolate single cells in tiny reaction for example. But making high-quality fluidics tools. chambers for detailed molecular biology devices takes expertise and resources Shrinky Dinks vs. Aiptasia studies. most labs don’t have. Tran said the device Team Traptasia “There’s this big chasm between the Before linking up with Fordyce’s class, came up with could provide opportu- bioengineers that develop devices and Tran had been working with Heather nities for the Pringle lab, as well as in the biologists that want to use them,” Cartwright, core imaging director at the education. Now an assistant professor at Fordyce said. Bioengineers know how to Carnegie Institution for Science’s De- California State University- Chico, Tran design sophisticated devices and biolo- partment of Plant Biology. Together they said she’ll be using the device with un- gists have important questions to answer, tried a more do-it-yourself approach dergraduates there. “Basically, this device but there is little overlap between the involving the children’s toy Shrinky has given me the opportunity to train the two. Dinks, an approach first proposed by next generation of biologists” in a new, To bridge the gap, Fordyce invited Michelle Khine at research-focused way, biology labs to propose projects to stu- the University of she said. Polly Fordyce (left) and graduate students Louai dents in her graduate-level microfluidics California-Irvine. “This year was Hunt, the chemical course. The idea, she said, was to give The effort did not engineering student in Labanieh, Sarah Lensch and Diego Oyarzun successful beyond my discuss the design of a microfluidic device built to students real-world experience while giv- work. “We got some Team Traptasia, said study coral bleaching. ing labs access to technology they might movies. They were dreams.” that his own research not have the time, money or expertise to mostly end-of-life on intestinal biology pursue otherwise. movies,” Cartwright could benefit from But Traptasia had to make it work. In fact, the desire to break down dis- said. microfluidics. “I’m hoping to take the ex- Cawa Tran, then a postdoctoral scholar, ciplinary boundaries was something that If Tran and Cartwright managed to pertise that I gained in the microfluidics and her research into climate change’s ef- attracted her to Stanford and to ChEM- trap Aiptasia, their Shrinky Dink de- design process to my own research,” he fects on coral bleaching were depending H in the first place. “One of the reasons vice crushed or twisted the sea anemo- said. Hunt is working in the lab of Sarah on them. (Sea anemones, it turns out, that I came to Stanford and ChEM-H nes apart. So when Fordyce approached Heilshorn, PhD,an associate professor of are a close relative of corals, but easier to was that I really love the idea of having them to work with what would become materials science and engineering. study.) interdisciplinary institutes that attempt Team Traptasia — graduate students Those are exactly the kinds of results And then there was the matter of the to cross the boundaries between disci- Salil Bhate, Hunt, Louai Labanieh, Sarah Fordyce had hoped for. team’s grades to consider, along with the plines,” she said. Lensch and Will Van Treuren — and “This year See TRAPTASIA, page 5

Stanford Medicine magazine reports on the future of vision By Rosanne Spector • A story about using adaptive optics technol- Many of the strategies being explored at the ogy, originally used to track spy satellites, to see in- School of Medicine to protect, improve and restore side the eye. vision sound seriously sci-fi. Among them: cornea • A feature on progress toward bionic vision transplants conducted with magnetic fields instead — using video glasses and a tiny implant to restore of scalpels, virtual reality workouts to repair dam- sight. aged retinas, and bionic vision. • A report on using terrifying virtual reality ex- The new issue of Stanford Medicine magazine, periences, such as being attacked by sharks, to un- a theme issue on eyes and vision, includes details derstand the neuroscience of fear. A video on the about these projects and others pushing the bound- subject accompanies the online version of the story. aries of biology and technology to help people see. • An article explaining how neuroscientist “Studies show that when it comes to their health, Carla Shatz’s studies of vision revolutionized the the thing people most worry about, after death, is understanding of brain development and continue losing their vision,” said Jeffrey Goldberg, MD, pro- to uncover surprises, such as interactions between fessor and chair of ophthalmology, in the report’s brain cells and the immune system. lead article. “People’s productivity and their activi- • A piece on a mountain-climbing doctor who ties of daily life hinge critically on vision, more than co-founded the Himalayan Cataract Project, which on any other sense.” has performed more than 600,000 cataract surger- The lead article explains the basic workings of ies in the developing world. the eye and describes an array of ophthalmological • A story about removing a tumor from a teen’s research, including Goldberg’s work to repair dam- eye, which not only restored her vision but changed aged corneas by injecting healthy cells into the eye her life. and using magnets to pull the cells into position. A The issue also includes an article about Stanford patient in a small early study entered the trial legally Medicine’s inaugural issue of Health Trends Report, blind, with 20/200 vision, and left it with 20/40 vi- an annual review and analysis of the health care sion — close to normal. A larger study is planned. sector. Lloyd Minor, MD, dean of the School of “The fear of vision loss, even for people in lesser Medicine, explains in the article: “In publishing this stages of disease, can be quite dramatic. So anything report, we hope to show how big data is the most of the anesthetic drug ketamine to treat obsessive- we can do to stabilize, better diagnose and hopefully important trend facing the sector and, in the pro- compulsive disorder; and an essay by bestselling au- one day restore vision in some of these diseases, I cess, inform and educate the entire medical commu- thor Joyce Maynard about living through a loved one’s think, will have an enormous global impact,” Gold- nity — including patients, doctors, the private and painful death from pancreatic cancer. berg said. public sectors — who are actively shaping the future The magazine is available online at http://stanmed. Also in the issue, which was produced in collabo- of health care.” stanford.edu. Print copies are being sent to subscrib- ration with Stanford’s Byers Eye Institute: Additional stories include a feature on the use ers. Others can request a copy at 723-6911. ISM

