On a February afternoon at New York-Presbyterian Hospital in northern Manhattan, the operating room has been filling for half an hour with a steady trickle of surgeons, anesthesiologists, nurses, medical researchers, and a few curious observers.
Some are here to help, others to witness something they have never seen before. The patient is heavily sedated but still awake; an LED screen suspended above the operating table displays the vital signs. Normal blood pressure is anything below 120 over 80. This patient's reading is 270 over 110. The astronomical numbers are why everyone has come today—to see whether chronic hypertension that drugs aren't helping will respond to a radical new procedure.
Ajay Kirtane, an interventional cardiologist and head of the surgical team, begins with a small incision near the patient's groin. He inserts a short, hollow sheath, his gloved hands speckling with blood. He then methodically threads a catheter—a long plastic tube—into the artery and, guided by a scan on an overhead display, to the blood vessels leading to the kidneys, which on the screen resemble giant gray beans. So far the procedure is a lot like any catheterization—complex yet utterly routine. The team pauses, however, while an assistant opens a 4-foot-long orange and white cardboard box marked with the word "symplicity" and removes what looks like a motorcycle throttle with an electrical cord at one end and a 3-foot-long wire on the other. He plugs the electrical cord into a generator and Kirtane threads the wire through the catheter till it reaches the kidneys. The assistant activates the generator. The patient doesn't flinch as an energy burst destroys a swath of the renal nerves. For the next 20 minutes, Kirtane manipulates the wire, wiping out various sets of nerves. Toward the end, he turns around and says, modestly, "That's all there is to it."
But in truth there is much more to it than that.
In the spring of 2003, Howard Levin and Mark Gelfand were just a couple of frustrated entrepreneurs banging around Silicon Valley, looking to sell a stake in an idea for the device that would become Symplicity. Over and over again, they made the rounds of the venture capital firms on Sand Hill Road, where they gave earnest but futile presentations to potential funders. With each passing month, they became more demoralized. Some VCs dismissed their idea as stupid, or crazy. Some thought it intriguing but too risky. All had a reason to say no. Gelfand recalls, "Everyone and their grandmother pissed on us."
They had expected a better reception. By the time they arrived in the Valley, the two men had already collaborated on several devices and had created several startups that either succeeded modestly or appeared to have real promise. One was a vest that could administer CPR to a patient in cardiac distress by automatically contracting and expanding; another was a blood-filtration device that alleviated symptoms of congestive heart failure. What's more, the potential pool of patients for their newest idea could be in the tens of millions. But you could see why the VCs had their doubts. For starters, the men didn't fit the Silicon Valley mold. Both were in their forties, well past the bloom of technological youth, and both were voluble New Yorkers. More to the point, their approach to medical innovation could kindly be described as audacious. They were pitching not just a new kind of machine but an entirely new kind of therapeutic treatment. In fact, their claims were tantamount to suggesting that rather than looking for the next miracle pill, the health care industry should be looking for the next miracle device. This stance cast them against the currents of medicine for the past half century. In an era when Big Pharma was spending billions on breakthrough products and patients would much rather take a pill than suffer a doctor's scalpel, why fund a device that sounded like a science experiment?
In the end, only one group of West Coast techies—a Menlo Park medical-device incubator known as the Foundry—was willing to bet on Levin and Gelfand's invention. Foundry CEO Hanson Gifford was intrigued by their research showing a relationship between the removal of renal nerves and improvements in cardiovascular health. In 2004, in exchange for a significant share of future profits, Gifford and his partners agreed to take over development of the project and set out to build, improve, and test a renal device. By 2007, the first human trials were starting to show that in some cases the new treatment might lower blood pressure far more than any single drug therapy could—and with few significant side effects. And these findings were the main reason Medtronic, the medical-device maker, bought the idea, now known as renal denervation, in 2011 for $800 million. It was the highest price ever paid for an early-stage medical-device technology.
At the moment, the treatment is being used in Europe on patients with drug-resistant hypertension and is in the midst of a large (and likely definitive) U.S. trial that includes New York-Presbyterian. Medtronic expects it to be on the market here within two years. Dr. Oz has already begun to blog about it. Until the trials are complete, the device elicits a wait-and-see caveat from most doctors. But in the half-dozen conversations I had with some of the country's leading cardiologists, a strain of barely contained excitement comes through, mainly because the preliminary results of the treatment are so astonishing, and the side effects so minimal, compared to new drug therapies. "You now have a technology that can potentially be done safely and reduce the blood pressure by 30, 40, 50 millimeters of mercury?" Mehdi Shishehbor, a cardiologist at the Cleveland Clinic, tells me. "That is just enormous."
