EFTA02585830.pdf

From: Sent: Sunday, July 13, 2014 2:42 AM To: Subject: vagus nerve I'm =ure you read the article below. This reminds me so much of my =ime in Germany, where there were both diagnostic and treatment devices =external to the body) that worked on ideas like the ones =elow. The body is an electrical system and this will =e the century of physics (vs. only chemistry) as a way of diagnosing =nd treating! 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> Magazine Can the =ervous System Be Hacked? SUBSCRIBE I LOG IN mobile.nytimes.com/2014/05/24magazine/can-the-nervous-system-be- hacked.html?J=1&gwhrCA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 1/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> Mirela Mustacevic, who suffers =rom rheumatoid arthritis, had a nerve stimulator implanted as part of a =edical trial. Her symptoms have lessened significantly. SARAH WONG FOR THE NEW =ORK TIMES By MICHAEL BEHAR May 23, 2014 EFTA_R1_01765565 EFTA02585830 One morning =n May 1998, Kevin Tracey converted a room in his lab at the Feinstein Institute for Medical Research in Manhasset, N.Y., into a =akeshift operating theater and then prepped his patient — a rat — =or surgery. A neurosurgeon, and also Feinstein Institute's president, Tracey =ad spent more than a decade searching for a link between nerves and the immune system. =is work led him to hypothesize that stimulating the vagus nerve with =lectricity would alleviate harmful inflammation. "The vagus nerve is behind =he artery where you feel your pulse," he told me recently, pressing his =ight index finger to his neck. The vagus =erve and its branches conduct nerve impulses — called action potentials — to every major organ. But communication between =erves and the immune system was considered impossible, according to the scientific =onsensus in 1998. Textbooks from the era taught, he said, "that the =mmune system was just mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 2/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> cells =loating around. Nerves don't float anywhere. Nerves are fixed =n tissues." It would have been "inconceivable," he added, to propose =hat nerves were directly interacting with immune cells. Nonetheless, =racey was certain that an interface existed, and that his rat would prove it. After anesthetizing the animal, Tracey cut an incision in its =eck, using a surgical microscope to find his way around his patient's =natomy. With a hand- held nerve stimulator, he delivered several one-second electrical pulses =o the rat's exposed vagus nerve. He stitched the cut closed and gave =he rat a bacterial toxin known to promote the production of tumor necrosis factor, or =.N.F., a protein that triggers inflammation in animals, including humans. "We =et it sleep for an hour, then took blood tests," he said. The =acterial toxin should have triggered rampant inflammation, but instead the production =f tumor necrosis factor was blocked by 75 percent. "For me, it was a =ife- changing moment," Tracey said. What he had demonstrated was that the =ervous system was like a computer terminal through which you could deliver commands to =top a problem, like acute inflammation, before it starts, or repair a body =fter it gets sick. "All the information is coming and going as electrical =ignals," Tracey said. For months, he'd been arguing with his staff, whose members =onsidered this rat project of his harebrained. "Half of them were in the hallway =etting against me," Tracey said. mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 3/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> The Health Issue The MacGyver Cure for Cancer By =ONNIE ROCHMAN To =revent a deadly disease, start with a headlamp. 2 EFTA_R1_01765566 EFTA02585831 WELL Inflammatory afflictions like =heumatoid arthritis and Crohn's disease are currently treated with drugs — painkillers, steroids and what =re known as biologics, or genetically engineered proteins. But such medicines, =racey pointed out, are often expensive, hard to administer, variable in their efficacy =nd sometimes accompanied by lethal side effects. His work seemed to =ndicate that electricity delivered to the vagus nerve in just the right intensity and =t precise intervals could reproduce a drug's therapeutic — in this =ase, anti-inflammatory — reaction. His subsequent research would also show that it could do so =ore effectively and with minimal health risks. Tracey'= efforts have helped establish what is now the growing field of bioelectronics. He has grand hopes for it. "I think this is the =ndustry that will replace the drug industry," he told me. Today researchers are =reating implants that can communicate directly with the nervous system in order to try to =ight everything from cancer to the common cold. "Our idea would be =anipulating mobile.nytimes.com/2014/05/24magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CAO1B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 