4 AUGUST 28, 2017 INSIDE STANFORD MEDICINE Hadza of Tanzania experience seasonal variation in gut-microbe diversity

By Bruce Goldman JEFF LEACH

More evidence that our intestinal microbes are pro- foundly influenced by the foods we eat — or don’t: The gut ecosystems of members of a small group of hunter- gatherers inhabiting Tanzania’s Rift Valley show a strong cyclicality consistent with the population’s seasonally changing diet. A study led by researchers at the School of Medicine is the first to look at seasonal variations in the gut-mi- crobial composition, or , of the Hadza, one of the world’s few remaining traditional hunter-gatherer populations. The research confirms that the Hadza mi- crobiota is more diverse than, and substantially different from, that of industrialized countries’ urban-dwelling denizens. The study is also the first to show that the microbi- ota of the Hadza population varies seasonally, and that this variation corresponds to their seasonally fluctuating dietary intake. And the research suggests that sweeping changes in the average person’s diet over the past 10,000 years could be the key driver in the loss of microbial diversity in the typical modern gut. “Surviving hunter-gatherer populations are the clos- est available proxy to a time machine we in the modern industrialized world can climb into to learn about the ways of our remote human ancestors,” said Justin Son- nenburg, PhD, associate professor of and immunology at Stanford. Sonnenburg is the senior author of the multi-institu- tion study, published Aug. 25 in Science. Lead author- ship is shared by Sonnenburg’s former graduate student Samuel Smits, PhD, and Jeff Leach, director of the Hu- man Food Project in Terlingua, Texas. The life inside our guts For more than 15 million years, human beings have (Clockwise from above) A Hadza woman crushes seeds of the co-evolved with thousands of microbial species that baobab tree. Meat plays a larger role in the Hadza diet during take up residence in the lowermost part of the intes- the dry season than it does in the wet season. During the rainy tine, earning their keep by helping us digest food season, berries are an important source of food for the Hadza. components we’re unable to break down by ourselves, chiefly dietary fiber; manufacturing vitamins and other health-enhancing molecules; training our immune sys- role; and wet, during which berries, tubers, honey tem and fostering the maturation of cells in our gut; and baobabs prevail. (Tubers and baobab are available and guarding our intestinal turf against the intrusion year-around.) of all-too-eager competing microbial species, including “The 100 to 200 Hadza sticking to this routine will pathogens. possibly lose it in a decade or two, maybe sooner. Some The advent of agriculture about 10,000 to 15,000 are using cell phones now,” Sonnenburg said. “We years ago has radically altered our diet. In the past cen- wanted to take advantage of this rapidly closing window tury alone, the typical person’s lifestyle has undergone to explore our vanishing microbiota.” further vast alterations: labor-saving devices’ encourage- Tracking the variation ment of a sedentary existence, the introduction of anti- tract where these microbes live, so they’ve evolved to biotics and of birth by cesarean section, and the gradual The investigators collected 350 stool samples from be very good at digesting it,” said Sonnenburg. “The supplanting of fiber-filled whole grains, fruits and veg- 188 separate Hadza individuals over a roughly one-year Hadza get 100 or more grams of fiber a day in their etables by increasingly processed and fiber-free foods. period encompassing a bit more than one full seasonal food, on average. We average 15 grams per day.” These environmental changes have wrought corre- cycle. A thorough analysis of the samples’ microbial In addition to the Sonnenburgs, Stanford co-authors sponding shifts in our microbial exposures, and in our contents revealed that the gut microbiota varied sea- include graduate student Carlos Gonzalez; former intestines’ ability to serve as hospitable hosts for these sonally, in harmony with the Hadza dietary intake. In graduate student Joshua Lichtman, PhD; and Joshua symbionts. But it’s been hard to apportion the relative particular, a subset of microbial species’ populations di- Elias, PhD, assistant professor of chemical and systems minished in the wet season, when honey accounted for biology. STEVE FISCH a significant portion of caloric intake, and rebounded in Researchers from the Lawson Health Research Insti- the dry season, when consumption of fiber-rich tubers tute and Western University in Ontario, Canada, the peaked. University of California at San Diego, the National In- That made sense, Sonnenburg said. “Our own mi- stitute for Medical Research in Tanzania, and the New crobiota can change significantly from day to day, or York University School of Medicine also contributed to even within hours, in response to what we’ve been the study. eating.” The study was funded by the National Institute of Samples collected during the same season, but a Diabetes and Digestive and Kidney Diseases, the Emch year apart, contained essentially identical