Levin admits, only half-seriously: "We are now the most famous people you've never heard of." But then he adds, "People come to us and say, 'Was that just a fluke that you guys did that, or was it real?' And so the answer is—"
"Well, our answer is, we have a system," Gelfand says.
"Right," adds Levin. "We don't think it's a fluke. We think it's a function of how we do things, rather than, you know, did we just get lucky."
The device industry has the distinction of being both immensely important and exceedingly obscure. It is not a business that consumers can easily follow: Like the rest of us, the patient on Kirtane's operating table had little awareness of the innovations that now allow for catheterized tubes to be pushed through the bloodstream, let alone the origins of the experimental device. Still, I came to spend time with Levin and Gelfand because their medical work over the past decade promises to have more of an impact—a life-and-death impact, that is—than so much of the gadgetry that clogs the web with speculation, chatter, and tweets. At the same time, their innovative process helps explain how new ideas, rather than just new technology, can alter the future.
The men work out of a shopworn building on West 26th Street in Manhattan, in a spare suite of rooms that houses their business incubator, Coridea (the accent is on the id). Their office is not a lab in the conventional sense of the word—no anatomy charts lining the walls, no half-built medical devices cluttering the shelves. Coridea is mainly Levin and Gelfand's foundry for ideas, which are transformed into hardware not in Manhattan but on the West Coast and then tested on rats and rabbits at university labs. First, though, the two men toss proposals back and forth, often for years on end.
Levin and Gelfand complement each other in a yin-yang way. Levin is a cardiologist with an abiding interest in the interactions of the body's organs; Gelfand is an engineer with expertise in the workings of mechanical systems. The men finish each other's ideas, and their sentences, too. "Mark and I will call each other up in the middle of the night," Levin tells me one day in the Coridea office, "and we'll say, 'Hey, I had this really good idea, let's think about this.' And we'll either say, 'Well, that's the stupidest idea I've ever heard' or 'Ah, that's really cool.'" Levin is the team's optimist. Born and raised in Staten Island, he has a blunt urban garrulousness that's lifted by a lighthearted bedside manner. Gelfand, the team pessimist—or realist, as he contends—has a sense of humor that dwells in the sardonic. A Russian native who spent his youth parsing Soviet political propaganda, he delights in stripping off layers of wishful thinking.
Both men describe themselves as dinosaurs in today's health care business. What they mean is that each has rejected, with conscious effort, the drift toward specialization forced on most medical professionals. "Besides the fact that I'm a heart-failure transplant cardiologist, and besides the fact that Mark is a systems engineer, what we really are are old-school physiologists," Levin says. A physiologist is a physician or scientist who considers the relationship of different systems within the body and how the functioning of one organ might affect another. Indeed, in talking with Levin and Gelfand you often come away with the sense that the human body is less like a biological organism and more like a fine machine, with exquisitely calibrated levers, pulleys, weights, and counterweights. A problem with the heart, say, manifests itself in the lungs, so a therapeutic push in one place can elicit a restorative pull in another. An advantage to thinking like a physiologist, in Levin's view, is that it lets him and Gelfand integrate many kinds of knowledge into an effective therapy. "We may see something in gastroenterology that gives us a hint about kidney disease," he explains.
To a considerable degree, their innovative process resembles detective work. Levin and Gelfand regularly visit medical libraries around the country to read medical histories that have not yet been digitized. They are especially fond of the libraries at Columbia Medical School and Johns Hopkins. In the stacks, they find clues—or, more precisely, partial clues. A report that appeared in a medical journal 15 years ago may lead them to another journal article from 30 years ago, and then another from 60 years ago. If the author of a compelling piece of research is still alive, the men call to ask questions. Usually, too, they pay a visit to find out more, whether the researcher is in California or (as was recently the case) Eastern Europe. In sum, their work seems a laborious effort to connect fragmented and sometimes forgotten pieces of medical knowledge scattered by time and geography.
They consider the middle part of the 20th century to be the golden age of American surgery. "Start your journey back in time to the 1940s and 1950s—brutal surgeries with very primitive tools," Gelfand tells me. At that point, many of the great modern drug therapies had not yet been invented. "Surgeons ruled the world," he says. "Whatever the problem, the surgeon would open you up and try to find out what's wrong, and then reconnect things." Gelfand seems darkly amused by this idea. Surgeons had no CAT scans then, he points out, and no minimally invasive therapies. And while he exaggerates the grisliness—"There was a surgeon with a butcher knife, and hopefully with anesthesia"—he is profoundly appreciative of what such ghastly operations achieved.