4/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> neural input =o delay the progression of cancer," says Paul Frenette, a =tem-cell researcher at the Albert Einstein College of Medicine in the Bronx who =iscovered a link between the nervous system and prostate tumors. "The =ist of T.N.F. diseases is long," Tracey said. "So when =e created SetPoint" — the start-up he founded in 2007 with a physician and researcher at =assachusetts General Hospital in Boston — "we had to figure out what =e were going to treat." They wanted to start with an illness that could be mitigated by blocking =umor necrosis factor and for which new therapies were desperately needed. =heumatoid arthritis satisfied both criteria. It afflicts about 1 percent of the =lobal population, causing chronic inflammation that erodes joints and eventually makes =ovement excruciating. And there is no cure for it. In September =011, SetPoint Medical began the world's first clinical trial to =reat rheumatoid-arthritis patients with an implantable nerve stimulator based =n Tracey's discoveries. According to Ralph Zitnik, SetPoine= chief medical officer, of the 18 patients currently enrolled in the ongoing trial, two-thirds have =mproved. And some of them were feeling little or no pain just weeks after =eceiving the implant; the swelling in their joints has disappeared. "We took =evin's concept that he worked on for 10 years and made it a reality for people in a =eal clinical trial," he says. 3 EFTA_R1_01765567 EFTA02585832 Kevin Tracey, = neurosurgeon, studies the effects of stimulating nerves with electricity to fight disease. KATHERINE WOLKOFF FOR =HE NEW YORK TIMES Conceptually, =ioelectronics is straightforward: Get the nervous system to tell the body to heal itself. But of course it's not that simple. "=hat we're trying to do mobile.nytimes.com/2014/05/24magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 5/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> here is =ompletely novel," says Pedro Irazoqui, a professor of =iomedical engineering at Purdue University, where he's investigating =ioelectronic therapies for epilepsy. Jay Pasricha, a professor of medicine and neurosciences at =ohns Hopkins University who studies how nerve signals affect obesity, =iabetes and gastrointestinal-motility disorders, among other digestive diseases, =ays, "What we're doing today is like the precursor to the Model T." The biggest =hallenge is interpreting the conversation between the body's =rgans and its nervous system, according to Kris Famm, who runs the newly =ormed Bioelectronics R. & D. Unit at GlaxoSmithKline, the world's =eventh-largest pharmaceutical company. "No one has really tried to speak the =lectrical language of the body," he says. Another obstacle is building small =mplants, some of them as tiny as a cubic millimeter, robust enough to run powerful =icroprocessors. Should scientists succeed and bioelectronics become widely adopted, =illions of people could one day be walking around with networked computers hooked =p to their nervous systems. And that prospect highlights yet another concern =he nascent industry will have to confront: the possibility of malignant =acking. As Anand Raghunathan, a professor of electrical and computer engineering at Purdue, puts it, bioelectronics "gives me a remote control to =omeone's body." Despite the =ncertainties, in August, GlaxoSmithKline invested $5 million in SetPoint, and its bioelectronics R. & D. unit now has partnerships =ith 26 independent research groups in six countries. Glaxo has also established = $50 million fund to support the science of bioelectronics and is offering a =rize of $1million to the first team that can develop an implantable device that =an, by recording and responding to an organ's electrical signals, exert =nfluence over its function. Instead of drugs, "the treatment is a pattern of =lectrical impulses," Famm says. "The information is the treatment." In =ddition to rheumatoid arthritis, Famm believes, bioelectronic medicine might someday treat hypertension, asthma, diabetes, epilepsy, infertility, obesity and =ancer. "This is not a one-trick pony." mobile.nytimes.com/2014/05/24magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CA016525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 6/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> Kevin Tracey, who is 56, came to bioelectronics because of two =ignificant deaths. The first occurred when he was in preschool. He was 5 when his =other died as a result of an inoperable brain tumor. Shortly after the =uneral, Tracey found his maternal grandfather, a professor of pediatrics at Yale, alone =n his den. "1 climbed onto his lap and asked what happened," Tracey =ays. "He explained that surgeons tried to take it out but couldn't separate the =rain-tumor 4 EFTA_R1_01765568 EFTA02585833 tissue from the normal neurons. I remember saying to him, 