microbial Family Foundation, the Forrest & Frances Lattner populations, indicating resilience to transitory dietary Foundation, the C&D Research Fund and the Discov- disruptions. ery Innovation Fund. More surprisingly, the bacterial species whose num- Stanford’s Department of Microbiology and Immu- bers diminish to sub-detectable levels in the wet season, nology also supported the work. ISM only to bounce back robustly in the next dry season, appear to be the same ones that — although shared by hunter-gatherers in locations as diverse as modern-day Justin Sonnenburg is the senior author of a study about the gut- Africa and South America — are resoundingly absent in microbial composition of a hunter-gatherer population in Tanzania. the guts of the vast majority of those who populate the Traptasia industrialized world. continued from page 4 This observed seasonal cyclicality, in combination contributions of technological and societal innovations with results of a previous study led by two of the study’s was successful beyond my dreams, and the reason is to the loss of microbial diversity in modern populations. co-authors, offers a possible hint about the case of the that the students in the course were incredibly creative The new study adds evidence that diet is a major missing microbes. and talented and driven,” Fordyce said. She also cred- factor. A 2016 study, published in Nature and led by Son- its her graduate student and teaching assistant Kara The Hadza number just over 1,000 people, fewer nenburg and senior research scientist Erica Sonnenburg, Brower, who won a teaching award for her efforts. “She than 200 of whom adhere to the traditional hunter- PhD, showed that while depriving mice of dietary fiber went way above and beyond what would be required gatherer lifestyle, which includes a diet composed greatly reduced their gut-microbial species diversity, this of a TA and really helped imagine and develop the mainly of five items: meat, berries, baobab (a fruit), tu- diversity was restored when the dietary-fiber restriction course,” Fordyce said. bers and honey. While Western diets are pretty much was lifted. But if this fiber deprivation was maintained “If you put this forward as a model for people at the same throughout the year, the Hadza lifestyle for four generations, microbial species that had initially other schools, that could actually make a difference,” doesn’t include refrigerators and supermarkets. So the bounced back robustly became permanently lost. both for students and the labs that could benefit from population’s diet fluctuates according to the season, of Could this be happening, or could it have already microfluidics, she said. which there are two in the Rift Valley: dry, when meat, happened, in us? Fordyce and Pringle are also members of Stanford baobab and tuber consumption play a relatively larger “Fiber’s all that’s left at the very end of our digestive Bio-X. ISM INSIDE STANFORD MEDICINE AUGUST 28, 2017 5 outside hers. “Which I finagled,” she Falkow closed his lab in 2005. self collaborating with microbiologists in Falkow said. “He was sitting in some office in Although he is reluctant to use the Indiana who had found a way to reveal continued from page 1 someone else’s lab and was kind of iso- term “legacy,” Falkow will allow that the nature of bacteria in soil without cul- “He would come in and tell all these lated. I knew if he was here and students Monack “shares something with me, and tivating them, and with scientists in the amazing stories about microbes,” Ami- had to walk through his office, he would I’m very grateful for that.” East Bay, one of whom had eva continued. “And he would say, ‘You like that. He loves it. And they love it. It’s And yet, he emphasizes, she just invented the polymerase know, I am on the side of the microbes.’” perfect.” has carried on her work in- chain reaction technique to Amieva joined Falkow’s lab as a post- A ‘gentle shove’ vestigating host-pathogen amplify DNA. Using a new doc after earning an MD and a PhD in relationships with her own experimental approach, Rel- cancer biology and completing a pedi- It also gives Falkow an up-close view style. “She has her own per- man and his colleagues iden- atrics and a fellowship in in- of how Monack mentors her students. sonality of science,” he said. tified the bacterium, now fectious diseases. “I realized that a lot “She does what I think is the most im- “It’s everything that you look classified as a Bartonella, of the best science comes from making portant thing: She has an open door,” he for in a student that you that causes the disease, bacil- connections between fields or looking said. “The student comes and says they train. You don’t want them lary angiomatosis. It turned at the same thing from a different focal want to talk; she drops what she’s do- to be clones of yourself — I David Relman out also to cause cat-scratch point,” he said. During his postdoctoral ing and invites them in if at all possible, don’t — it doesn’t behoove disease. training, he studied the relationship of closes the door and talks to them as long you. And she’s turning out students who “It was just because of Stanley’s cu- as they want. I saw her do are in their own right successful, and she riosity, his willingness to put himself STEVE FISCH it today.” takes great joy in their success.” in someone else’s world and think hard Monack and Falkow That, Monack said, is something she about their problem, and then as is often have been working to- learned from her mentor. “I do think I’ve the case with Stanley, he has an idea of gether in close quarters modeled my managing style after Stan- where the right direction might be,” Rel- since 1984, when Falkow ley’s, and it clearly has worked for him. I man said. “He might not know the de- hired her, fresh out of col- give graduate students and postdocs a lot tails of how to get it done, but he knows, lege at UC-Davis, as a lab of freedom, but I monitor what they’re ‘Head in that direction; you’ll see some- technician. For the next doing, and if they’re struggling, I help thing that way.’ I have since then found 14 years, Monack man- them. I think it’s best to allow people myself and maybe deliberately put myself aged Falkow’s lab and con- to be creative on their own. You get the in the position of being one of relatively ducted her own research best out of people when you make it few clinicians working in an area of sci- experiments, develop- clear that you trust them and you respect ence that is mostly populated by non- ing an animal model for them.” clinicians, but who have an interest in pertussis and investigat- Curiosity and intuition understanding the clinical ramifications ing host cells’ proclivity of the story.” to commit suicide rather Relman was a postdoc in Falkow’s Relman used the same method on than be infected with lab for 5½ years, until a faculty position other diseases, and he ended up using salmonella. opened up in the Division of Infectious it to look at commensals in the human Manuel Amieva joined Falkow’s lab as a postdoctoral scholar. Now, “We had to learn more Diseases. “Stanley always used to say he body. Today, that research is he’s an associate professor of pediatrics and of microbiology and and more about the biol- would have to take out adoption papers, his main focus. immunology at Stanford. ogy of animal cells and because this was getting to be a bit long,” “That event led to my beginning to human cells, and it was a Relman said. It was a joke, but the famil- do this work on the human microbi- difficult transition, but we ial regard was authentic. “He was warm ome, and that was clearly influenced by Helicobacter pylori to its human hosts. made it,” said Falkow. “And in no small and direct and funny and genuinely in- Stanley’s worldview,” said Relman, who “It had just been discovered that it had measure thanks to her, because she was terested in me and in his people and in is now the Thomas C. and Joan M. Mer- these little microneedles, and it injected a the common denominator through all his role as a mentor,” Relman said. “But I igan Professor. “He’d always been inter- protein into the host cells, and it seemed these generations of students, and she realized that he didn’t view that relation- ested in commensals, although nobody like a form of communication between was the giver of lore to the lab. It got to ship as a hierarchical one at all. It was his was studying them, but also promoted the bacteria and the host,” Amieva said. the point where if you wanted to know creation of an extended community with the general value of curiosity and explo- “That injection system and the protein something, you asked Denise.” a familylike feel.” ration and risk-taking. I think I pursued were associated with cancer, so that kind That said, Falkow was concerned Relman found the gateway to much all of that work on the microbiome be- of sold the project for me. But I was a about his lab manager’s future. “She was of his life’s work one day when he and cause of him, and about 15 years ago little hesitant because I’m a pediatrician; able to publish, but she was stuck here, Falkow attended the weekly clinical con- that became the only thing I did.” this is a disease of adults.” and there was no way for her to advance ference of the infectious diseases division. Falkow is impressed by Relman’s abil- Soon enough, Amieva found himself ity to collaborate broadly. “David is in on the side of the microbe. “As I started RYAN MORRIS / NATIONAL SCIENCE & TECHNOLOGY MEDALS FOUNDATION full command of at least a cruiser, if not a to study it, I realized that this is a pedi- battleship,” he said. “He walks two lines atric infection,” he said. “We acquire it of infectious diseases and basic science, in childhood, and we really don’t know and a lot of people who don’t know him much about this interaction until some wonder at that. I don’t know how he people get sick later on. And then I handles that many students. That’s the started realizing, ‘Oh, it’s been in hu- amazing thing to me.” mans since humans began.’ So it’s one of The admiration, of course, is mutual. those few microbes that have really co- Falkow’s mentoring legacy “is exactly the evolved with humans. The more I think kind of contribution that has a much about it, it’s the perfect microbe to study. longer-lasting impact than any particular It’s part of our normal microbiota, and finding,” Relman said. “With the pace it has some beneficial aspects, but it can of science, there is no paper, no matter turn nasty and lead to cancer, so it is in how important, that will have continu- this balance between being a pathogen ing impact in the way that a subsequent and being a commensal,” or symbiotic, generation of people will, who if trained organism, Amieva said. “And Stanley’s especially well or potently, or with suf- always asking these kinds of philosophi- ficient power of influence, will in turn cal questions, like ‘What’s a pathogen?’ bestow that upon their trainees. There I’ve been trying to figure that out for H. are second- and third-generation Stan- pylori since I was in his lab, and I think ley people now who recognize Stanley’s that’s led to a lot of adventures for my In 2016, Falkow received the National Medal of Science for his work studying how bacteria can contribution to the way in which they students.” cause human disease and how resistance spreads. do science as not via direct means but by Falkow said, “Manuel and I share a vertical inheritance. I think all of us can great love of teaching. He mentors one- only dream to have the kind of influence on-one and is very hands-on. And he in the system,” he said. “She was basically The presenter was Lucy Tompkins, MD, the way Stanley has had.” is an exquisite teacher. To see him in a giving away a lot of her knowledge and PhD, the Lucy Becker Professor in Medi- ‘A microcosm of my life’ classroom is to understand seeing some- her skill to other people.” cine and professor of microbiology and body at the center of their being.” It