A decade ago, he and Levin were reading through medical reports from the earlier era and discovered a body of surgical research that reinforced a few of the ideas they were already kicking about—namely, that the removal of certain chains of nerves near the kidney would have dramatic effects on how the body gets rid of fluids, or how the brain regulates blood pressure. "Strangely enough," Levin points out, "hypertension was a surgical disease until the 1970s." For patients with dangerously high blood pressure that did not respond to the usual treatments—drugs, weight loss, exercise—doctors sometimes would remove certain nerves to reduce the symptoms. The problem was that the cure could be as dangerous as the original disease. Patients might stop sweating. Or they might have serious and sometimes fatal problems with their breathing and heart rate.
These were the kinds of studies that piqued the Foundry's interest in Levin and Gelfand's idea. But the team wasn't setting out to replicate what surgeons had done, rather crudely, 50 years ago. The goal was to develop a medical device that would be minimally invasive and easy to build and that would disable precisely the right nerves to reduce blood pressure without side effects. And even if they could create the device, they had no guarantee of success in the marketplace. Building a good medical device and building a good medical-device business are very different things.
At the start of their careers, neither Levin nor Gelfand had any intention of becoming full-time inventors. In 1985, Gelfand left his job as an engineer in a paper factory in St. Petersburg, Russia, gave his car to a friend, and locked his front door. He went to the airport with $100 in his pocket. "I landed in New York with $96," he recalls, "since I bought a beer and a pack of cigarettes on the way." He had friends and relatives in the United States, and within a year he was working at a Johns Hopkins cardiology lab. A supervisor hired him because he could write computer code.
It was at the lab, not long after, that he met Levin, who was balancing full-time work as a cardiologist at Hopkins with a part-time interest in bioengineering. Levin had imagined that he would become a professor with a clinical practice on the side. He saw the light of entrepreneurship a few years later, when his wife was expecting twins and he was scraping to earn a higher income. His boss at Hopkins assured him that he had a bright career ahead, but that the chances of getting tenure at the medical school were not much better than winning the lottery. So why not work on medical devices full time? Still, the setup at Hopkins gave Levin no confidence that he and Gelfand were destined for wealth or distinction. "Howard and I shared a desk," Gelfand recalls. "We didn't even get our own desk, which shows the level we were valued."
Designing medical devices isn't something you learn overnight. Device innovators, Gelfand tells me, pursue one of three general objectives. The first is better plumbing—"there's no blood flow, so you stick a shunt in," he says. The second is better electrical flow—"there's no current, so you put in a pacemaker." The third is the repair or introduction of structural elements—titanium screws, plates, rods, hips—"like building a house," says Gelfand. "It's just carpentry."
Within each of these categories, moreover, are two possible strategies. You can build a gadget that improves on established technologies, such as a better pacemaker. Or you can build a gadget that stakes out new territory, such as the renal denervation device. Levin stresses that he and Gelfand don't sit around talking about technology. Mostly, they talk about the problems they can solve through a new therapeutic idea that happens to involve technology. It sounds like a semantic difference. But it is not.
The men spend the first six months of a project drawing up a list of about 25 to 30 ideas and winnowing them down with the help of a few trusted advisers. They spend very little time tinkering with actual technologies. In fact, the technologies they eventually use are unremarkable and mostly off-the-shelf. The two are mainly concerned with running each of their ideas through a matrix of risk factors. "First of all," says Levin, "does it meet an unmet need? Because it drops off the list if it doesn't." The next step is to assess technical risk. Can you transform the idea into a device? And if so, can you use it on a patient easily? Then comes clinical risk. A device might be effective in animals, but what if it doesn't help humans or creates terrible side effects?
Intellectual property risks are everywhere too. Can you patent your technology so that investors and big companies will want to acquire it? You will also have to consider the regulatory risks, since every device must pass through long clinical trials to demonstrate safety and efficacy. "I like to say that the hardest thing in the world is to open a restaurant in New York and have it succeed for six months," says Paul LaViolette, a venture capitalist with SV Life Sciences, which recently invested in Levin and Gelfand's work. Building a radical new medical device and then commercializing it, he continues, "is not as hard as that, but it's second." LaViolette, a former executive at the medical-device company Boston Scientific, notes that a medical device takes at least 5 years—and more likely 10—to come to market, and it might take another 5 or 10 years to catch on. Clearly, you have to think in decades.