'Somebody should do =omething about that.' That was when I decided to be a neurosurgeon. I =anted to solve problems that were insolvable." SHOCK TREATMENT During = 20-minute operation, a neurosurgeon will slide SetPoint Medical's bioelectronic implant onto the vagus nerve on the left side of a patient's neck, and then snap on an outer housing called the Pod to hold the device in place. Once the implant is activated, electrical impulses transmitted from the implant will communicate directly with immune cells in the spleen and the gastrointestinal tract, inducing them to reduce the production of cytokines — molecules that are involved in inflammation. To recharge the device's batteries and update its software, patients and physicians will use an iPad app to control a wearable collar that transmits power and data wirelessly through the skin. VAGUS NERVE IMPLANT mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 7/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com chttp://NYTimes.com> POD Illustration by =lint Ford Tracey'= second formative experience took place in May 1985. Having trained for neurosurgery at Cornell, he was on rotation for his residency in the =mergency room at New York Hospital when an 11-month-old baby girl named Janice =rrived in an ambulance with burns covering 75 percent of her body. Her =randmother was cooking when she tripped and doused Janice with a pot of boiling =oodles. After three weeks in the burn unit recovering from skin grafts, Janice =ppeared to stabilize. Tracey joined Janice's family to celebrate her first =irthday in her mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 8/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> hospital =oom. Janice was upbeat, smiling and giggling. The next day, she was dead. "I =as haunted by her case," Tracey says. When the autopsy report =as inconclusive, Tracey redirected his energy into medical research, =pecifically inflammation related to sepsis, which he believed contributed to =anice's unexpected death. Sepsis occurs when the immune system goes into =verdrive, producing a potentially lethal inflammatory response to fight a severe =nfection. At the time of her death, however, Janice did not have an infection. It =ook another year to figure out that it was an overproduction of tumor =ecrosis factor — the catalyst for inflammation — that caused Janice =99s septic shock, though her death remains a mystery. 5 EFTA_R1_01765569 EFTA02585834 "Her =rakes had failed," Tracey says. "She made too much =.N.F. The obvious question was, why?" He credits Linda Watkins, a neuroscientist =t the University of Colorado, Boulder, for furnishing the pivotal clue. In the mid-1990s, =atkins was exploring possible neural connections between the brain and the =mmune system in rats by injecting them with cytokines — molecules =hat, like tumor necrosis factor, contribute to inflammation — to cause fevers. =ut when she cut their vagus nerves, the fever never materialized. Watkins concluded that =he vagus nerve must be the conduit through which the body signals the brain to =nduce fever. Tracey =ollowed her lead by giving mice a toxin known to cause inflammation and then dosing them with an anti- inflammatory drug he had been =nvestigating. "We injected it into their brains in teeny amounts, too small to get into =heir bloodstream," he says. The drug did what it was supposed to do: =t halted the production of tumor necrosis factor in the brain. Surprisingly, it also =alted the production of tumor necrosis factor in the rest of the body. When Tracey =ut the vagus nerve, however, the drug had no effect in the body. mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 9/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> SetPoint Medical's new =eural implant (currently being tested on animals). KATHERINE =OLKOFF FOR THE NEW YORK TIMES "That =as the eureka moment," he says. The signal generated by the =rug had to be traveling from the brain through the nerve because cutting it blocked =he signal. "There could be no other explanation." Tracey then =ondered if he could eliminate the drug altogether and use the nerve as a means of speaking directly to the immune system. "But there =as nothing in the scientific thinking that said electricity would do anything. It was =nathema to logic. Nobody thought it would work." After that first surgery on the rat in 1998, Tracey spent 11years mapping =he neural pathways of tumor-necrosis-factor inflammation, charting a route =rom the vagus nerve to the spleen to the bloodstream and eventually to =itochondria inside cells. "We now know more about this electrical circuit to =reat [inflammation) than is known about some clinically approved drugs,"=Tracey says. By 2009, =etPoint felt ready to test Tracey's work on people with =heumatoid arthritis, and Ralph Zitnik was approached about joining the company. =E2 It was nuts," Zitnik told me. "Sticking something on the vagus =erve