was time for what Falkow called a immunology. (She’s a Falkow lab alumna When Falkow looks at the careers of Amieva and his colleagues have re- “gentle shove.” As Monack remembered herself, and now his wife.) Amieva, Monack and Relman, he sees, vamped the microbiology course in it, “He said, ‘You know, Denise, I really “She was presenting an interesting “more or less, a microcosm of my life.” which he and Falkow’s paths first crossed. think you, in the future, would be hap- case of a disease that clearly seemed to Each, he said, has a segment of his per- “We made it a very modern flipped class- piest if you got your PhD. When I go to be caused by a bacterium, but no one sonality. “If David is Darwin walking room, where students watch videos at the big petri dish in the sky, it’s going to had been able to grow this organism, around the Galapagos measuring beaks, home and then they come and do activi- be hard for you to find another position and because of that, no one knew what Manuel is Darwin walking around the ties,” Amieva said. “Stanley is now one where you have the freedom that you’re it was, and the usual kinds of testings Galapagos enjoying the beauty of the of our best facilitators. He’ll come and used to, and you might be miserable.’ were all negative,” Relman remembered. situation,” he said. “Denise is more of a tell some story, like when he put poop And I thought about this, and I realized, “So Stanley said, listening and looking generalist and she’s moving into immu- in pills for patients before they went into ‘He’s 100 percent right.’” at these clumps of bacteria sitting in the nology — places I didn’t go. She’s a very the hospital [at Walter Reed], to prevent During graduate school at Stanford, spleen or liver, ‘There’s got to be a way to practical, pragmatic person. diarrhea — essentially, he started doing Monack rotated through several faculty identify these things that doesn’t involve “When it all comes down to it, when fecal transplants and got fired for it. Stu- members’ labs, ultimately completing trying to cultivate them.’ So I said, ‘Well, the four of us — or any group of us — dents love it.” her PhD in Falkow’s. “I guess I had been I’m interested.’” are together, we’re talking about science,” Monack also makes sure Falkow stays brainwashed by then,” she said. She ac- With a couple of well-placed hunches he said. “And the science is the most fas- in touch with students. His office is right cepted a faculty position shortly after from Falkow, Relman soon found him- cinating part of it.” ISM 6 AUGUST 28, 2017 INSIDE STANFORD MEDICINE embryonic stem cells, which are natu- immune systems quickly dispatched both “Many in the fields of pluripotent Mouse rally pluripotent, and to induced plu- forms of human pluripotent stem cells. stem cell research and regenerative medi- continued from page 1 ripotent stem cells. Although iPS cells The researchers obtained similar re- cine are pushing the use of the human- can be made from a patient’s own tissues, sults when they transplanted endothelial ized mice to study the human immune Wu shares senior authorship of the future clinical applications will likely rely cells derived from the pluripotent stem response,” said Kooreman. “But if we research, which was published Aug. 22 on pre-screened, FDA-approved banks of cells. start to make claims using this model, as- in Cell Reports, with Dale Greiner, PhD, stem cell-derived products developed for A new mouse model suming that these cells won’t be rejected professor in the Program in Molecular specific clinical situations, such as heart by patients, it could be worrisome. Our Medicine at the University of Massa- muscle cells to repair tissue damaged To understand more about what was work clearly shows that, although there is chusetts Medical School, and Leonard by a heart attack, or endothelial cells to happening, Kooreman and his colleagues some human immune cell activity, these Shultz, PhD, professor at the Jackson stimulate new blood vessel growth. Un- created a new mouse model similar to the animals don’t fully reconstitute the hu- Laboratory. Former postdoctoral schol- like patient-specific iPS cells, these cells humanized mice. Instead of reconstitut- man immune system.” ars Nigel Kooreman, MD, and Patricia would be reliable and immediately avail- ing the animals’ nonexistent immune The researchers are hopeful that re- de Almeida, PhD, and graduate student able for clinical use. But because they systems with human cells, however, they cent advances may overcome some of the Jonathan Stack, DVM, share lead au- won’t genetically match each patient, it’s used immune and bone marrow cells current model’s limitations. thorship of the study. likely that they would be rejected with- from a different strain of mice. They “The immune system is highly com- “Although these mice are fully func- out giving the recipients immunosup- then performed the same set of experi- plex and there still remains much we tional in their immune response to HIV pressive drugs. ments again. need to learn,” said Shultz. “Each road- infection or after transplantation of other Humanized mice were first developed Unlike the humanized mice, these block we identify will only serve as a tissues, they are unable to completely re- in the 1980s. Researchers genetically en- new mice robustly rejected human plu- landmark as we navigate the future. Al- ject the stem cells,” said Kooreman. “Un- gineered the mice ripotent stem cells ready, we’ve seen recent improvements derstanding why this is, and whether we to be unable to as well as mouse in humanized mouse models that fos- can overcome this deficiency, is a critical develop their own “Each roadblock we stem cells from a ter enhancement of human immune step in advancing stem cell therapies in immune system. identify will only serve genetically mis- function.” humans.” They then used matched strain Wu is a member of Stanford Bio-X, “Humanized mice are critical preclini- human immune as a landmark as we of mice. In other