The competitive risk, ultimately, lies in Big Pharma, which casts a shadow over any new endeavor. Levin says, "No device exists today where, if there's a drug that does [the therapy] as well, people wouldn't use the drug first." But the pharmaceutical industry is still far from curing chronic illnesses. Hypertension, for instance, remains the leading cause of cardiovascular diseases. At the moment, about 70 million people in the United States take drugs for high blood pressure. Yet probably 5 million to 10 million of those patients are resistant to the benefits of those drugs or suffer debilitating side effects from taking a cocktail of several medications. A one-time medical procedure could address both deficits. It would also solve the problem of compliance. "We can prescribe whatever drugs we want," says the Cleveland Clinic's Shishehbor, "but it doesn't mean people will take them." Some studies show that even when doctors tell people that failure to take a medication could be fatal, 25% of patients will stop after one month.
Most of the physicians I spoke with, including Levin, don't see the future of cardiovascular treatment as a choice between a renal device or a drug. An ideal application might be to use both. But economics will affect the balance and in the end may determine whether the renal denervation device succeeds modestly or changes the nature of medical care worldwide. "Let's say it's a $5,000 device therapy," says Levin. "And let's say someone is on two drugs that each cost $100 a month. If it saves you three years of drugs, then $5,000 is cost effective." And if the device succeeds, says Rajiv Gulati of the Mayo Clinic, "it means fewer strokes, fewer heart attacks, fewer hospitalizations"—a huge potential cost savings.
One hurdle remains: the "build to fit" imperative. Even if a device is efficacious and economical, to succeed it must mesh with the existing medical machine. "Interventional cardiology is a huge investment by society, hospitals, insurance companies, doctors," Gelfand says. "People go to medical school for this long training to acquire the dexterity and skill." These doctors—Ajay Kirtane at New York-Presbyterian is a good example—regularly install stents in heart patients. Gelfand refers to them as Magellans of the bloodstream. "So now there's a bunch of these people," he says, "and these amazing catheter labs and imaging tools. And to bring this hypertension-device idea to their door? You can use the same skills, the same imaging." Without that human and institutional apparatus at the ready, a device may never find a market.
Gelfand and Levin decided to tailor the description of their device to the medical industry's inertia. In other words, to lessen resistance to the idea of renal denervation, they would point to the history of hypertension—the long-ago surgical treatment of the disease—and make a coy and arguably untrue argument that amounted to saying: This new thing we invented is no big deal.
"We try to sell ideas," Gelfand explains. "When you're selling ideas, you don't sell them on novelty—well, you sell them on novelty only to the patent office. Doctors are conservative and easy to scare. So you try to build a story for them. You say, 'No, this is not new. This has actually been known for a while.' Because if you bring a new theory to physicians, they freak out."
"You say, 'Known but unexploited,'" says Levin.
"It's a better way of doing it," adds Gelfand. "And this is how you raise money for a medical-device venture. Sorry, but you don't want to say, 'It's a quantum leap, a revolution.'"
That seems the opposite of what happens in the electronics and software industries, I say. There, everyone wants an innovation that's disruptive. Here, everyone wants what's incremental.
"You want it to look incremental," Levin says, not missing a beat. "But it really is disruptive."
One day in his office, Gelfand remarks that a lot of his and Levin's ideas arise from a single overarching theory. It has to do with how the human body functions and malfunctions—and in particular the evolutionary lag in our response to the environment. "Hypertension, heart failure, diabetes, sleep apnea, all of them basically have the same root cause," Gelfand asserts. "This is one disease in different guises." His is not a conventional view. He and Levin believe that at the center of all these maladies—the most prevalent diseases in the Western world, with the exception of cancer—is a nervous system that has not yet adapted to our longevity or recognized that we inhabit a technologically advanced world. Evolution, Gelfand points out, works in 50,000-year increments, not in decades. And so we still carry within us the remnants that helped us survive in a very different world, where life spans were brief and everyday threats were mortal and fight-or-flight responses were crucial. "We don't fight or flight a lot these days," Gelfand remarks. Yet a primitive branch of our nervous system—known as the sympathetic branch—lets us respond to perceived dangers instantly and automatically. Suddenly, there is a quickening of the pulse or breath, a spike in blood pressure, an internal drenching of adrenaline.
Long ago, such responses helped us stay alive until the end of the day. But in a world lacking in acute dangers—as the Foundry's Gifford asks me, "When was the last time you ran from a saber-toothed tiger?"—the sympathetic system can get out of whack and prime us for nonexistent threats. Levin and Gelfand's theory blames the disproportionate response on sensors—the renal nerves, for instance—that start acting like a broken thermostat, making the house too hot or too cool. Their devices aim to interrupt the orders from these broken sensors, which might tell the brain to, say, constrict the blood vessels and raise blood pressure. "We decided that the most interesting way to hack into the system is to mess with information that the beast receives," Gelfand says. If you can interrupt a faulty signal from the renal nerves, you can improve health and possibly avoid some chronic diseases entirely. A prescription drug can interrupt such signals. But a medical device can often do so with more power and precision.