to take away R.A.? People would think it's witchcraft." Zitnik's =ackground was in pharmaceuticals; at Amgen, he contributed to the development of Enbrel, a =heumatoid-arthritis drug that had $4.7 billion in sales last year, which made it No. 7 on =he industry's best-seller list. But the more he talked with Tracey and pored over the =esearch, the more he said to himself: "There is good science behind this. = thought, This could =ork." 6 EFTA_R1_01765570 EFTA02585835 mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 10/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> Zitnik'= first task at SetPoint was to recruit a lead scientist to set up a =linical trial. Many scientists in the United States and Europe were hesitant to =o it, he says, but eventually he hired Paul-Peter Tak, a well-regarded =mmunologist and rheumatologist based at the Academic Medical Center, the University of Amsterdam's teaching hospital. "He was a =orward-thinking person willing to try an unconventional approach like this," Zitnik says. Tak in turn =fired Frieda Koopman, who was working on her Ph.D. in rheumatology at A.M.C., to find potential patients in the Netherlands and elsewhere in Europe. The day after =n article about the planned trial appeared in a Dutch newspaper, Koopman's office got more than a thousand calls from =heumatoid-arthritis patients begging to participate. "We never saw that coming,"=Koopman says. "We thought we might get one or two patients to join, and wouldn't =hat be nice." Invasive surgery was involved, after all. Koopman's team =eturned almost every call and selected several subjects based on what medications they had =ried and the severity of the pain and swelling in their joints. Over the next two =ears, her team continued to enroll new patients. The subjects =n the trial each underwent a 45-minute operation. A neurosurgeon fixed an inchlong device shaped like a corkscrew to the vagus nerve on =he left side of the neck, and then embedded just below the collarbone a =ilver-dollar- size "pulse generator" that contained a battery and =icroprocessor programmed to discharge mild shocks from two electrodes. A thin wire made of a =latinum alloy connected the two components beneath the skin. Once the implant was =urned on, its preprogrammed charge — about one milliamp; a small LED =onsumes 10 times more electricity — zapped the vagus nerve in 60-second bursts, =p to four times a day. Typically, a patient's throat felt constricted and tingly =or a moment. After a week or two, arthritic pain began to subside. Swollen joints shrank, and =food tests that checked for inflammatory markers usually showed striking =eclines. Koopman told =e about a 38-year-old trial patient named Mirela Mustacevic whose rheumatoid arthritis was diagnosed when she was 22, and who had =ince mobile.nytimes.com/2014/05/24magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CAO1B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 11/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> tried nine =ifferent medications, including two she had to self-inject. Some of them helped but had nasty side effects, like nausea and skin rashes. =efore getting the SetPoint implant in April 2013, she could barely grasp a pencil; now =he's riding her bicycle to the Dutch coast, a near-20-mile round trip from =er home. Mustacevic told me: "After the implant, I started to do things I =adn't done in years — like taking long walks or just putting clothes on in the =orning without help. I was ecstatic. When they told me about the surgery, I was a bit =orried, because what if something went wrong? I had to think about whether it =as worth it. But it was worth it. I got my life back." 7 EFTA_R1_01765571 EFTA02585836 In February, I met Moncef Slaoui, Glaxo's chairman of Global Research =nd Development, at one of the company's 16 facilities he oversees =orldwide, this one in King of Prussia, Pa. Slaoui, who is 55 and has a Ph.D. in =olecular biology and immunology, was instrumental in developing the first malaria vaccine =nd is considered one of the most influential executives in the pharmaceutical =ndustry. "When =ris came to me in early 2012 with this idea of vagus nerve =timulation," Slaoui told me, "I was like: Cmon? You're gonna =ive a shock and it changes the immune system? I was very skeptical. But finally I agreed to visit =evin's lab. I wanted the data, the evidence. I don't like hot air." He =ent to Tak, the lead scientist for the trials. "I asked him, 'Paul-Peter, is =t really real?'" After getting =n endorsement from Tak, who is now Glaxo's global head of immuno-inflammation research, Slaoui committed to financing SetPoint. =he investment was modest, though, because he felt that Tracey's =evice was "just a starting point. It was still very broad — you touch the vagus =erve, you touch most of your viscera. We had wanted something very specific." What he =idn't want was "the bulldozer approach" that