Hacking the Soul New Technologies That Look Inside the Mind Will Make It Possible to Change What We Think, Feel, and Remember

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Untitled-2 3 FS:7.5625” 6/3/14 3:50 PM MIT TECHNOLOGY REVIEW VOL. 117 | NO. 4 TECHNOLOGYREVIEW.COM From the Editor

ludwig wittgenstein was not tech- Wittgenstein would have been LeDoux on memory, page 30; Antonio nologically illiterate: he had studied especially derisive of the claims of neu- Damasio on emotions, page 48; and aeronautical engineering at the Univer- roscientists to meaningfully explain Rebecca Saxe on empathy, page 60). sity of Manchester before World War I, mental phenomena. In his Zettel (or Finally, we report on the interven- researching the behavior of kites and posthumously collected remarks), he tions the new technologies may make designing a propeller with little rockets writes about the psychology of his possible, including treatments for at its tips. But the philosopher was vio- own time: “No supposition seems to intractable mental illnesses such as lently opposed to scientism, which me more natural than that there is no schizophrenia (see “Shining Light on Trenton Jerde, in his review of James process in the brain correlated … with Madness,” by David Rotman, page 34) Klagge’s Wittgenstein in Exile, describes thinking; so that it would be impos- and the use of brain-machine inter- as “a preoccupation with the scientific sible to read off thought processes from faces to help paralyzed patients (“The method, the appeal to the sciences to brain processes.” Thought Experiment,” by Antonio solve problems that are beyond their Wittgenstein’s interdiction is now Regalado, page 52). reach, and a misuse of scientific termi- a commonplace among philosophers. Are the philosophers convinced nology.” The philosopher insisted on an Many argue that understanding the by any of this? Not really. Respond- unbridgeable divide between philoso- causes of events in our brains cannot ing to Gabriel Kreiman’s research into phy and science, which Klagge calls tell us much about the mind, because decision-making, Hilary Bok, a philoso- “Wittgenstein’s insulation thesis,” one inferring anything about the lat- pher at Johns Hopkins, is reserved: “I of whose consequences was that science ter from the former is a kind of “cat- love these experiments and think they cannot resolve philosophical problems. egory mistake.” But the attitude is are really interesting, but I’m less con- becoming a rearguard defense against vinced whether they have shown any- the encroachments of an advancing thing crucial about free will.” But they explanatory method. Questions such are intrigued. Patricia Churchland, a as “What is consciousness?” or “Do we philosopher at the University of Cali- have free will?” or “How do we ethically fornia, San Diego, says of the same reason?” are of abiding interest, and experiments, “Self-control is an entirely because philosophers have made little real brain phenomenon. Insofar as progress in answering them, neurosci- self-control is a key component of free entists have felt at liberty to try. Think- choice, we do in fact have free choice.” ing, feeling, and deciding are the most But perhaps it doesn’t matter much intimately human of all things, and yet what professional philosophers think. we understand them hardly at all. They’ve had 2,000 years to answer That neuroscientists can make the these questions in their own way. The attempt is the result of recent techno- power of an explanation is its capac- logical advances, including (but not ity to satisfyingly illuminate something limited to) new kinds of brain imag- hitherto obscure and to allow us to do ing and the emerging field of optoge- things we could not before (here, effec- netics. This issue of MIT Technology tively treat mental illnesses and build Review describes those emerging tech- brain prosthetics). Insofar as traditional nologies (see “Neuroscience’s New philosophy has an important role in Toolbox,” by Stephen S. Hall, page 20, understanding the mind, it may be to and “Cracking the Brain’s Codes,” by pose questions and parse answers, and Christof Koch and Gary Marcus, page the questions we ask will become more 42) and explains some of the surprising interesting because of the conceptual early insights they have suggested (see breakthroughs of neuroscience. “Searching for the ‘Free Will’ Neuron,” But write to me at jason.pontin@ by David Talbot,” page 64, and inter- technologyreview.com and tell me what

views with the neuroscientists Joseph you think. VITTIGUIDO

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Front Back

BUSINESS REPORT 2 From the Editor 72 The Internet of Things 8 Feedback Billions of computers that can communicate from any- VIEWS where are everywhere. What does it mean for business? 10 Virtually There Oculus Rift and related devices will create new social REVIEWS settings. 80 My Life, Logged 10 Scare Tactics The downsides of capturing Vermont got it dead wrong July/August 2014 every moment of your life for on labeling for GMOs. posterity. By Rachel Metz 11 Our Lagging Laws Lawmakers can’t keep up 20 | Neuroscience’s New Toolbox 84 A Plan B for Climate Agreements with the technology they’re Researchers go hunting for the sources of consciousness, supposed to be regulating. The U.N.’s approach is a bust. memory, and emotions. By Stephen S. Hall Let’s find something better. By Kevin Bullis UPFRONT 30 | Q&A: Joseph LeDoux 87 Imposing Security 13 The Next Startup Craze Your memory can be manipulated—but that could be Coders are overconfident Silicon Valley wants to a good thing. By Brian Bergstein about their own work. Time remake food in its image. to send in the automated 15 Smashup on the Internet 34 | Shining Light on Madness inspectors. Fast Lane Drugs for psychiatric illness aren’t very effective. New By Simson L. Garfinkel The fall of net neutrality is techniques and insights offer hope. By David Rotman bad news for some startups. 53 YEARS AGO 42 | Cracking the Brain’s Codes 16 Malware on the Move How does the brain speak to itself? 92 Mind Reading If you use your smartphone Finding a physical basis By Christof Koch and Gary Marcus for financial transactions, for the mind could lead to take heed. all kinds of wild advances, 48 | Q&A: Antonio Damasio 17 Can Young Blood Fix Aging? speculated a 1961 essay. Biologists made a huge blunder by bypassing emotions It works in mice. Now in favor of more “interesting” topics. By Jason Pontin researchers are looking for ON THE COVER human treatments. 52 | The Thought Experiment 18 Ads That Know All Your Paralyzed people can use their minds to control a robot Driving Habits As in-car apps collect data, arm. Will it work beyond the lab? By Antonio Regalado ad companies try to figure out how to make use of it. 60 | Q&A: Rebecca Saxe Knowing how the brain deals with other people could 19 The Dirty Reason That lead to smarter computers. By Courtney Humphries Teslas Won’t Save China Electric cars aren’t such a boon if they’re powered by 64 | Searching for the “Free Will” Neuron Illustration by Oliver Hibert coal plants. Gabriel Kreiman explores whether we can gain more for MIT Technology Review control over our decisions. By David Talbot SCULPTURE: JOSHUA HARKER; PHOTOGRAPH: BRUCE PETERSON BRUCE PHOTOGRAPH: HARKER; JOSHUA SCULPTURE:

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Editor in Chief and Publisher CORPORATE ADVERTISING SALES MIT ENTERPRISE FORUM, INC. Jason Pontin Chief Financial Officer Director of Advertising Sales Executive Director Rick Crowley James Friedman Antoinette Matthews EDITORIAL Chief Operating Officer Senior Producer, Content and Community Editor Midwest Sales Director James Coyle Susan Kaup David Rotman Maureen Elmaleh Chief Strategy Officer [email protected] Director of Chapter Leadership and Process Deputy Editor Kathleen Kennedy 303-975-6381 Gaylee Duncan Brian Bergstein New England, Detroit, and Canada Director of International Director of Communications Creative Director Barry Echavarria Business Development Joyce Chen Eric Mongeon Antoinette Matthews [email protected] 603-924-7586 Chairman News and Analysis Editor Executive Assistant Jason Pontin Will Knight Leila Snyder Mid-Atlantic and Southeast Clive Bullard President Chief Correspondent Manager of Information Technology [email protected] Kathleen Kennedy David Talbot Colby Wheeler 845-231-0846 Treasurer Senior Editor, Energy Office Manager West Coast James Coyle Kevin Bullis Linda Cardinal Rob Finley [email protected] Senior Editor, Business Reports CUSTOMER SERVICE AND 415-659-2982 Nanette Byrnes PRODUCT DEVELOPMENT SUBSCRIPTION INQUIRIES Chief Digital Officer and Europe Senior Editor, MIT News National: 800-877-5230 VP, Product Development Anthony Fitzgerald Alice Dragoon Erik Pelletier [email protected] International: 818-487-2088 Senior Editor, Business 44-1488-680623 Project Manager E-mail: technologyreview@ Antonio Regalado Jane Allen France pubservice.com Senior Editor, IT Philippe Marquezy Senior Software Engineers Web: www.technologyreview.com/ Tom Simonite [email protected] Shaun Calhoun 33-1-4270-0008 customerservice Senior Web Producer Molly Frey MIT Records: 617-253-8270 Kyanna Sutton Germany User Interface/Digital Designer Michael Hanke (alums only) Managing Editor Emily Dunkle [email protected] Timothy Maher 49-511-5352-167 Reprints: Donna Summers [email protected] EVENTS Copy Chief China 281-419-5725 Linda Lowenthal Director of Events and Strategic Partnerships Tao Lin Amy Lammers [email protected] Licensing and permissions: IT Editor, Web and Social Media [email protected] Rachel Metz Director of Events Programming Japan Laura Janes Wilson Akiyoshi Ojima Biomedicine Editor [email protected] Senior Content Producer Technology Review Susan Young Rojahn 813-3261-4591 Marcy Rizzo One Main Street, 13th Floor Research Editor Spain and South America (Online) Cambridge, MA 02142 Event Coördinator Mike Orcutt Pedro Moneo Laín Tel: 617-475-8000 Lina Umansky [email protected] Assistant Art Director 34-667-732-894 MIT Technology Review identifies Colin Jaworski CONSUMER MARKETING the new technologies that matter— Advertising Services Coördinator Editorial Assistant VP, Consumer Revenues and Marketing explaining how they work, decipher- Ken Collina J. Juniper Friedman Bruce Rhodes ing their impact, and revealing how Sales & Marketing Associate Production Director Marketing Communications Manager they’ll change our lives. Founded Julie Swanson James LaBelle David W.M. Sweeney at the Massachusetts Institute of Custom Editor Technology in 1899, we are a digitally Contributing Editors FINANCE Anne Stuart oriented global media company that Katherine Bourzac General Ledger Manager publishes serious journalism in maga- Jon Cohen Olivia Male zines and on websites and mobile Peter Fairley Advertising Services Accountant devices. We also host events around Simson L. Garfinkel [email protected] Letitia Trecartin 617-475-8004 the world. Technology Review, Inc., is Robert D. Hof an independent nonprofit 501(c)(3) Courtney Humphries Media Kit BOARD OF DIRECTORS corporation wholly owned by MIT; Martin LaMonica www.technologyreview.com/media Reid Ashe the views expressed in our publica- John Pollock Judith M. Cole tions and at our events are not always Amanda Schaffer Jerome I. Friedman shared by the Institute. Israel Ruiz Megan J. Smith De Technologia non multum scimus. Sheila E. Widnall Scimus autem, quid nobis placeat. 6

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Five Most Popular Stories MIT Technology Review Volume 117, Number 3

1 2 3 4 5 Smart Wind and Ultraprivate Oculus Rift Brain Mapping Q&A: Sarah Lewis

Solar Smartphones Anybody who has had We will never mimic the Art is exploration and If the grid can’t manage What if Silent Circle and the opportunity to try human brain in silicon or curiosity, so in that sense the tiny fraction of power Blackphone are actu- side by side the Google carbon. The physiology of it shouldn’t be consid- now produced by wind and ally operating by order of Glass and the Oculus Rift neurons is not nearly as ered much di erent from solar, just imagine how bad the NSA, set up to catch (as I could at a recent intriguing as the behavior science. The scientifi c the problem would be if exactly those who really conference in Brussels) that allows them to self- process—hypothesis, they were increased fi ve value privacy and therefore would quickly understand assemble into pattern- designed experiment, times or more. are prime targets? Do we Zuckerberg’s acquisi- matching engines that can results analysis, and all —big.league.slider have any guarantees? tion decision. Between be recalled and reapplied. over again—can be applied —bluppfi sk the “cool” factor and the —marcvky everywhere. — vnedovic @big.league.slider: It’s “wow!” e ect, the fact that It would have been nice My art skills are minimal, actually easy to imag- Sometimes I wonder about Glass is less obstructive if you’d addressed what but I’ve been interested in ine, just like in Colorado this fanatical need for (allegedly allowing you to we expect to gain by see- the relationship between or Texas when inclement secrecy. I take my wife to keep in contact with the ing the brain cells. Can we art and science since col- weather throws thermal an Indian restaurant and real world) may eventually decipher thoughts, ideas, lege. Having worked in and nuclear plants o ine the waiters begin prepar- play against Glass com- fears, by just seeing? Can video-game design since and poor old intermittent ing her favorite samosas mercially. Young people we understand condi- the 1970s, I’ve seen bril- power has helped utilities when we drive into the might be more reluctant tions like autism? Can we liant engineers enjoy jug- to ride it through. That’s parking lot. It is part of life to look like a “dandy geek” enhance the brain func- gling, chemists coding what this article implies: and a nice part of it at that. (as they would with Glass) tions of healthy individu- intricate game logic, a stronger modeling allows I don’t want to walk around than to stake their claim as als? What is the problem whale-study scientist cre- utilities to understand bet- being suspicious of every- a “dedicated nerd” (as they we are trying to solve, and ating a game, and software ter what they are facing. It’s one and everything in my would with Oculus Rift). how far are we from that? engineers writing science a learning curve. —je hre vicinity. —tag —borisazais —ankur fi ction. —ricklev

JA14_feedback.indd 8 6/2/14 10:01 AM DON’T More Nukes Is Not the Answer In “Irrational Fears” (Views, May/ June), Nathan Myhrvold tells us that the JUST FILL Fukushima accident followed numerous disastrous design decisions and was entirely preventable. The real lesson, he says, is that we should build modern reactors—but hindsight bias can POSITIONS, be used rhetorically to trivialize design errors made 40 years ago. The mistakes made then weren’t trivial or obvious at FULFILL the time, and the mistakes being made today aren’t, either. If they were, we wouldn’t make them. The lesson is that we need to try to reduce risk from critical design errors. Until we have more careful thinking on VISIONS the pertinent issues, the simplest way to lower risks in nuclear reactor design is to have fewer reactors, not more. Harold Thimbleby Swansea University, Wales

Better Living Through Big Data? Nicholas Carr’s review of Sandy Pent- land’s book Social Physics (“The Lim- its of Social Engineering,” May/June) reminded me of my work in the artiﬁ cial- intelligence community in the 1980s. I think most of us working in the industry didn’t believe the hype that surrounded AI at the time, but the hype was necessary to sustain the R&D dollars to keep even the more pragmatic developments going. Many of those developments, I might add, we see today in what Google, Apple, and Facebook have done. I per- sonally enjoyed reading Pentland’s book. We need the Pentlands of the world to show us the possibilities. —llocklee We become your strategic partner to find contract employees who fit perfectly. Your Aerotek account manager lives and breathes your Pentland is an engineer and perhaps industry and organization and works with you to create a staffing overoptimistic that “engineering approx- plan that meets your business needs. Our recruiters interview imations” will allow him to do useful candidates and recommend only the ones who fit your requirements things with all that data. A computer to a T. To learn more, call 888-616-4117 or visit MIT.Aerotek.com. scientist would probably take comfort Aerotek is an equal opportunity employer. An Allegis Group Company. ©2014 in fundamental social phenomena that make societies unpredictable. —Dean L Learn about our Perfect Fit® process and download a free whitepaper.

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each other while talking in the “real” COMPUTING world can work in a virtual one. We can Virtually There feel empathy and connection, interrupt each other, and smoothly and rapidly A new generation of virtual reality will exchange thoughts. At less than 100 compete with the physical world. milliseconds of delay you can reach out recent months have been good and virtually touch or shake hands with ones for virtual reality. The Facebook another person and find the perception acquisition of Oculus has galvanized the of the resulting collisions and motion to idea that “something wonderful” will be perfectly believable and immersive. happen if we put on these strange head- If virtual reality can replace (or even sets and visually enter other worlds. improve upon) videoconferencing or Most people assume this means long-distance travel as a way of getting gaming. And while it’s true that the new together with people, it will surely dis- Philip Rosedale headsets will immerse users in amazing rupt and restructure many basic human gaming experiences, that’s not the big exchanges that have nothing to do with part of the story. playing games. After we’ve tried the Oculus for a few For many of the everyday things months and the novelty has worn off, we we do—talking face to face, working might find ourselves asking: “Where are together, or designing and building the other people?” That is where things things—the real world will suddenly are going to get interesting. have real competition. The Oculus Rift is only one of several advances in hardware that are going Philip Rosedale is CEO of High Fidelity, a to dramatically change our ability in the startup working on a new virtual world. coming year to immerse ourselves in a He was previously CEO of Second Life. 3-D world. For one thing, we’ll be able to communicate with others while we’re inside these worlds: the Internet is now BIOTECHNOLOGY fast enough to allow us to be in a virtual Scare Tactics environment with other people who are Pamela Ronald How Vermont got it wrong on GMOs, accessing it from elsewhere, even half- and how that hurts people everywhere. way across the world. Updating imagery shown to the eyes in early may, vermont governor with a delay of less than 10 millisec- Peter Shumlin signed a bill into law that onds relative to head movements gener- required a label for any foods produced ates a magical sense of being “present” with genetic engineering. This made in a virtual space. My own experiments Vermont the first U.S. state to require have shown that a second kind of pres- mandatory GMO labeling. (More than ence—the feeling of really being face to 50 countries already require such labels, face with another person—requires an and more than a dozen states are con- end-to-end delay (including hardware, sidering similar laws.) Many food software, and network transmission) of activists viewed the bill’s passage as a around 100 milliseconds or less between boon—GMOs cause cancer, they claim, your movement and the other person’s and force farmers to use more toxic perception of that movement. chemicals. Below that threshold, the small head But if Vermont had honestly assessed

Vivek Wadhwa and eye movements that we use with genetically engineered crops, the bill KERR SAM

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would have indicated that there is not of current supplementation programs multimillion-dollar war machines, and a single credible report of dangerous more than a decade ago. But regulatory supercomputers were for secret govern- health effects from GMOs. It would have bodies in India, Bangladesh, and else- ment research. Today, hobbyists build mentioned that the technology has been where have still not approved Golden drones, and poor villagers in India used safely in food and medicine for 30 Rice for release. UC Berkeley agricul- access Facebook accounts on smart- years. It would have stated that farm- tural economist David Zilberman calcu- phones more powerful than the Cray 2 ers’ use of GMO crops has reduced by a lates that swifter implementation would supercomputer, which in 1985 cost $17.5 factor of 10 the amount of insecticide have saved at least one million people million and weighed 2,500 kilograms. sprayed on corn over the last 15 years. from blindness and prevented the death We haven’t come to grips with what Aside from being disingenuous, the of thousands of children. is ethical in relation to technologies Vermont bill is inconsistent. It doesn’t So let’s label food, but let’s do it right. such as social media, let alone with what require labeling for cheese made with Let’s label food with details about how the laws should be. Consider the ques- genetically engineered enzymes or red the crop was grown and what is actually tion of privacy. There is a public outcry grapefruit developed through radia- in the food. Let’s apply these labels to all today about surveillance by the National tion mutagenesis. It doesn’t require foods, so consumers can draw their own Security Agency, but the breadth of labeling for animals that have been fed conclusions about the risks and ben- that surveillance pales in comparison GMO crops, or labels for crops sprayed efits. A right to know is only useful if the with the data that Google, Apple, Face- with carcinogenic compounds. The law information is accurate. book, and legions of app developers doesn’t require crops sprayed with the are collecting. Our smartphones track organic pesticide Bt to be labeled, but Pamela Ronald is coauthor of Tomorrow’s our movements and habits. Our Web crops genetically engineered to produce Table: Organic Farming, Genetics, and searches reveal our thoughts. Where do Bt must be labeled. the Future of Food. we draw the line on what is legal—and So the law won’t give consumers ethical? access to food that’s more sustainable, The Genetic Information Nondis- more healthful, or less “corporate.” INTERNET crimination Act of 2008 prohibits the Should you care? After all, any indi- Our Lagging Laws use of genetic information in health vidual consumer can either pay heed to insurance and employment. But it pro- Making new laws is a slow process. a label or ignore it. But political cam- vides no protection from discrimina- Technology moves too fast to care. paigns that reject science can have dev- tion in long-term-care, disability, and astating consequences. Aside from the laws forbid lenders from life insurance. There are no laws to stop obvious example of climate skepticism, discriminating on the basis of race, gen- companies from using genomic data in there’s the antivaccination movement, der, and sexuality. Yet lenders can refuse the same way that lending companies which has led to outbreaks of measles to give a loan to people if their Facebook and employers use social-media data. and whooping cough. friends have bad payment histories, if We will have similar debates about self- The anti-GMO movement has their work histories on LinkedIn don’t driving cars, drones, and robots. already made consumers fearful. Many match their bios on Facebook, or if a As a society, we need to be mindful are now willing to pay more for “non- computer algorithm judges them to be that powerful innovation now occurs GMO” foods—providing an incentive socially undesirable. too quickly for existing ethical frame- for farmers to use older, more toxic, Such regulatory gaps exist because works and laws. This means question- more expensive chemicals and farming laws haven’t kept up with technology. ing, rethinking, and reframing those practices. And the gaps are getting wider. values, as a culture, at an accelerated GMO scaremongering campaigns Technology now touches practi- speed. And it means creating a legal sys- have also harmed the poor. Vitamin A cally everyone, everywhere. Changes tem that can keep pace with a new era of deficiency causes blindness in half a of a magnitude that once took centu- techno-socioeconomic transformation. million people a year in the develop- ries now happen in decades, sometimes ing world. A genetically engineered rice in years. Not long ago, Facebook was a Vivek Wadhwa is a fellow at Stanford called Golden Rice could have provided dorm-room dating site, mobile phones University’s Arthur and Toni Rembe Rock the nutrient at a fraction of the cost were for the ultrarich, drones were Center for Corporate Governance.

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ost tech startups startup’s egg-free Just Mayo in Septem- The Next are silent spaces ber 2013, and four other mainstream where earbud-wear- grocery chains are lined up for the first Startup Craze: ing engineers peer half of this year. And thanks to a recent into monitors. Not investment round that boosted Hamp- Food 2.0 Hampton Creek ton Creek’s funding to $30 million and Foods. The two- drew in Li Ka-shi ng, the wealthiest person Silicon Valley investors and year-old company’s office—a filled-to- in Asia, Just Mayo will soon be sold by a bursting M space in San Francisco’s South large online grocer in Hong Kong. startups are trying to improve our food. Do they bring anything of Market tech hotbed—grinds, clatters, Hampton Creek Foods and other and whirs like a laundromat run amok. startups have big dreams of restructuring to the table? That’s the sound of industrial-strength the food supply so that it uses less land, By Ted Greenwald mixers, grinders, and centrifuges churn- water, energy, and other resources. They ing out what the company hopes is a key are taking on corporate giants such as ingredient in food 2.0: an animal-free ConAgra, General Mills, and Kraft, which replacement for the chicken egg. spend billions on research and technology Silicon Valley venture capitalists have development. funded several food-related startups in Similar ambitions have run up against the past year, but Hampton Creek has considerable challenges in industries such gathered the most momentum. It has as clean tech. But those involved in the A-list investors including Founders Fund, food craze might prefer a different exam- Horizon Ventures, and Khosla Ventures, ple. Hampton Creek’s CEO, Josh Tetrick, and two undisclosed industrial food com- wants to do to the $60 billion egg industry panies are experimenting with its plant- what Apple did to the CD business. “If we based egg substitute. The prepared-food were starting from scratch, would we get counter at Whole Foods began using the eggs from birds crammed into cages so PING ZHU PING

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small they can’t flap their wings, shitting The rear of Hampton Creek’s facil- ing. Some of them also can be functionally all over each other, eating antibiotic-laden ity is devoted to finding them. There more effective than eggs. soy and corn to get them to lay 283 eggs Josh Klein, a biochemist who formerly Competition isn’t the only challenge. per year?” asks Tetrick, a strapping for- worked on an AIDS vaccine, runs a high- First, while Tetrick is intent on conquer- mer West Virginia University linebacker. throughput screening pipeline designed ing the mainstream, his egg-free products While an egg farm uses large amounts of to comb through millions of plant culti- risk being relegated to the vegan aisle. “I vars for proteins with certain characteris- think their success is going to be limited tics. So far, Hampton Creek has examined to a niche market for now,” says Christine 3,000 plants and discovered 11 desir- Alvarado, an associate professor of poul- try science at Texas A&M. And should “I consider a broken food the company discover a compelling protein that comes from an unusual plant, it system my enemy,” says must convince farmers to supply that crop Hampton Creek’s CEO, in huge quantities without raising costs. Josh Tetrick. “The more specialized your raw material, the higher the risks the supply chain will able proteins, seven of which are already face,” observes Jon Stratford of Natural allowed in food by the U.S. Food and Drug Products, which makes a soy-based egg Administration. One is the Canadian yel- substitute for the food industry. low pea protein that emulsifies the oil and Then there’s the fundamental ques- water in Just Mayo. Another binds the tion of whether Hampton Creek’s proteins company’s cookie dough, called Eat the are, indeed, better than traditional egg Dough, which is due to hit store shelves replacements. In fact, Hampton Creek’s this month. A third goes into a prototype own patent application offers egg replace- viscous yellow liquid that looks much ment recipes made entirely of off-the-shelf like a beaten egg and possesses a similar ingredients (with additional processing nutritional profile, minus the cholesterol. such as grinding into very small particles). When Hampton Creek chef Chris Jones, “Food scientists have been doing this for water and burns 39 calories of energy for late of the Chicago restaurant Moto, pours 100 years or more,” says Gregory Ziegler, every calorie of food produced, Tetrick the prototype into a heated pan, it solidi- a professor of food science at Penn State says he can make plant-based versions on fies as though it came out of a shell. The University. (Tetrick says the recipes in the a fraction of the water and only two calo- fake egg looks and feels authentic, but in patent applications came from an earlier ries of energy per calorie of food—free of a test last winter it was rife with off fla- stage of research.) cholesterol, saturated fat, and allergens, vors, and the team is still working to make Nonetheless, Hampton Creek’s and without risk of avian flu or cruelty to the formula satisfying under all possible approach is working so far. Tetrick expects animals. For half the price of an egg. conditions in which it might be prepared to have his egg-free mayo in 15,000 stores That’s a tall order. The lowly chicken and eaten. by late summer, up from 3,500 now, and egg is a powerhouse of high-quality, low- Hampton Creek’s emulsifiers and he has his eye on fast-food chains and cost nutrition. Yet in prepared foods, it’s binders won’t have the market to them- food service companies. He plans to triple prized less for its nutrients than for its selves. They’ll compete with an array of the size of his workforce by the end of the culinary properties: emulsifying, foaming, existing egg substitutes—never mind eggs year and expand his floor space thirtyfold. binding, gelling, and many more. Those themselves. Egg replacers are widely used And once he has established a toehold functions are conferred by its unique com- in packaged foods to cut costs and mit- in the egg market, Tetrick plans to start plement of proteins. Rather than trying to igate fluctuations in egg prices. These putting his plant-protein database to use reproduce the egg wholesale, Hampton products, usually derived from soy, milk, in other areas; he hints at substitutes for Creek focuses on discovering vegetable gums, or starches, are typically cost- chicken or beef. “I consider a broken food proteins that replicate specific functions. competitive with Hampton Creek’s offer- system my enemy,” he says.

