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daniel S. levine

40 The Journal of Life Sciences fall 2009 Lost in Translation Eric Topol doesn’t just want to understand the genes that drive illness and wellness, he wants to make sure that such knowledge actually changes the way doctors practice medicine.

By Daniel S. Levine

hortly after arriving in La Jolla, Califor- the hospital and makes sure you have coffee nia nearly three years ago, Eric Topol and know where the restrooms are,” he says. Sfound himself addressing a room full of Individualized medicine is “not about treating San Diego’s business leaders at the exclusive someone as a VIP.” University Club with its grand views of the city It wasn’t surprising that weeks after landing in below. The former top cardiologist at Cleveland San Diego, Topol would declare that the city’s Clinic had just recently come to town to become future lies in individualized medicine. After all, director of the Translational Science Institute he was leading an effort in translating an under- at the Institute, the world’s standing of human genetics into better medi- largest independent non-prof- cine. But it was not an it biomedical research facili- idle boast. Since he first ty. Topol, who was speaking The future of medicine settled in at the Scripps about the future of medicine, Institute in January told the crowd at the end of his is going to be integrating 2007, Topol has been talk in March 2007, “You folks genomic science into doing everything in are known for wireless and you his power to make it are known for tourism. But in the clinical treatment of so. As a high-profile the future you are going to be individuals and there are researcher and clini- known for the future of medi- cian, his goal is not just cine, for genomics, and indi- not very many physicians to find genes that can vidualized medicine.” make medicine more If Topol succeeds in his who are equipped today predictive, preventive, efforts to lead broad genom- to perform that or to and, individualized. He ics studies at Scripps—that wants also to make sure talk won’t be the last time that bring genomics into the these findings get test- San Diego’s business elite hear clinic. In that sense, Eric is ed in the clinic and put about individualized medicine. into practice. The term refers to whole medi- already a global leader. “The future of medi- cal approach that incorporates —David Gollaher, President and CEO, cine is going to be inte- the knowledge of a particular California Healthcare Institute grating genomic sci- individual’s genetics to deliv- ence into the clinical er appropriate care. “It’s about treatment of individu- being able to understand what makes a person als and there are not very many physicians who Eric Topol, director of the Scripps either susceptible, or protected, or responsive, are equipped today to perform that or to bring Translational Science or unresponsive to various treatments, devices, genomics into the clinic,” says David Gollaher, Institute, is branching drugs, or whatever,” says Topol, who at 55 has president and CEO of the California Healthcare out beyond Institute, a La Jolla, California-based biophar- genomics to include the fit appearance you’d expect in a cardiologist wireless healthcare (at least one you’d trust). Topol, however, bris- maceutical industry advocacy group. “In that technology in his tles at the mention of “personalized medicine,” sense, Eric is already a global leader. There’s no work in the hopes of the more commonly used term for this new question about it. That’s the mission he’s taken translating findings about genes into field, saying it confuses patients. “It sounds like up. He’s the prophet of genomics and genomic improved care for a concierge, the person who takes you around science.” patients

4 1 The Journal of Life Sciences fall 2009 daniel S. levine

This is something that’s very near and dear to him. Can we leverage genetics and genomics? That’s one question—can we design drugs or trials that target people with certain genetic profiles. The other one is to maybe leverage wireless technologies.