characterizes already =xisting stimulators for treating Parkinson's, chronic pain and epilepsy. (Pacemakers =iffer because they stimulate muscle, not nerves.) These devices are indiscriminate, =lasting electricity into billions of neurons and hoping for the best. As Slaoui =aw it, SetPoint's stimulator was a primitive forerunner to "a =evice that reads your mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CAO1B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 12/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYlimes.com> electrical =mpulses and sees when something is wrong, then corrects what needs correcting." In 2006, =laoui continued, "when I became chairman of R. & D., R. =amp; D. was a liability to this company. We were spending lots of money and not =roducing new molecules for new medicines. I had to acknowledge that the current way =f doing R. & D. wasn't likely to be successful." Four years =ater, Slaoui put together a 14- member think tank and discussed, among other topics, the Human Brain =roject. The multinational endeavor, directed by the neuroscientist and Fulbright =cholar Henry Markram, at the Swiss Federal Institute of Technology in Lausanne, =s trying to create a computer simulation of the human brain. That got =laoui "thinking about electrical signaling, an opportunity to make =edicine — a therapeutic intervention — that's super highly specific =n terms of its geographic position. I'm going to go to the nerve that goes to your kidney =nd nowhere else, and only to your left kidney, and to a particular area of the left =idney." That degree =f precision would address one of Slaoui's major criticisms of conventional drugs: They flood the body, and then doctors have to hope =hat they will perform only where they're supposed to. "It is =eally difficult to design a molecule that will only interact where you want it, because it goes =verywhere." The upshot, usually: side effects. Bioelectronics could potentially =liminate those, as well as the costly redundancy involved in the drug-discovery process, =n which every promising molecule must be independently evaluated. "There =s very little that is transposable from one molecule to the next," Slaoui =aid. "You have to redo everything." Bioelectronics attracted him, he says, because =E2 95 percent of the hardware is the same," no matter what disease it treats. So Slaoui =ound himself working for a drug company while devoting himself to the idea of treating illness without drugs. In July 2012, he and Famm toured Markram's facilities in Lausanne. There Markram showed them a =-D digital visualization on a giant screen of 100,000 synapses actively firing in a =ouse brain. 8 EFTA_R1_01765572 EFTA02585837 mobile.nytimes.com/2014/05/24magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA016525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 13/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> At that =oment, Famm says, he and Slaoui realized they were "biting off =oo much." Slaoui and Famm concluded that starting with the brain =E2 which seemed logical, given that it's the body's C.P.U. — =ould take decades to yield viable treatments. The human brain's circuitry, with 100 billion =eurons, seemed far too complex. "Why don't we just skip the brain and go =traight to the organs?" Slaoui suggested. Right then, =laoui said, "we decided to focus on the peripheral nervous =ystem." The peripheral nerves link the brain and spinal cord (the central =ervous system) to the organs and limbs. Rather than try to fathom the brain — a =lack box, basically, with its 100 trillion neural connections — Slaoui =roposed that they put "an interface between a nerve and the organ with an electrical =evice." To eavesdrop on a telephone call, his thinking went, you don't tap =nto the switching center and search for the conversation. You go to the line nearest the =aller's location. Compared with the brain, the cablelike bundles that are the =eripheral nerves contain vastly fewer fibers — hundreds versus billions. When I joined Famm in Philadelphia in February, he referred to his role as Glaxo's bioelectronics chief as "like being a =issionary." Famm, who lives in London, was in the U.S. to attend half a dozen meetings with =ioelectronics researchers. His challenge is coaxing those from disparate disciplines =o embrace a singular vision. Whereas drug discovery primarily involves like-minded =hinkers — molecular biologists, chemists, geneticists — =ioelectronics calls for alliances between experts in fields that in many cases have little to do with =edicine — nanotech, optics, electrical engineering, materials science, computer programming, wireless networking and data mining. At the moment, Famm is focused on getting what he called a "transdisciplinary" =roup of scientists to agree on how to solve two key technical challenges. The first is =hrinking the hardware. It must be small enough to attach to virtually any nerve