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QUOTED

Talk of an Internet Fast Lane Is “OpenSSL is like a faulty engine part that’s been Hurting Some Entrepreneurs used in every make and model of car, golf cart, The FCC’s net neutrality plan will raise costs for companies that and scooter.” need fast connections or use a lot of bandwidth. —Jonathan Sander, of StealthBits, on a soft- By David Talbot ware library that left thousands of websites vulnerable to attack in April.

ome venture capitalists at the cut- media businesses, and it will also avoid Less financially invested observers ting edge of Internet innovation investing in payment systems or in have little sympathy for this argument. Rob Ssay they will shun startups requir- mobile wallets, which require ultrafast Faris, research director at the Berkman ing fast connections for video, audio, or transaction times to make sense. “This is Center for Internet & Society at Harvard other services, mindful that ISPs may a bad scene for innovation in those areas,” University, notes that broadband provid- soon be able to charge extra fees to major Burnham says. ers typically have had very high profit mar- content providers to ensure speedy ser- History does suggest that some Web gins and often charge tiered rates based on vice. Progress toward so-called Internet products have benefited from an open the speeds consumers desire. “You can’t fast lanes has been accelerated by the U.S. Internet. The founders of Foursquare, credibly argue that consumers aren’t pay- Federal Communications Commission’s as an example, were able to set up their ing enough for access to maintain higher- recent vote to advance a plan that would mobile social-networking service and bandwidth services,” he says. allow such charges. reach 100,000 users with a mere $25,000 If the FCC does let ISPs impose access The cable industry says the charges budget, Burnham says. fees, new business models and technol- are sensible, especially when a few content Other VCs, particularly those who ogies for imposing those charges will providers like Netflix can make up a large fund broadband providers, say the explo- emerge. Wireless carriers like Verizon fraction of traffic. But if deep-pocketed sion of video services has triggered mas- are working on fast-lane technology, players can pay for faster, more reliable sive costs that far exceed the growth in as are Web optimization companies service, then startups face a crushing dis- subscribers. Gillis Cashman, a managing like Akamai. And AT&T already offers advantage, says Brad Burnham, managing partner at MC Partners in Boston, says it so-called sponsored data that allows a partner at Union Square Ventures, a VC makes sense to charge extra to big con- broadcaster to subsidize its bits so you firm based in New York City. tent providers like Netflix, whose service can watch shows (and ads) free on your Burnham says that his firm will steer at peak hours can account for more than smartphone, though other streams of data clear of startups working on video and 30 percent of total Internet traffic. still count against your monthly caps.

TO MARKET Microsoft Oslo is a predictive virtual assistant for office Personal Assistant workers. It draws on online content and a company’s internal data to offer up important information, context, Oslo and contacts when they are needed, before you even think to ask. Oslo examines what you’re working on to COMPANY: curate a selection of articles to read, Web pages to Microsoft visit, videos to view, and podcasts, all presented on PRICE: a page of clickable tiles. Currently available for test- $9.99 per month (for Office 365) ing, it will be included in Office 365, Microsoft’s

AVAILABILITY: subscription productivity software for Second half of 2014 PCs and mobile devices. COURTESY OF MICROSOFT (OSLO); COURTESY OF STEALTHBITS (SANDER) (SANDER) STEALTHBITS OF COURTESY (OSLO); MICROSOFT OF COURTESY

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MOBILE BANKING TROJAN INFECTIONS

Malware on the Move

obile devices are increasingly used for NUMBER OF MOBILE 3,500 BANKING TROJANS M financial transactions, and cybercriminals are taking notice. Trojan apps designed to steal log-in 3,000 information are appearing much faster than other types of mobile malware, especially in Russia and 2,500 other former Soviet states. The majority of malware is made for Google’s Android operating system, which 2,000 allows unscreened software to be installed, but as 1,500 long as these schemes pay off, thieves may soon look

to other platforms, in more parts of the world. 1,000

500

J FM A M JJ ASONDJFMA 2012 2013 Data from Kaspersky

MOBILE MALWARE VARIANTS MOBILE MALWARE MOTIVATION

Data from F-Secure COURTESY OF LIDA KATSIMPARDI (BLOOD); DAVID TALBOT/MIT TECHNOLOGY REVIEW (STYLUS) REVIEW TECHNOLOGY TALBOT/MIT DAVID (BLOOD); KATSIMPARDI LIDA OF COURTESY

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Average Internet speed for users 1.6 vs. 466 in the 20 slowest and fastest kilobits per second countries on earth.

Can Compounds in Young Blood Fix Aging? Animal studies on the revitalizing power of young blood suggest new drug targets for treating age-related conditions. A 3-D reconstruction shows how the deterioration of blood vessels in the brains of older mice (left) can be reversed by treatment with young blood (right). By Susan Young Rojahn

esearchers and investors are ings and earlier results. Previous find- that we can understand at a mechanistic dreaming up medical treatments ings by Amy Wagers, a coauthor on two level, we can start to build out the net- R based on the near-fantastical find- of the new studies, had caught the eye of work of what is changing in the blood, ing that the blood of young mice can reju- the VC firm in 2013, and the new results find things that interact with GDF11, and venate older mice. In some cases, a single “increased the excitement for the role regulate it to give us a clearer view of the protein found circulating in the blood is of GDF11 in aging,” says partner Peter network,” she says. sufficient to restore muscle tissue and Barrett. “Now it’s the blocking and tack- Though the results are exciting, there improve brain activity. The excitement ling of trying to understand what would are many outstanding questions. Potential is spurred by three studies published in be the best therapeutic approach to make side effects are not yet known. Other such Science in May, showing that components this a commercial product.” growth factors, which encourage cell divi- of blood from young mice, including a The company might target heart fail- sion, have been linked to cancer. Further- protein growth factor called GDF11, can ure first, since Wagers’s team has shown more, blood-vessel growth is a common repair damage and improve muscle and that the growth factor can reverse age- feature of cancer development, and genes brain function in older mice. related thickening of heart muscle in involved in stem-cell function and regen- The Boston-area venture capital firm mice. GDF11 alone does not provide the eration have been linked to tumor growth. Atlas Venture has started a still-unnamed full beneficial effects of young blood, says And researchers have never studied the company on the basis of the new find- Wagers. “But now that we have a molecule treated mice for more than 60 days.

TO MARKET Feel the Force A new haptic stylus that lets you “feel” virtual objects and textures costs far less than existing devices, whose Touch prices range from $2,400 to $13,000. It is part of a trend toward cheaper tools for 3-D imaging, modeling, and COMPANY: printing in a variety of applications. The product from 3D Systems which the Touch was derived, called Phantom, was origi- PRICE: nally invented by an MIT startup called Sensable, whose $649 technology 3D Systems acquired. “There has always

AVAILABILITY: been a high cost barrier to doing this,” says Ping Fu, chief July entrepreneur officer at 3D Systems. “This brings that kind of ability right down into the consumer space, so anybody can pick up the haptic device and start sculpting.” COURTESY OF LIDA KATSIMPARDI (BLOOD); DAVID TALBOT/MIT TECHNOLOGY REVIEW (STYLUS) REVIEW TECHNOLOGY TALBOT/MIT DAVID (BLOOD); KATSIMPARDI LIDA OF COURTESY

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Upfront QUOTED

“Having information one minute earlier can actually be quite life-saving.”

—Steve Horng, an emergency physician at Beth Israel Deaconess Medical Center in Boston, who uses Google Glass to view patient records.

Sprague says that getting access to data from a car’s engine and safety systems could unlock new approaches to ad targeting. “It could be you just had a little fender bender, and you need something to lift you up,” he says. He also says that connected home gadgets, such as thermostats or home automation systems, could allow for creative new ads. Kiip currently sells ads to brands including General Mills and American Apparel. These ads target coupons on the basis of actions taken in a mobile Startups Experiment with Ads app, such as completing a game. Jeremy Lockhorn, vice president for emerging That Know How You Drive media at the ad agency Razorfish, says that kind of promotion could work on the road, A mobile ad company plans to offer deals based on data collected too. “There’s potential there for sure,” he from in-car apps. says of Kiip’s experiments in the car. Kiip is far from the only ad company By Tom Simonite looking for ways to use online-style ad tactics in the real world. Razorfish and some s businesses race to connect our Internet-connected home automation competitors are testing devices that can homes and cars to the Internet, equipment, and cars with integrated detect and interact with nearby smart- Aone mobile ad company scents a data connections head to market. Those phones, allowing ads to be targeted in new opportunity. San Francisco–based new data streams could form the basis for retail stores, for example. “That kind of Kiip plans to sell a new kind of ad targeted many new services and products, but they microtargeting becomes the real-world according to people’s actions at home or also bring new privacy concerns. version of the targeting we can do online,” on the road, offering rewards or deals in Ads tailored to driving behavior will be Lockhorn says. exchange for certain behavior. “You get possible thanks to a partnership between However, Kiip and other companies to your meeting early and you should get Kiip and fellow startup Mojio. It expects moving in that direction must find a way a free coffee from the place around the to launch a $149 device this summer that to reach people without leaving those block,” Michael Sprague, head of partner- plugs into a car’s diagnostic port and people feeling that they no longer control ships for Kiip, said at the Ad:tech confer- streams vehicle data to a smartphone app their data. “The user that’s going to inter- ence in San Francisco in March. to help users track their driving, their fuel act with your brand really needs to know Kiip’s move comes at a time when economy, and their vehicle’s maintenance what they are giving up,” says Jay Giraud, more and more data on people’s actions status. Kiip will use data from that device CEO and cofounder of Mojio. “The way is becoming available as wearable devices, to target promotions inside the Mojio app. I drive my car is personal information.” NEIL WEBB; COURTESY OF BETH ISRAEL DEACONESS MEDICAL CENTER (HORNG); CENTER MEDICAL DEACONESS ISRAEL BETH OF COURTESY WEBB; NEIL (PIRJANIAN) IROBOT OF COURTESY TESLA; OF COURTESY

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The number of electric cars that Elon Musk says Tesla’s “gigafactory” will be able to produce each year. This year 500,00 his company sold 35,000 cars in total.

Selling Teslas in China Won’t 3 QUESTIONS Paolo Pirjanian Do Much for the Environment The CTO of iRobot dis- cusses the company’s Because China relies so As in the U.S., electricity production efforts to build smarter heavily on coal for power, in China is cleaner in some places than household robots. electric vehicles aren’t in others. Whereas northern China relies almost completely on coal plants, a quar- You say you want robots to take on necessarily an improvement. ter to a third of the power delivered to more tasks around the home. What technologies must you develop? By Mike Orcutt central and southern regions comes from hydroelectric dams. The missing link in robotics is low-cost ales of electric vehicles in China, This means that increased sales of manipulation. We’re working on mak- the world’s largest auto market, EVs are likely to have a mixed environ- ing manipulation much cheaper—for Shave been minuscule despite gov- mental impact. Electric vehicles could example, using plastic parts, not steel, ernment incentives meant to put five mil- help clear the air in Chinese cities, many that can tolerate less precision. Naviga- lion of the cars on the nation’s roads by of which have dangerous levels of pollution is also a key area, because it allows 2020. Tesla Motors hopes to change that. tion. Much of that is caused by fine par- robots to move around freely and intel- It has ambitions to break into the Chi- ticulate matter emitted from the tailpipes ligently. We’re being helped by the avail- nese market, and it made its first deliv- of gas-powered cars. EVs don’t have tail- ability of low-cost 3-D sensors. If you eries of Model S sedans to customers in pipes, of course. combine photos with a 3-D map of a China in April. But this progress could come at a room, you get something like a CAD But while having more EVs significant environmental cost: higher model. I can say “Mop the kitchen on might help China reach its emissions of particulate matter Tuesdays,” or even “Find this book.” transportation goals, it in rural areas, where most probably won’t help power plants are Can you really make robots smart the environment, located. Because enough to do that? given the country’s burning coal pro- A robot can use the cloud to start reliance on coal for duces far more learning things about its environment. more than 70 per- particulates than For example, this object is a cup, and cent of its electric- burning gasoline, so I have to grab it like this; it looks ity. Making matters Cherry and his col- like it’s glass, so I need to grip it tight worse, coal in China is often Tesla Model S leagues have found enough so it doesn’t slip but not too dirtier than it is elsewhere, and that on average, an EV in hard so it breaks. many power plants don’t employ modern China is associated with about 19 times emission-control technologies. as much fine particulate matter as a com- What might robots built with this tech- Recent research led by Christopher parable gasoline car. nology do in our homes? Cherry, a professor of engineering at the China’s government is aiming to Consumer research tells us that laun- University of Tennessee, has shown that in clean up its electric grid by increasing its dry is the number one household task much of China, an electric vehicle the size nuclear capacity in the coming years and that people spend their time on, so a of a Nissan Leaf accounts for roughly the aggressively deploying renewables. But laundry robot would be on top of the same amount of carbon dioxide per mile recent projections suggest that by 2020, list. But that is a ways off. Through our driven as a comparable gasoline-powered coal’s share will still be at least as high government and defense business, we car. On top of that, he found that EVs in as 60 percent. The bottom line is that have a lot of experience with things China account for a larger amount of China’s grid, and the increasing number that work in rugged outdoor environ- dangerous particulate emissions than of EVs that run off it, will be fairly dirty ments, so you can imagine us going conventional cars. for a long time. into the backyard. —Tom Simonite COURTESY OF TESLA; COURTESY OF IROBOT (PIRJANIAN) IROBOT OF COURTESY TESLA; OF COURTESY

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Neuroscience’s New Toolbox

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With the invention investigate the source BY of optogenetics and of emotions, memory, Stephen S. Hall other key technologies, and consciousness for SCULPTURE Neuroscience’s New Toolbox researchers can the fi rst time. Joshua Harker

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at particular locations in the brain of a What might be called the “make love, not war” branch of behav- living, breathing, feisty, and occasionally ioral neuroscience began to take shape in (where else?) Califor- canoodling male mouse. Using a hair-thin nia several years ago, when researchers in David J. Anderson’s fiber-optic thread inserted into that living laboratory at Caltech decided to tackle the biology of aggres- brain, they could then turn the neurons in the hypothalamus on and off with a sion. They initiated the line of research by orchestrating the burst of light. murine version of Fight Night: they goaded male mice into Anderson and his colleagues used tangling with rival males and then, with painstaking molecular optogenetics to produce a video dra- matizing the love-hate tensions deep detective work, zeroed in on a smattering of cells in the hypo- within rodents. It shows a male mouse thalamus that became active when the mice started to fight. doing what comes naturally, mating with a female, until the Caltech researchers The hypothalamus is a small structure out to be an assembly of roughly 5,000 switch on the light, at which instant the deep in the brain that, among other func- neurons, all marbled together, some of murine lothario flies into a rage. When the tions, coördinates sensory inputs—the them seemingly connected to copulating light is on, even a mild-mannered male appearance of a rival, for example—with and others to fighting. mouse can be induced to attack whatever instinctual behavioral responses. Back “There’s no such thing as a generic target happens to be nearby—his repro- in the 1920s, Walter Hess of the Univer- neuron,” says Anderson, who estimates ductive partner, another male mouse, a sity of Zurich (who would win a Nobel that there may be up to 10,000 distinct castrated male (normally not perceived in 1949) had shown that if you stuck an classes of neurons in the brain. Even tiny as a threat), or, most improbably, a rubber electrode into the brain of a cat and elec- regions of the brain contain a mixture, glove dropped into the cage. trically stimulated certain regions of the he says, and these neurons “often influ- “Activating these neurons with opto- hypothalamus, you could turn a purr- ence behavior in different, opposing direc- genetic techniques is sufficient to acti- ing feline into a furry blur of aggression. tions.” In the case of the hypothalamus, vate aggressive behavior not only toward Several interesting hypotheses tried to some of the neurons seemed to become appropriate targets like another male explain how and why that happened, but active during aggressive behavior, some mouse but also toward inappropriate there was no way to test them. Like a lot of them during mating behavior, and a targets, like females and even inanimate of fundamental questions in brain sci- small subset—about 20 percent—during objects,” Anderson says. Conversely, ence, the mystery of aggression didn’t go both fighting and mating. researchers can inhibit these neurons in away over the past century—it just hit the That was a provocative discovery, but the middle of a fight by turning the light usual empirical roadblocks. We had good it was also a relic of old-style neurosci- off, he says: “You can stop the fight dead questions but no technology to get at the ence. Being active was not the same as in its tracks.” answers. causing the behavior; it was just a cor- Moreover, the research suggests that By 2010, Anderson’s Caltech lab had relation. How did the scientists know for lovemaking overrides war-making in the begun to tease apart the underlying mech- sure what was triggering the behavior? calculus of behavior: the closer a mouse anisms and neural circuitry of aggression Could they provoke a mouse to pick a fight was to consummation of the reproduc- in their pugnacious mice. Armed with a simply by tickling a few cells in the hypo- tive act, the more resistant (or oblivious) series of new technologies that allowed thalamus? he became to the light pulses that nor- them to focus on individual clumps of A decade ago, that would have been mally triggered aggression. In a paper cells within brain regions, they stumbled technologically impossible. But in the last published in Biological Psychiatry, onto a surprising anatomical discovery: 10 years, neuroscience has been trans- titled “Optogenetics, Sex, and Violence the tiny part of the hypothalamus that formed by a remarkable new technology in the Brain: Implications for Psychiatry,” seemed correlated with aggressive behav- called optogenetics, invented by scien- Anderson noted, “Perhaps the imperative ior was intertwined with the part associ- tists at Stanford University and first to ‘make love, not war’ is hard-wired into ated with the impulse to mate. That small described in 2005. The Caltech research- our nervous system, to a greater extent duchy of cells—the technical name is the ers were able to insert a genetically modi- than we have realized.” We may be both

ventromedial hypothalamus—turned fied light-sensitive gene into specific cells lovers and fighters, with the slimmest of PETERSON BRUCE BY PHOTOGRAPH SPREAD: PREVIOUS

JA14_toolbox.indd 22 6/4/14 4:29 PM MIT TECHNOLOGY REVIEW TECHNOLOGYREVIEW.COM VOL. | NO. KEY PLAYERS Optogenetics: Gero Miesenböck Edward Boyden Light Switches for Neurons University of Oxford MIT Karl Deisseroth Feng Zhang Stanford University Broad Institute of MIT and Harvard

Flip on Flip o Blue light can activate Red light can silence neurons genetically other neurons modiﬁ ed modiﬁ ed to make a with a di erent protein. specialized protein.

Thought control Thin cables guide light into a mouse’s brain.

Circuit relay A neuron activated by light can then send a signal to adjoining neurons.

mong the billions of neurons in a a behavior or disorder. With opto- proteins were most e cient at acti- human brain, what role do spe- genetics, researchers can manipu- vating neurons; silencing occurred A cifi c neurons play in controlling late neurons in worms, fl ies, mice, only slowly and weakly. But movement or cognition, or caus- and even monkeys. The technology recently, researchers engineered ing disorders like depression and has been used to study neural pro- proteins that can also e ciently autism? Figuring out the functions cesses underlying epilepsy, addic- silence neurons, expanding the of various neurons and circuits in tion, depression, and more. toolkit for studying the roles that mice or other lab animals can o er Optogenetics requires genetic di erent neurons play in the brain’s answers. modifi cations to neurons so that many circuits. A technique called optogenet- they produce light-reactive pro- While it’s unlikely to be used in ics gives scientists the power to teins, as well as a source of wave- human brains anytime soon, opto- turn neurons on or o . Scientists length-tuned light that is often genetics can in the short term point can then explore whether a particu- delivered through a hole in the skull. the way to new treatment strate-

GRAPHIC BY JOHN MACNEILL JOHN BY GRAPHIC lar set of neurons is responsible for For some time, the light-sensitive gies for devastating brain disorders.

JA14_graphic.opto.indd 23 6/4/14 10:17 AM MIT TECHNOLOGY REVIEW VOL. 117 | NO. 1 TECHNOLOGYREVIEW.COM Growing Neurons: 1 in 4 5 400 Proportion of Number of major Number of genes Studying What Goes Wrong people worldwide brain disorders, or chromosomal who will have a including schizo- regions that may mental disorder phrenia, that share be involved in in their lifetime. genetic variations. autism risk.

Patients Researchers start the experiment by he cellular and genetic changes gathering cells from that drive most brain disor- people with and with- ders aren’t well known. But out a brain disorder. T new technologies are making it possible to understand these changes, which could help scientists identify new drugs or other treatments. 2 For example, scientists can grow a patient’s neurons Reprogramming in a petri dish. All the scientists Chemical or genetic factors need to begin are skin cells or cause the mature cells to another easily accessed type regress into what are known as induced pluripotent stem of cell; these cells are trans- cells, or IPS cells. formed first into stem cells and then into neurons. The neurons in the dish can be examined for changes in appearance and function. Scientists can also test drugs on these neurons to see whether any compounds ameliorate the defects. 3 Scientists can also use genome editing to introduce Specialization into stem cells the precise With further treatments, changes that are believed to be the IPS cells will develop involved in a disorder. They can into neurons. then check whether the resulting neurons are abnormal.

Inspection 4 Scientists look for differences between neurons in the two populations, such as whether those derived from the person with the disorder are smaller or form fewer connections. GRAPHIC BY JOHN MACNEILL JOHN BY GRAPHIC

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neurological distances separating the two Connections scientists can begin to pinpoint the func- impulses. More than 2,000 years ago, Hippocrates tion of the thousands of different types of No one is suggesting that we’re on the noted that if you want to understand the nerve cells among the roughly 86 billion verge of deploying neural circuit break- mind, you must begin by studying the in the human brain. ers to curb aggressive behavior. But, as brain. Nothing has happened in the last Nothing testifies to the value of a new Anderson points out, the research high- two millennia to change that impera- technology more than the number of sci- lights a larger point about how a new tive—except the tools that neuroscience entists who rapidly adopt it and use it to technology can reinvent the way brain is bringing to the task. claim new scientific territories. As Edward science is done. “The ability of optogenet- The history of neuroscience, like the Boyden, a scientist at MIT who helped ics to turn a largely correlational field of history of science itself, is often a story of develop optogenetics, puts it, “Often when science into one that tests causation has new devices and new technologies. Luigi a new technology comes out, there’s a bit been transformative,” he says. Galvani’s first accidental electrode, which of a land grab.” What’s radical provoked the twitch And even as researchers grab those about the technique of a frog’s muscle, has opportunities in genomics and optoge- is that it allows sci- inspired every subse- netics, still other advances are coming entists to perturb quent electrical probe, on the scene. A new chemical treatment a cell or a network from Walter Hess’s cat is making it possible to directly see nerve Optogenetics and other of cells with exqui- prod to the current fibers in mammalian brains; robotic new techniques mean site precision, the therapeutic use of microelectrodes can eavesdrop on (and key to sketching out scientists can begin to deep brain stimulation perturb) single cells in living animals; the circuitry that pinpoint the function of to treat Parkinson’s and more sophisticated imaging tech- affects various types the thousands of different disease (approxi- niques let researchers match up nerve of behavior. Whereas types of neurons among mately 30,000 people cells and fibers in brain slices to create older technologies the roughly 86 billion in worldwide now have a three-dimensional map of the connec- like imaging allowed the human brain. electrodes implanted tions. Using these tools together to build researchers to watch in their brains to treat up an understanding of the brain’s activ- the brain in action, this condition). The ity, scientists hope to capture the biggest optogenetics enables them to influence patch clamp allowed neuroanatomists to of cognitive game: memory, decision- that action, tinkering with specific parts see the ebb and flow of ions in a neuron as making, consciousness, psychiatric ill- of the brain at specific times to see what it prepares to fire. And little did Paul Laut- nesses like anxiety and depression, and, happens. erbur realize, when he focused a strong yes, sex and violence. And optogenetics is just one of a suite magnetic field on a single hapless clam In January 2013, the European Com- of revolutionary new tools that are likely in his lab at the State University of New mission invested a billion euros in the to play leading roles in what looks like York at Stony Brook in the early 1970s, launch of its Human Brain Project, a a heyday for neuroscience. Major initia- that he and his colleagues were laying the 10-year initiative to map out all the con- tives in both the United States and Europe groundwork for the magnetic resonance nections in the brain. Several months aspire to understand how the human imaging (MRI) machines that have helped later, in April 2013, the Obama admin- brain—that tangled three-pound curd of reveal the internal landscape and activity istration announced an initiative called neurons, connective tissue, and circuits— of a living brain. Brain Research through Advanced Inno- gives rise to everything from abstract But it is the advances in genetics and vative Neurotechnologies (BRAIN), thought to basic sensory processing to genomic tools during the last few years which is expected to pour as much as $1 emotions like aggression. Consciousness, that have truly revolutionized neurosci- billion into the field, with much of the free will, memory, learning—they are ence. Those advances made the genetic early funding earmarked for technology all on the table now, as researchers use manipulations at the heart of optogenet- development. Then there is the Human these tools to investigate how the brain ics possible. Even more recent genome- Connectome Project, which aims to use achieves its seemingly mysterious effects editing methods can be used to precisely electron microscope images of sequential (see “Searching for the “Free Will” Neu- alter the genetics of living cells in the lab. slices of brain tissue to map nerve cells ron,” page 64). Along with optogenetics, these tools mean and their connections in three dimen-