—Nicholas Schork, Director of Research, Scripps Genomic Medicine Program

Gollaher notes there is always a big lag between West Foundation to launch the West Wireless basic scientific discoveries and their application Health Institute. The organization is set to con- in the clinic. He points to the 19th-century dis- duct clinical research on the use of wireless sen- coveries of Robert Koch and Louis Pasteur and sors to prevent, monitor, and manage disease the germ theory of disease, which took more in patients. And, he’s mapped out plans for a than a generation to be incorporated into clini- medical school at Scripps with a focus on trans- cal medicine in the form of antiseptics. “There lational medicine. But that project for now is will be a lag,” he says, “and it will be people like stalled over resolving the issue of a $100-mil- Eric who compress that and make it available lion naming grant. earlier rather than later.” Were all that not enough, he’s been earning Though Topol’s office sits along the fabled Tor- style points, too. In 2008, he was one of 10 medi- rey Pines Golf Course, he says he doesn’t get to cal researchers named a “Rock Star of Science.” play often enough to be any good. It’s no wonder. The distinction resulted in Topol being fea- Topol examines a map Since arriving in La Jolla, he’s been quite busy. tured in a GQ magazine photo spread wear- of the United States Among the accomplishments he can already ing designer garb alongside Sheryl Crow, Seal, that tracks patients check off on his list: He’s brought together basic Will.i.am, Joe Perry, and Josh Groban. It was in the Wellderly Study. His daughter science researchers and clinicians from the dis- part of a campaign by designer Geoffrey Beene Sarah Topol (right), parate arms of Scripps to launch the Scripps called “Geoffrey Beene Gives Back” to call atten- a registered nurse, Translational Science Institute. He led the insti- tion to the contributions of medical research- heads up recruitment of participants for the tute’s successful effort to land a $20-million ers and the need to accelerate the translation of groundbreaking look grant from the National Institutes of Health discoveries into cures. “I never have enough to at the genes of healthy under its Clinical and Translational Science do,” says Topol. “I require a lot of stimulation or people older than Awards program—the only non-university to I get bored.” 80 who have never suffered from chronic date to win such an award. He’s also attracted Boredom shouldn’t be a problem for Topol diseases. $45 million in funding from the Gary and Mary at the Scripps Translational Science Institute.

42 The Journal of Life Sciences fall 2009 Already, the genomics projects are stacking up. African Americans cannot properly metabolize Among the most compelling is the “Wellderly the drug. The study is being run in conjunction Study,” an examination of the DNA of people 80 with all of the Scripps medical facilities, giving and older who have had no history of chronic researchers access to data from a broad patient disease. The goal is to unlock the genetic secrets cross-section. “They’re taking a drug for $4 a to longevity. Topol says to date, medical research day for the rest of their lives or whatever, and it has largely centered on finding genetic markers doesn’t work,” says Topol, who notes there are for disease. This focus on sickness has neglected other therapies available for such patients. “It’s the genetics of health. an exciting project because using this test could Already, 750 people have enrolled in the study. become the norm some day.” Though the results are preliminary, the findings Topol’s interest in genetics started long before so far are surprising. The wellderly appear to his medical career. Born in Queens, New York have the same bad genes—those that have been and raised in the Long Island suburb of Ocean- linked to such illnesses as Alzheimer’s, heart side, Topol was bored with high school, having disease, and cancer—as everyone else. However, skipped two grades. At just 15, he entered the there is an early indication that they may also in Charlottesville. As a col- have modifier genes that are unique to them. lege student in 1975 he wrote his thesis on “The These genes appear to mediate the expression Prospects for Genetic Therapy in Man.” of the disease-linked genes. He supported himself in college by work- Another major study underway is an effort ing the night shift at the UVA hospital. He had to find out the behavioral impact of personal planned to become a biomedical engineer, but genetic testing on people who want to learn that changed when he saw patients in the inten- their potential risk for developing certain dis- sive care unit. Patients who looked as if they eases. About 5,000 participants have enrolled were going to die eventually transformed and in the Scripps Genomic Health Initiative as became well again. “I said, ‘This medical stuff is it’s called. The study is a joint effort between pretty impressive,’” he recalls. “Of course I was Scripps, software giant Microsoft, consumer seeing the rare bird—the person that was actu- genetics company Navigenics, and genetic anal- ally helped—because most people in the inten- ysis tools maker Affymetrix. The study will fol- sive care unit don’t necessarily do so well. But it low participants for as many as 20 years to see colored my thinking about how medicine could what the near-term and long-term changes they take people who were critically ill and get them make in their behavior, lifestyle, and the medi- in a much better state.” cal care they seek. Topol went on to study medicine at the Uni- Though just begun, the study is already having versity of Rochester. There, in his third year, an effect, Topol says. One participant, a relative he met his wife Susan, a nurse at the time. His of Topol’s who had resisted getting a colonos- housemates told him to invite some nurses to a copy, decided to have the diagnostic procedure party they were throwing. He was in the midst after she learned she had a three-times greater of an obstetrics rotation. He wanted to invite than normal risk for developing colon cancer. In Susan, but he didn’t know how to overcome another instance, one colleague learned he had his shyness. His solution was to invite all of the a six-fold elevated risk for psoriasis, a chronic nurses in the department, most of whom were condition characterized by red, scaly patches of over 50. The ruse worked. Within two weeks, he skin. In fact, the testing helped him discover he and Susan were engaged. After 31 years, they’re had already been walking around with the con- still married and have two grown children. dition on his leg for 10 years. Growing up, Topol had a close view of the toll Other studies at the institute examine genetics of chronic disease. His father had developed to better tailor drug therapies to patients. One type 1 diabetes as a teenager and suffered many such study involves using a simple saliva geno- of the ill-effects from it later in life, including typing on patients before prescribing the blood- losing his sight. Though Topol thought he might thinner Plavix. The drug is commonly used eventually focus on endocrinology, he became to prevent heart attack and stroke in patients interested in while doing an extern- at risk for developing blood clots. Plavix relies ship. He started in the intensive care unit at the on the metabolic action of the body to convert University of California, San Francisco in 1979. the drug into its active form, but patients with There, he became influenced by the cardiolo- a common genetic variant are unable to do so. gist Kanu Chatterjee, whom he calls one of his In fact, 50 percent of Asians and 40 percent of mentors. It was an unusual time in cardiology as