yet still have enough battery power and circuitry to run =lgorithms that generate the patterns of electrical impulses needed to treat various =iseases. At mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CAO1B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 14/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> the Charles =tark Draper Laboratory in Cambridge, Mass., we met with a team working on miniaturization. Draper is best known for internal navigation =ystems that guide things like ballistic missiles and spaceships. Bryan =cLaughlin, who directs bioelectronics development at Draper, showed me the latest =rototype mock-up — a dime-size implant. It's small, he said, but =ot nearly small enough. McLaughlin wants to get its electrodes, microprocessor, battery and a =ireless transmitter into a device no larger than a jelly bean. "W= also important to make it closed-loop, with the ability to read and write to the nervous system. =90 The goal, in other words, is to end up with something that can continuously =onitor a patient and then dispense bioelectronic therapy as needed. The second =hallenge is devising a method to make sense of signals emanating simultaneously from hundreds of thousands of neurons. Accurate recording =nd analysis are essential to bioelectronics in order for researchers to 9 EFTA_R1_01765573 EFTA02585838 =dentify the discrepancies between baseline neural signals in healthy individuals and =hose produced by someone with a particular disease. The conventional approach =o recording neural signals is to use tiny probes with electrodes inside =ailed patch clamps. A prostate-cancer researcher, for example, could attach patch =lamps to a nerve linked to the prostate in a healthy mouse and record the activity. =he same thing would be done with a mouse whose prostate had been genetically engineered to produce malignant tumors. Comparing the output from both =ight allow the researcher to determine how the neural signals differ in =ancerous mice. From such data, a corrective signal could be programmed into a =ioelectronic device to treat the cancer. But there are =rawbacks to using patch clamps. They can sample only one cell's activity at a time, and therefore fail to gather enough data to see the =ig picture. As Adam E. Cohen, who teaches chemistry and physics at Harvard, puts it, =E2 It's like trying to watch an opera through a straw." Cohen, an expert in an emerging field called optogenetics, thinks he can overcome the limitations of the patch clamps. His research is trying to =se mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 15/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> optogenetics =o decipher the neural language of disease. "Getting patch =lamps into a single [neuron] is extremely slow and laborious — about =n hour per cell," Cohen told me when I visited his lab recently. "The bigger =roblem is that [neural] activity comes not from the voices of individual neurons but from a =hole orchestra of them acting in relation to each other. Poking at one at a =ime doesn't give you the global view." Optogenetics =rose out of a series of developments in the 1990s. Scientists knew that proteins, called opsins, in bacteria and algae generated =lectricity when exposed to light. Optogenetics exploits this mechanism. Opsin genes are =nserted into the DNA of a harmless virus, which is then injected into the brain =r a peripheral nerve of a test subject. By choosing a virus that prefers =ome cell types over others, or by altering the virus's genetic sequence, =esearchers can target specific neurons — cold- or pain-sensing, for example — =r regions of the brain known to be responsible for certain actions or behaviors. Next, an =ptical fiber — a spaghetti-thin glass cable that transmits light from its tip — =s inserted through the skin or skull to the site of the virus. The fiber's light =ctivates the opsin, which in turn conducts an electrical charge that forces the neuron to fire. =esearchers have already controlled mouse behavior with optogenetics — =nducing sleep and aggression on command. Before opsins =an be used to activate neurons involved in specific ailments, however, scientists must determine not only which neurons are =esponsible for a particular disease but also how that disease communicates with the =ervous system. Like computers, neurons speak a binary language, with a =ocabulary based on whether their signal is on or off. The specific sequence, =nterval and intensity of these on-off shifts determine how information is conveyed. =ut if each disease can be thought of as speaking its own language, then a =ranslator is needed. What Cohen and others recognized was that optogenetics can do =hat job. So Cohen reverse-engineered the process: Instead of using light to =ctivate neurons, he used light to record their activity. mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 16/22 10 EFTA_R1_01765574 EFTA02585839 