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sions. Complementary connectome and “Shining Light on Madness,” page 34). acquired a precocious expertise in the mapping initiatives are getting under way Boyden, who was pursuing graduate work techniques of both molecular biology at the Howard Hughes Medical Institute in brain function, had an omnivorous and gene therapy as a high school stu- in Virginia and the Allen Institute for curiosity about neurotechnology. At first dent in Des Moines, Iowa, showed that Brain Science in Seattle. They are all part they dreamed about deploying tiny mag- the gene for the desired protein could of a large global effort, both publicly and netic beads as a way to manipulate brain be introduced into neurons by means privately funded, to build a comprehen- function in intact, living animals. But at of genetically engineered viruses. Again sive picture of the human brain, from the some point during the next five years, a using pulses of blue light, the Stanford level of genes and cells to that of connec- different kind of light bulb went off. team then demonstrated that it could turn tions and circuits. Since the 1970s, microbiologists had electrical pulses on and off in the virus- Last December, as an initial step in the been studying a class of light-sensitive modified mammalian nerve cells. In a BRAIN Initiative, the National Institutes molecules known as rhodopsins, which landmark paper that appeared in Nature of Health solicited proposals for $40 mil- had been identified in simple organisms Neuroscience in 2005 (after, Boyden says, lion worth of projects like bacteria, fungi, it was rejected by Science), Deisseroth, on technology devel- and algae. These pro- Zhang, and Boyden described the tech- opment in the neu- teins act like gate- nique. (No one would call it “optogenetics” rosciences. “Why is Scientists speculated that keepers along the for another year.) the BRAIN Initiative cell wall; when they Neuroscientists immediately seized on if you could smuggle the putting such a heavy detect a particular the power of the technique by inserting gene for a light-sensitive emphasis on tech- wavelength of light, light-sensitive genes into living animals. nology?” says Cor- protein into a neuron they either let ions Researchers in Deisseroth’s own lab used nelia Bargmann, the and then pulse the cell into a cell or, con- it to identify new pathways that control Rockefeller Univer- with light, you might versely, let ions out anxiety in mice, and both Deisseroth’ s sity neuroscientist trigger it to fire. You could of it. This ebb and team and his collaborators at Mount who co-directs the turn specific neurons on flow of ions mir- Sinai Hospital in New York used it to planning process for and off. rors the process by turn depression on and off in rats and the project. “The real which a neuron fires: mice. And Susumu Tonegawa’s lab at MIT goal is to understand the electrical charge recently used optogenetics to create false how the brain works, at many levels, in within the nerve cell builds up until the memories in laboratory animals. space and time, in many different neu- cell unleashes a spike of electrical activ- When I visited Boyden’s office at MIT’s rons, all at once. And what’s prevented ity flowing along the length of its fiber (or Media Lab last December, the scientist us from understanding that is limitations axon) to the synapses, where the message called up his favorite recent papers involv- in technology.” is passed on to the next cell in the path- ing optogenetics. In a rush of words as way. Scientists speculated that if you could rapid as his keystrokes, Boyden described Eavesdropping smuggle the gene for one of these light- second-generation technologies already Optogenetics had its origins in 2000, sensitive proteins into a neuron and then being developed. One involves eavesdrop- in late-night chitchat at Stanford Uni- pulse the cell with light, you might trigger ping on single nerve cells in anesthetized versity. There, neuroscientists Karl it to fire. Simply put, you could turn spe- and conscious animals in order to see Deisseroth and Edward Boyden began cific neurons in a conscious animal on—or “the things roiling underneath the sea of to bounce ideas back and forth about off—with a burst of light. activity” within a neuron when the ani- ways to identify, and ultimately manip- In 2004, Deisseroth successfully mal is unconscious. Boyden said, “It liter- ulate, the activity of specific brain cir- inserted the gene for a light-sensitive mol- ally sheds light on what it means to have cuits. Deisseroth, who had a PhD in ecule from algae into mammalian neurons thoughts and awareness and feelings.” neuroscience from Stanford, longed to in a dish. Deisseroth and Boyden went on Boyden’s group had also just sent off understand (and someday treat) the men- to show that blue light could induce the a paper reporting a new twist on opto- tal afflictions that have vexed human- neurons to fire. At about the same time, genetics: separate, independent neural kind since the era of Hippocrates, a graduate student named Feng Zhang pathways can be perturbed simultane- notably anxiety and depression (see joined Deisseroth’s lab. Zhang, who had ously with red and blue wavelengths of

JA14_toolbox.indd 26 6/5/14 9:55 AM Brain Mapping: 86 10,000 1,000 Charting the Information BILLION Upper range of the TRILLION Number of neurons number of synapses, An estimate of in the adult brain. or connections, one the number of Superhighways neuron can form. synapses in the human brain.

any of the brain’s functions result from processes in which bun- M dles of neurons work together to transmit signals between different regions. Mapping these pathways will help scientists understand how the brain works. The task is immense, but many teams are contributing to the effort, looking at different aspects of the brain’s anatomy.

1 2 3

Brain prep Slice and scan Stack and map At the Jülich Research Centre in The brain is sliced into The individual images of slivers are Germany, a human brain is removed ultrathin slivers that can be computationally processed into a during autopsy, chemically preserved, stained and scanned. three-dimensional model. and then scanned in an MRI machine to help guide virtual reconstruction.

Other Mapping Technologies

Clarity BrainSpan Atlas The NIH Human Connectome Project By removing the fats from mammalian brains, The Allen Institute for Brain Science has An advanced form of MRI enables scientists scientists can stain and image fine details of created three-dimensional maps of struc- to visualize microscopic cell structures and

GRAPHIC BY JOHN MACNEILL; COURTESY OF THE DEISSEROTH LAB (CLARITY); COURTESY OF ALLEN ALLEN OF COURTESY (CLARITY); LAB DEISSEROTH THE OF COURTESY MACNEILL; JOHN BY GRAPHIC PROJECT CONNECTOME HUMAN OF COURTESY (BRAINSPAN); SCIENCE BRAIN FOR INSTITUTE neurons, as seen in this mouse brain. tures and gene activity in prenatal brains. large brain structures simultaneously.

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light. The technique has the potential to Transparency ment in symptoms of Parkinson’s disease. show how different circuits interact with Back at Stanford, when he’s not seeing In other words, it wasn’t the neighbor- and influence each other. His group is patients with autism spectrum disorders hood of the brain that mattered so much also working on “insanely dense” record- or depression in the clinic, Deisseroth as which neural highways happened to ing probes and microscopes that aspire to continues to invent tools that he and oth- pass nearby. Scientists often employ words capture whole-brain activity. The ambi- ers can use to study these conditions. Last like “surprising” and “unexpected” to char- tions are not modest. “Can you record all summer, his lab reported a new way for acterize such recent results, reflecting the the cells in the brain,” he says, “so that you scientists to visualize the cables of nerve impact that optogenetics has had on the can watch thoughts or decisions or other fibers, known as “white matter,” that con- understanding of psychiatric illness. complex phenomena emerge as you go nect distant precincts of the brain. The In the same vein, Caltech’s Anderson from sensation to emotion to decision to technique, called Clarity, first immobilizes points out that the public and scientific action site?” biomolecules such as protein and DNA in infatuation with functional MRI stud- A few blocks away, Feng Zhang, who is a plastic-like mesh that retains the physi- ies over the last two decades has created now an assistant pro- cal integrity of a post- the impression that certain regions of the fessor at MIT and a mortem brain. Then brain act as “centers” of neural activity— faculty member at the researchers flush a that the amygdala is the “center” of fear, Broad Institute, listed kind of detergent for example, or the hypothalamus is the age-old neuroscience through the mesh to “center” of aggression. But he likens fMRI Scientists often employ questions that might dissolve all the fats to looking down on a nighttime landscape words like “surprising” now be attacked with in brain tissue that from an airplane at 30,000 feet and “try- the new technolo- and “unexpected” to normally block light. ing to figure out what is going on in a sin- gies. “Can you do a characterize recent The brain is rendered gle town.” Optogenetics, by contrast, has memory upgrade and results, reflecting the transparent, suddenly provided a much more detailed view of increase the capac- impact optogenetics has exposing the entire that tiny subdivision of cells in the hypo- ity?” he asked. “How had on the understanding three-dimensional thalamus, and thus a much more com- are neural circuits of psychiatric illnesses. wiring pattern to view. plex and nuanced picture of aggression. genetically encoded? Together, the new Activating specific neurons in that little How can you repro- tools are transform- town can tip an organism to make war, gram the genetic instructions? How do ing many conventional views in neurosci- but activating the neurons next door can you fix the genetic mutations that cause ence. For example, as Deisseroth noted in nudge it to make love. miswiring or other malfunctions of the a review article published earlier this year The new techniques will give scien- neural system? How do you make the old in Nature, optogenetics has challenged tists the first glimpses of human cogni- brain younger?” some of the ideas underlying deep brain tion in action—a look at how thoughts, In addition to helping to invent opto- stimulation, which has been widely used feelings, forebodings, and dysfunctional genetics, Zhang played a central role to treat everything from tremors and epi- mental activity arise from the neural cir- in developing a gene-editing technique lepsy to anxiety and obsessive-compulsive cuitry and from the activity of particular called CRISPR (see “10 Breakthrough disorder. No one knows just why it works, types of cells. Researchers are just begin- Technologies: Genome Editing,” May/ but the operating assumption has been ning to gain these insights, but given the June). The technology allows scientists that its therapeutic effects derive from recent pace of technology development, to target a gene—in neurons, for exam- electrical stimulation of very specific brain the picture might emerge sooner than ple—and either delete or modify it. If it’s regions; neurosurgeons exert extraordi- anyone dreamed possible when the light modified to include a mutation known or nary effort to place electrodes with the of optogenetics first flickered on a few suspected to cause brain disorders, sci- utmost precision. years ago. entists can study the progression of those In 2009, however, Deisseroth and col- disorders in lab animals. Alternatively, leagues showed that specifically stimulat- Stephen S. Hall is a science writer and researchers can use CRISPR in the lab ing the white matter, the neural cables author in New York City. His last feature to alter stem cells that can then be grown that happen to lie near the electrodes, pro- for MIT Technology Review was “Repair- into neurons to see the effects. duced the most robust clinical improve- ing Bad Memories” in July/August 2013.

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When it comes to the study of memory, we might be living in something of a golden age. Researchers are exploring provocative questions about what memory fundamen- tally is—and how it might be manipulated. Some scientists are tweaking the brains of lab rats in order to implant false memories or remove specific memories. Others are looking into how memory might be enhanced. Such research often sounds creepy, but it could lead to ways of staving BB: Giving people a pill as they reconsoli- off dementia, neutralizing post-traumatic stress disorder, date a troubling memory sounds like an elegant treatment for PTSD and other reducing anxiety, treating depression, or curbing addiction. disorders. How well has the research Much of this work is possible because neuroscientists progressed? have realized that memory is more plastic than previously JL: The idea is still viable. The drug that’s thought. Think of something that you did long ago—on a going to do the trick in humans—we sunny afternoon when you were a child, let’s say. Does your don’t yet know what it is. brain rummage around for that memory, show it to you,

BB: Why not the antianxiety drug proprano- and put it back intact, as you might do with a photograph lol, which has been used in several in a trunk in the attic? For decades, the prevailing answer experiments? was essentially yes—that strong memories were “consoli- JL: We know this thing works very well in dated” in the brain and remained static. But it now appears rats. [In humans] there’s been some the opposite is true: every time you remember something, success, but it doesn’t seem that’s actu- your brain rewrites or “reconsolidates” the memory. Your ally going to be a very robust solution. memory of any sunny day in your childhood is merely a

BB: What are the prospects for improving version of the last time you thought about it. the memory of people with dementia— Among the stunning implications is that intervening or any of us, for that matter? in the reconsolidation process can alter a memory and JL: The issue you get at whenever you’re change how it feels. Some of the most intriguing research dealing with a memory failure of any on this idea has been led by Joseph LeDoux, a neuroscien- kind is: is the problem an inability to retrieve a memory that’s there, or is tist who has been working since the 1970s to investigate it that the memory is no longer there how processes in the brain generate emotions. In recent and by no means could you retrieve years, he and colleagues have investigated whether giving it? And it’s definitely the case that we people an antianxiety drug as they recall a traumatic experience can reduce the dread they feel upon further recol- lections. If it works, it could be one of many opportunities for reshaping memory, as LeDoux told MIT Technology Review’s deputy editor, Brian Bergstein, in his NYU office.

Q+A Joseph LeDoux 30

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LeDoux researches how mechanisms in the brain work to make us who we are.

Adam Lerner31

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“You can’t remember have retrieval problems, right? You BB: We don’t know the route to something, you kind of can’t remember something, you kind get there? know it’s there, and then of know it’s there, and then a couple of JL: I don’t know the route. a couple of hours later hours later it pops up. There is stuff in Memory is, first of our brain that we can’t easily retrieve. all, not in one spot—it’s it pops up. There is stuff I think that’s where there’s hope. You distributed across prob- in our brain that we can’t can do things that would facilitate the ably multiple brain areas, easily retrieve. I think retrieval process. many millions of synapses that’s where there’s in those brain areas. So I hope. You can do things BB: What might that be? don’t know how you recon- that would facilitate the JL: The simplest idea would be that it’s a figure it, fix it. I don’t know problem of low arousal in the brain. how you regenerate the retrieval process.” We know that emotionally arousing right patterns of connectiv- situations are more likely to be remem- ity. I don’t think you could bered than mundane ones. A big part restore lost memories. But what you ory. But if you give them isoproterenol of the reason for this is that in signifi- might conceivably do is restore some [which has the opposite effect on the cant situations chemicals called neu- ability to store new memories. brain’s neurostimulators], the memory romodulators are released, and they is now stronger. If you have some way enhance the memory storage process. BB: Messing with memory is a huge deal. It to strengthen memory after retrieval, The brain is more alert and attentive. goes to the core of who we are. Treat- it could be stronger and better. All the spokes are working and all the ing PTSD would be wonderful, but isn’t gears are oiled. it also possible to make people artificial BB: What’s a situation in which people Pollyannas? would want to do that? BB: So could we develop memory vitamins JL: Or fearless monsters. There’s always JL: In general, people who have sluggish that offer that same boost? going to be ethical implications. But memories, they’re not forming memo- JL: [The effects of the neuromodulators] we’ll just have to sort that out. ries very well. Were they to be on a low can be mimicked with drugs that do the When we first published this work dose of isoproterenol, they might get a same thing. Or if you want to remem- [on reconsolidation], someone wrote little extra boost. ber something, put the information in a commentary in the New York Times The other idea is that we might be a significant context. In other words, saying, “Let’s say you were a Holocaust able to give people positive experiences make it meaningful by thinking of it in survivor. You lived 50 years with these and a shot of isoproterenol, and store a way that adds some positive or nega- awful memories, and all of a sudden those instead of negative experiences. tive charge, or by doing something that you’re erasing memories of the Holo- increases your level of arousal—exer- caust. What would that do to your per- BB: You could build up more positive memo- cise, for example. sonality? It’s who you are now.” [After ries in them? further research], the conclusion that JL: Right, right. BB: Would a memory prosthetic be pos- we came up with is that a patient and sible—something put into the brain to therapist would have to slowly chip BB: I imagine that could be useful in helping restore lost memories in someone with away at a memory to a level they were people struggling with depression. dementia or a brain injury? comfortable with. [And] the research JL: And as far as I know it’s never been JL: DARPA [the U.S. military’s R&D so far suggests it reduces the zing, done. It’s doable. agency] seems to be going full steam takes the emotional valence out of ahead on these kinds of technologies. the situation, rather than erases the BB: So why hasn’t it been done? What they plan to do is put chips in memory itself. JL: Well, you know, I had the idea a while [the brain]. It would be like a pros- The other side of that is you can ago, and then I kind of forgot about thesis—instead of moving your arm, also intensify memories. So we did it. And now the memory of it—maybe you’re fixing memory. I have no idea studies in rats where we give them pro- I’ll think about doing something. [He how they would achieve that. pranolol, and that weakens the mem- laughs.]

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at novartis’s research lab in cambridge, Massachusetts, a large incubator- like piece of equipment is helping give birth to a new era of psychiatric drug Shining discovery. Inside it, bathed in soft light, lab plates hold living human stem cells; robotic arms systematically squirt nurtur- It’s been decades since there ing compounds into the plates. Thanks to was a true breakthrough in drugs a series of techniques perfected over the for psychiatric illness. last few years in labs around the world, such stem cells—capable of developing into specialized cell types—can now be created from skin cells. When stem cells derived from people with, say, autism or schizophrenia are grown inside the incubator, Novartis researchers can nudge them to develop into functioning brain Light cells by precisely varying the chemicals in the cell cultures. But better research tools and new They’re not exactly creating schizo- phrenic or autistic neurons, because the insights into the genetics of brain cells aren’t working within the circuitry disorders could revive the moribund of the brain, but for drug-discovery pur- effort to improve treatment. poses it’s the next best thing. For the first time, researchers have a way to directly examine in molecular detail what’s going wrong in the brain cells of patients with these illnesses. And, critically for the pharmaceutical company, there is now on a reliable method of screening for drugs that might help. Do the neurons look different from normal ones? Is there a flaw in the way they form connections? Could drugs possibly correct the abnormalities? By David Rotman The answer to each of these questions is a very preliminary yes. The technique is so promising that Novartis has resumed trying to discover new psychiatric drugs after essentially abandoning the quest. What’s more, it’s been introduced at a time when knowl- Madness

An incubator at Novartis’s labs is used to grow stem cells. Scientists can derive such cells from patients and, under the right conditions, prompt them to develop into neurons for research and drug screening.

Photographs by Adam DeTour 35

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The Worldwide Cost Disability-adjusted life years (DALY) is a commonly used public-health metric meant to express the number of years lost as a result of bad health, disability, or premature death. edge about the genetics behind brain dis- living. Existing drugs also have orders is expanding rapidly and other no effect on the way schizophre- Disorder DALYs new tools, including optogenetics and nia can impair concentration, more precise genome editing (see “Neu- decision-making, and working Unipolar depressive disorders 65,000,000 roscience’s New Toolbox,” page 20), are memory (critical in such tasks as Bipolar affective disorder 14,000,000 enabling neuroscientists to probe the language comprehension). These

brain directly. All these developments debilitating cognitive problems Schizophrenia 17,000,000 offer renewed hope that science could make it impossible for people to finally deliver more effective treatments work and difficult for them even Epilepsy 8,000,000 for the millions of people beset by devas- to make the seemingly simple tating brain disorders. logical choices involved in every- Alcohol use disorders 24,000,000 A revival in psychiatric drug devel- day life. Insidiously, such symp- opment is badly needed: there hasn’t toms can strike high-performing Alzheimer’s and other dementias 11,000,000 been a breakthrough medicine for any of individuals, often in their late Drug use disorders 8,000,000 the common mental illnesses, including teens. “People don’t understand,” schizophrenia, bipolar disorder, or severe says Guoping Feng, a professor of Post-traumatic stress disorder 3,000,000 depression, in roughly 50 years. From the neuroscience at MIT who stud- late 1940s through the 1960s, a series of ies the neural basis of psychiat- Obsessive-compulsive disorder 5,000,000 serendipitous discoveries, beginning with ric disorders. “They ask, once a the finding that lithium could help bipo- patient is given antipsychotic Sources: Harvard School of Public Health and the World Economic Forum (2011) lar patients, transformed the treatment of the mentally ill. It became possible to quiet the hallucinations and delusions “We were led down a path that said depression is about of schizophrenia and offer a drug to the severely depressed. The sudden availabil- being a quart low in serotonin, and schizophrenia means ity of pharmacological relief transformed you have a bit too much dopamine on board. But that just psychiatry and played a role in closing isn’t how the brain works. The brain isn’t a bowl of soup.” down many of the mammoth mental hospitals of the era. But then, almost as medicine, ‘Why can’t you go to work?’ But the National Institute of Mental Health suddenly as it had started, the revolution [those with schizophrenia] can’t work (NIMH) in Rockville, Maryland, 26 stalled. because they don’t have cognitive func- percent of American adults suffer from Many of the drugs discovered in the tions, they don’t have normal executive a “diagnosable mental disorder” in any 1950s and 1960s are still the most effec- functions. And there are no drugs for this.” given year. Severe depression, the most tive treatments available for schizophre- On top of that are the side effects of anti- common of these disorders, is the leading nia, anxiety disorders, and depression. But psychotic medicines, which can include cause of disability in the U.S. for individu- while these medications have improved Parkinson’s-like movement disorders, dra- als between 15 and 44. Around 1 percent the lives of some patients, they are inef- matic weight gain, or a potentially deadly of the American population suffers from fective for others, and they are woefully loss of white blood cells. In short, the ill- schizophrenia; one in 68 American chil- inadequate in treating many of the worst ness destroys many patients’ lives. dren is diagnosed with an autism spec- symptoms. What’s more, the drugs can Finally, many people with brain disor- trum disorder. have severe side effects. ders are simply not helped at all by avail- Though the need for better treat- Take schizophrenia, for example. Exist- able drugs. Antidepressants work well ments is unquestionable, drug companies ing antipsychotic drugs can make the hal- for some people but do nothing for many had until very recently simply run out of lucinations and delusions disappear, but others, and there are no effective drug good ideas. The drugs developed in the they don’t improve the so-called negative treatments for the social disabilities or 1950s and 1960s were discovered by acci- symptoms—the disruption of emotions repetitive behaviors caused by autism. dent, and no one knew how or why they such as pleasure, which can leave people Overall, neuropsychiatric illness is a worked. In the subsequent decades, drug uninterested in communicating or even in leading cause of disability. According to researchers reverse-engineered the medi-

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cations to identify the brain molecules cuits involved in brain disorders. Still, he Cornell Medical College in New York, they that the drugs acted on, such as dopamine says, the search for treatments is slowed are simply molecular knockoffs of older and serotonin. In retrospect, however, by “our profound ignorance of the brain.” ones. Some of the newer medications are scientists now realize that while tweaking Another obvious impediment to find- somewhat safer, he says, but essentially, the levels of these chemicals addressed ing better drugs is that there haven’t been drug companies are just “tweaking the some symptoms of psychiatric disorders, reliable ways to screen them. Because same molecules.” Given the lack of ideas it was a crude strategy that ignored the researchers have had limited ability to for effective new compounds and the high biological mechanisms underlying the measure how potential psychiatric drugs rate of failure for psychiatric drugs in illnesses. affect the biology of lab animals, they’ve expensive clinical trials—only about 8 per- “By studying the drugs, we were led “concocted” tests based on the way exist- cent succeed, compared with 15 percent down a path that said depression is about ing drugs affect animal behavior, says for drugs overall—it’s no wonder that, in being a quart low in serotonin, and schizo- Steven Hyman, director of the Stanley Friedman’s words, pharmaceutical com- phrenia means you have a bit too much Center for Psychiatric Research at the panies have “gotten cold feet.” Broad Institute of Harvard and Indeed, in 2011 Novartis announced Sales of Psychiatric Drugs MIT. One conventional assay for it was shutting down its center for basic antidepressants, for example, is neuroscience research in Basel, Switzer- Despite a dearth of effective medicines for many brain called the “forced swim test.” land. The company wasn’t alone in step- disorders, demand is very strong. When rats given the commonly ping away from the search for psychiatric used drug imipramine, which drugs. Over the last five years, other drug Drug class or indication Global sales was invented in the 1950s and is makers, including GlaxoSmithKline and

Antipsychotics $22 billion still considered one of the most AstraZeneca, have all scaled back efforts effective medicines for depres- and decreased investments in neuro- Antidepressants $20 billion sion, are dropped in a bucket science and related drug discovery. But of cold water, they swim longer Novartis’s move was particularly notewor- Antianxiety $11 billion before giving up. The animals’ thy because the discovery of psychiatric propensity to stop struggling has drugs plays such a big part in its history. Stimulants $5.5 billion been rationalized as a measure In the 1960s, Basel-based Sandoz, which of “behavioral despair,” Hyman merged with Ciba-Geigy in 1996 to form Dementia $5.5 billion says, but there’s actually no Novartis, was instrumental in developing proof that the behavior in the clozapine, still one of the most effective Sleep disorders $4.5 billion test reflects human depression. treatments for severe schizophrenia. And Substance use and addictive disorders $3 billion Though the swim test has been Ciba, another Swiss parent of Novartis, used for 50 years to test antide- had introduced imipramine in the late Source: Science Translational Medicine (2012), citing 2010 sales pressants and is still widely used, 1950s. all it probably does is select for Now, in Cambridge, Novartis is back dopamine on board,” says Thomas Insel, drugs that mimic the effects of imipra- on the search. Ricardo Dolmetsch, the the director of NIMH. “But that just isn’t mine in allowing a rodent to swim longer, company’s global head of neuroscience, how the brain works. The brain isn’t a he says. That has led to a series of “me- is the one tasked with translating what bowl of soup; it’s really a complex net- too drugs.” he calls the recent revolutions in genetics work of networks.” Psychiatric illnesses The discovery of new psychiatric drugs and genomic tools into safe and effective such as schizophrenia, severe depression, is “dangerously stalled,” Hyman says: in medicines. A former professor of neuro- and bipolar disorder, Insel says, “are fun- terms of efficacy, antidepressants “maxed science at Stanford, Dolmetsch joined the damentally disorders of the brain circuits.” out” in the 1950s and antipsychotics in the company last August and immediately It is only in the last few years, he adds, 1960s. Though a number of new psychi- began hiring. Less than a year later, his that technologies such as optogenetics atric drugs have been marketed in recent colleagues are conducting experiments have allowed neuroscientists to shift their decades, says Richard A. Friedman, a pro- among stacks of plastic moving crates, thinking from “soups to sparks”—electri- fessor of clinical psychiatry and director even as they continue to set up the lab. cal impulses—and begin exploring the cir- of the psychopharmacology clinic at Weill Though there is a sense of excitement on

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his team, Dolmetsch’s words are mea- York. The conventional approach to dis- details of the genetics, but at least you can sured: “We now have the tools to give it covering drugs for diseases with a strong see the results. What’s more, new genome- another shot.” genetic component is to identify the gene editing methods make it possible to pre- causing or playing a prominent role in the cisely alter the genes of the stem cells Jigsaw Puzzle illness, and then test compounds against from which the neurons develop, adding Faulty genes have a significant role in the protein it codes for. That approach is a mutation associated with the illness to causing brain disorders. If you have an not likely to work for most psychiatric ill- see how it affects the resulting neurons. identical twin with schizophrenia, the nesses, given that they are caused by com- likelihood that you will also have the dis- binations of so many genetic variants. But order is between 40 and 65 percent; if a Sklar obviously leans toward optimism. Researchers such as Stanford’s Amit Etkin (below) and MIT’s Kay Tye (right) believe sibling has the illness, you have about a She suggests that the numerous variants improved understanding of neurocircuits 10 percent chance. Statistics are similar provide more chances to home in on key and connections is critical to finding better for autism and bipolar disorder. While pathways involved in the disorders, and treatments for psychiatric disorders. genes are somewhat less of a factor in more opportunities to come up depression than in the other disorders, with clever ways to fix them. they play a critical role there too. But, says The hope is that all those Broad’s Hyman, it’s only in recent years genetic variants will tend to that researchers have realized how com- affect common sets of molecu- plex the genetics are. When he was the lar pathways, types of cells, or director of NIMH in the 1990s, Hyman specific neurocircuits. That could says, it was already clear to him and oth- help scientists pinpoint what’s ers that there was no single schizophrenia going wrong, and it could also or autism gene. “But I thought that there give them new targets for poten- were at most 20 or, at the extreme, 100 tial treatments. Yet Sklar, who genes,” he adds. “We were way off.” specializes in searching for the So far, researchers have identified genetic causes of schizophrenia hundreds of genetic variants associated and bipolar disorder, acknowl- with increased risk for schizophrenia, and edges that despite the rapid Hyman guesses the number could go as advances in genetics over the last high as a thousand. Some of the mutations few years, large gaps in under- appear to be common, while some rare standing remain. “We don’t know variants seem to cause the same symp- all the risk factors,” she says, “and toms as those experienced by individu- with so few pieces of the puzzle, als with a completely different set of rare it’s still hard to know how it all mutations. Moreover, different variants hangs together.” seem to confer different degrees of risk, Add to this genetic mystery the fact But how do these neurons function and recent studies have shown that mul- that the brain has roughly 86 billion neu- in an actual brain, with its immense net- tiple disorders, including schizophrenia rons and around a quadrillion synapses works of circuits and connections? How and autism, share a number of culpable (the connecting points between neurons), are the genetic mutations implicated in genes. Hyman calls it an immensely com- and it becomes obvious how overwhelm- autism and schizophrenia actually affect- plicated jigsaw puzzle. ing it will be to understand the causes ing those circuits to alter behavior? New Whether you think the extreme of brain disorders. It’s why the ability to research is starting to investigate those genetic complexity of brain disorders por- take cells from a patient and turn them questions. tends well for drug discovery depends on into neurons in a dish has researchers so Later this summer, a colony of mar- whether you’re a pessimist or an optimist, excited. Now they have a way to directly moset monkeys, primates native to says Pamela Sklar, who directs the depart- examine how genetic variants have South America, will begin living at MIT’s ment of psychiatric genomics at the Icahn affected the neurons of a patient with an McGovern Institute for Brain Research.