the Stanford Cancer Institute and the cal models in many biomedical fields and bone marrow navigate the future.” words, their newly Stanford Child Health Research Insti- helping to bring basic science into the precursor cells to acquired immune tute. He is also the Simon H. Stertzer clinic, but as this work shows, it is criti- reconstitute the animals’ immune sys- systems appeared to be in much better Professor. cal to frame the question properly,” said tem. Over the years subsequent studies working order. Additional Stanford co-authors Greiner. “Multiple laboratories remain have shown that the human immune Although more research needs to be are former research assistant Raman committed to advancing our under- cells survive better when fragments of done to identify the cause of the discrep- Nelakanti; former postdoctoral schol- standing and enhancing the function of the human thymus and liver are also im- ancy between the two types of animals, ars Sebastian Diecke, PhD, and Veron- engrafted human immune systems.” planted into the animals. the researchers speculate it may have ica Sanchez-Freire, PhD; postdoctoral Greiner and Shultz helped to pioneer Kooreman and his colleagues found something to do with the complexity scholar Ning-Yi Shao, MD, PhD; in- the use of humanized mice in the 1990s that two varieties of humanized mice of the immune system and the need to structor Elena Matsa, PhD; and associate to model human diseases and they pro- were unable to completely reject unre- further optimize the humanized mouse professor of pathology Andrew Connolly, vided the mice used in the study. lated human embryonic stem cells or iPS model to perhaps include other types of MD, PhD. Understanding stem cell transplants cells, despite the fact that some human cells or signaling molecules. In the mean- The research was funded by the Cali- immune cells homed to and were active time, they are warning other researchers fornia Institute of Regenerative Medi- The researchers were studying plu- in the transplanted stem cell grafts. In of potential pitfalls in using this model to cine, the National Institutes of Health ripotent stem cells, which can become some cases, the cells not only thrived, but screen for immunosuppressive drugs that and the Helmsley Charitable Trust. any tissue in the body. They tested the grew rapidly to form cancers called tera- could be effective after human stem cell Stanford’s Department of Medicine animals’ immune response to human tomas. In contrast, mice with unaltered transplants. also supported the work. ISM

Privacy 2001, it was hailed as a remarkable achievement. For of a simple algorithm on their own computer or smart continued from page 1 the first time, the 3 billion nucleotides that encode the phone) into a linear series of values describing the pres- approximately 20,000 genes that keep our bodies run- ence or absence of the gene variants under study, with- ning smoothly were tidily listed as a string of letters. out revealing any other information about their genetic Using the technique, the researchers were able to But every human has many variations from the pub- sequence. The encrypted information is uploaded into identify the responsible gene mutations in groups of pa- lished, consensus sequence. These individual differences the cloud and the researchers then use a secure, multi- tients with four rare diseases; pinpoint the likely culprit are what make us unique, but they can also confer in- party computation (a cryptographic technique that of a genetic disease in a baby by comparing his DNA creased risk of genetic diseases. ensures the input data remain private) to conduct the with that of his parents; and determine which out of More than 7,000 diseases analysis and reveal only those hundreds of patients at two individual medical centers are caused by variations in the gene variants likely to be perti- with similar symptoms also shared gene mutations. sequence of a single gene. But nent to the investigation. They did this all while keeping 97 percent or more in order to determine which “In this way, no person or of the participants’ unique genetic information com- variations cause the condi- computer, other than the indi- pletely hidden from anyone other than the individuals tion, it has been necessary viduals themselves, has access themselves. until now to compare the ge- to the complete set of genetic “We now have the tools in hand to make certain netic sequences of hundreds or information,” said Bejerano. In that genomic discrimination doesn’t happen,” said Gill thousands of individuals with each case, the analysis was per- Bejerano, PhD, associate professor of developmental and without the disease, letter formed within seconds or min- biology, of pediatrics and of computer science. “There by letter. Geneticists (or their Dan Boneh Gill Bejerano utes with moderate computing are ways to simultaneously share and protect this infor- computer software) then make power. They hope to extend mation. Now we can perform powerful genetic analy- a list of all the differences and the technique to include dis- ses while also completely protecting our participants’ identify which are found primarily in people with the eases caused by combinations of multiple genetic vari- privacy.” disease under study but rarely in any unaffected people. ants or to handle tens of thousands of sequences such as Bejerano shares senior authorship of the research, Those variations are then considered to be prime dis- those found in genomewide association studies. which was published Aug. 18 in Science, with Dan ease-causing suspects. Ultimately the goal is to find the best way to both Boneh, PhD, professor of computer science and of elec- “There is a general conception that we can only share the genetic information with researchers while trical engineering. Graduate students Karthik Jagadeesh find meaningful differences by surveying the entire also protecting each patient’s privacy in order to ad- and David Wu share lead authorship of the