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> Cohen showed =e his "Optopatch" machine. It consisted of red and blue =asers, mirrors, lenses, a high-speed digital camera, a video projector, a =icroscope and several quiet cooling fans. After he turned it on, a postdoc fellow who =orks in his lab, Shan Lou, inserted a petri dish under its microscope. The dish =ontained 11live neural cells from mice, harvested from dorsal-root ganglia, which =elay sensory input to the brain. Lou added a few drops of capsaicin extract, =he irritant in pepper spray, and then turned the camera on for 14 seconds. In that =rief period, it snapped 7,000 frames, totaling 12 gigabytes of data. To =nalyze it, Cohen had written software that searches for patterns by employing techniques developed for digital voice and face recognition. "We also use =lgorithms and optical tricks derived from astrophysics," Cohen said. Seconds =ater, an analysis appeared on Lou's computer screen. Three of the 11 cells had =een identified as firing in response to the capsaicin, indicating that they were =ain-sensing neurons. It would have taken Cohen more than a day to record and make sense of =hat cellular information with a patch clamp. This sort of effort was a step, =e said, "toward imaging large numbers of neurons in parallel, hundreds, =erhaps thousands." Cohen is =ollaborating with Ed Boyden, a professor of neuroscience at M.I.T. and = pioneer in optogenetics, to develop the so-called closed-loop implant =nvisioned by Bryan McLaughlin at Draper Labs. Optogenetics, Boyden told me, =nables him to "aim light at some subset of cells (without) activating all =he stray cells nearby." Opsins might point the way to future treatments for all kinds of diseases, but researchers will most likely have to develop bioelectronic devices that =on't use them. Using genetically engineered viruses is going to be tough to get =ast the F.D.A. The opsin technique hinges on gene therapy, which has had limited =uccess in clinical trials, is very expensive and seems to come with grave =ealth risks. Cohen =entions two alternatives. One involves molecules that behave like =psins; another uses RNA that converts into an opsinlike protein — =ecause it doesn't mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 17/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> alter DNA, it =oesn't have the risks associated with gene therapy. Neither approach is very far along, however. And "you still face the =roblem of getting the light in," he says. Boyden is developing a brain implant with a =uilt-in laser, but Cohen believes an external light source is more likely for most =ioelectronics applications. Surmounting =hese sorts of technical hurdles "might take 10 years," =amm figures. That seems somewhat optimistic if you consider Glaxo's =nvestment so far in bioelectronics. Melinda Stubbee, the company's director of =ommunications, says it has spent roughly $60 million in the area, a pittance compared =ith its $6.5 billion in total R. & D. expenditures in 2013. Slaoui, =efending the number, said, "Funding of R. & D. is like an investment" =94 money only flows toward bankable ideas. While he thinks the area shows promise, he seems to want independent researchers to do the legwork before Glaxo buys in further. At one point, =amm referred to detractors who say bioelectronics is "too =isky, will take too long and is maybe even a bit bonkers." In trying =o find some of them, I contacted a number of financial analysts who track Glaxo and the pharmaceutical industry. One, Mark Clark, at Deutsche Bank, said to me =n an email: "I know next to nothing about this early-stage =echnology! I am prepared to bet you will not find a single Glaxo analyst that knows anything about =his! 11 EFTA_R1_01765575 EFTA02585840 Research technologies were a vogue thing to be expert on in the '9=s and tech- bubble years, but we only care about drugs that are actually in the =finical pipeline these days, not how they get there — to be brutally blunt!"= In short, the =ledgling bioelectronics industry is nowhere near mature enough for analysts to make meaningful estimates about its revenue potential. But =eople like Clark will certainly begin paying closer attention if =ioelectronics starts to capture even a sliver of the lucrative pharmaceutical market. Drug sales =or rheumatoid arthritis alone were $12.3 billion in 2012. That looks like a =ig opportunity to an outfit like SetPoint. mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CAO1B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 18/22 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> Yet if large =umbers of patients someday choose bioelectronics over drugs, another issue awaits resolution: security. Bioelectronics devices will =eature wireless connectivity so they can be fine-tuned and upgraded, "jus= like the software on your iPhone," Famm says. And wireless means =ackable, an unsettling fact that worries two