The two knew they were on the right track with renal denervation. They likewise knew that the nerves near the kidney weren't the only ones, or even the most powerful ones, that could send bad information to the brain. And so, in December 2010, as the sale of their renal denervation device to Medtronic was closing, Levin and Gelfand sat down to figure out their next project. They never considered retiring. A medical-device inventor typically gets only a small percentage of any sale, often 5% to 10%, and in their case most of the money will come as royalties against future sales. As Levin says, they weren't going to be buying $10 million mansions. But the proceeds to date have given them the resources to concentrate on building whatever they wanted.
On each side of the human neck, the carotid arteries fork into two parts as they bring blood from the heart to different parts of the face and brain. At each fork is a small bundle of cells and nerves, about the size of a grain of rice, known as the carotid body. It is a kind of sensor, wired to the brain through the sinus nerve, that informs the brain when oxygen is running very low. The idea that eventually made it to the top of Levin and Gelfand's list in 2010 was to get rid of the carotid body in people where it malfunctions, creating a treatment for heart or kidney disease. They gave the prospective device a name: Cibiem. Levin surmised that only about a dozen people in the world had a deep understanding of the carotid body and its significance in controlling blood pressure and kidney function. So he began to seek those people out.
While he did, he and Gelfand explored the libraries. In the 1940s, they discovered, a Japanese surgeon by the name of Komei Nakayama began removing the carotid body in about 4,000 asthma patients. As Gelfand relates the story, he goes to another room and returns with a huge, musty cloth-covered book. He drops it on the table with a thud. "We had to order this from Japan," he tells me. He turns to the page that shows the Nakayama surgeries. "Just incredible," he says, and flips it around to show me. The drawing is grotesque: a neck, with the muscles and sinews pulled back to show how the carotid body was removed from its deep lodging. The surgeries did not cure asthma in the patients, Levin says, but helped alleviate their symptoms—letting them walk further, for instance. But what captivated the device inventors was proof that life without the carotid body was possible and apparently not dangerous. It seemed likely, in other words, that their idea could surmount the clinical risks. "These people had their carotid bodies removed," Levin says, "and didn't keel over."
In the time since, the men began animal tests of a prototype device that destroys the carotid body. The procedure appears to have an even greater effect on blood pressure than renal denervation. Early this year, they began a clinical trial in Poland on 10 human subjects. So far, the partners tell me, the results are extremely promising. Yet Cibiem still has a long road ahead. The men will need more proof that the device has no significant side effects. They will have to optimize the catheters for the new procedure. And they'll need to find a large device company to bring it to market. Assuming it clears these hurdles and the regulatory process, too, I ask Levin if it would compete with the renal device. He seems to think it would complement it. Medical tests could likely determine whether a patient was a better candidate for one device or the other. And a patient might receive both treatments, along with drug therapy.
By the time Cibiem comes to market, though, Levin and Gelfand will have long since moved on to other things. Over the past few months, they've been helping a different team take over day-to-day management of Cibiem so they can go back to their incubator work. They will begin again with a blank sheet of paper and make a list of 25 ideas. "First thing we want to do is identify the biggest problems and what we want to do about it," Levin says.
The two men fall into their usual rap.
"Pacemaker industry," announces Gelfand. "Very expensive gadgets, break all the time."
"Right," says Levin. "Can we figure out a way to do pacemaking without a pacemaker? Can we eliminate the need for a pacemaker? Can we find a way to slow the progression of chronic renal disease to avoid dialysis?"
"Spinal fusion—now there's a big problem." It's Gelfand speaking.
"They're fixing things in the disc to get rid of pain," says Levin. "But fixing it may transiently get rid of the pain but doesn't really fix the problem. The pain comes back. So we're wondering: Why don't we do something to get rid of the pain and leave the thing that doesn't matter whether you fix it anyway?"
"Most surgeries are not done to correct deformities," adds Gelfand, "but to correct pain." What he's implying is that they could simply get rid of the pain signal through a device. And then: voila. No surgery. And no pain, either.
They talk for a few minutes more, batting ideas back and forth. Then they assure me they'll need to discard most of these projects. Their VCs want what's doable and potentially most profitable. But Levin and Gelfand are fortunate: The industry moves slowly. "With social media, if you don't do it this week, it's over," Gelfand says. "But hypertension is not going anywhere. Neither is diabetes." He smiles. "So if you don't like our idea? Five years from now we can go back to it and it will still be there."
[Photos by Grant Cornett]