study. genome,” said Bejerano. “But these meaningful differ- vance medical knowledge. Applying cryptography techniques ences make up only a very tiny proportion of our DNA. “Often people who have diseases, or those who know There are now amazing tools in computer science and that a particular genetic disease runs in their family, are The researchers hope that routine implementation cryptography that allow researchers to pinpoint only the most reluctant to share their genomic informa- of their technique will help individuals overcome any these differences while keeping the remainder of the ge- tion because they know it could potentially be used qualms about privacy that may keep them from sharing nome completely private.” against them in some way,” said Bejerano. “They are their genome sequences. In particular, people may be In 2008, President George W. Bush signed the Ge- missing out on helping themselves and others by allow- concerned that DNA sequences or genetic variants cur- netic Information Nondiscrimination Act, which pro- ing researchers and clinicians to learn from their DNA rently unassociated with diseases may in the future be hibits discrimination in matters of health insurance and sequences.” linked with as-yet-unidentified increases in risk. employment based on an individual’s genetic informa- Bejerano is a member of Bio-X, the Stanford Child “These are techniques that the cryptography com- tion. But there are many other arenas in which such Health Research Institute, the Stanford Cancer Insti- munity has been developing for some time,” said discrimination could potentially occur, including the tute and the Stanford Neurosciences Institute. Boneh, who is the Rajeev Motwani Professor in the purchase of life or disability insurance or the applica- Another Stanford study co-author is graduate stu- School of Engineering. “Now we are applying them tion for a loan. dent Johannes Birgmeier. to biology. Basically, if you have 1 million people with Giving power to the individual The study was funded by Stanford University fel- genomic data they would like to keep private, this ap- lowship grants, the National Science Foundation, the proach lets researchers analyze the data in aggregate and Jagadeesh and Wu worked together to adapt a cryp- Defense Advanced Research Projects Agency, the David only report on findings that are pertinent. An individ- tographic approach known as Yao’s protocol and cloud and Lucile Packard Foundation, Microsoft and the Si- ual might have dozens of anomalous genes, but the re- computing for use with human genomes. A key com- mons foundation. searchers and clinicians will only learn about the genes ponent of the technique is the involvement of the in- Stanford’s departments of Developmental Biology, of relevant to the study, and nothing else.” dividual whose genome is to be studied. In particular, Pediatrics and of Computer Science also supported the When the human genome was fully sequenced in each individual encrypts their genome (with the help work. ISM INSIDE STANFORD MEDICINE AUGUST 28, 2017 7 Med X to focus on promoting positive change in health care STANFORD MEDICINE X By Tracie White his late wife, Amy Reed, MD, PhD, who was harmed during a medical procedure, and the journey they be- Medicine X, Stanford’s premier conference on gan to change U.S. medical practices. emerging health care technology and patient-centered Conference sessions will include: community orga- medicine, will return to campus Sept. 15-17. nizing and how to create meaningful and lasting change This year’s conference, which will be held at the Li in health care; the challenges of digital health; and a Ka Shing Center for Learning and Knowledge, will fo- panel session moderated by ProPublica reporter Charles cus on the responsibilities of health care citizenship and Ornstein on partnering to develop shared resources for how individuals can take action to improve health care cancer patients. in the United States. Events over the three-day conference will also feature “Medicine X 2017 will focus on how we can take presentations and panels on a range of topics, including: action to create the change that we want to see in the • Ideas and experiences from experts in the dis- health care system and move beyond ideas into action,” ability community on what access means to them and said Lawrence Chu, MD, professor of anesthesiology, a discussion of exploring ways to encourage providers perioperative and pain medicine and founder and direc- Lawrence Chu, founder and director of Stanford Medicine X, speaks and institutions to go beyond compliance. tor of Medicine X. “With the current uncertainty in the at the event in 2016. • A discussion on the current state of clinical tri- future of health care, it’s important to stop and consider als and how to move from serving only the needs of how each of us might work to create a new culture of in terms of health care. We hope this conference will researchers to those of patients who participate. caring in health care that doesn’t exist right now.” give people both the inspiration and the tools and re- • A device demonstration providing hands-on ex- Medicine X aims to bring together everyone who sources they need to take action and create change.” perience with health care technologies presented by plays a role in health care — researchers, patients, Keynote speakers include: the innovators behind them. providers, designers, technologists and policy lead- • Amy Edmondson, PhD, professor of leadership Pre-conference events will take place Sept. 14 from ers — and encourage them to work together to build and management at the Harvard Business School, who 7:30 a.m. to 5:30 p.m., and will include a day-long a framework for health care transformation, Chu said. will speak on “The importance of creating psycho- summit to explore how technology and patient voices This framework, known as “Everyone Included,” is a logical safety when a patient is a part of a health care can guide the future of employer-based