School of Medicine at Mount Sinai in New illness. You still might not know all the Monkeys and people share a highly devel- FASTEN LEAH

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The monkeys could provide a is well known to be involved in fear and more reliable way to test psychi- anxiety, she was “surprised by just how atric drugs than rodents, whose sudden and robust the change was,” she brain circuitry is much less simi- says: “It was almost instantaneous. I was lar to ours. The idea is not to cre- blown away. It has changed how I think ate animals with schizophrenia or about the brain.” autism—the complex mixture of How can this increasing knowledge of aberrant human behaviors can’t brain circuits and connections—and their be truly replicated even in other role in such feelings as anxiety—be trans- primates—but rather to see how lated into actual therapies? Can research- the genetic mutations change ers find effective, safe ways to intervene the circuitry at a molecular level in these circuits and connections in and how the animals’ behavior is patients’ brains—ways to fix what has altered as a result. “The behavior gone wrong? may not be identical to that in Optogenetics, at least in its existing humans,” says Feng, “but at least version, doesn’t look like the way to do it’s a readout. It becomes a con- that. It requires genetic modification of firmation that we can correct the the cells that researchers want to acti- circuits and that the changes lead vate and the intrusive use of a fiber-optic to improvements in behavior.” thread in the brain. That’s why it’s largely limited to rodents, though a few monkey experiments have been done. Using the How can this increasing knowledge of brain circuits and technology to directly fix malfunctioning brain circuits in humans is not now practi- connections—and their role in such feelings as anxiety— cal, and it may never be. But as a research be translated into actual therapies? Can researchers find technique, it could give drug research- effective and safe ways to intervene? ers what they so desperately need: new molecular targets. Researchers like Tye oped prefrontal cortex, the region near the Don’t Worry and Feng believe that their optogenetic front of the skull. And, says MIT’s Feng, The mouse cowers in one corner of the experiments can help identify specific there’s increasing evidence that many of maze. Even in the video of the experiment, types of cells in the circuits underlying the intractable defects of schizophrenia its anxiety seems palpable as it presses certain psychiatric symptoms. Then they and the deficiencies of social communica- against a wall. A thin fiber-optic thread is will have to spot distinguishing markers tion and behavior found in autism can be connected to the animal’s skull. Suddenly, on those cells that allow the drug to rec- traced to this area of the brain. after a burst of blue light through the fiber, ognize them. It’s an extremely promising To begin to unravel what’s going the mouse begins scurrying about, explor- approach; recent results do in fact suggest wrong, Feng and his colleagues plan to use ing the four branches of the maze with that there are ways to single out critical genome editing to breed monkeys with new energy and courage. cells as targets for drug compounds. But precise mutations associated with psy- The invention of optogenetics has rev- the research is still in its very early days. chiatric disorders. Initially, the scientists olutionized the study of neurocircuitry. One alternative is to try to intervene will focus on a rare mutation in a gene But even among all the impressive studies directly in the circuits, skipping the use of called SHANK3. Because it is an unusual using the technology, this mouse experi- drugs. A standard treatment for Parkin- example of a single gene that causes clear, ment, which Kay Tye conducted in 2011 as son’s is to implant an electrode array in a autism-like changes in behavior, it’s a a postdoc at Stanford, stands out. Tye, now patient’s brain to calm tremors. It’s called simple place to start. Later generations an assistant professor at MIT, showed she deep brain stimulation, and researchers of monkeys could have the multiple muta- could turn anxiety on and off with a flip of at Emory University are attempting to tions found in most forms of autism and a switch. Though she was targeting a part adapt the technology to treat depression, schizophrenia. of the brain called the amygdala, which inserting an electrode into a region of the

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brain called Area 25. Others are using but there is a gap with what is doable in abnormalities can be studied. It’s that deep brain stimulation to treat obsessive- the real world. And sometimes the gap is technology, along with the revolution in compulsive disorder with promising significant.” genetics created in part by fast, cheap results. DNA sequencing, that he believes will be There might also be ways to directly Chasing Drugs the linchpin of Novartis’s revived effort to affect faulty circuits without resorting to At Novartis, Ricardo Dolmetsch is respon- identify new psychiatric drugs. surgery. Amit Etkin, an assistant professor sible for trying to close that gap between “It allows you to start with the patient,” of psychiatry at Stanford, is using a com- the exploding scientific understanding says Dolmetsch. While oncologists have bination of functional magnetic resonance of brain disorders and the availability of long had the ability to biopsy tumors, “you imaging (fMRI) and noninvasive mag- more effective drugs. And he’s realistic can’t just drill holes in people’s brains and netic stimulation to map the circuitry that about the prognosis: “I hope it will be a take little bits out,” he notes. “But now we goes wrong in patients. His goal is to tailor story of excitement. But we don’t know have the capacity to make biopsies out of magnetic stimulation, which is already yet. It takes a long time.” stem cells.” Pushing the technology even widely used to treat intractable cases of Dolmetsch is not your typical drug- further, the Novartis researchers are gear- depression, to the specific problems in a industry manager. Less than a year ago, ing up to make organoids, small chunks patient’s neurocircuitry. he was still running a lab at Stanford and of brain that form in a petri dish as the The therapy, which is administered helping to create a library of neurons neurons mature and lump together into using an electromagnetic coil placed from autism patients, to be hosted at the three-dimensional structures. Not only against the scalp, uses magnetic pulses to Allen Brain Institute in Seattle. And his can the researchers look for abnormali- create an electric current that can increase Stanford website—he’s officially taking a ties, they can screen compounds in Novar- or decrease brain activity. The commercial version of the technique is designed to target the same small part of the prefrontal It’s far from clear how or even whether the growing cortex in all patients, but by combining it with imaging technology, Etkin hopes knowledge of what goes wrong in the brains of those with to aim the stimulation more precisely to psychiatric disorders can lead to medicines. But at least where a patient needs it. It won’t be a mir- now, researchers have the tools they need. acle cure. The method seems to help only some people. But driving his work, says leave of absence from the university—still tis’s vast library of potential drugs to see Etkin, is his frustration at not being able reflects his quirky persona. It has links to how the chemicals affect the neurons. to offer patients more successful options. stories that describe his “impish humor” Designing drugs to precisely target Etkin, who also works at a clinic at the and his attempts to commute on a pogo circuits in the brain remains a more dis- Palo Alto VA Hospital for veterans suffer- stick during his early days at the university. tant opportunity. “We now have some ing from severe anxiety and depression, About a decade ago, his research took idea of the kinds of cells and regions of uses a variety of tools to help patients, a dramatic turn. He had started out at the brain that we need to inhibit or acti- including drugs and psychotherapy as Stanford looking into basic questions vate to make someone happier or less well as magnetic stimulation. The key to about the biochemistry in brain cells, anxious. We no longer need to treat the making all the approaches more effec- work that was impressive enough to gain brain as one mush of signaling molecules,” tive, he says, is to learn more about how him an appointment as an assistant pro- Dolmetsch acknowledges. But that still faulty neural circuits and connections fessor. But then, in 2005, his son received leaves the daunting challenge of devel- lead to aberrant behavior. In trying to fix a diagnosis of autism. Frustrated by the oping a drug that selectively activates or those problems, he says, “I try not to be lack of treatment options, Dolmetsch inactivates certain types of cells in certain chauvinistic about the [treatment] tech- rebuilt his lab around researching the dis- circuits. “How do you do that?” he asks. nology.” Working with patients not only order. Since then, he has helped pioneer “It’s not been done before.” He adds: “It’s motivated his research on potentially bet- methods that take skin cells from indi- not where drug discovery is now, though ter treatments, he adds, but also teaches viduals with autism, reprogram those cells it’s where it is going.” him about its practical limitations: “Lots to become stem cells, and then induce Dolmetsch joined the pharmaceuti- of scientific studies might make sense, them to develop into neurons in which cal industry because he realized that the

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science and technology had advanced far enough to create opportunities for developing new psychiatric drugs. He also realized after years of academic research that commercializing a new drug requires the resources, money, and patient populations available to a company like Novar- tis. It was, he says, “time to walk the walk” after years of talking about potential treatments for autism and schizophrenia. Still, the failure to find effective new drugs for brain disorders—and the stigma that has grown around the high cost of those failures—is clearly never far from the minds of those in the industry. Com- panies “have developed some fantastic drugs over the last 10 years or so that were safe and engaged the target,” says Dolmetsch, before delivering the punch line: the drugs were as ineffective as water. While he’s convinced that he and his team have “a better way to discover new drugs,” he also acknowledges that it will be five to eight years before they know whether their strategy based on the new genetic and stem-cell tools is working. For those trying to discover new medicines, it’s all about finding novel molecular targets that a chemical compound can safely affect in a way that will address the symptoms of a disease. That’s a daunting challenge. And it’s still far from clear how or even whether the growing knowledge of what goes wrong in the brains of those with psychiatric disorders can lead directly to such medicines. But at least now, after decades of dead ends, drug researchers finally have some of the tools they need to begin methodically testing strategies for finding and acting on those targets. When at last we have a better way to chase drugs for such disorders as autism and schizophrenia, says Dolmetsch, “it would be a bit of a crime Ricardo Dolmetsch hopes not to take advantage of it.” to resurrect psychiatric drug discovery at Novartis, using advances in genetics and stem- David Rotman is the editor of MIT Tech- cell technologies. nology Review.

JA14_madness.indd 41 6/4/14 5:45 PM Matt Dorfman

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Cracking In What Is Life? (1944), one of the fun- their thoughts (see “The Thought Experi- the damental questions the physicist Erwin ment,” page 52). Future biofeedback sys- Schrödinger posed was whether there tems may even be able to anticipate signs Brain’s was some sort of “hereditary code- of mental disorder and head them off. Codes script” embedded in chromosomes. A Where people in the present use key- decade later, Crick and Watson answered boards and touch screens, our descen- Schrödinger’s question in the affirmative. dants a hundred years hence may use The brain Decoding Genetic information was stored in the direct brain-machine interfaces. relays how those simple arrangement of nucleotides along But to do that—to build software information systems long strings of DNA. that can communicate directly with the The question was what all those strings brain—we need to crack its codes. We in complex work could of DNA meant. As most schoolchildren must learn how to look at sets of neurons, ways based deepen now know, there was a code contained measure how they are firing, and reverse- on the firing our grasp within: adjacent trios of nucleotides, so- engineer their message. of neurons. of mental called codons, are transcribed from DNA illness, lead into transient sequences of RNA mole- A Chaos of Codes to brain cules, which are translated into the long Already we’re beginning to discover clues chains of amino acids that we know as about how the brain’s coding works. Per- chips that proteins. Cracking that code turned out haps the most fundamental: except in enhance our to be a linchpin of virtually everything some of the tiniest creatures, such as the memories, that followed in molecular biology. As it roundworm C. elegans, the basic unit of and enable happens, the code for translating trios of neuronal communication and coding is computers nucleotides into amino acids (for example, the spike (or action potential), an elec- to literally the nucleotides AAG code for the amino trical impulse of about a tenth of a volt acid lysine) turned out to be universal; that lasts for a bit less than a millisecond. anticipate cells in all organisms, large or small—bac- In the visual system, for example, rays our needs. teria, giant sequoias, dogs, and people— of light entering the retina are promptly use the same code with minor variations. translated into spikes sent out on the optic By Will neuroscience ever discover some- nerve, the bundle of about one million Christof Koch thing of similar beauty and power, a mas- output wires, called axons, that run from and ter code that allows us to interpret any the eye to the rest of the brain. Literally pattern of neural activity at will? everything that you see is based on these Gary Marcus At stake is virtually every radical spikes, each retinal neuron firing at a dif- advance in neuroscience that we might ferent rate, depending on the nature of be able to imagine—brain implants that the stimulus, to yield several megabytes of enhance our memories or treat mental visual information per second. The brain disorders like schizophrenia and depres- as a whole, throughout our waking lives, sion, for example, and neuroprosthet- is a veritable symphony of neural spikes— ics that allow paralyzed patients to move perhaps one trillion per second. To a large their limbs. Because everything that you degree, to decipher the brain is to infer the think, remember, and feel is encoded in meaning of its spikes. your brain in some way, deciphering the But the challenge is that spikes mean activity of the brain will be a giant step different things in different contexts. It toward the future of neuroengineering. is already clear that neuroscientists are Someday, electronics implanted unlikely to be as lucky as molecular biolo- directly into the brain will enable patients gists. Whereas the code converting nucle- with spinal-cord injury to bypass the otides to amino acids is nearly universal, affected nerves and control robots with used in essentially the same way through-

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Some of the most important out the body and throughout the natural Consider, for example, neurons in codes in any cells signal motion in sev- world, the spike-to-information code is the visual cortex, the area that receives animal’s eral cardinal directions; likely to be a hodgepodge: not just one impulses from the optic nerve via a relay others specialize in sig- code but many, differing not only to some in the thalamus. These neurons rep- brain are the naling overall image degree between different species but even resent the world in terms of the basic ones it uses brightness or local con- between different parts of the brain. The elements making up any visual scene— to pinpoint its trast; still others carry brain has many functions, from control- lines, points, edges, and so on. A given location in information pertaining ling our muscles and voice to interpret- neuron in the visual cortex might be space. How to color. Each of these ing the sights, sounds, and smells that stimulated most vigorously by verti- does our own populations streams its surround us, and each kind of problem cal lines. As the line is rotated, the rate own data, in parallel, to necessitates its own kinds of codes. at which that neuron fires varies: four internal GPS different processing cen- A comparison with computer codes spikes in a tenth of a second if the line work? How ters upstream from the makes clear why this is to be expected. is vertical, but perhaps just once in the do patterns eye. To reconstruct the Consider the near-ubiquitous ASCII code same interval if it is rotated 45° counter- of neural nature of the information representing the 128 characters, includ- clockwise. Though the neuron responds activity that the retina encodes, ing numbers and alphanumeric text, used most to vertical lines, it is never mute. encode scientists must track not in communications such as plain-text No single spike signals whether it is only the rate of every e-mail. Almost every modern computer responding to a vertical line or some- where we are neuron’s spiking but also uses ASCII, which encodes the capital thing else. Only in the aggregate—in the as we move the identity of each cell letter A as “100 0001,” B as “100 0010,” neuron’s rate of firing over time—can about? type. Four spikes com- C as “100 0011,” and so forth. When it the meaning of its activity be discerned. ing from one type of cell comes to images, however, that code is This strategy, known as rate coding, is may encode a small colored blob, whereas useless, and different techniques must be used in different ways in different brain four spikes from a different cell type may used. Uncompressed bitmapped images, systems, but it is common throughout encode a moving gray pattern. The num- for example, assign strings of bytes to rep- the brain. Different subpopulations of ber of spikes is meaningless unless we resent the intensities of the colors red, neurons encode particular aspects of the know what particular kind of cell they are green, and blue for each pixel in the array world in a similar fashion—using firing coming from. making up an image. Different codes rep- rates to represent variations in bright- And what is true of the retina seems resent vector graphics, movies, or sound ness, speed, distance, orientation, color, to hold throughout the brain. All in all, files. pitch, and even haptic information like there may be up to a thousand neuronal Evidence points in the same direc- the position of a pinprick on the palm of cell types in the human brain, each pre- tion for the brain. Rather than a single your hand. Individual neurons fire most sumably with its own unique role. universal code spelling out what pat- rapidly when they detect some preferred terns of spikes mean, there appear to be stimulus, less rapidly when they don’t. Wisdom of Crowds many, depending on what kind of infor- To make things more complicated, Typically, important codes in the brain mation is to be encoded. Sounds, for spikes emanating from different kinds involve the action of many neurons, not example, are inherently one-dimensional of cells encode different kinds of infor- just one. The sight of a face, for instance, and vary rapidly across time, while the mation. The retina is an intricately lay- triggers activity in thousands of neurons images that stream from the retina are ered piece of nervous-system tissue that in higher-order sectors of the visual cor- two-dimensional and tend to change at lines the back of each eye. Its job is to tex. Every cell responds somewhat differ- a more deliberate pace. Olfaction, which transduce the shower of incoming pho- ently, reacting to a different detail—the depends on concentrations of hundreds of tons into outgoing bursts of electrical exact shape of the face, the hue of its airborne odorants, relies on another sys- spikes. Neuroanatomists have identi- skin, the direction in which the eyes are tem altogether. That said, there are some fied at least 60 different types of retinal focused, and so on. The larger meaning general principles. What matters most is neurons, each with its own specialized inheres in the cells’ collective response. not precisely when a particular neuron shape and function. The axons of 20 dif- A major breakthrough in understand- spikes but how often it does; the rate of ferent retinal cell types make up the optic ing this phenomenon, known as popula- firing is the main currency. nerve, the eye’s sole output. Some of these tion coding, came in 1986, when Apostolos

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Georgopoulos, Andrew Schwartz, and often when the animal is near a maze’s “big,” “brown and black,” and so on, while Ronald Kettner at the Johns Hopkins branch point; another might respond many other neurons, such as those that University School of Medicine learned most actively when the animal is close to respond to vehicles or cats, fail to fire. Col- how a set of neurons in the motor cor- the entry point. The husband-and-wife lectively, this large population of neurons tex of monkeys encoded the direction in team of Edward and May-Britt Moser dis- might represent a concept. which a monkey moves a limb. No one covered a second type of spatial coding An alternative notion, called sparse neuron fully determined where the limb based on what are known as grid cells. coding, has received much less attention. would move, but information aggregated These neurons fire most actively when an Indeed, neuroscientists once scorned across a population of neurons did. By cal- animal is at the vertices of an imagined the idea as “grandmother-cell coding.” culating a kind of weighted average of all geometric grid representing its environ- The derisive term implied a hypotheti- the neurons that fired, Georgopoulos and ment. With sets of such cells, the animal cal neuron that would fire only when its his colleagues found, they could reliably is able to triangulate its position, even in bearer saw or thought of his or her grand- and precisely infer the intended motion the dark. (There appear to be at least four mother—surely, or so it seemed, a prepos- of the monkey’s arm. different sets of these grid cells at differ- terous concept. One of the first illustrations of what ent resolutions, allowing a fine degree of But recently, one of us (Koch) helped neurotechnology might someday achieve spatial representation.) discover evidence for a variation on this builds directly on this discovery. Brown Other codes allow animals to con- theme. While there is no reason to think University neuroscientist John Donoghue trol actions that take place over time. An that a single neuron in your brain repre- has leveraged the idea of population cod- example is the circuitry responsible for sents your grandmother, we now know ing to build neural “decoders”—incorpo- executing the motor sequences under- that individual neurons (or at least com- rating both software and electrodes—that lying singing in songbirds. Adult male paratively small groups of them) can interpret neural firing in real time. finches sing to their female partners, represent certain concepts with great Donoghue’s team implanted a brushlike each stereotyped song lasting but a few specificity. Recordings from microelec- array of microelectrodes directly into seconds. Neurons of one type within a trodes implanted deep inside the brains of the motor cortex of a paralyzed patient particular structure are completely quiet epileptic patients revealed single neurons to record neural activity as the patient until the bird begins to sing. Whenever that responded to extremely specific stim- imagined various types of motor activities. the bird reaches a particular point in its uli, such as celebrities or familiar faces. With the help of algorithms that inter- song, these neurons suddenly erupt in a One such cell, for instance, responded to preted these signals, the patient could use single burst of three to five tightly clus- different pictures of the actress Jennifer the results to control a robotic arm. The tered spikes, only to fall silent again. Dif- Aniston. Others responded to pictures “mind” control of the robot arm is still ferent neurons erupt at different times. It of Luke Skywalker of Star Wars fame, or slow and clumsy, akin to steering an out- appears that individual clusters of neu- to his name spelled out. A familiar name of-alignment moving van. But the work rons code for temporal order, each rep- may be represented by as few as a hun- is a powerful hint of what is to come as resenting a specific moment in the bird’s dred and as many as a million neurons in our capacity to decode the brain’s activ- song. the human hippocampus and neighbor- ity improves. ing regions. Among the most important codes in Grandma Coding Such findings suggest that the brain any animal’s brain are the ones it uses to Unlike a typewriter, in which a single key can indeed wire up small groups of pinpoint its location in space. How does uniquely specifies each letter, the ASCII neurons to encode important things it our own internal GPS work? How do pat- code uses multiple bits to determine a encounters over and over, a kind of neuro- terns of neural activity encode where we letter: it is an example of what computer nal shorthand that may be advantageous are? A first important hint came in the scientists call a distributed code. In a simi- for quickly associating and integrating early 1970s with the discovery of what lar way, theoreticians have often imagined new facts with preëxisting knowledge. became known as place cells in the hip- that complex concepts might be bundles pocampus of rats. Such cells fire every of individual “features”; the concept “Ber- Terra Incognita time the animal walks or runs through a nese mountain dog” might be represented If neuroscience has made real progress in particular part of a familiar environment. by neurons that fire in response to notions figuring out how a given organism encodes In the lab, one place cell might fire most such as “dog,” “snow-loving,” “friendly,” what it experiences in a given moment, it

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There is has further to go toward understanding complex, encompassing 86 billion neu- some cause ing spiking patterns with how organisms encode their long-term rons linked by something on the order for hope. a behavior, experimental- knowledge. We obviously wouldn’t survive of a quadrillion synaptic connections. ists will be able to write for long in this world if we couldn’t learn Another is that our observational tech- Optogenetics in patterns of informa- new skills, like the orchestrated sequence niques remain crude. The most popu- now allows tion and directly study of actions and decisions that go into driv- lar imaging tools for peering into the researchers the effects on the brain ing a car. Yet the precise method by which human brain do not have the spatial to switch circuitry and behavior of we do this remains mysterious. Spikes are resolution to catch individual neurons genetically live animals. necessary but not sufficient for translating in the act of firing. To study neural cod- identified Deciphering neu- intention into action. Long-term mem- ing systems that are unique to humans, ral codes is only part of ory—like the knowledge that we develop such as those used in language, we prob- classes of the battle. Cracking the as we acquire a skill—is encoded differ- ably need tools that have not yet been neurons on brain’s many codes won’t ently, not by volleys of constantly circulat- invented, or at least substantially bet- and off at will tell us everything we ing spikes but, rather, by literal rewiring ter ways of studying highly interspersed with colored want to know, any more of our neural networks. populations of individual neurons in the beams of than understanding That rewiring is accomplished at least living brain. light. It could ASCII codes can, by itself, in part by resculpting the synapses that It is also worth noting that what neu- tell us how a word proces- connect neurons. We know that many dif- roengineers try to do is a bit like eaves- greatly speed sor works. Still, it is a vital ferent molecular processes are involved, dropping—tapping into the brain’s own up the search prerequisite for building but we still know little about which syn- internal communications to try to fig- for codes. technologies that repair apses are modified and when, and almost ure out what they mean. Some of that and enhance the brain. nothing about how to work backward eavesdropping may mislead us. Every Take, for example, new efforts to use from a neural connectivity diagram to the neural code we can crack will tell us some- optogenetics to remedy a form of blind- particular memories encoded. thing about how the brain operates, but ness caused by degenerative disorders, Another mystery concerns how the not every code we crack is something the such as retinitis pigmentosa, that attack brain represents phrases and sentences. brain itself makes direct use of. Some of the light-sensing cells of the eye. One Even if there is a small set of neurons them may be “epiphenomena”—accidental promising strategy uses a virus injected defining a concept like your grandmother, tics that, even if they prove useful for engi- into the eyeballs to genetically modify it is unlikely that your brain has allo- neering and clinical applications, could retinal ganglion cells so that they become cated specific sets of neurons to complex be diversions on the road to a full under- responsive to light. A camera mounted on concepts that are less common but still standing of the brain. glasses would pulse beams of light into immediately comprehensible, like “Barack Nonetheless, there is reason to be the retina and trigger electrical activity Obama’s maternal grandmother.” It is optimistic that we are moving toward that in the genetically modified cells, which similarly unlikely that the brain dedicates understanding. Optogenetics now allows would directly stimulate the next set of particular neurons full time to represent- researchers to switch genetically identi- neurons in the signal path—restoring ing each new sentence we hear or pro- fied classes of neurons on and off at will sight. But in order to make this work, sci- duce. Instead, each time we interpret or with colored beams of light. Any popula- entists will have to learn the language of produce a novel sentence, the brain prob- tion of neurons that has a known, unique those neurons. As we learn to communi- ably integrates multiple neural popula- molecular zip code can be tagged with cate with the brain in its own language, tions, combining codes for basic elements a fluorescent marker and then be either whole new worlds of possibilities may (like individual words and concepts) into made to spike with millisecond precision soon emerge. a system for representing complex, com- or prevented from spiking. This allows binatorial wholes. As yet, we have no clue neuroscientists to move from observing Christof Koch is chief scientific officer of the how this is accomplished. neuronal activity to delicately, transiently, Allen Institute for Brain Science in Seattle. One reason such questions about the and reversibly interfering with it. Opto- Gary Marcus, a professor of psychology at brain’s schemes for encoding informa- genetics, now used primarily in flies and New York University and a frequent blog- tion have proved so difficult to crack is mice, will greatly speed up the search for ger for the New Yorker, is coeditor of the that the human brain is so immensely neural codes. Instead of merely correlat- forthcoming book The Future of the Brain.