4 3 The Journal of Life Sciences fall 2009 there were new breakthroughs in the treatment he thought, ‘this guy is freakin’ crazy,’” recalls of heart patients. Among them was the injec- Topol. “‘What did I do accepting him in our tion of streptokinase into the coronary arteries fellowship program?’” But after a few days— of heart attack patients to dissolve clots. There and the realization that the study of the treat- was also the use of new technologies, such as ment could attract grant money—the chief grew balloon angioplasty. interested, he says. Topol began by studying tPA “That timing, and having a great mentor at in rabbits with atherosclerotic clots. Eventually, UCSF, really captivated me,” says Topol. “It was in 1984, he did deliver the first dose to a patient. Chatterjee and that era. It was just so exciting. He remembers the moment in great detail. You could hardly not feel the palpable excite- “People were cheering and jumping up and ment of the field at that time.” down and crying that we had actually opened Shortly before moving on to a fellowship at up the artery,” he says. “It was one of the most , he read a study striking moments of my life. February 11, 1984 at around 2:30 in the afternoon. It still plays back as one of those monumental moments. It Genomics only tells about biology. In any definitely had a big impact on me and my sub- sequent career.” In retrospect, Topol says the given person all I can say is they have a dose was too low to work. But he believes that predisposition to atrial fibrillation or sleep the process of repeatedly injecting dye into the patient with a catheter for imaging probably disorders, or this or that. With physiology—the broke apart the clot. Nevertheless, the event drew national headlines. elegant phenotyping we’ve never been able Topol continued working on tPA at the Uni- to do before—we can have an entire ICU in versity of Michigan. There, he became a profes- sor and met his goal of being tenured by the age someone’s home monitoring all of their vital of 35. He spent six and a half years there, even- signs. It gives us a different look at a patient. tually serving as both a professor of internal medicine and director of the catheter lab and It gives us their continuous physiology. director of intervention. At Michigan, Topol started a series of major, multi-center clinical —Eric Topol, Director, Scripps Translational Science Institute trials including the TAMI trial and later the GUSTO trial—both major tirals of tPA in heart attack patients. At the time, GUSTO was the about a new treatment being developed to dis- largest randomized trial of any kind initiated in solve clots called tissue plasminogen activator or the United States with 41,000 patients. A third tPA. The journal article examined the use of tPA trial—EPIC—looked at the use of the monoclo- to dissolve vein clots in dogs. He discussed tPA nal antibody ReoPro to prevent clots in patients with a colleague, who pointed him to a young undergoing angioplasty. biotech company with a handful of employees Topol left Michigan for the at the time called Genentech. The company in 1991, bringing all three trials with him. While was thinking of developing tPA to treat phlebi- there, he raised Cleveland Clinic’s profile in car- tis, a condition associated with deep vein blood diology, building it into the country’s leading clots. When Topol contacted Genentech, he told cardiology program from its ranking as fourth. them it would be great to try using it to treat Despite the clinical successes, by the early heart attack patients. He met with Bob Swift, the 1990s Topol had grown troubled that heart director of research at the time, who suggested attack therapy had “hit the wall.” Patients, he join the company to lead the clinical effort on when he looked at data from the late 1980s for- tPA. Topol explained he couldn’t because he was ward, were still dying at the same rate. Despite about to begin a fellowship at Johns Hopkins. So improvements in treatment, patients weren’t Swift suggested Topol be the first to give tPA to coming into the hospital any earlier—about heart attack patients. two and a half hours on average after suffer- Once at Hopkins in Baltimore, Topol imme- ing a heart attack. And by the time a doctor dis- diately went to the chief of cardiology and told solved a clot, much of the damage was already him about the unique opportunity. The hospi- done. “Even though it did save lives, nothing tal could be the first to put this new clot-bust- was really taking it to the next level,” says Topol. ing biotechnology product in patients. “At first “I started thinking there is only one way we are