health benefits trademark of Stanford Medicine X and was co-devel- team.” programs, and an IDEO design workshop in which oped with a diverse group of health care stakeholders • Ai-jen Poo, a 2014 MacArthur “genius grant” ePatients can collaborate with designers, researchers, over the past seven years at the conference. recipient and executive director of the National Do- technologists and health care providers to spark new “In January during President Obama’s farewell mestic Workers Alliance, who will speak on “The new ideas for improving patient care. speech, he talked about how his future role was going caring majority.” Registration for Medicine X is available online at to be as a citizen,” Chu said. “That inspired me to think • Hooman Noorchashm, MD, PhD, a cardiotho- medicinex.stanford.edu. Pre-conference events require about how we, as individuals, might consider this role racic surgeon and activist, who will share the story of separate registration. ISM

CARLOS GONZALEZ, a gradu- of note ate student in chemical and reports on significant honors and awards systems biology, was named a for faculty, staff and students Gilliam Fellow by the How- ard Hughes Medical Institute. RAAG AIRAN, MD, PhD, assistant pro- The honor recognizes doctoral fessor of radiology, has been named the students with the potential to runner-up of the 2017 Science & PINS be leaders in their fields and Prize for Neuromodulation. The prize the desire to support diver- recognizes outstanding research per- sity in science. He will receive Raag Airan Themistocles Assimes Samuel Cheshier Iris Gibbs formed during the last three years that $46,000 a year for up to three is described in an essay. His essay, “Neu- years. In addition, his mentor, Joshua lar physiology and of structural biology, for the early detection and treatment of romodulation with nanoparticles,” ap- Elias, PhD, assistant professor of chemi- effective June 1. His research focuses on the disease. Wilson’s research interests peared in Science on Aug. 4. cal and systems biology, will receive the application of cryo-electron micros- include pediatric endocrinology and the THEMISTOCLES ASSIMES, MD, PhD, training in mentorship. copy for the 3-D visualization of protein role of technology in the management of was promoted to associate professor of ANUPAMA NARLA, MD, assistant pro- complexes, primarily signaling cell sur- diabetes. medicine, effective June 1. He is a cardi- fessor of pediatrics, has received a bridge face receptors, with the goal of under- CAROLINE YU, a medical student, has ologist who conducts human molecular grant from the American Society of He- standing how they function. received a summer student fellowship epidemiology studies of traits related to matology. The grant provides $150,000 DARRELL WILSON, MD, professor of pe- from the Parkinson’s Foundation and the complex cardiovascular disease. for one year to support blood disease re- diatrics, in collaboration with David Sef- American Parkinson Disease Association. SAMUEL CHESHIER, MD, PhD, assistant search. Her research examines the patho- tel, MD, of Enable Biosciences, has been The $6,000 award will support her work professor of neurosurgery, was awarded a physiology of ribosomopathies, with the awarded a $700,000 grant from JDRF, on neuroophthalmic clinical markers $115,000 scholar extension grant for his goal of developing new therapies. an organization that funds Type 1 diabe- for Parkinson’s disease with her mentor, Ty Louis Campbell Foundation award MARLENE RABINOVITCH, MD, the tes research. The team plans to develop Joyce Liao, MD, PhD, associate professor from St. Baldrick’s Foundation, which Dwight and Vera Dunlevie Professor an ultrasensitive auto-antibody panel of ophthalmology and of neurology. ISM supports research on childhood cancers. in Pediatric Cardiology and a professor He is working to block a signal expressed of pediatrics, was named an American JEREMY BITTERMAN / INTERSTICE ARCHITECTS on cancer cells that protects them from Heart Association Distinguished Science the immune system, with the goal of tar- Lecturer for the AHA meeting in No- geting pediatric brain tumors. vember. The honor recognizes scientists IRIS GIBBS, MD, was promoted to and clinicians who have advanced the professor of radiation oncology, effective understanding of cardiovascular disease June 1. She is the associate dean of MD and stroke. Her research focuses on sup- admissions. She specializes in the treat- porting lung vascular development to ment of central nervous system tumors ameliorate the effects of heart failure. and in the development of new radio- GEORGIOS SKINIOTIS, PhD, was ap- therapy techniques. pointed professor of molecular and cellu-

A rock’s purpose When the industrialist C. J. Huang funded the construction of Stanford Medicine’s Asian Liver Center, a nonprofit focused on reducing the incidence of hepatitis B and liver cancer in Carlos Gonzalez Anupama Narla Marlene Rabinovitch Asians, he asked that the building design reflect the cultural traditions of the Asian community. To this end, Stanford worked with feng shui master Jetsun Ma Ho Lynn to provide advice on colors and landscaping elements that would have a healing effect on the center’s visitors. So what’s the deal with that boulder? Recently, Ho Lynn explained its mystical purpose: “This volcanic rock is composed of fire, earth and metal elements, and the lichen on its surface represents water and wood elements. Wood is energetically related to the liver and brings forth an enhancing, productive chain of the five elements’ spiritual powers to support the goals of the Asian Liver Center’s work. The empty space under the roof overhang of the center’s entrance was a feng shui variable that could disrupt the flow of chi, vital energy, into the building. Adding the large boulder calls attention to the center’s establishing goal with its heavy weight and powerful presence.” ISM Georgios Skiniotis Darrell Wilson Caroline Yu 8 AUGUST 28, 2017 INSIDE STANFORD MEDICINE