JA14_braincodes.indd 46 6/4/14 8:29 AM THE SPARK OF INNOVATION

R&D FUNDING PROGRAM The National Reconnaissance Ofﬁ ce Director’s Innovation Initiative (DII) Program funds cutting-edge scientiﬁ c research in a high-risk, high-payoff environment to discover innovative concepts and creative ideas that transform overhead intelligence capabilities and systems for future national security intelligence needs. The program seeks out the brightest minds and breakthrough technologies from industry, academia, national laboratories, and U.S. government agencies.

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http://dii5.westfields.net

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Damasio has written highly acclaimed books that connect science to philosophy.

Brad48 Swonetz

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For decades, biologists spurned emotion and feeling as uninteresting. But Antonio Damasio demonstrated that they were central to the life-regulating processes of almost all living creatures. Damasio’s essential insight is that feelings are “mental experiences of body states,” which arise as the brain interprets emotions, themselves physical states arising from the body’s responses to external stimuli. (The order of such events is: I am threatened, experience fear, and feel horror.) He has suggested that consciousness, whether the primi- tive “core consciousness” of animals or the “extended” self-conception of humans, requiring autobiographical memory, emerges from emotions and feelings. His insight, dating back to the early 1990s, stemmed from the clinical study of brain lesions in patients unable to make good decisions because their emotions were impaired, but whose reason was otherwise unaffected— research made possible by the neuroanatomical studies of his wife and frequent coauthor, Hanna Damasio. Their work has always depended on advances in technology. More recently, tools such as functional neuroimaging, which measures the relationship between mental processes and activity in parts of the brain, have comple- Q+A mented the Damasios’ use of neuroanatomy. A professor of neuroscience at the University of South- Antonio Damasio ern California, Damasio has written four artful books that

explain his research to a broader audience and relate its JP: When you were a young scientist in the late discoveries to the abiding concerns of philosophy. He 1970s, emotion was not thought a proper field believes that neurobiological research has a distinctly of inquiry. philosophical purpose: “The scientist’s voice need not AD: We were told very often, “Well, you’re going to be the mere record of life as it is,” he wrote in a book on be lost, because there’s absolutely nothing there Descartes. “If only we want it, deeper knowledge of brain of consequence.” We were pitied for our poor choice. and mind will help achieve … happiness.”

Antonio Damasio talked with Jason Pontin, the editor JP: How so? in chief of MIT Technology Review. AD: William James had tackled emotion richly and intelligently. But his ideas [mainly that emotions are the brain’s mapping of body states, ideas that Damasio revived and experimen- tally verified] had led to huge controversies in the beginning of the 20th century that ended nowhere. Somehow researchers had the sense

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that emotion would not, in the end, be suf- a collection of things happen in my body that ficiently distinctive—because animals had change me and make me behave in a certain emotions, too. But what animals don’t have, way whether I want to or not. As that is hap- researchers told themselves, is language like pening to me, I have a mental representation we do, nor reason or creativity—so let’s study of that body state as much as I have a mental that, they thought. And in fact, it’s true that representation of what frightened me. most creatures on the face of the “Mind begins at the earth do have something that could JP: And out of that “mapping” of something hap- level of feeling. It’s be called emotion, and something pening within the body comes a feeling, which that could be called feeling. But that is different from an emotion? when you have a feeling doesn’t mean we humans don’t use AD: Exactly. For me, it’s very important to separate (even if you’re a very emotions and feelings in particular emotion from feeling. We must separate the little creature) that you ways. component that comes out of actions from the begin to have a mind component that comes out of our perspective and a self. I’m ready JP: Because we have a conscious sense on those actions, which is feeling. Curiously, it’s to give the very teeny of self? also where the self emerges, and consciousness AD: Yes. What’s distinctive about itself. Mind begins at the level of feeling. It’s brain of an insect ... the humans is that we make use of fun- when you have a feeling (even if you’re a very possibility of having damental processes of life regulation little creature) that you begin to have a mind feelings. In fact, I would that include things like emotion and and a self. be flabbergasted to feeling, but we connect them with discover that they don’t intellectual processes in such a way JP: But that would imply that only creatures with have feelings.” that we create a whole new world a fully formed sense of their minds could have around us. fully formed feelings— AD: No, no, no. I’m ready to give the very teeny JP: What made you so interested in emotions as an brain of an insect—provided it has the possi- area of study? bility of representing its body states—the pos- AD: There was something that appealed to me sibility of having feelings. In fact, I would be because of my interest in literature and music. flabbergasted to discover that they don’t have It was a way of combining what was impor- feelings. Of course, what flies don’t have is all tant to me with what I thought was going to be the intellect around those feelings that could important scientifically. make use of them: to found a religious order, or develop an art form, or write a poem. They JP: What have you learned? can’t do that; but we can. In us, having feelings AD: There are certain action programs that are somehow allows us also to have creations that obviously permanently installed in our organs are responses to those feelings. and in our brains so that we can survive, flour- ish, procreate, and, eventually, die. This is the JP: Do other animals have a kind of responsiveness world of life regulation—homeostasis—that I to their feelings? am so interested in, and it covers a wide range AD: I’m not sure that I even understand your ques- of body states. There is an action program of tion. thirst that leads you to seek water when you are dehydrated, but also an action program of JP: Are dogs aware that they feel? fear when you are threatened. Once the action AD: Of course. Of course dogs feel. program is deployed and the brain has the possibility of mapping what has happened in the JP: No, not “Do dogs feel?” I mean: is my dog body, then that leads to the emergence of the Ferdinando conscious of feeling? Does he have mental state. During the action program of fear, feelings about his feelings?

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AD: [Thinks.] I don’t know. I would have my function all the time: with diet, with alcohol, doubts. and with medications. So it’s not that surgical interventions will be any great novelty. What JP: But humans are certainly conscious of being will be novel is to make those interventions responsive. cleanly so that they are targeted. No, the more AD: Yes. We’re aware of our feelings and are con- serious issue is the moral situations that might scious of the pleasantness or unpleasantness arise. associated with them. Look, what are the really powerful feelings that you deal with every day? JP: Why? Desires, appetites, hunger, thirst, pain—those AD: Because it really depends on what the interven- are the basic things. tion is aimed at achieving. Suppose the intervention is aimed at resus- JP: How much of the structure of civilization is citating your lost ability to move a limb, or to devoted to controlling those basic things? see or hear. Do I have any moral problem? Of Spinoza says that politics seeks to regulate course not. But what if it interferes with states such instincts for the common good. of the brain that are influential in how you AD: We wouldn’t have music, art, religion, science, make your decisions? Then you are entering technology, economics, politics, justice, or a realm that should be reserved for the per- moral philosophy without the impelling force son alone. of feelings. JP: What has been the most useful technology JP: Do people emote in predictable ways regard- for understanding the biological basis of con- less of their culture? For instance, does every- sciousness? one hear the Western minor mode in music as AD: Imaging technologies have made a powerful sad? contribution. At the same time, I’m painfully AD: We now know enough to say yes to that ques- aware that they are limited in what they give tion. us. At the Brain and Creativity Institute [which Damasio directs], we have been doing cross- JP: If you could wish into existence a better tech- cultural studies of emotion. At first we thought nology for observing the brain, what would it we would find very different patterns, espe- be? cially with social emotions. In fact, we don’t. AD: I would not want to go to only one level, because Whether you are studying Chinese, Americans, I don’t think the really interesting things occur or Iranians, you get very similar responses. at just one level. What we need are new tech- There are lots of subtleties and lots of ways in niques to understand the interrelation of levels. which certain stimuli elicit different patterns There are people who have spent a good part of of emotional response with different intensi- their lives studying systems, which is the case ties, but the presence of sadness or joy is there with my wife and most of the people in our with a uniformity that is strongly and beauti- lab. We have done our work on neuroanatomy, fully human. and gone into cells only occasionally. But now we are actually studying the state of the func- JP: Could our emotions be augmented with tions of axons [nerve fibers in the brain], and implants or some other brain-interfacing tech- we desperately need ways in which we can scale nology? up from what we’ve found to higher and higher AD: Inasmuch as we can understand the neural pro- levels. cesses behind any of these complex functions, once we do, the possibility of intervening is JP: What would that technology look like? always there. Of course, we interface with brain AD: I don’t know. It needs to be invented.

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Neurophysiologist Andrew Schwartz at the laboratory where he connects brains to computers. TH——E—— ——THOUGHT

In a remarkable experiment, a paralyzed woman used her mind E —— X P —— to control a robotic arm.

If only there were a realistic way to get this technology out of the lab and into real life. By Antonio Regalado E —— R I —— M E —— N T

i was about 15 minutes late for my ried, with two kids,” she says. One night, where her family could take care of her first phone call with Jan Scheuermann. during a dinner she’d organized, it felt as children. Eventually she was diagnosed When I tried to apologize for keeping her if her legs were dragging behind her. “I with a rare disease called spinocerebel- waiting, she stopped me. “I wasn’t just sit- chalked it up to being a cold snowy night, lar degeneration. She can feel her body, ting around waiting for you, you know,” but there were a couple of steps in the but the nerves that carry signals out from she said, before catching herself. “Well, house and boy, I was really having trou- her brain no longer work. Her brain says actually I was sitting around.” ble,” she says. “Move,” but her limbs can’t hear. Scheuermann, who is 54, has been Anguished months of doctor’s visits Two and a half years ago, doctors paralyzed for 14 years. She had been liv- and misdiagnoses followed. A neurolo- screwed two ports into Scheuermann’s ing in California and running a part-time gist said she had multiple sclerosis. By skull (she calls them “Lewis and Clark”). business putting on mystery-theater din- then, she was using an electric wheelchair The ports allow researchers to insert ners, where guests acted out roles she and “fading rapidly.” She thought she was cables that connect with two thumbtack- made up for them. “Perfectly healthy, mar- dying, so she moved home to Pittsburgh, size implants in her brain’s motor cortex.

Photographs by Scott Goldsmith 53

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Two or three times a week, she joins a team of scientists at the University of Pittsburgh and is plugged into a robotic arm that she controls with her mind. She uses it to move blocks, stack cones, give high fives, and pose for silly pictures, doing things like pretending to knock out a researcher or two. She calls the arm Hector. Scheuermann, who says that in her dreams she is not disabled, underwent brain surgery in 2012 after seeing a video of another paralyzed patient controlling a robotic arm with his thoughts. She immediately applied to join the study. During the surgery, doctors used an air gun to fire the two tiny beds of silicon needles, called the Utah Electrode Array, into her motor cortex, the slim strip of brain that runs over the top of the head to the jaws and controls voluntary movement. She awoke from the surgery with a pounding headache and “the worst case of buyer’s Jan Scheuermann stacks remorse.” She couldn’t believe she’d had cones with a mind-controlled voluntary brain surgery. “I thought, Please, robot arm as research God, don’t let this be for nothing. My great- assistant Brian Wodlinger est fear was that it wouldn’t work,” she watches her work. says. But within days, she was controlling the robotic arm, and with unexpected suc- A third of these patients have under- cal activity of a few dozen cells in the brain cess: “I was moving something in my envi- gone surgery since 2011, when the U.S. can give a fairly accurate picture of where ronment for the first time in years. It was Food and Drug Administration said someone intends to move a limb. “We gasp-inducing and exciting. The research- it would loosen rules for testing “truly are technologically limited to sampling ers couldn’t wipe the smile off their faces pioneering technologies” such as brain- a couple of hundred neurons, from bil- for weeks either.” machine interfaces. More human experi- lions in your brain, so it’s actually amazing Scheuermann is one of about 15 to 20 ments are under way. One, at Caltech, they can get a signal out at all,” says Kip paralyzed patients who have joined long- wants to give a patient “autonomous Ludwig, director of the neural engineer- term studies of implants that can convey control over the Google Android tablet ing program at the National Institute of information from the brain to a computer. operating system.” A team at Ohio State Neurological Disorders and Stroke. She is the first subject at Pittsburgh. Nine University, in collaboration with the R&D The technology being used at Pitts- others, including people in the advanced organization Battelle, put an implant in burgh was developed in physiology labs stages of ALS, have undergone similar a patient in April with the intention of to study animals, and it is plainly still tests in a closely related study, called using the patient’s brain signals to control experimental. The bundled wires lead BrainGate. Another four “locked-in” stimulators attached to his arm. Battelle from Scheuermann’s cranium to a bulky patients, unable to move or speak, have describes the idea as “reanimating a para- rack of signal processors, amplifiers, and regained some ability to communicate lyzed limb under voluntary control by the computers. The nine-pound robotic arm, thanks to a different type of electrode participant’s thoughts.” paid for by the military, has a dexterous developed by a Georgia company called These nervy first-of-a-kind studies hand and fingers that can make lifelike

Neural Signals. rely on the fact that recording the electri- movements, but it is finicky, breaks fre- UPMC OF COURTESY

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quently, and is somewhat dangerous. like brushing teeth. During the study, Reanimation When things don’t work, graduate stu- Scheuermann’s abilities were examined The researcher who planned the Pitts- dents hunt among tangles of wires for using the Action Research Arm Test, the burgh experiment is Andrew Schwartz, a loose connections. same kit of wooden blocks, marbles, and lean Minnesotan whose laboratory occu- John Donoghue, the Brown Univer- cups that doctors use to evaluate hand pies a sunlit floor dominated by three gray sity neuroscientist who leads the longer- dexterity in people with recent injuries. metal towers of equipment that are used running BrainGate study, compares She scored 17 out of 57, or about as well to monitor monkeys in adjacent suites. today’s brain-machine interfaces to the as someone with a severe stroke. Without Seen on closed-circuit TVs, the scenes first pacemakers. Those early models also Hector, Scheuermann would have scored from inside the experimental rooms defy featured carts of electronics, with wires zero. The findings made 60 Minutes. belief. On one screen, a metal wheel punched through the skin into the heart. Since the TV cameras went away, repeatedly rotates, changing the position Some were hand-cranked. “When you however, some of the shortcomings of of a bright orange handle. After each rev- don’t know what is going on, you keep the technology have become apparent. olution, an outsize robotic hand reaches as much as possible on the outside and At first Scheuermann kept demonstrat- up from the edge of the screen to grab the as little as possible on the inside,” says ing new abilities. “It was success, success, handle. Amid the spinning machinery, it’s Donoghue. Today, though, pacemakers are success,” she says. But controlling Hector easy to miss the gray and pink face of the self-contained, powered by a long-lasting has become harder. The reason is that rhesus monkey that is controlling all this battery, and installed in a doctor’s office. the implants, over time, stop recording. from a cable in its head. Donoghue says brain-machine interfaces The brain is a hostile environment for The technology has its roots in the are at the start of a similar trajectory. electronics, and tiny movements of the 1920s, with the discovery that neurons convey information via electrical “spikes” that can be recorded with a thin metal At first it was “success, success, success,” but wire, or electrode. By 1969, a researcher named Eberhard Fetz had connected a Scheuermann says no one told her the implant might stop single neuron in a monkey’s brain to a dial working. Gradually, it is recording from fewer neurons. Her the animal could see. The monkey, he dis- control over the robot arm is weakening. covered, learned to make the neuron fire faster to move the dial and get a reward For brain-controlled computers to array may build up scar tissue as well. The of a banana-flavored pellet. Although Fetz become a medical product, there has to effect is well known to researchers and didn’t realize it at the time, he had created be an economic rationale, and the risks has been observed hundreds of times in the first brain-machine interface. must be offset by the reward. So far, animals. One by one, fewer neurons can Schwartz helped extend that discovery Scheuermann’s case has come closest to be detected. 30 years ago when physiologists began showing that these conditions can be met. Scheuermann says no one told her. recording from many neurons in living In 2013, the Pittsburgh team reported its “The team said that they were expecting animals. They found that although the work with Scheuermann in the medical loss of neuron signals at some point. I was entire motor cortex erupts in a blaze of journal the Lancet. After two weeks, they not, so I was surprised,” she says. She now electrical signals when an animal moves, reported, she could move the robot arm in routinely controls the robot in only three a single neuron will tend to fire fastest in three dimensions. Within a few months, to five dimensions, and she has gradually connection with certain movements—say, she could make seven movements, includ- lost the ability to open and close its thumb moving your arm left or up, or bending ing rotating Hector’s hand and moving the and fingers. Was this at all like her experi- the elbow—but less quickly otherwise. thumb. At one point, she was filmed feed- ence of becoming paralyzed? I asked her Record from enough neurons and you can ing herself a bite of a chocolate bar, a goal the question a few days later by e-mail. get a rough idea of what motion a person she had set for herself. She replied in a message typed by an aide is making, or merely intending. “It’s like The researchers tried to show that who stays with her most days: “I was dis- a political poll, and the more neurons you they were close to something practical— appointed that I would probably never poll, the better the result,” he says. helping with so-called “tasks of daily liv- do better than I had already done, but The 192 electrodes on Scheuermann’s ing” that most people take for granted, accepted it without anger or bitterness.” two implants have recorded more than

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The Utah Electrode Array, invented in the 1990s, has 96 silicon needles that record the electrical impulses of neurons inside the brain.

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270 neurons at a time, which is the most humorous way of acknowledging that ever simultaneously measured from a these experiments depend on human vol- human being’s brain. Schwartz says this unteers. “They are not nearly as hard to Five Milestones is why her control over the robot has been train as these guys,” Schwartz says, jerk- in Brain Control so good. ing a thumb to the row of monkey rooms. The neuronal signals are interpreted These volunteers are trapped; some of Scientists discover the by software called a decoder. Over the them desperately hope science can provide 1870 motor cortex. They years, scientists built better and better an escape. Realistically, that is unlikely in apply electricity to the decoders, and they tried more ambitious their lifetimes. The first BrainGate volun- brains of dogs, causing control schemes. In 1999, the Duke Uni- teer was a 25-year-old named Matt Nagle, their limbs to move. versity neuroscientist Miguel Nicolelis who had breathed through a ventilator At the University of trained a rat to swing a cantilever with since his spinal cord was severed during 1969 Washington, monkeys its mind to obtain a reward. Three years a knife fight. He was able to move a cur- are taught to move later, Donoghue had a monkey moving a sor on a screen in 2004. But Nagle also a dial using nerve cursor in two dimensions across a com- wanted to commit suicide and tried to get impulses recorded puter screen, and by 2004 his BrainGate others to help him do it, according to The from their brains. It is team had carried out the first long-term Man with the Bionic Brain, a book written the first brain-machine human test of the Utah array, showing by his doctor. He died of an infection in interface. that even someone whose limbs had been 2007. On online chat boards where para- Electrical firing of neu- paralyzed for years could control a cursor lyzed people trade hopeful news about 1982 rons in the motor cortex is shown to predict which way a monkey’s Some paralyzed people are starting to look at electronics limb is moving. The discovery forms the basis as their best chance for recovery. “I’ll take it! Cut off my for thought-controlled dead arm and give me a robotic one that I can FEEL with robots. please!” wrote one.

Doctors implant a sin- 1998 gle electrode into the mentally. By 2008, Schwartz had a mon- possible cures, like stem cells, some dis- brain of a paralyzed key grabbing and feeding itself a marsh- miss brain-machine interfaces as wacky. man who cannot speak. mallow with a robotic hand. Others are starting to think it’s their best He is able to move a Scheuermann has been able to quickly chance. “I’ll take it! Cut off my dead arm cursor to select mes- attempt many new tasks. She has been and give me a robotic one that I can FEEL sages from a computer asked to control two robot arms at once with please!” wrote one. menu. and lift a box (“I only managed it once or Schwartz says he hopes try to gener- twice,” she says). Some results are strange: ate physical sensations from the robotic Ohio doctors launch an 2014 attempt to “reanimate” Scheuermann is able to close Hector’s fin- arm this year, if he can find another quad- a paralyzed man’s limb gers around a plastic cone, but often only riplegic volunteer. Like Scheuermann, the by means of thought if she shuts her eyes first. Is the presence next patient will receive two arrays in the control. His brain sig- of the cone somehow reflected in the neu- motor cortex to control the robotic arm. nals will activate elec- rons’ firing patterns? Schwartz has spent But Schwartz says surgeons will place two trodes on his arm, months trying to figure it out. Behind additional implants into the volunteer’s making it move. such points of uncertainty may lie major sensory cortex; these will receive signals discoveries about how the brain prepares from pressure sensors attached to the and executes actions. robotic fingertips. Studies by Nicolelis’s Scheuermann once had her aide dress Duke laboratory proved recently that ani- her in stick-on rat whiskers and a fuzzy mals do sense and respond to such electri- tail to greet researchers. It was a darkly cal inputs. “We don’t know if the subject

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will feel it as touch,” says Schwartz. “It’s very crude and simplistic and an undoubt- edly incorrect set of assumptions, but you can’t ask the monkey what he just felt. We think it will be a new scientific finding. If the patient can say how it feels, that is going to be news.” Another key aim, shared by Schwartz and the BrainGate researchers, is to connect a volunteer’s motor cortex to electrodes placed in his or her limbs, which would make the muscles contract—say, to open and close a hand. In April, the Ohio surgeons working with Battelle announced that they would be the first to try it. They put a brain implant in a man with a spinal-cord injury. And as soon as the patient recovers, says Battelle, they’ll initiate tests to “reanimate” his fingers, wrist, and hand. “We want to help someone gain control over their own limb,” says Chad Bouton, the engineer in charge of the project, who previously collaborated with the BrainGate group. “Can someone pick The Modular Prosthetic Limb was designed by Johns up a TV remote and change the channel?” Hopkins University’s Applied Although Battelle has not won approval Physics Laboratory and from regulators to attempt it, Bouton says funded by DARPA. the obvious next step is to try a bidirec- tional signal to and from a paralyzed limb, cortex, initially of cats, with minimal whether such surface electrodes, although combining control and sensation. trauma to the brain. It’s believed that less precise, could be used in a decoder for scar tissue builds up around the needle- speech, potentially allowing a person like Interface Problems like recording tips, each 1.5 millimeters Stephen Hawking to speak via a brain- Brain-machine interfaces may seem as if long. If that interface problem is solved, computer interface. In an ambitious proj- they’re progressing quickly. “If you fast- says Miller, he doesn’t see any reason why ect launched last year at the University of forward from the first video of that mon- there couldn’t be 100,000 people with California, Berkeley, researchers are trying key to someone moving a robot in seven brain implants to control wheelchairs, to develop what they call “neural dust.” dimensions, picking things up, putting computer cursors, or their own limbs. The goal is to scatter micron-size piezo- them down, it’s pretty dramatic,” says Schwartz adds that if it’s also possible to electric sensors throughout the brain and Lee Miller, a neurophysiologist at North- measure from enough neurons at once, use reflected sound waves to capture elec- western University. “But what hasn’t someone could even play the piano with trical discharges from nearby neurons. changed, literally, is the array. It’s the a thought-controlled robotic arm. Jose Carmena, a Berkeley researcher Stanley Steamer of brain implants. Even Researchers are pursuing several ideas who, like Schwartz, works with monkeys if you demonstrate control, it’s going to for improving the brain interface. There to test the limits of thought control, now peter out in two to three years. We need are efforts to develop ultrathin electrodes, meets weekly with a group of a dozen sci- an interface that will last 20 years before versions that are more compatible with the entists to outline plans for better ways to this can be a product.” body, or sheets of flexible electronics that record from neurons. But whatever they The Utah array was developed in the could wrap around the top of the brain. come up with would have to be tested in

early 1990s as a way to record from the In San Francisco, doctors are studying animals for years before it could be tried LAB PHYSICS UNIVERSITY/APPLIED HOPKINS JOHNS AND DARPA OF COURTESY

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in a person. “I don’t think the Utah array Yet even locked-in patients can often medical device, which can cost $100 mil- is going to become the pacemaker of the move their eyes. This means they have lion. “There is not a single company out brain,” he says. “But maybe what we end simpler ways to communicate, like using there willing to put the money in to create up using is not that different. You don’t an eye tracker. A survey of 61 ALS patients a neuroprosthetic for quadriplegics, and see the newest computer in space mis- by the University of Michigan found that the market is not big enough for a venture sions. You need the most robust technol- about 40 percent of them would consider capitalist to get in,” says Gotshalk. “The ogy. It’s the same kind of thing here.” undergoing surgery for a brain implant, numbers don’t add up.” but only if it would let them communicate Others think the technology behind Numbers Game more than 15 words a minute (a fifth of brain-machine interfaces may have unex- To succeed, any new medical device needs the people who responded to the survey pected applications, far removed from to be safe, useful, and economically viable. were already unable to speak). BrainGate controlling robot arms. Many research- Right now, brain-machine interfaces don’t has not yet reported speeds that high. ers, including Carmena and the team at meet these requirements. One problem All the pieces of the technology “have Battelle, are trying to determine whether is the riskiness of brain surgery and the at some level been solved,” says Andy the interfaces might help rehabilitate chance of infection. At Brown, Donoghue Gotshalk, CEO of Blackrock Microsys- stroke patients. Because they form a large says the BrainGate team is almost finished tems, which manufactures the Utah array market, it “would be a game changer,” developing a wireless transmitter, about and has acquired some of the BrainGate Carmena says. Some of the recording the size of a cigarette lighter, that would technology. “But if you ask me what is technologies could be useful for under- go under a person’s skin and cut the infec- the product—is it a prosthetic arm or is it standing psychiatric diseases like depres- tion risk by getting rid of the pedestals a wheelchair you control?—then I don’t sion or obsessive-compulsive disorder. In Scheuermann’s case, at least, her brain-machine interface has proved to be Without a clearly defined product to shoot for, no large powerful medicine. When she first arrived at Pittsburgh, her doctors say, her affect company has jumped in to create a neuroprosthetic for was flat, and she didn’t smile. But being quadriplegics. A startup went out of business after raising part of the experiment energized her. “I more than $30 million. was loving it. I had coworkers for the first time in 20 years, and I felt needed,” and wires that make brain-machine inter- know. There is a high-level product in she says. She finished dictating a mystery faces so unwieldy. Donoghue says that mind, which is to make life for quadri- novel, Sharp as a Cucumber, that she’d with a wireless system, implants could be plegics a lot easier. But exactly what it started before she became ill and pub- a realistic medical option soon. would be hasn’t been defined. It’s just lished it online. Now she’s working on a But that raises another tricky prob- not concrete. The scientists are getting second one. Scheuermann told me she’d lem: what will patients control? The arm some high-level publications, but I have like to have a robotic arm at home. She’d Scheuermann controls is still a hugely to think about the business plan, and that be able to open the door, roll onto her expensive prototype, and it often breaks. is a problem.” lawn, and talk to neighbors. Maybe she’d She worries that not everyone could afford Without a clear product to shoot for, open the refrigerator and grab a sandwich one. Instead, Leigh Hochberg, a neurol- no large company has ever jumped in. And that her aide had prepared for her. ogist at Massachusetts General Hospi- the risks for a business are especially high Our call was ending. The moment was tal who runs the BrainGate study with because there are relatively few patients awkward. I could hang up the phone, but Donoghue, thinks the first users will prob- with complete quadriplegia—about she couldn’t. Her husband had gone out ably be “locked-in” patients who can nei- 40,000 in the U.S.—and even fewer with shopping. Hector was back in the lab. She ther move nor speak. Hochberg would advanced ALS. A company Donoghue was alone and couldn’t move. “That’s all consider it a “breakthrough” to afford such created, Cyberkinetics, went out of busi- right,” Scheuermann said. “I’ll just let the patients reliable thought control over a ness after raising more than $30 million. phone slip to the floor. Good-bye.” computer mouse. That would let them Researchers instead get by on small grants type out words or change the channel on that are insignificant compared with a Antonio Regalado is MIT Technology a television. typical commercial effort to develop a new Review’s senior editor for business.