44 The Journal of Life Sciences fall 2009 Practicing What He Preaches Though he is conducting cutting-edge research in genomics, translational medicine, and wireless healthcare technology, Eric Topol still practices medicine with an approach that’s informed by his interest in prevention and wellness.

With a long list of titles and a full spate of Institute, among other responsibilities, is also research projects, it’s easy to forget that Eric focused on prevention in his clinical practice. Topol continues to practice cardiology. Among “In the past, I went in, had a stress test and an the people who haven’t forgotten, of course, echo—the normal things cardiologist do every are his patients like telemarketing tycoon Gary couple of years. They’d say ‘you’re doing great, West. West’s doctor-patient relationship was a have a good day,’ and didn’t mention I was 30 tad unusual in that it helped give shape to the pounds overweight. I’m like anybody else—that West Wireless Health Institute, a first of its kind was good news to me,” says West. “Eric took a research institute to focus on the use of wireless different approach.” technologies to improve human health. But at Even though Topol is younger than West, the end of the day, Topol has also been his car- West says Topol sat him down in a fatherly diologist, providing West with an up-close and manner. He told him that while his test results personal view of Topol the doctor. could be fine, sooner or later his bad habits The connection began in 2007 when West, would catch up to him. One day, his stress test the founder and chairman of the West Wireless results wouldn’t be as good as he would like

daniel S. levine

Health Institute, had been looking for a cardi- them to be, West recalls Topol telling him. ologist. A friend suggested he try Topol. The “He’s the only cardiologist who has had suc- two hit it off and West invited Topol to lunch. cess in getting me to do what I’m doing now,” Over the course of the meal, West discovered says West. He credits Topol with persuading they shared a mutual interest in wireless medi- him to lose weight, adhere to an exercise plan, cine and the potential it offered to cut health- and change his eating habits including giving care cost and transform the field. The think- up red meat. ing is that by monitoring patients as they go “Eric is a big wellness and prevention guy,” about their everyday lives with wireless devices, says West. “He just flat out believes the stuff doctors can detect problems early before they and he’s right about it. That’s the same thing become expensive to treat. we have to carry over into our whole medi- West says Topol, who now serves as chief cal system.” medical officer for the West Wireless Health —D.S.L