experts on medical- device security: Niraj Jha, a =rofessor of electrical engineering at Princeton University, and Anand Raghunathan, =ho runs the Integrated Systems Laboratory at Purdue. Fears of =edical devices being hacked aren't new. In 2007, Dick =heney's cardiologist disabled the wireless functionality in the former vice =resident's defibrillator to prevent terrorists from trying to stop his heart. Jha =nd Raghunathan, along with the lead author, Chunxiao Li, detailed how this =ight be accomplished in a seven-page paper they wrote, "Hijacking an =nsulin Pump," published in June 2011. The paper described a hack they performed in =heir lab using inexpensive, off-the-shelf hardware. According to =ha and Raghunathan, there are no known cases of malicious attacks on medical devices. Nevertheless, Raghunathan says, "Society should be warned about these possibilities." The Department of Homeland Security =s no doubt worried, addressing the potential threat in an alert it issued last =une. In August, the F.D.A. offered guidelines to medical-device manufacturers, =ecommending "wireless protection" to reduce "risks to =atients from a security breach." Whether bioelectronics developers do anything to thwart hacking (the ..D.A. guidelines are not mandatory) may ultimately depend on whether Jha and Raghunathan's fears are realized. Draper= McLaughlin doesn't dismiss these concerns but notes that there =s no "incentive for device companies to do anything about =ecurity." He adds: "Nobody has been sued. No patient has died. But the first event that occurs with =ne of these devices — companies will jump on it and create secure =latforms." SetPoint's chief technology officer is Mike Faltys, a medical engineer who =as mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CAO1B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 5/27/14 19/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> 12 EFTA_R1_01765576 EFTA02585841 integral to =esigning the modern cochlear implant. Faltys worked for six years out of his garage, first re-engineering an existing electrical stimulator, =sed to stop seizures, that became the device implanted in patients in SetPoint'= trial, and more recently finishing a significantly more advanced implantable unit =hat he calls "the microregulator." Housed in a =od shaped like a hot-dog bun and the size of a multivitamin, the entire microregulator is entirely self- contained — onboard =attery, microprocessor and electrodes are integrated into a single unit. It can =e wirelessly recharged, and adjusted and updated with an iPad app. The =urgery to clamp it onto the vagus nerve will take about 20 minutes, and once in =lace, it will provide pain relief to a rheumatoid-arthritis patient for a decade or =ore before it needs servicing. On one =ccasion during my travels with Famm, I got to hold SetPoint's newfangled microregulator. For now, it's only capable of =ransmitting very crude signals to communicate with the nervous system — more like =runts and groans rather than the precise vocabulary that Slaoui envisions for =ioelectronic therapies. Even so, the microregulator felt elegant and powerful and =romising in my palm. "A patient gets a device like this implanted once for =ne disease, and they're done," Tracey says. "No prescriptions, =o medicines, no injections. That's the future. That's what gets me out of bed in the morning."= Michael Behar writes about science and the environment. His =ork has appeared in "The Best American Travel Writing" and "The =est American Science and Nature Writing." Editor: Dean Robinson SHARE SAVE 70 COMMENTS More In Magazine » mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 20/22 5/27/14 Can the Nervous =ystem Be Hacked? - NYTimes.com <http://NYTimes.com> My No-Soap, No-Shampoo, =acteria-Rich Hygiene Experiment What happens when you =eave cleanliness up to your microbiome? THE HEALTH ISSUE The MacGyver Cure for Cancer To prevent a =isease that kills a woman every two minutes in the developing world, =tart with a headlamp. WELL 4 Days, 11Pounds A new study =uggests that minimal calories and maximal exercise can significantly reduce body fat in just four days — and the loss lasts for =onths. 13 EFTA_R1_01765577 EFTA02585842 Back to top Home World U.S. Politics The Upshot N.Y. / Region Business Day Technology Sports Opinion Science Health Arts Style Photos Video Most Emailed mobile.nytimes.com/2014/05/2=/magazine/can-the-nervous-system-be- hacked.html?_r=l&gwh=CA01B525=89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 21/22 5/27/14 Can the Nervous System Be Hacked? - NYTimes.com More Sections Settings Help Download the NYTimes app Feedback =erms of Service Privacy © 2014 The New York Times Company 14 EFTA_R1_01765578 EFTA02585843 mobile.nytimes.com/2014/05/2-/magazine/can-the-nervous-system-be- hacked.html?J=1&gwh=CA016525.89ABED1E295E68FDD9790E2&gwt=pay&assetType=nyt_now&referre= 22/22 15 EFTA_R1_01765579 EFTA02585844