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The ability to discern what other people are thinking and feeling is critical to social interaction and a key part of the human experience. So it’s not surprising that the human brain devotes a lot of resources to so-called social cognition. But only recently has neuroscience begun to tease apart which brain regions and processes are devoted to thinking about other people.

CH: Is social cognition something seen Understanding how the brain perceives, interprets, only in humans? and makes decisions about other people could help RS: There’s every reason to believe that at advance treatments and interventions for autism and least in some ways, we are uniquely other disorders in which social interactions are impaired. good at this kind of thing. Humans are by far the most social species, other It could also help us build more socially intelligent com- than insects. Even the interaction you puters. So far, artificial intelligence has struggled to pro- and I are having, that two strangers gram computers that make the kinds of social judgments could meet and for no particular rea- that come easily to us, such as interpreting ambiguous son act coöperatively for an hour— facial expressions or deciding whether a person’s words that’s unheard of outside of humans. If convey anger or sadness. two ants did it, they would be sisters. Our extraordinary social lives and our More than a decade ago, neuroscientist Rebecca Saxe hugely complex cognitive capacities discovered a brain region that develops a “theory of combine to make human social cogni- mind”—a sense of what other people are thinking and tion distinctive. feeling. More recently, she became an investigator in MIT’s Center for Minds, Brains, and Machines, and she’s CH: How do you study it in the brain? been studying autism and social cognition in children and RS: Nothing invasive—no genetic engineering, no optogenetics, none of adults. Saxe and MIT Technology Review contributing these things. We are limited to what editor Courtney Humphries discussed the implications are called noninvasive neuroimag- of this new research on the social brain. ing technologies, and the most well known of these is functional MRI, which uses blood flow as an index of neural activity.

CH: So you can see which areas of the Q+A brain are active when people are thinking about other people. Was it a sur- prise to find brain regions devoted to Rebecca Saxe social cognition? RS: In a sense, that had been predicted about 15 or 20 years earlier, when people noticed that kids with autism seemed disproportionately bad at that kind of thing. But otherwise this was completely unknown. In some ways, I think it was the most important, most surprising new discovery of human cognitive neuroscience. All the visual

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Saxe studies how theory of mind develops and which systems in the brain support it.

Jared Leeds61

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“There’s a huge focus in AI right now on trying to take the natural language regions, all the sensory regions, all the CH: What do you mean by motor control regions—we predicted “ingredients”? people use and figure out they would be there. But the social RS: Let’s say you hear about [whether they like some- brain was not predicted at all. It just a friend of yours. She thing]. Now take it up to emerged. That was wild. was told she was being the level of distinguishing In the last 10 years [we’ve been] called to her boss’s office, between language when trying to refine our interpretation and she thought she was you feel disappointed, about what information is in those finally getting the promo- brain regions, how they interact tion she’d been waiting for. lonely, or terrified. That’s with one another, how they develop, But it turned out she actu- the kind of problem that whether or not those brain regions do ally got fired. Let’s say the we want to solve.” have anything to do with autism. next day you see her coming down the street and CH: And do these regions indeed not func- she has a huge smile on her face. Prob- dict human judgments about the per- tion well in people with autism? ably not what you had expected, right? son’s goal in a really simple context. RS: That was the original hypothesis that You take that and you build a What do you need to know about a we went after. Maybe [people with whole interior world. Maybe it’s a fake goal? We’re trying to build models that autism] are trying to solve social prob- smile and she’s putting on a brave face. describe that knowledge. lems with the machinery we would use Maybe she’s relieved because now she for other problems, instead of having can move to the other side of the con- CH: That’s very different from having a the dedicated machinery. There is no tinent and live with her boyfriend. computer look at millions of examples evidence that that is right. Too bad, You need to figure out: What were to find patterns. because I like that idea. Autism has her goals? What did she want? What RS: Exactly. This is not big data; it’s trying turned out to be a much, much harder changed her mind? There are all kinds to describe the structure of the knowl- problem at every level of analysis than of features of that story that you were edge. That’s always been viewed as an I think anyone expected. Ten years able to extract in the moment. opposition: the people who want big- ago people thought that cognitively, If a computer could extract [such] ger data sets and the people who want neurally, genetically, autism would be features, we could [improve its ability the right knowledge structures. My crackable. Now it looks like maybe to do] sentiment analysis. There’s a impression right now is that there’s a there are thousands of genetic varia- huge focus in AI right now on trying lot more intermediate ground. What tions of autism. to take the natural language people use used to be viewed as opposite tradi- and figure out: Did they like or not like tions in AI should now be viewed as CH: How might your work help lead to more that thing? Did they like that restau- complementary, where you try to fig- socially capable computers? rant or not like that restaurant? Now ure out probabilistic representations RS: To me, the signature of human social take it up to the level of distinguishing that learn from data. cognition is the same thing that makes between language when you feel disap- good old-fashioned AI hard, which is pointed, lonely, or terrified. That’s the CH: But the prospect of replicating social its generativity. We can recognize and kind of problem that we want to solve. cognition in a computer seems far off, think about and reason through a liter- right? We don’t yet understand how ally infinite set of situations and goals CH: How can computers learn to do that? the brain does it. and human minds. And yet we have a RS: You need to translate those words into RS: It feels pretty plausible that the full very particular and finite machinery to more abstract things—goals, desires, understanding is not in the grasp of do that. So what are the right ingredi- plans. My colleague Josh Tenenbaum me in my lifetime, and that’s good, ents? If we know what those are, then and I have been working for years just because it means I have a lot of work we can try to understand how the com- to build a kind of mathematical rep- to do. So in the meantime, I do what- binations of those ingredients generate resentation of what it means to think ever seems likely to produce a little bit this massively productive, infinitely of somebody as having a plan or a of instrumental progress toward that generalizable human capacity. goal, such that this model can pre- bigger goal.

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it was an expedition seeking something never caught before: a single human neuron lighting up to create an urge, albeit for the minor task of moving an index finger, before the subject was even aware of feeling anything. Four years ago, Itzhak Fried, a neurosurgeon at the Uni- Searching versity of California, Los Angeles, slipped several probes, each with eight hairlike for the electrodes able to record from single neurons, into the brains of epilepsy patients. “Free Will” (The patients were undergoing surgery to diagnose the source of severe seizures and Neuron had agreed to participate in experiments during the process.) Probes in place, the patients—who were conscious—were given instructions to press a button at any time of their choosing, but also to report when they’d first felt the urge to do so. Later, Gabriel Kreiman, a neurosci- work—caught in the act of formulating a with obsessive-compulsive disorder,” says entist at Harvard Medical School and volitional, or freely willed, decision. Now Christof Koch, chief scientist at the Allen Children’s Hospital in Boston, captured Kreiman and his colleagues are planning Institute of Brain Science in Seattle (see the quarry. Poring over data after sur- to repeat the feat, but this time they aim “Cracking the Brain’s Codes,” page 42). geries in 12 patients, he found telltale to detect pre-urge signatures in real time “Many of these people perfectly well know flashes of individual neurons in the pre- and stop the subject from performing the that what they are doing is dysfunctional supplementary motor area (associated action—or see if that’s even possible. but feel powerless to prevent themselves with movement) and the anterior cingu- A variety of imaging studies in humans from engaging in these behaviors.” late (associated with motivation and atten- have revealed that brain activity related Kreiman, 42, believes his work chal- tion), preceding the reported urges by to decision-making tends to precede con- lenges important Western philosophical anywhere from hundreds of milliseconds scious action. Implants in macaques and ideas about free will. The Argentine-born to several seconds. It was a direct neural other animals have examined brain cir- neuroscientist, an associate professor at measurement of the unconscious brain at cuits involved in perception and action. Harvard Medical School, specializes in But Kreiman broke ground by directly visual object recognition and memory measuring a preconscious decision in formation, which draw partly on uncon- Gabriel Kreiman’s humans at the level of single neurons. To scious processes. He has a thick mop of single-neuron be sure, the readouts came from an aver- black hair and a tendency to pause and measurements of age of just 20 neurons in each patient. think a long moment before reframing a unconscious decision- (The human brain has about 86 billion question and replying to it expansively. making may not topple of them, each with thousands of connec- At the wheel of his Jeep as we drove tions.) And ultimately, those neurons fired down Broadway in Cambridge, Massa- Descartes, but they only in response to a chain of even earlier chusetts, Kreiman leaned over to adjust could someday point events. But as more such experiments peer the MP3 player—toggling between Viv- to ways we can learn deeper into the labyrinth of neural activity aldi, Lady Gaga, and Bach. As he did to control ourselves. behind decisions—whether they involve so, his left hand, the one on the steering moving a finger or opting to buy, eat, or kill something—science could eventually tease out the full circuitry of decision-making and perhaps point to behavioral therapies or treatments. “We need to understand the By neuronal basis of voluntary decision-mak- David Talbot ing—or ‘freely willed’ decision-making— and its pathological counterparts if we want to help people such as drug, sex, food, and gambling addicts, or patients

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wheel, slipped to let the Jeep drift a bit the brain. A key research milestone was by neurons. For the star-struck kid from over the double yellow lines. Kreiman’s reached in the early 1980s when Benja- Argentina, “it was really life-changing,” view is that his neurons made him do it, min Libet, a researcher in the physiology he recalls. “Several decades ago, people and they also made him correct his small department at the University of Califor- said this was not a question serious sci- error an instant later; in short, all actions nia, San Francisco, made a remarkable entists should be thinking about; they are the result of neural computations and study that tested the idea of conscious free either had to be smoking something or nothing more. “I am interested in a basic will with actual data. have a Nobel Prize”—and Crick, of course, age-old question,” he says. “Are decisions Libet fitted subjects with EEGs— was a Nobelist. Crick hypothesized that really free? I have a somewhat extreme gadgets that measure aggregate electri- studying how the brain processed visual view of this—that there is nothing really cal brain activity through the scalp—and information was one way to study con- free about free will. Ultimately, there had them look at a clock dial that spun sciousness (we tap unconscious processes are neurons that obey the laws of phys- around every 2.8 seconds. The subjects to quickly decipher scenes and objects), ics and mathematics. It’s fine if you say were asked to press a button whenever and he collaborated with Koch on a num- ‘I decided’—that’s the language we use. they chose to do so—but told they should ber of important studies. Kreiman was But there is no god in the machine—only also take note of where the time hand was inspired by the work. “I was very excited neurons that are firing.” when they first felt the “wish or urge.” It about the possibility of asking what seems Our philosophical ideas about free turns out that the actual brain activity to be the most fundamental aspect of cog- will date back to Aristotle and were sys- involved in the action began 300 milli- nition, consciousness, and free will in a tematized by René Descartes, who argued seconds, on average, before the subject reductionist way—in terms of neurons that humans possess a God-given “mind,” was conscious of wanting to press the and circuits of neurons,” he says. separate from our material bodies, that button. While some scientists criticized One thing was in short supply: endows us with the capacity to freely the methods—questioning, among other humans willing to have scientists cut open choose one thing rather than another. things, the accuracy of the subjects’ self- their skulls and poke at their brains. One Kreiman takes this as his departure point. reporting—the study set others thinking day in the late 1990s, Kreiman attended But he’s not arguing that we lack any con- about how to investigate the same ques- a journal club—a kind of book club for trol over ourselves. He doesn’t say that our tions. Since then, functional magnetic scientists reviewing the latest literature— decisions aren’t influenced by evolution, resonance imaging (fMRI) has been and came across a paper by Fried on how experiences, societal norms, sensations, used to map brain activity by measuring to do brain science in people getting elec- and perceived consequences. “All of these blood flow, and other studies have also trodes implanted in their brains to iden- external influences are fundamental to the measured brain activity processes that tify the source of severe epileptic seizures. way we decide what we do,” he says. “We take place before decisions are made. But Before he’d heard of Fried, “I thought do have experiences, we do learn, we can while fMRI transformed brain science, it examining the activity of neurons was the change our behavior.” was still only an indirect tool, providing domain of monkeys and rats and cats, not But the firing of a neuron that guides very low spatial resolution and averaging humans,” Kreiman says. Crick introduced us one way or another is ultimately like data from millions of neurons. Kreiman’s Koch to Fried, and soon Koch, Fried, and the toss of a coin, Kreiman insists. “The own study design was the same as Libet’s, Kreiman were collaborating on studies rules that govern our decisions are similar with the important addition of the direct that investigated human neural activity, to the rules that govern whether a coin single-neuron measurement. including the experiment that made the will land one way or the other. Ultimately When Libet was in his prime, Kreiman direct neural measurement of the urge there is physics; it is chaotic in both cases, was a boy. As a student of physical chem- to move a finger. “This was the opening but at the end of the day, nobody will istry at the University of Buenos Aires, shot in a new phase of the investigation argue the coin ‘wanted’ to land heads or he was interested in neurons and brains. of questions of voluntary action and free tails. There is no real volition to the coin.” When he went for his PhD at Caltech, will,” Koch says. his passion solidified under his advi- Testing Free Will sor, Koch. Koch was deep in collabora- Better Decisions It’s only in the past three to four decades tion with Francis Crick, co-discoverer A perennial debate in philosophy is that imaging tools and probes have been of DNA’s structure, to look for evidence whether, if our choices are caused by some-

able to measure what actually happens in of how consciousness was represented thing (anything), we can still be said to pos- PETERSON BRUCE

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Inserted into the brain, brain regions associated with self-control actions or defer gratification and those electrodes such as this one and empathy). Fallon has described how whose capacity is diminished.” detect neural activity. he now makes a conscious effort to modify Kreiman, too, sees practical potential his everyday decisions and behaviors— in teasing apart the circuitry of decision- such as his tendency to want to defeat his making but deflects my questions about young grandchildren at games. “When I how his work could lead to new drugs or sess free will. Hilary Bok, a philosopher at think about freedom of the will, a part of therapies. “The main question at the sci- Johns Hopkins University, says many mod- what is required is that we have some abil- entific level is to understand the mecha- ern philosophers—perhaps most—believe ity to control our own actions,” Bok says. nism by which volitional decisions are freedom of decision is possible, but that of “It would be important to me to discover made: where, when, and how they are course neural processes lead to urges and whether a psychopath who decides to use orchestrated,” he says. actions. “The idea that your choice might his or her narcissism to defeat that narcis- In his quest for a better picture of how be caused—including by something hap- sism can actually succeed.” that orchestration works, Kreiman now pening in the brain—occurred to us a long Though it’s still at an early stage, has a new collaborator in Ed Boyden, a time before the neuroscientists started Kreiman’s work adds to this kind of neuroscientist at MIT who has developed filling in the details of how it happened,” understanding, says Patricia Church- novel tools for analyzing brain circuits. she says. Freedom doesn’t require a ghost land, a philosopher at the University of Among other efforts, Boyden is testing far in the machine; we might still have some California, San Diego, who avers that denser neural probes in mice; these have sort of free will if it can be shown that our neuroscience can illuminate old philo- the potential to record from as many as neural circuits give us the capacity to weigh sophical questions. Churchland believes 100 times more neurons simultaneously options and choose the right ones. “I love that the experiments could be important (see “Neuroscience’s New Toolbox,” page these experiments and think they are really in shedding light on whether decisions 20). This technology could allow scientists interesting,” she says, “but I’m less con- can be altered or urges held in check, and to identify many of the neurons involved vinced whether they have shown anything might help explain why some people have in making an “urge” neuron fire. “If we can crucial about free will.” difficulty controlling their impulses after get that, it would be transformative for What’s really important about the brain damage. “The explanations are far this project as well as many others,” Krei- experiments, she adds, is that they start from complete, but a pattern of results man says. Projects around the world that to provide insights into human behavior. is fitting together in illuminating ways,” are currently working to map the brain’s This could someday lead to therapies, but she says. “Self-control is an entirely real circuitry would especially stand to benefit. until then, insight alone can help. Con- brain phenomenon. Insofar as self-control With such tools, rather than just see- sider the case of James Fallon, a neuro- is a key component of free choice, we do ing a single neuron light up, you might see scientist at the University of California, in fact have free choice. From a range of a network of electrical signals that made Irvine, who discovered that his own fMRI data it is becoming quite clear that there it happen. Then you could, perhaps, see scan bore similarities to those of known are significant neural differences between what lit the neuron that makes you wiggle psychopaths (it indicated low activity in people who have the capacity to cancel the finger, and the neuron that makes you reach for the bottle. “If you can map the neural activity and see how neurons are dynamically generating the outcomes—it’s like seeing how the brain is computing a decision,” Boyden says. “You’d like to be able to see how the emotions, sensations, and memories work together.” There is no “god in While Kreiman sees no free will, he the machine”—only does believe mechanisms of self-control neurons that are are built into the circuits that guide him down Broadway and through life. He firing, Kreiman says. wants to discover them, but he concedes that even if he were to do so today, “tonight, everything will be the same.” It may be that the illusion of free will is part of the wiring—and impossible to shake off.

David Talbot is chief correspondent of MIT Technology Review.

JA14_free.will.indd 67 6/5/14 11:26 AM CONTENTS

The Big Question

The Economics of the Internet of Things BUSINESS REPORT The Lowly Thermostat, Now Minter of Megawatts

The Light Bulb Gets a Digital Makeover

GE’s $1 Billion Software Bet

The Internet of You

The Internet Silicon Valley to Get a Cellular Network, Just for Things

Find additional material for this report of Things at technologyreview.com/business Billions of computers that can sense and communicate from anywhere are coming online. What will it mean for business?

The Big Question Business Adapts to a New Style of Computer

Are companies ready for billions of everyday objects to join the Internet?

● The technology industry is preparing for the Internet of things, a type of computing characterized by small, often dumb, usually unseen computers attached to objects. These devices sense and transmit data about the environment or offer new means of controlling it. For more than a decade technolo- gists have predicted and argued about the onslaught of these ubiquitous devices. “There is a lot of quibbling about what to call it, but there’s little doubt that we’re seeing the inklings of a new class of computer,” says David Blaauw, who leads a lab at the University of Michigan that makes functioning computers no bigger than a typed letter o. A key feature is very cheap radios, etched right into silicon. There’s one in your smartphone. But now prices are

falling to around $5. As they get BRADFORD STUART

JA14_business.excerpt.indd 68 6/2/14 1:09 PM There’s a way to do it better. Find it. – Thomas Edison

Untitled-1 1 6/2/14 4:36 PM Each year, over 35,000 companies choose a better approach to measurement and control.

©2014 National Instruments. All rights reserved. National Instruments, NI, and ni.com are trademarks of National Instruments. Other product and company names listed are trademarks or trade names of their respective companies. 17198

Untitled-3 2 6/2/14 5:22 PM As engineers, you have the power to solve today’s biggest challenges. This includes

developing cyber-physical systems that will better connect our world through

advanced technology.

This emerging technology infrastructure is known as the Internet of Things, and its use of

massive data sets is poised to improve daily life through predictive and real-time analysis.

But bringing it to life is going to take integrated software and hardware platforms that

simplify and accelerate application design, development, and deployment.

Find them at ni.com.

Untitled-3 3 6/2/14 5:22 PM MIT TECHNOLOGY REVIEW VOL. 117 | NO. 4 TECHNOLOGYREVIEW.COM BUSINESS REPORT — THE INTERNET OF THINGS

groping to find the winning combination Machines Go Online of software, interfaces, and processors for n n The number of everyday objects, or “things,” connecting Things PCs & laptops whatever comes next. to the Internet will exceed PCs and smartphones. n Tablets n Mobile phones And it’s not just technology companies Connected devices (billions) that must stay alert this time around. The reason, explains Marshall Van Alstyne, 30 a professor at Boston University, is that as ordinary products become connected, 25 their manufacturers may enter information businesses whose economics are alien 20 to them. It’s one thing to manufacture shoes, but what about a shoe that com- 15 municates? Products could turn out to be valuable mainly as the basis for new services. “You might find the data is more 10 valuable than the shoe,” says Van Alstyne. In this MIT Technology Review busi- 0 ness report we decided to explore the big 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 question of what new businesses will arise as things get connected. One company making the point is Nest Labs, maker of As computers with wireless capability become cheap, it’s becoming a slick-looking smart thermostat that’s affordable to connect more things to the Internet, like sensors in sewer coupled to the Internet. Nest, which was pipes, factory machinery, lights, and home appliances. acquired by Google this year, has been clobbering rival thermostat makers. But now that it has a network of thermostats cheaper, it’s becoming affordable to con- has 60 microprocessors in it, according and can control them from afar, it’s start- nect more things, like sewer pipes or to the Center for Automotive Research. ing to offer services to electric utilities. On trash cans. At the University of California, Electronics account for 40 percent of the hot days it can selectively turn down air Berkeley, researchers are even designing cost of making a car. conditioners, controlling demand. computers the size of a pinhead to col- The Internet of things is especially Nest’s tests with utilities are still lect data inside the brain and transmit it important for companies that sell net- small. But one day, with a few bits sent through the skull. The idea is that human work equipment, like Cisco Systems. across a network, the company might bodies will join the network, too. Cisco has been enthusiastically predict- put a power plant or two out of business. It can all sound far-fetched and over- ing that 50 billion “things” could be con- No wonder this year, in his annual let- hyped. Does anyone really need a smart nected to communications networks ter to shareholders, Jeff Immelt, CEO of coffee pot or a refrigerator with a Web within six years, up from around 10 General Electric, the world’s largest browser? Plenty of the inventions do billion mobile phones and PCs manufacturer, told his investors seem silly. On Amazon, product review- today. Another beneficiary is 60 that “every industrial company ers have had a field day with a $78 digital the $300 billion semiconduc- Number of will be a software company.” microprocessors “egg minder” that reports to a smart- tor industry. As Blaauw notes, Gordon Bell, a Microsoft in the average phone which egg in a refrigerator is oldest. “Every time there has been a new car researcher and a pioneer of the “Wonderful product!” sneered one. “So new class of computing, the total original computer revolution, many gray hairs avoided by never having revenue for that class was larger than believes no one knows exactly what form to worry about my eggs again.” the previous ones. If that trend holds, it computing will take on the Internet of Yet for every killer app that wasn’t, means the Internet of things will be big- things. But he says that’s unsurprising. The there’s another computer-sensor combi- ger yet again.” importance of the PC and the smartphone nation that has quietly added to the capa- But every shift promises pain, too. became clear only after their development. bilities of some machine. Since 2007, for Large companies like Intel are already “The ‘Internet of things’ is a way of saying instance, every new car in the United reeling from the rapid emergence of that more of the world will become part States has had a chip in each tire that smartphones. Intel, with its power- of the network,” he says. “That is what is measures pressure and sends data by ful, power-hungry chips, was shut out going on. We are assimilating the world radio to the car’s central computer. It’s of phones. So was Microsoft. Now both into the computer. It’s just more and more

starting to add up. The average new car these companies, and many others, are computers.” —Antonio Regalado GSMA SOURCE:

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ers connect to it, together with a gover- platform business models are like play- Leaders nance model, which is the rules of who ing 3-D chess. gets what. Business platforms are often engaged in consummating a match. It’s You estimate that half the top 20 com- The Economics a match between riders and drivers with panies in the world, like Google, own Uber. It’s between travelers and spare platforms. Why are they winning? of the Internet capacity of guest rooms in Airbnb. There is a strong argument that platforms beat products every time. Think of Things Is connecting ordinary objects, like of how the iPhone is absorbing the fea- toasters, to the Internet going to trigger tures of the voice recorder, the calcula- As everyday objects get connected, new platforms? tor, and game consoles. The reason for brace yourself for network effects, says Absolutely, yes. But you can’t stop at this is that as a stand-alone product, one economist. the connectivity. The technologist’s mis- you’re going to have a certain pace of take is often to stop simply at the stan- innovation. But if you have opened ● Product companies compete by build- dards, the connections. You also have your product so that third parties can ing ever bigger factories to turn out ever to add the reasons for other people to add value, and you have designed the cheaper widgets. But a very different add value. That often means allowing rules of the ecosystem such that they sort of economics comes into play when recombination of features in ways that want to, your innovation curve is going those widgets start to communicate. It’s you, the original designer, just cannot to be faster. called the network effect—when each new anticipate. People have combined the To me this means there are huge user of a product makes its value higher. functions of the iPhone into hundreds of opportunities to take away business Think of the telephone a century ago. thousands of apps that Apple never even from existing players in all different The greater the number of people who conceived of. That is also what the Inter- kinds of goods. Or for existing players used Bell’s invention, the more valuable net of things enables if you design it in to expand their markets if they are pay- it became to all of them. The telephone the right way. ing attention. became a platform for countless new businesses its inventor never imagined. Now that more objects are getting “Most companies compete by adding new features to wired up into networks—street lights, products. They haven’t been in the business of thinking of wind turbines, automobiles—there how to add new communities or network effects.” are opportunities for new platforms to —Marshall Van Alstyne emerge. That’s why some companies are seeking the advice of Marshall Van Alstyne, a business professor at Boston What’s an example of this happening? What are some of the next areas for University who has studied the econom- Philips Lighting just called me. They platforms? ics of e-mail spam and social networks. are adding a series of APIs to their LED It’s where you see connectivity is coming These days, Van Alstyne studies “plat- lights so anyone can create millions of in. Cities, health care, education, elec- form economics,” or why companies such colors, create romantic mood apps or tricity grids. as Uber, Apple, and Amazon are so suc- the colors of a sunset from one of your cessful—and what traditional product favorite trips. You can change the lights What are the biggest challenges? makers can do to emulate them. MIT in your study in conjunction with the In many cases, the governance mod- Technology Review’s senior editor for stock market conditions. That is the els have not been established. For business, Antonio Regalado, visited Van Internet of things, and they’re opening instance, population density can be Alstyne at his office in Boston. it to anyone. determined by mobile-phone distri- bution. A telecom company owns that How can I tell if a business is a platform? Do product companies have a difficult data. How do you motivate them to If you produce the value, then you are a time making this kind of transition? share it? All these sensors are captur- classic product company. But there are They have a really difficult time with ing data, but how do you divide the new systems where value is being cre- the mental models. It’s fascinating. value? Those are the rules that need ated outside the firm, and that’s a plat- Most companies compete by adding to be worked out, and that’s the miss- form business. Apple gets 30 percent new features to products. They haven’t ing piece of most of these discussions of the cut from other people’s innova- been in the business of thinking of how about the Internet of things. You have tions in its app store. I define a platform to add new communities or network to build economic incentives around it,

COURTESY OF REDACTIE EMERCE REDACTIE OF COURTESY as a published standard that lets oth- effects. One of the points I make is that not simply connectivity.