4 5 The Journal of Life Sciences fall 2009 Topol wrote what was to become the most oft- cited paper of his career. Published in the Jour- nal of the American Medical Association, the paper Eric Topol At-A-Glance was the first to document that use of painkill- er Vioxx, a drug being used by 20 million peo- ple, carried an elevated risk of heart attack and Current Appointments stroke. “It kind of took over my life in 2004,” he • Director, Scripps Translational Science Institute says. “It wasn’t pleasant in 2001 when I pub- • Professor of translational genomics, department of molecular and lished the paper because Merck sent all sorts of experimental medicine, The Scripps Research Institute people to go after me, whether it was in the press or in other ways. But then in 2004, when they • Chief Academic Officer, Scripps Health withdrew the drug, it got much uglier. It was the • Chief Medical Officer The West Wireless Health Institute most unpleasant time in my career.” Education Topol, who remained a vocal critic of Merck, • University of Virginia, BA found himself under attack both professional- ly and personally. Press reports at the time say • , MD Merck sent letters to doctors across the country • University of California, San Francisco Internal Medicine Residency seeking to discredit Topol. He found himself the • Johns Hopkins Fellowship in Cardiology subject of an article in Fortune about conflicts • , Tenured Professor of interest because he served on the medical • Cleveland Clinic, Provost and Chief Academic Officer advisory board of a hedge fund that had short- • Founder of the Cleveland Clinic Lerner College of Medicine of Case ed Merck’s stock. He and his family received Western Reserve University threatening phone calls late at night warning him to stop talking about Vioxx and Merck. Awards & Activities Press accounts at the time quoted him as say- • Elected to Institute of Medicine, National Academy of Sciences, 2004 ing that then-Merck CEO Ray Gilmartin took • Simon Dack Award, American College of Cardiology his complaints to Cleveland Clinic chairman of • Andreas Gruntzig Award, European Society of Cardiology the board of trustees Malachi Mixon, whom he • Johns Hopkins Society of Scholars knew personally. Cleveland Clinic never con- • American Association of Physicians firmed or denied such conversations took place, but Topol was removed in 2005 as head of the • American Society of Clinical Investigation clinic’s medical college. Topol declined to discuss • American Heart Association Top 10 Advance (2000,2004) details of what happened at the Cleveland Clinic, saying only that he left voluntarily. It was not the first time that Topol’s research may have angered the medical establishment. going to get this thing better, and it is by prevent- Nicholas Schork, director of research at the ing the event in the first place.” Scripps Genomic Medicine Program, recalls It was then that Topol started the very first Topol ruffling feathers around 1990 when the cardiovascular gene bank at Cleveland Clin- two met at the University of Michigan. At the ic. To study the genetics of heart attack, he time, Schork was a graduate student called upon won an $18-million, five-year NIH grant. The to help analyze an insurance database. Topol effort began in 1995 and was built out within suspected too many bypass procedures were Topol appeared three years to 10,000 patients. Part of the proj- being performed and that surgeons weren’t fol- in a spread in GQ ect included collecting DNA from 400 families lowing guidelines to determine if the proce- (opposite) with the in which parents and siblings suffered heart dures were warranted. The study indeed showed musical performer Seal attacks. The study concluded with major find- as one of the Rock Stars that bypass procedures were being done more of Science, a campaign ings, including one that linked heart attacks to often than they should be. It looked at region- from Geoffrey Beene people that had a rare gene deletion and the al differences in the use of bypass procedures, Gives Back to win other involved the discovery of a genetic variant differences by type of hospitals, and the dollars support for accelerating the development that puts people at elevated risk for heart attack. involved. Schork says it was a “hot potato.” The of medical research The study won recognition from the American study was eventually published, he says, but it from the bench to the Heart Association, which honored the work with took a while because editorial boards were reluc- bedside. Information a Top 10 Advance award in 2000 and 2004. on the campaign can tant to run it. be found at www. It was while at Cleveland Clinic as chairman “I thought, here’s a man who wants to push rockstarsofscience.org. of the cardiovascular medicine department that the envelope a little bit,” Schork says. “It wasn’t

46 The Journal of Life Sciences fall 2009 Rock Stars of Science Ads from GQ. Photo by Ben Watts for GQ coutesy of Geoffrey Beene Gives Back®