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Peak Power Wired Home On a 104° day in Austin, remote control of home thermostats helped cut power demand. TVs, heaters, and other appliances will account Megawatts for more of the Internet-connected devices in the average U.S. home. 2,650 Projected demand n Home appliances 2,610 n Home computers and routers

2,570 Actual demand 2,530 THERMOSTATS ACTIVATED 2,490

2,450 2:00 p.m. 4:00 p.m. 6:00 p.m. 2010 2014 2018

electricity use can be lowered just enough dents’ habits and preferences and can pro- Case Studies at peak times, utilities can avoid firing up gram heating and AC settings. A Wi-Fi costly (and dirty) backup plants. connection brings in weather data and Demand response is a neat trick. The allows consumers to control the system The Lowly Nest thermostat manages it by combin- with a phone or Web browser. ing two things that are typically sepa- Data is just the start. Just as Google Thermostat, rate—price information and control over parlays what it knows about you into demand. It’s consumers who control the tools for advertisers on the Web, Nest is Now Minter air conditioners, electric heaters, and using its capabilities to create new types furnaces that dominate a home’s energy of services for utilities to buy. “We can of Megawatts diet. But the actual cost of energy can vary go to utilities and say, ‘We’ve actually got widely, in ways that consumers only dimly a lot of customers in your service terri- How Nest is turning its consumer hit into appreciate and can’t influence. tory who already have a Nest,’” says Scott a service for utilities. While utilities frequently carry out McGaraghan, Nest Labs’ head of energy demand response with commercial cus- products. “And [then we] can flip it on.” ● Google’s $3.2 billion acquisition of Nest tomers, consumers until now have shown Austin’s municipal utility, Austin Labs in January put the Internet of things little interest. Nest Labs’ breakthrough Energy, is one of five utilities that have on the map. Everyone had vaguely under- was to make a device that has popular signed up for Nest Labs’ Rush Hour stood that connecting everyday objects to the Internet could be a big deal. Here was an eye-popping price tag to prove it. Once inside a home, Nest starts its real work: gathering Nest, founded by former Apple engi- data. It has a motion detector; sensors for temperature, neers in 2010, had managed to turn the humidity, and light; and algorithms that learn residents’ humble thermostat into a slick, Internet- habits and preferences. connected gadget. By this year, Nest was selling 100,000 of them a month, according to an estimate by Morgan Stanley. appeal. “There’s a lot of digital Internet Rewards, as the service is called. Air At $249 a pop, that’s a nice busi- thermostats out there, but Nest was able to conditioners account for half of Texas’s ness. But more interesting is what Nest create a concept around it. They’ve created electricity demand on hot days, and that has been up to since last May in Texas, something that people are relating to,” demand for cooling drives the wholesale where an Austin utility is paying Nest says Mary Ann Piette, a demand response cost of electricity from less than $40 per to remotely turn down people’s air con- expert and head of the Building Technol- megawatt-hour to well over $1,000. ditioners in order to conserve power on ogy and Urban Systems Department at Twelve months ago Austin Energy hot summer days—just when electricity Lawrence Berkeley National Laboratory. started offering a one-time $85 rebate to is most expensive. Once inside a home, Nest starts its real customers who agreed to let it automat- For utilities, this kind of “demand work: gathering data. It has motion detec- ically trim their air-conditioning using response” has long been seen as a killer tors; sensors for temperature, humidity, smart thermostats sold by Nest and other

app for a smart electrical grid, because if and light; and algorithms that learn resi- companies. Each company earns $25 for NEST OF COURTESY ENERGY; AUSTIN SOURCE: MASON; ANALYSIS SOURCE:

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every thermostat it enrolls, and another tricity consumption tests the grid’s lim- A moment later, the conference room $15 per thermostat each year after that. its most. But if demand response can where we were sitting darkened. The “vast majority” of the 5,500 expand to cover the 300 or 400 hours of It may seem like Rube Goldberg’s idea thermostats registered so far are Nests, peak usage, it could entirely shut down the of how to turn off a light. Or it could be according to Sarah Talkington, the Aus- market for “peakers,” or gas-fi red plants the beginning of how lighting companies tin Energy engineer leading the program. that come online only to sell expensive such as Philips fi nd their way from selling Nest says it fi nds that roughly half its cus- electricity. “That’s a big chunk of money lighting hardware into networks, soft- tomers will sign up for demand response that’s at stake,” says Tom Osterhus, CEO ware, apps, and new kinds of services. when the opportunity is off ered. of Integral Analytics, a Cincinnati-based The introduction of networked lights By the end of last summer, Talkington maker of smart-grid analytics software. is happening because of another trend. says, she could log on to a Nest portal and, “It’s in the billions.” —Peter Fairley Manufacturers have been replacing incan- with a few keystrokes, dial down the next descent and fl uorescent lights with ultra- day’s demand by nearly 5.7 megawatts. That effi cient LEDs, or light-emitting diodes. may seem small compared with the 2,800 Case Studies The U.S. Department of Energy says that megawatts that often sizzle across the Aus- LEDs had 4 percent of the U.S. lighting tin grid, but every watt counts. On hot days market in 2013, but it predicts this fi gure like September 3, 2013, as temperatures The Light Bulb will rise to 74 percent of all lights by 2030. rose to 104 °F, the cost of power spiked to Because LEDs are solid-state devices a record $4,900 per megawatt-hour. Gets a Digital that emit light from a semiconductor chip, Austin had tried residential demand they already sit on a circuit board. That response before, using one-way pagers to Makeover means they can readily share space with turn air conditioners on and off . But the sensors, wireless chips, and a small com- utility couldn’t know if customers were Electric lights are 135 years old. The puter, allowing light fi xtures to become home, so it wasn’t able to shut off any one Internet is 45. They’re ﬁ nally getting networked sensor hubs. air conditioner for long. Nest, in contrast, connected. For example, last year Philips gave builds a thermal model of each house and outside developers access to the soft- predicts how quickly it will warm up. It ware that runs its Hue line of residential can also guess whether people will be LED lights. Now it’s possible to down- home. The result, says McGaraghan, is load Goldee, a smartphone app that turns that Nest can maximize energy savings your house the color of a Paris sunset, or

and minimize annoyance to residents. Reﬂ ector Ambify, a $2.99 app created by a German Talkington predicts the residential programmer that makes the lights fl ash to 7 LEDs program will enroll enough homes to save Heat spreader music as in a jukebox. more than 13 megawatts through demand That’s a very diff erent kind of business Circuit boards: response this summer. Even if Austin gives from selling light bulbs, as Philips has out $2 million in rebates, that is cheaper • Radio chip done since 1891. “With the new digitiza- than increasing power supply by build- • 512k of tion of light, we have only begun to scratch computer ing a natural-gas-fi red generator. Accord- the surface on how we can control it, inte- Philips storage ing to Michael Webber, co-director of the Hue grate it with other systems, and collect clean-energy incubator at the University LED light rich data,” says Brian Bernstein, Philips’s of Texas in Austin, new power supply costs Price: global head of indoor lighting systems. $500,000 to $4,000,000 per megawatt of $59 each Another look at how lighting systems capacity, depending on the type of plant. are changing will emerge this Novem- Webber believes that within fi ve years ber, when a 14-story regional headquar- the “vast preponderance” of Texans will ters for Deloitte, nearing completion in have smart thermostats. And Nest knows ● To demonstrate how the Internet is Amsterdam, will be festooned with net- that whoever builds this network first changing one of the oldest and least excit- worked LEDs in each fixture—the first could win big, especially as other energy- ing technology businesses around, Shane such installation for Philips. consuming devices, like electric cars and De Lima, an engineer at Philips Lighting, Each of 6,500 light fi xtures will have hot-water heaters, also get wired up. took out his smartphone. A flick across an IP address and fi ve sensors—all of them Eventually, the effects of demand the screen sent a message to a nearby wired only to Ethernet cables. (They’ll response could be profound. Austin’s pro- Wi-Fi router and then to a wireless hub, use “power over Ethernet” technology to gram is designed to manage demand only which shot a radio command to a chip in deliver the juice to each fi xture as well as

COURTESY OF PHILIPS OF COURTESY during the 50 hours each year when elec- the base of an LED lamp in front of us. data.) The fi xtures include a light

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sensor to dim the LEDs during the day, many of them programmers and data and a motion detector that covers the area Service Play scientists. directly beneath each light and turns the GE’s industrial revenues are split between sell- “People have told companies like GE ing products and servicing them. light off when no one is there. “We expect for years that they can’t be in the software to spend 70 percent less on light, because Revenue in billions ($) in 2013 n Products business,” Immelt said last year. “We’re too n Services systems [give] us much more control,” slow. We’re big and dopey. But you know says Erik Ubels, chief information officer 30 what? We are extremely dedicated to win- at Deloitte in the Netherlands. Additional 25 ning in the markets we’re in. And this is sensors in the LED fixtures can monitor 20 a to-the-death fight to remain relevant to temperature, humidity, carbon dioxide, 15 our customers.” and heat, turning the lights into a kind of 10 Peter Evans, then a GE executive, was given the job of shaping what he calls the building-management system. 5 Prices for LEDs are high but falling “meta-narrative” around GE’s big launch.

quickly. A “dumb” LED that puts out as Q1 Q2 Q3 Q4 Industrial companies, which prize reliabil- much light as a $1.25 incandescent bulb ity, aren’t nearly as quick to jump for new now sells for $9 (but uses one-sixth the energy and lasts much longer). That’s down

from $40 each a couple of years ago. A con- “This is a to-the-death fight to remain relevant to our nected LED bulb from Philips’s Hue line customers.” retails in the U.S. for $59. But these will —General Electric CEO Jeffrey Immelt get cheaper, too. Philips says a third of its lighting revenue now comes from LEDs, and about 1.7 percent from the newer LEDs that can connect to the Internet. Internal surveys had discovered that technology as consumers. So GE’s indus- Many other uses are being explored. A GE sold $4 billion worth of industrial soft- trial-Internet pitch was structured around department store in Dusseldorf, Germany, ware a year—the kind used to run pumps the huge economic gains even a 1 percent is using LEDs to send out light frequen- or monitor wind turbines. That’s as much improvement in efficiency might bring to cies that communicate with shoppers’ as the total revenue of Salesforce.com. But a number of industries if they used more smartphones. Philips has placed street these efforts were scattered and not always analytics software. That number was fairly lights in Barcelona that react to how many state-of-the-art. And that gap was turning arbitrary—something safe, “just 1 percent,” people are strolling by. —David Talbot dangerous. GE had always believed that recalls Evans. But here Immelt’s marketing since it knew the materials and the physics skills came into play. “Not ‘just 1 percent’,” of its jet engines and medical scanners, no he said, flipping it around. GE’s slogan Leaders one could best it in understanding those would be “The Power of 1 Percent.” machines. But companies that specialize In a stroke, GE had shifted the discus- in analytics, like IBM, were increasingly sion about where the Internet was going GE’s $1 Billion spooking GE by figuring out when big- next. Other companies had been talking ticket machines like a gas turbine might about connecting cars and people and Software Bet fail—just by studying raw feeds from toasters. But manufacturing and industry gauges or vibration monitors. account for a giant slice of global GDP. To protect lucrative business servicing This was no small thing. GE sells $60 “All the appliances in your home could be machines, GE turns to industrial Internet. billion a year in industrial equipment. But wired up and monitored, but the kind of its most lucrative business is servicing the money you make in airlines or health care ● To understand why General Electric is machines. Now software companies were dwarfs that,” Immelt remarked. plowing $1 billion into the idea of using looking to take a part of that pie, to get There is another constituency for the software to transform industry, put your- between GE and its largest source of prof- campaign: engineers inside GE. To them, self in the shoes of Jeff Immelt, its CEO. its. As Immelt would later say, “We cannot operational software isn’t anything new. As recently as 2004, GE had reigned as afford to concede how the data gathered in Nor are control systems—even a steam the most valuable company on the planet. our industry is used by other companies.” locomotive has one. But here Immelt was But these days, it’s not even the largest in In 2012, GE unveiled its answer to betting they could reinvent these systems. America. Apple, Microsoft, and Google are these threats, a campaign it calls the “You do embedded systems? My God, how all bigger. Software is king of the hill. And, “industrial Internet.” It included a new boring is that? It’s like, put a bullet in your as Immelt came to realize, GE is not that research lab across the bay from Silicon head,” says Brian Courtney, a GE man-

great at software. Valley, where it has hired 800 people, ager based in Lisle, Illinois. “Now it’s the GE OF COURTESY GE; SOURCE:

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hottest job around.” At the Lisle center, year—barely a flicker next to the billion or part of GE’s Intelligent Platforms divi- Emerged Technologies so smartphones sold in 2013. sion, former field engineers sit in cubicles Wearables are still looking for their monitoring squiggles of data coming off killer app. Now some people have begun turbines in Pakistan and oil rigs in onetime The Internet to imagine that the Internet of things will Soviet republics. Call this version 1.0 of provide it. If indeed our houses become the industrial Internet. On the walls, staff of You filled with smart devices like door locks, a hang pictures of fish; each represents a watch or wristband may be the most con- problem, like a cracked turbine blade, that As wearable devices get better-looking venient way to control them or let them was caught early. More and more, GE will and more powerful, we’ll trust them to know our needs. be using data to anticipate maintenance monitor and control more of our lives. “Your car should know that you’re needs, says Courtney. tired because you didn’t sleep that well, A challenge for GE is that it doesn’t ● The Internet of things typically con- so it should be alert to that, how awake yet have access to most of the data its jures images of “smart” light bulbs and are you when you’re driving, those things,” machines produce. Courtney says about automatic door locks. Yet with an ever says Hosain Rahman, the CEO of Jaw- five terabytes of data a day comes into larger number of smart watches, activity bone, a 14-year-old company that makes GE. Facebook collects 100 times as much. trackers, and head-worn computers hit- earphones, speakers, as well as wrist-worn According to Richard Soley, head of the ting the market, we’re becoming part of fitness trackers. “I just think that things Industrial Internet Consortium, a trade the Internet of things, too. that are on your body—wearables—ulti- group GE created this year, industry has Slowly but surely, a few wear- mately will [control] all the smart been hobbled by a “lack of Internet think- able devices—mainly high-tech stuff and be kind of at the center ing.” A jet engine has hundreds of sensors. pedometers like those from Fit- 19 point.” But measurements have been collected bit and Jawbone—are catch- Jawbone is among the first only at takeoff, at landing, and once mid- ing on with consumers, and million to try to turn a wearable into Number of watches, flight. GE’s aviation division only recently many researchers and com- such a lifestyle remote. Jaw- bands, and other found ways to get all the flight data. “It panies are certain that body- wearables expected bone’s Up24 wristband can act sounds crazy, but people just didn’t think worn computers will become to ship in 2014 as a trigger for the Web service about it,” says Soley. “It’s like the Internet second nature—sensing, recording, IFTTT (“If This, Then That”) by revolution has just not touched the indus- and transmitting data to and from our using its low-energy Bluetooth radio to trial revolution.” bodies, to networks around us. share the data it gathers about you with GE is trying to close that gap. Its soft- For the most part, wearables still an app on your smartphone. For now, it ware center in San Ramon created an lack wide appeal. Some, like Google does only simple things. If you have an adaptation of Hadoop, big-data software Glass, elicit ambivalence. IDC estimates Internet-connected heater, the wristband used by the likes of Facebook. GE also that manufacturers will ship 19 million can signal it to turn on when you get up in invested $100 million in Pivotal, a cloud watches, bands, and other wearables next the morning. The idea is that the environ- computing company. On the crowdsourc- ment reacts to you. ing site Kaggle, it launched public compe- Such ideas are in their infancy. Many titions to optimize algorithms for routing Wearable Wireless companies are still struggling to get airline flights, which can save fuel. Wireless electronic devices are gathering anyone to put a wearable computer on. All this could sound familiar to anyone useful data about people. Another problem is power. With Google who works with consumer Internet tech- Glass, for instance, you’ll get a few hours nology, acknowledges Bernie Anger, gen- OMSignal OMShirt (gathers of use before it needs to be recharged. $240 biometric data) eral manager of GE’s Intelligent Platforms And the biggest power draw is usually

division. But he says GE is thinking about Jawbone Up24 wireless wrist- the wireless chip that lets these devices what to do next to use connectivity, and $150 band activity tracker communicate. That’s why MC10, a startup more computers, to inject “new behavior” manufacturing soft, thin electronics, is into machines. He gives the example of a OMG Life Autographer wear- experimenting with “every novel form field of wind turbines that communicate $399 able camera of power source,” says cofounder Ben and move together in response to changes Schlatka. One possibility comes from a Google Glucose-sensing in wind. “We are moving into big data, research stage wireless contact lens project at Columbia University called but it’s not because we want to become Enhants. Researchers there are devel- Google,” he says. “It’s because we are dra- Proteus Biomedical Battery-powered oping small, flexible tags that harvest matically evolving manufacturing.” research stage drugs energy from light or as they are shaken

SOURCE: MIT TECHNOLOGY REVIEW TECHNOLOGY MIT SOURCE: —Antonio Regalado by movement. In an upcoming

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research paper, they describe outfitting are saying ‘What is next?’” says David 40 people with flat sensors attached to Global Wireless Boom Blaauw, a professor of engineering at the different parts of their bodies while they Devices that make up the Internet of things University of Michigan. Blaauw builds walked, ran, or relaxed. Sensors were able will compete for space on networks dominated millimeter-scale wireless computers that by phones, games, and video. to harvest enough energy to transmit data he believes may one day report data from continuously at a rate of one kilobit per Wirelesss traffic, in terabytes per month just about anywhere, even from inside a second. That’s not much, but it could patient’s tumor. be enough for simple applications like 12,000,000 A SigFox base station can serve a

authenticating someone’s ID or reading Phones radius of tens of kilometers in the coun- the local temperature. Enhants researcher 8,000,000 tryside and five kilometers in urban areas. Peter Kinget, a professor of electrical engi- To connect to the network, a device will neering at Columbia, says enough energy 4,000,000 need a $1 or $2 wireless chip that’s com- can typically be harvested to wirelessly link Tablets patible, and customers will pay about $1 Things a sensor on your body to a smartphone— in service charges per year per device.

something we’re already comfortable car- 2013 2014 2015 2016 2017 2018 By reaching into the Bay Area first rying everywhere we go. —Rachel Metz (with expansion to tech hubs such as Austin, Cambridge, and Boulder in its Luke D’Arcy, director of SigFox’s opera- sights), SigFox hopes to catch the inter- Emerged Technologies tions in the U.S. est of a region where venture capital- SigFox’s network will cover the San ists poured nearly $1 billion into startup Francisco peninsula from its urban tip companies focusing on the Internet of Silicon Valley to the sprawling Silicon Valley region 40 things last year, according to the research miles to the south. It will be the compa- firm CB Insights. One of those startups, to Get a Cellular ny’s first U.S. deployment of a network Whistle, makes a fitness-tracking collar technology that already covers the whole for dogs. It has raised $6 million and is Network, of France, most of the Netherlands, and located in a corner of San Francisco that’s parts of Russia and Spain. SigFox built been called “IoT Town” thanks to its pro- Just for Things those by adding its own equipment to fusion of similar ventures. existing cell towers and radio antennas. Ben Jacobs, Whistle’s CEO, says the A French company plans to build a Customers include the French insurance collar communicates by Bluetooth to a wireless slow lane for small, low-power company MAAF, which offers smoke and phone, or via a home Wi-Fi router. That devices. motion detectors that notify homeown- limits what it can do. But a new version ers with a text message on their phones using SigFox’s technology will have a con- ● San Francisco is set to get a new cellular when a sensor is triggered or needs stant Internet connection anywhere network later this year, but it won’t help a new battery. in town, letting it act as a bea- fix the city’s spotty mobile-phone cover- The Silicon Valley network 100 con for lost pets. Previously, age. This wireless network is exclusively will use the unlicensed 915- bits per that would have required an for things. megahertz spectrum band second expensive and power-hungry The French company SigFox says commonly used by cordless Speed at which objects cellular phone on the collar. it picked the Bay Area to demonstrate phones. Objects connected to connected to SigFox’s SigFox is in a hurry to a wireless network intended to make it SigFox’s network can operate at network can operate get its network in place before cheap and practical to link anything to the very low power but will be able to competitors arrive. Jacob Sharony, Internet, from smoke detectors to dog col- transmit at only 100 bits per second— a principal at the wireless consultancy lars, bicycle locks, and water pipes. slower by a factor of 1,000 than the net- Mobius Consulting, says large wireless Regular mobile networks are jammed works that serve smartphones. But that companies are preparing machine-only with traffic from phone calls and people could be enough for many applications. networks as well, and these may operate downloading videos. But for the Inter- Indeed, semiconductor companies at much higher speeds. A new long-range, net of things to become a reality, similar like Intel and Broadcom are also in a low-power Wi-Fi standard that has the capabilities will need to be extended to race to make far cheaper, far smaller, and backing of some major U.S. companies, billions of objects, many of them embed- much-lower-power wireless chips. Sev- including Qualcomm, could hit the mar- ded in the environment and powered by eral showed off these “miniature comput- ket in 2016. “It will likely be a major con- small batteries. “If you want to get to bil- ers” at the Consumer Electronics Show tender even though it is somewhat late to lions of connections like that, you require this year. “They saw the cell phone turn the game,” says Sharony.

a completely new type of network,” says into the smartphone, and so companies —Tom Simonite INDEX NETWORKING VISUAL CISCO SOURCE:

JA14_business.excerpt.indd 78 6/2/14 1:09 PM Start with big data. End with an unfair advantage.

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80 Illustration by Brian Cronin

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I even be able to sort through the resulting deluge of photographs?

Point and shoot I hated wearing a camera at first. I felt extremely self-conscious, especially with the bulkier Autographer around my neck. It packs a wide-angle lens and sensors— My Life, Logged including an accelerometer, magnetom- eter, and thermometer—into a package If a device could capture every moment in life about the size and heft of an anchovy can. for your easy recall later, would you want it to? I found myself apologizing to friends and There are plenty of things I’d rather forget. store clerks, blaming my unusual tech gear on a professional assignment, but By Rachel Metz that just called even more attention to it. Still, it’s good that the devices announce themselves. They look geeky, always knew I was short, but it are widespread, with cameras and apps but not sneaky. People can (and will) ask wasn’t until recently that I realized affording plenty of opportunities to log why you have a weird square (Narrative exactly how short. and share the minutiae of life, and the Clip) or shiny black bar (Autographer) That’s because I’ve been trying costs of bandwidth and storage have on your shirt collar, and especially in the a couple of life-logging devices— dropped precipitously. And now we case of the Autographer and its wide- gadgets that clip to my shirt or hang have access to life-logging gadgets like angle lens, they’ll be able to identify it as around my neck, automatically tak- the Autographer and the Narrative Clip: a camera. The Narrative Clip’s lens is less Iing photos of the world around me. The small, clip-on cameras that continually obvious, but it gleams when hit by light results? Some neat shots of family, friends, take pictures on their own. Their makers to at least hint at what it is. If somebody and Silicon Valley life tucked in amongst believe you want to wear a gadget that will has a problem with it, you can simply countless photos of torsos, legs, sidewalks, document life for you, no effort required. take it off. and bicycle handlebars. I was open to the possibility. After And you will frequently take it off any- Life logging has long been an activity all, I often whip out my smartphone to way. Autographer, with its sensors, GPS, for a few diehard data fanatics and aca- capture snippets of life as it happens— and Bluetooth connection to my iPhone, demics. Early adherents included Uni- firemen washing their trucks down the sucked up battery life; I got only a few versity of Toronto professor Steve Mann, street from my office, flowers hours out of it when it was set to who as a graduate student at MIT in 1994 artfully arranged in my living take photos at a “medium” fre- began wearing a wireless camera that room, a raccoon hanging out Autographer quency, which is up to 240 images could record images from his point of view next to my apartment building. $399 per hour. The Narrative Clip was and display them online (see “Wearable My aim is to share them and, able to last more than a day, Narrative Clip Technology as a Human Right,” March/ occasionally, take a stroll down $279 owing to the fact that it has no April). In 1998, Microsoft researcher Gor- the digital memory lanes that display and fewer sensors, and, don Bell started collecting as much digital are Instagram and Facebook. Perhaps a irritatingly, plugs into a computer to sync information about his life as he could in device that captures my life as it unfolds, photos. an effort to create a searchable archive of without my having to take time out to Remembering to charge and wear the his memories. He even wrote a book, Total compose images, might yield enough ben- Autographer or Narrative Clip regularly Recall, arguing that cataloguing every- efit to outweigh the annoyance of having felt like a chore. Though I eventually got thing was a better way to live and would to wear (and charge) yet another gadget. I into the habit, there was still a big prob- eventually become pervasive. wondered: would it make family time and lem: the content of the photos. My days We’re not yet there, but we’ve been bike rides more enjoyable? Would it help often consist of hours spent gazing at a moving in that direction. Smartphones me remember people and events? Would glowing monitor while my fingers tickle

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a keyboard. I felt embarrassed looking back at days’ worth of photos that showed the same shots of my desk, computer, and offi ce skylight. What saved both gadgets from being tossed in a drawer was special occa- sions. Envisioning the ease with which they might capture time with family and The Narrative Clip, left, weighs friends, I took the Narrative Clip on a 20 grams. The spring ride with a friend through the ﬂ eet- Autographer, ingly green hillsides of Northern Califor- which has a wide-angle lens, nia and the Autographer to a playdate sensors, and with my one-year-old niece. display, weighs The most interesting—and surreal— 58 grams. photos of the whole experiment captured my bike ride. The fi rst few images show my garage, with bike helmets and bikes hung neatly on hooks. Then it’s outside on the streets of San Francisco, followed by miles of mostly blurry trees, blue skies, and power lines—apparently, the camera was pointed nearly straight up.

In search of focus These photos were fun to look back on, but are they really compelling enough to justify buying a camera for my lapel? It didn’t seem so, but I decided to ask someone who has devoted years to life log- but Bell says he continues to save about For the MyLifeBits project, research- ging. With the Narrative Clip attached to as much information as he did when it ers catalogued events for later recall by my shirt collar, I visited Gordon Bell, 79, was going. He had a kidney removed in storing all those images and messages now a researcher emeritus at Microsoft April to treat cancer, and during our talk in a database; users could select several Research in San Francisco. he wore a Basis health-monitoring watch items and assign them keywords, or fi le As part of a project called MyLife- that he’s using to track his heart rate, an item in several places at once. Bell says Bits, Bell archived pretty much all fac- which he says has risen since the opera- the database was eventually discontinued ets of his life except conversations (to tion (he suspects a beta blocker’s interac- because researchers didn’t think many avoid legal issues) from 1998 to 2007. He tions with his pacemaker). people would want to use something so scanned photos and books, saved e-mails After 15 years of life logging, he says, complex. These days, he uses the basic and instant messages, and captured the he often finds it helpful to consult his desktop search on his computer. He’s world around him by hanging a Micro- digital evidence store for details of trans- divided folders into “personal” and “pro- soft-developed wearable camera called the actions and “professional articles,” in addi- fessional” categories, with an “active” or SenseCam around his neck. (The Autog- tion to photos of his daily whereabouts. “archival” designation within each cat- rapher, which is produced by a subsid- He doesn’t see the point of relying primar- egory to make them easier to sort through. iary of Oxford Metrics Group, a maker ily on our fi ckle memories. “I want the real He annotates fi le names with metadata of imaging sensors and software, is actu- record, the real ground truth,” he says. Just indicating details such as who is in a ally based on the SenseCam technology.) knowing he has these memories at hand photo and what it documents. MyLifeBits ended in 2007 because two of makes him feel more confi dent than he Still, Bell acknowledges that we’re far

his colleagues left to join other projects, was before he started tracking everything. from having good ways to organize and AUTOGRAPHER OF COURTESY NARRATIVE; OF COURTESY

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revisit these memories. I noticed that The value of forgetting my life-logging cameras that I’d rather not quickly in my life-logging experiment. The No matter how organized these tools may relive, like one particularly stressful Satur- iPhone apps for the Narrative Clip and the become, though, there’s something I just day night I spent at the wood shop helping Autographer look more like photo dump- can’t get past: sometimes forgetting is my fiancé, Noah, finish up a project. The ing grounds than organized collections of even more helpful than remembering. Narrative Clip’s camera captured hours of memories. A lot of interface design and Anind Dey, an associate professor of exhaustion and irritation as we fumbled to computer-vision work is needed before a human-computer interaction at Carnegie glue little pieces of wood into small slots life-logging device will appeal to consum- Mellon University, has been studying how cut out of a giant map. I had pretty much ers and endure over months and years. self-monitoring or life logging can serve as forgotten about that miserable night until Autographer’s iPhone app hints at one a memory aid for Alzheimer’s patients or I glanced back at a set of images that show potentially smart organization method: it a tool to learn more about what’s going on Noah in the corner of the frame with a sad has a map on the bottom half of the dis- in the lives of people with autism. Beyond look on his face. Every time I look at it, I play, and as you browse images, it shows that, he says, “I still think this is a niche wince. And this wouldn’t even register on a dot indicating where each photo was market.” my lifetime scale of awful memories. It’s taken. Tapping a picture calls up detailed One big reason is that retaining every- hard to imagine how much more difficult sensor information gathered at the time thing we experience “doesn’t really match it would be to face photo evidence of, say, the image was snapped—including the the way we think,” Dey says. “I think of a friend’s or family member’s death. brightness of the light, the temperature, bad incidents in my life, and in my head The Narrative Clip lets you swipe and the direction of the camera. A lot of I’ve made them better, or I’d be really to the left on any collection of images this data is just noise, but seeing the geo- unhappy.” to reveal a delete button; Autographer graphic location of photos was valuable Me too. While I’m happy recalling makes it more complicated. Either way, because it jogged my memory: “Oh yeah, events like the bike ride with my friend, I have to make a decision to delete these that’s where I was when that happened.” there were some moments captured by images, which brings the unpleasant memories to mind again. I asked Bell whether recording everything makes him more likely to remember the things he’d rather forget. Laughing, he suggested that rather than deleting something, I put it in a folder labeled “Don’t Ever Look at This, and Forget It.” He’s not joking. Although he realizes there will be some photographs you never want to see again, he still thinks these logged memories can be useful: “The value, I think, is—well, this is something you can give to your therapist.” I’d rather continue with my targeted Clockwise from top left: an awkward shot taken by the Autographer; the approach to capturing, organizing, and Autographer’s view from a bike; a sharing my life. There’s something nice Narrative Clip picture of Gordon Bell. and deliberate about taking a photo, even if I’m just pressing a virtual shutter button on my iPhone screen. Gadgets like the Autographer and the Narrative Clip take some of the work out of it, but like me, they come up short.

Rachel Metz is IT editor for Web and social

RACHEL METZ/MIT TECHNOLOGY REVIEW TECHNOLOGY METZ/MIT RACHEL media at MIT Technology Review.

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This April, the IPCC released a long- awaited report assessing just how far we’ve come since Pachauri’s stark pro- nouncement. The news was grim. There has yet to be any sign of the global action that Pachauri and others had desperately sought. In 2007, the IPCC called for emissions to level off by 2015, but the world is emitting greenhouse gases faster than ever. Even now, Pachauri and some other IPCC leaders remain publicly optimistic, saying it’s still possible to avoid cata- strophic climate change if we act “very soon.” But delve into the new IPCC report itself and you’ll find a much less hopeful picture. “What the report overall shows is that the only way you’re going to stop climate change is by assuming that governments will make a whole series of Climate Change heroic efforts,” says 2014: Mitigation of Climate Change David Victor, direc- Working Group III tor of the Labora- Contribution to the tory on International Intergovernmental Law and Regulation Panel on Climate at the University of Change’s Fifth Assessment California at San Report Diego and one of the lead authors of the report. For example, if we’re to meet the U.N. goal of limiting the increase in the world’s average temperature to 2 °C above preindustrial levels, all key technologies— A Plan B for Climate Agreements wind, solar, nuclear, power plants that capture and store carbon dioxide, and so U.N. negotiations are going nowhere, and greenhouse-gas on—have to scale up quickly, even though emissions are soaring. It’s time to move on. some haven’t been growing at all and carbon capture at power plants has yet to By Kevin Bullis be commercially deployed. The report says the world’s governments must also immediately agree to binding and effec- in 2007, just before he accepted the astrophic global warming. “If there’s tive climate policies—even though mas- Nobel Prize on behalf of the U.N.’s Inter- no action before 2012, that’s too late,” sive efforts over the past two decades have governmental Panel on Climate Change Pachauri told the New York Times. “What failed to produce any such agreements. (IPCC), Rajendra Pachauri, the organi- we do in the next two or three years will “A lot of publicity was given to the zation’s leader, declared that the world determine our future. This is the defin- fact that the IPCC says limiting warming

was running out of time to prevent cat- ing moment.” is doable,” says Robert Stavins, director BAJTLIK JAN

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of the Harvard Environmental Econom- tious goal of stabilizing greenhouse gases that matters ics Program and also a key IPCC author. “at a level that would prevent dangerous But the situation “is not as rosy as it’s been anthropogenic (human-induced) interfer- to your characterized,” he says. “When you intro- ence with the climate system.” business. duce political reality, then you’re talking The most famous agreement to about [2 °C] not being feasible.” emerge so far is the Kyoto Protocol, a 1997 treaty that established Achieving consensus among nearly binding emissions limits on 200 countries is one challenge for some industrial countries and set up a mechanism to climate policy, but it’s not necessarily fi nance emissions-reducing the main one. Another problem is the projects in poor countries. U.N.’s focus on emissions limits. Kyoto expired in 2012 and has yet to be replaced. The The report inadvertently suggests new IPCC report concludes the obvious, another conclusion: after more than two stating that Kyoto accomplished very decades of the U.N. climate-treaty pro- little—the economic collapse in Eastern cess, long thought to be our best shot Europe after the fall of the Soviet Union at getting governments to act on global did more to reduce emissions, according warming, it’s time for a new approach. to Victor. Since Kyoto, U.N. actions have Although there are many reasons emis- been largely symbolic; an example is the sions have continued to increase, an obvi- nonbinding emissions targets that came ous one is simply that the U.N. approach out of a meeting in Copenhagen in 2009. to climate change—which involves gath- The goal of a global, all-inclusive treaty Spies, Technology, ering representatives from nearly 200 keeps getting kicked down the road. The and Business countries and trying to hash out treaties most recent meeting, in Warsaw, ended How the NSA eaves- that articulate global, binding limits on with nations promising they’d come up dropping scandal could greenhouse gases—isn’t working. The new with a universal agreement in Paris next balkanize the Internet or IPCC report itself notes that governments year. Don’t hold your breath. make it safer. Download are increasingly turning to forums outside Achieving consensus among nearly the full Business Report the U.N. to make progress. 200 countries is one challenge for the today for only $20. United Nations on climate policy, but it’s Out of control not necessarily the main one. Another The U.N. became seriously involved in problem is the U.N.’s focus thus far on addressing climate change in 1988, when specifi c emissions limits. Governments technologyreview.com/ it created the IPCC, an organization don’t know how much it will cost to com- businessreports tasked with assessing the science on cli- ply with these limits, because it’s often mate change and laying the foundation for unclear how much low-carbon tech- climate treaties. The IPCC produces volu- nologies will cost to deploy. Climate minous reports every six years or so; the negotiators don’t want to commit their report in April was part of the organiza- governments to a treaty whose economic tion’s fi fth such assessment. An organiza- eff ects are unpredictable. tion designed to actually produce climate What’s more, not every government policy came later, in 1994, when the U.N. is capable of enforcing such regulations. established the Framework Convention Even countries with signifi cant regulatory on Climate Change, which laid ground powers would struggle to monitor and rules for international coöperation on cli- control their overall carbon dioxide emis- mate policy and set the vague yet ambi- sions. As an example, the United States

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Finding technical and management tal- ent for software, financial servicesservices, andand recently set aggressive fuel-economy the European Union, could make a big other technology-driven companies standards for cars. These could reduce impact. Ten countries account for nearly emissions, but total emissions ultimately 70 percent of the world’s total emissions. Paul Edelman, ’78 [email protected] depend on how much people drive. If China, the world’s largest emitter, were A far more effective strategy for reduc- to take measures to reduce emissions (and Rick Kunin, ’79 ing carbon dioxide emissions would be it’s starting to, in part to cut pollution), it [email protected] to encourage international coöperation could then plausibly influence other coun- For confidential consideration, send on investing in new, cleaner energy tech- tries—particularly its key trading part- your resume to [email protected]. nologies and to establish incentives for ners—to implement technology changes. We love working with fellow MIT alums. such investments. But instead, the U.N. Meanwhile, large, wealthy countries has obsessed over setting specific bind- could help poor countries adopt greener www.edeltech.com 508-947-5300 ing emissions limits on greenhouse gases. policies as a way to reap immediate health benefits. For example, the IPCC report Changing climate notes work by a consortium of coun- There is no simple alternative to the U.N. tries to find ways to promote the use of Tech Incubator Space process. But to stand a chance of being cleaner cookstoves in poor countries. Available in Davis Square adopted and making an impact, interna- Conventional stoves used in such coun- tional climate policy will probably have to tries emit soot, which causes respiratory Startups Welcomewelcome start with smaller groups of countries and problems and warms the atmosphere by 32003,200 SFSF inin aa commercialcommercial buildingbuilding focus on single industries or economic absorbing sunlight. Reducing soot emis- sectors. These kinds of policies won’t be sions would have an immediate impact Direct access to bike path enough to stabilize greenhouse-gas levels on warming, because soot—unlike carbon Open layout, Bathrooms,bathrooms, shower,Shower, on their own, but they could slow global dioxide, which lingers in the atmosphere Kitchenette,kitchenette, HVACHVAC warming in the near term. And collab- for centuries—disappears quickly after orations between countries could lay a emissions stop. $4,000 per month plus electric or foundation for more ambitious policies Actions like these don’t have to replace can share half when the costs of low-carbon technolo- the U.N. process—they can easily happen Contact: Brendan at gies come down. alongside it. But diplomats might want to [email protected] The U.S. and China, which can afford spend less time on U.N. talks that aren’t to spend money on R&D and demonstra- making progress and more on smaller tion projects for new energy technologies, efforts that can. Going forward, the U.N. Events need to redouble their efforts. One impor- should focus on things it does well. It may tant area for investment is technology for not be a good forum for hashing out uni- EmTech MIT capturing carbon dioxide from fossil-fuel versal agreements that affect every econ- September 23-25,23–25, 2014, Cambridge MA power plants and permanently storing it. omy in the world, but as countries forge www.technologyreview.com/emtech/14 Carbon capture and storage hasn’t been new agreements, the U.N. can verify that EmTech Spain demonstrated anywhere at a large scale, they’re meeting their obligations. November 11-12,11–12, 2014, Valencia, Spain yet the IPCC says that without it, the cost Simply investing in technology and www.emtechspain.com of stabilizing greenhouse-gas levels could establishing piecemeal policies won’t limit double. At least for some key technolo- warming to two degrees. The IPCC report EmTech Singapore gies, R&D collaborations are happening suggests it’s already too late for that. But January 26-27,26–27, 20152015 Marina Bay Sands, Singapore now: the U.S. and China are collaborating unlike the U.N.’s approach, these efforts www.emtechsingapore.com/ on advanced nuclear power plants that could at least make tangible progress. The could be cheaper and safer. That kind of U.N.’s approach isn’t working. It’s time to coöperation could serve as a model for recognize that and move on. To place your event, program or recruit- future projects. ment ad in MIT Technology Review’s Even a handful of countries, such as Kevin Bullis is MIT Technology Review’s Professional Resources, please contact the U.S., China, India, and members of senior editor for energy. [email protected]. 86

JA14_review.ipcc.indd 86 6/4/14 11:26 AM MIT TECHNOLOGY REVIEW REVIEWS TECHNOLOGYREVIEW.COM VOL. 117 | NO. 4

But even if we can’t get rid of that language, we can force those who use it to do a better job. We would borrow a concept used every day in the physical world.

Obvious in retrospect Of the three flaws, Heartbleed was by far the most significant. It is a bug in a program that implements a protocol called Secure Sockets Layer/Transport Layer Security (SSL/TLS), which is the fundamental encryption method used to protect the vast majority of the financial, medical, and personal information sent over the Internet. The original SSL protocol made Internet commerce possible back in the 1990s. OpenSSL is an open-source implementation of SSL/TLS that’s been around nearly as long. The program has steadily grown and been extended over the years. Today’s cryptographic protocols are thought to be so strong that there is, Imposing Security in practice, no way to break them. But Heartbleed made SSL’s encryption irrel- Computer programmers won’t stop making dangerous errors on evant. Using Heartbleed, an attacker their own. It’s time they adopted an idea that makes the physical anywhere on the Internet could reach world safer. into the heart of a Web server’s memory and rip out a little piece of private data. By Simson L. Garfinkel The name doesn’t come from this meta- phor but from the fact that Heartbleed is a flaw in the “heartbeat” protocol Web three computer bugs this year and the ease with which it leads program- browsers can use to tell Web servers that exposed passwords, e-mails, financial mers to make all manner of errors. Using they are still connected. Essentially, the data, and other kinds of sensitive infor- C to write critical Internet software is like attacker could ping Web servers in a way mation connected to potentially billions using a spring-loaded razor to that not only confirmed the of people. The flaws cropped up in differ- open boxes—it’s really cool until connection but also got them ent places—the software running on Web you slice your fingers. “Heartbleed” to spill some of their contents. servers, iPhones, the Windows operating Alas, as dangerous as it is, flaw in OpenSSL It’s like being able to check into

system—but they all had the same root we won’t eliminate C anytime “Goto fail” a hotel that occasionally forgets cause: careless mistakes by programmers. soon—programs written in C flaw in Apple to empty its rooms’ trash cans Each of these bugs—the “Heart- and the related language C++ operating systems between guests. Sometimes bleed” bug in a program called OpenSSL, make up a large portion of the these contain highly valuable the “goto fail” bug in Apple’s operat- software that powers the Inter- CVE-2014-1776 information. flaw in Internet ing systems, and a so-called “zero-day net. New projects are being Explorer Heartbleed resulted from a exploit” discovered in Microsoft’s Inter- started in these languages all combination of factors, includ- net Explorer—was created years ago by the time by programmers who think they ing a mistake made by a volunteer work- programmers writing in C, a language need C’s speed and think they’re good ing on the OpenSSL program when he

NEIL WEBB NEIL known for its power, its expressiveness, enough to avoid C’s traps and pitfalls. implemented the heartbeat protocol.

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Astro Teller Although any of the mistakes could have it goes ahead and uses that memory again. Captain of happened if OpenSSL had been written According to the security firm FireEye, Moonshots, in a modern programming language like which tracked down the bug after hackers Google[x] Java or C#, they were more likely to hap- started using it against high-value targets, pen because OpenSSL was written in C. the flaw had been in Internet Explorer Apple’s flaw came about because some since August 2001 and affected more than programmer inadvertently duplicated a half of those who got on the Web through Jennifer Lewis Hansjörg Wyss line of code that, appropriately, read “goto traditional PCs. The bug was so signifi- Professor of fail.” The result was that under some con- cant that the Department of Homeland Biologically ditions, iPhones and Macs would silently Security took the unusual step of telling Inspired ignore errors that might occur when try- people to temporarily stop running Inter- Engineering, ing to ascertain the legitimacy of a website. net Explorer. (Microsoft released a patch Harvard University With knowledge of this bug, an attacker for the bug on May 1.) could set up a wireless access point that might intercept Internet communications Automated inspectors between iPhone users and their banks, There will always be problems in anything silently steal usernames and passwords, designed or built by humans, of course. Michael Rhodin Senior Vice and then reëncrypt the communications That’s why we have policies in the physical President, IBM and send them on their merry way. This is world to minimize the chance for errors to Watson Group called a “man-in-the-middle” attack, and occur and procedures designed to catch it’s the very sort of thing that SSL/TLS the mistakes that slip through. was designed to prevent. Home builders must follow building Remarkably, “goto fail” happened codes, which regulate which construc- because of a feature in the C programming tion materials can be used and govern language that was known to be problem- certain aspects of the building’s layout— Erik Brynjolfsson atic before C was even invented! The “goto” for example, hallways must reach a mini- Director, MIT Initiative on the statement makes a computer program mum width, and fire exits are required. Digital Economy jump from one place to another. Although Building inspectors visit the site through- such statements are common inside the out construction to review the work and computer’s machine code, computer sci- make sure that it meets the codes. Inspec- entists have tried for more than 40 years tors will make contractors open up walls to avoid using “goto” statements in pro- if they’ve installed them before getting grams that they write in so-called “high- the work inside inspected. level language.” Java (designed in the early The world of software development 1990s) doesn’t have a “goto” statement, is completely different. It’s common for but C (designed in the early 1970s) does. developers to choose the language they Although the Apple programmer respon- write in and the tools they use. Many Register today: sible for the “goto fail” problem could have developers design their own reliability made a similar mistake without using tests and then run the tests themselves! technologyreview.com/emtech the “goto” statement, it would have been Big companies can afford separate much less probable. quality-assurance teams, but many small MIT Technology Review We know less about the third bug firms go without. venE in large compa- subscribers save 15%. because the underlying source code, part nies, code that seems to work properly is Use promotional code: TRSub of Microsoft’s Internet Explorer, hasn’t frequently not tested for lurking security at registration. been released. What we do know is that it flaws, because manual testing by other was a “use after free” error: the program humans is incredibly expensive—some- tells the operating system that it is fin- times more expensive than writing the Questions? E-mail: ished using a piece of memory, and then original software, given that testing can [email protected]

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reveal problems the developers then have gets() function to make it print the mes- to fix. Such flaws are sometimes called sage “Warning: this program uses gets(), “technical debt,” since they are engineer- which is unsafe.” Soon afterward, devel- ing costs borrowed against the future in opers everywhere removed gets() from the interest of shipping code now. their programs. The solution is to establish software The same sort of approach can be building codes and enforce those codes used to prevent future bugs. Today many with an army of unpaid inspectors. software development tools can analyze Crucially, those unpaid inspectors programs and warn of stylistic sloppiness should not be people, or at least not only (such as the use of a “goto” statement), people. Some advocates of open-source memory bugs (such as the “use after free” software subscribe to the “many eyes” flaw), or code that doesn’t follow estab- theory of software development: that if a lished good-programming standards. Often, though, such warn- Many developers design their own ings are disabled by default reliability tests and then run the tests because many of them can be merely annoying: they themselves. Even in large companies, require that code be rewrit- code that seems to work properly is ten and cleaned up with no frequently not tested for lurking flaws. corresponding improvement in security. Other piece of code is looked at by enough peo- bug-finding tools aren’t even included ple, the security vulnerabilities will be in standard development tool sets but found. Unfortunately, Heartbleed shows must instead be separately downloaded, the fallacy in this argument: though installed, and run. As a result, many OpenSSL is one of the most widely used developers don’t even know about them, Become an EmTech Partner. Email: open-source security programs, it took let alone use them. adsales@ paid security engineers at Google and the To make the Internet safer, the most technologyreview.com Finnish IT security firm Codenomicon to stringent checking will need to be enabled find the bug—and they didn’t find it until by default. This will cause programmers two years after many eyes on the Internet to write better code from the beginning. first got access to the code. And because program analysis tools work Instead, this army of software building better with modern languages like C# and inspectors should be software develop- Java and less well with programs written ment tools—the programs that developers in C, programmers should avoid start- use to create programs. These tools can ing new projects in C or C++—just as it needle, prod, and cajole programmers to is unwise to start construction projects Register today: do the right thing. using old-fashioned building materials This has happened before. For exam- and techniques. technologyreview.com/emtech ple, back in 1988 the primary infection Programmers are only human, and vector for the world’s first Internet worm everybody makes mistakes. Software com- MIT Technology Review was another program written in C. It used panies need to accept this fact and make subscribers save 15%. a function called “gets()” that was com- bugs easier to prevent. Use promotional code: TRSub mon at the time but is inherently insecure. at registration. After the worm was unleashed, the engi- Simson L. Garfinkel is a contributing neers who maintained the core libraries of editor to MIT Technology Review and a the Unix operating system (which is now professor of computer science at the Naval Questions? E-mail: used by Linux and Mac OS) modified the Postgraduate School. [email protected]

6/2/14 11:45 AM JA14_review.heartbleed.inddads.emtech.indd 47 91 6/2/146/3/14 11:45 1:35 PMAM MIT TECHNOLOGY REVIEW VOL. 117 | NO. 4 TECHNOLOGYREVIEW.COM 53 Years Ago

Reading the Mind A 1961 essay speculated on where research into the physical basis of thinking and communication might eventually lead.

biologists of my generation have dealt effectively with two major problems: 1) the search for physical and mental health and the conquest of disease and aging; 2) the search for an understanding of the biochemical foundations of life. We are now beginning a third: the search for the physical basis of mind. To communicate with his fellows, man now transduces his thoughts to spoken or written symbols. These are reasonably sat- isfactory for simple messages, but inadequate for conveying complex conceptual ideas, human emotion, and spirit. Will biophysical research on mind pave the way for bypassing sensory mechanisms? It may not be unreasonable to imagine that this might eventually occur, perhaps at first requiring instrumental prosthetic aids. Pool- ing the diversity of individuals’ learning and endowments by such interpersonal communication could inaugurate a new hierarchy of intelligence and a new kind of science. Other implications of human interthinking as a new advance in evolution have been projected by Teilhard de Chardin and by other speculative thinkers. All advances in our understanding of mental processes, as of other natural phenomena, are made through science, and therefore do not directly touch the ontological problem of the nature of the inner self. Implied here is no attempt by research or sheer intellectual genius to grasp reality by its quantized fore- lock, no suggestion that man’s mind is no more than a quantum mechanical automaton. On the contrary, even such revolutionary discoveries as are here projected would still be science, therefore susceptible, like all scientific endeavor, to beneficent application—but also to ultimate desecration!”

Excerpted from “Life, Science, and Inner Commitment,” by Francis O. Schmitt, in the July 1961 issue of Technology Review.

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