4 7 The Journal of Life Sciences fall 2009 like he was doing it for fame. It was more a mat- tinuously measures heart rhythm, fluid status, ter that this is the truth and let’s get it out there. respiratory rate, activity, position, temperature, I thought that was a great quality to have quite and heart rate variability. frankly. He was clearly going to piss off his col- A recent study found nearly 27 percent of leagues. I have respect for that.” Medicare patients with heart failure, after being But, Schork notes, the study also speaks to discharged from a hospital, are readmitted with- something else at Topol’s core—the desire to in 30 days. That revolving door costs the health- put things to the test. Schork says vetting tech- care system an estimated $10 billion annually. nologies, new drugs, and devices through clini- The hope is that the device, by providing doctors cal tests to answer the basic questions like “Does with an early warning of worsening symptoms, this drug save lives?” has long been Topol’s bread can notify a patient to come in for preemptive and butter. But now, Topol is concerned about treatment before they have another incident. how can we make those more efficient so we can Topol sees similar wireless sensors being devel- get quality drugs out there to save people’s lives. oped to do everything from monitoring sleep “This is something that’s very near and dear to disorders, to providing people concerned about him. Can we leverage genetics and genomics? their weight with real-time reports on their cell That’s one question—can we design drugs or tri- phones about their caloric intake and physical als that target people with certain genetic pro- activity. files,” says Schork. “The other one is to maybe “Genomics only tells about biology,” says Topol. leverage wireless technologies. Instead of hav- “In any given person, all I can say is they have a ing people come back every six months to have predisposition to atrial fibrillation or sleep dis- their blood pressure taken, why not give a little orders or this or that. With physiology—the ele- band-aid device that measures blood pressure gant phenotyping we’ve never been able to do 24-7. Maybe you don’t need 10,000 patients in a before—we can have an entire ICU in someone’s study because you’ll have so much data.” home monitoring all of their vital signs. It gives Marrying wireless technology with genomics is us a different look at a patient. It gives us their clearly on Topol’s radar. Topol, who also serves continuous physiology.” as the chief medical officer of the newly estab- It is that marriage of genomics and wireless— lished West Wireless Health Institute, which is biology and physiology—that Topol believe sets exploring applications of wireless technologies off Scripps from other research centers. There to advance human health, sees an opportunity are plenty of what he calls “gene hunters,” cen- to tap into the vast network of wireless compa- ters that do sequencing, identify genes that may nies in the region. Initially, he had talks with Don be involved in disease, and publish their findings Jones, vice president of health and life sciences out for others to follow up on. But for Topol, it is for the San Diego wireless giant Qualcomm. the convergence of technologies, the ability to The discussions covered what Scripps might do the translational work, that is so powerful. be able do with the technology, but Scripps was “The end strategy is changing medicine, says constrained by resources. That changed when Topol. “You can’t just find a gene and put it out Topol began treating Gary West, a man who there. That doesn’t change medicine at all. You made his fortune in telemarketing. West quickly have to actualize that information, like what discovered he and Topol shared a mutual inter- we’re doing with the saliva genotyping with Pla- est in wireless medicine. “He’s passionate about vix. You can’t just show that the wellderly have changing the way medicine is practiced today,” these protective genes if you don’t go beyond says West. “He thinks it’s just wrong.” that. That’s a nice, fascinating discovery that we The belief that the current practice of medi- hope to have, but you got to drill down to much, cine is dysfunctional is driving The West Wire- much more than that.” less Health Institute, which will be housed on Changing medicine is no small goal, but it is the Scripps campus, about 200 yards from a worthy one. And Topol is by no means seek- Topol’s office. Though its home won’t be ready ing to do this by himself. He is marshalling for occupancy until October 2009, the institute the resources not only of Scripps, but also of was spending the summer gearing up for its first the surrounding biomedical and technologi- clinical trial. The study will seek to reduce heart- cal talent in the greater San Diego area to do failure readmission through the use of technol- so. There will be financial, scientific, and even ogy developed by San Jose, California-based cultural obstacles along the way, to be sure. But Corventis. Corventis’ device, which looks like an then again, they don’t call Topol a rock star for oversized band-aid and sticks to the chest, con- nothing.

48 The Journal of Life Sciences fall 2009