The Chemistry of Discovery

YOU’VE JUST WON THE NOBEL PRIZE.

Congratulations! So what’s the first thing you do?

If you’re Duke’s Robert Lefkowitz, you start sorting through those congratulatory e-mail messages—some 1,500 within the first week after the announcement. You deal with the media interview requests, along with pleas for your signature on various worthy-cause petitions. With a large family to accommodate, you ponder how to distribute the strictly limited fourteen tickets to the Nobel ceremony in Stockholm. You start preparing your Nobel lecture.

You even think up jokes about getting your medal through the airport security line: “I was coming back from Hong Kong five, six years ago,” Lefkowitz recalls. He had just received the Shaw Prize in Life Science and Medicine, which was $1 million and a medal. “It’s made out of eighteen-karat gold. I had it in my carry-on bag. Of course, they picked up that there was something in there, so they took it out, and the guy said, ‘Oh, what a beautiful medal. What’s that for?’ And I said, ‘The hundred-meter dash.’”

And, if you’re Lefkowitz, you put aside your heavy-duty project of re-reading Don Quixote (a book he originally encountered in college). Lefkowitz says he feels a bit like the hyper-focused character Don Quixote; for him, creativity and audaciousness exist in a kind of feedback loop. He’s a physician-scientist who embraces the technical term “chutzpah”: “I’m probably working on the most challenging problems I’ve ever worked on. I have no idea whether I can solve them. But this is what I want to do, and I know damn well that if I can do it, it’ll be a really big deal.”

The big deal for Lefkowitz has hinged on tiny receptors that snake in and out of the cell membrane and serve as one of the main methods of communication within the body—conveying chemical messages into the cell’s interior from outside the membrane. For a long time, it remained a mystery how cells could sense their environment. Scientists knew that hormones such as adrenalin had powerful effects: increasing blood pressure and making the heart beat faster. They suspected that cell surfaces contained some kind of recipient for hormones. But, before Lefkowitz applied his focus to the problem, what these receptors actually consisted of, and how they carried out their assignment, remained obscure. As Scientific American put it, Lefkowitz’s team “extracted the receptor from its hiding place in the cell wall and gained an initial understanding of how it works.”

Scientists have identified roughly 800 different G-protein-coupled receptors, or GPCRs. The receptors react to a host of hormones and neurotransmitters; they regulate the beating of our hearts, the workings of our brains, and nearly every other physiological process. About 40 percent of all medications— used to treat conditions ranging from schizophrenia to stomach ulcers—target the receptors.

In October, Lefkowitz, a professor at Duke University Medical Center and a Howard Hughes Medical Institute researcher, along with Brian Kobilka HS ’87 of Stanford University School of Medicine, received the Nobel Prize in Chemistry for their work on receptors. In the 1980s, Kobilka was a postdoctoral fellow at Duke working under Lefkowitz. From his clinical experience in cardiology, Kobilka sensed that receptor biology was becoming more important and more interesting. “It was an amazing time to be in the Lefkowitz lab,” he recalls in a late October conversation, just after the latest in his ongoing Skype chats with his mentor. “Of course, everyone who’s trained with him probably says the same thing. With the people who were there and the techniques we were immersed in, there was no place in the world that would have better prepared me for my own future.”

At a press conference the day of the announcement, Lefkowitz observed that this is Duke’s first homegrown Nobel—but not the last, he predicted. The Nobel recognized work that Lefkowitz had done at Duke, where he’s spent most of his career. “Duke was not the powerhouse in 1973 that we are today. And it never occurred to me that I’d be here for my entire career. But, you know, it worked very well, and at every stage I couldn’t imagine leaving.” He added, “If you were a fly on the wall in 1973 and now, my daily activities wouldn’t look very different. The lab is bigger, but I’ve been pretty much doing what I’ve been doing,” including “having a hell of a good time.”

He also is celebrated for having trained some 200 graduate and postdoctoral students, many of whom have gone on to prominent roles in medical science. “Bob is very much a part of what a university is about, which is identifying talent and helping that talent grow,” says Andy Wallace M.D. ’59, former chief of cardiology at Duke, who had a major role in attracting him to Duke. “You don’t get a Nobel Prize for training other people. But if there was one, he would be getting it, too.”

Lefkowitz considers himself primarily a basic researcher. Still, his work carries a translational, or patient-centered, component. “If you’re a basic researcher, your sole goal is to understand something. What’s a receptor? What’s its molecular structure? How is it regulated? How does it function? How does it signal? So it’s not my intention to develop a drug or a treatment, or even to necessarily understand a disease. But it’s an inextricable part of what I’m doing. I can’t help it; I’m a physician. That’s the way I think.”

For Lefkowitz, it’s made more sense to define himself in terms of the problems he was working on rather than the discipline-specific approaches he brought to them. “You could say I’m a receptor biologist. I think a lot like a biochemist. I’m certainly a cell biologist. Some would say I’m a pharmacologist or molecular pharmacologist. Am I a neurobiologist? Certainly some of the things we do are neurobiological in their importance. So I guess I’m kind of hard to pigeonhole.”

Having grown up in the Bronx, New York, Lefkowitz was an undergraduate chemistry major at Columbia University. He went to medical school at Columbia’s College of Physicians and Surgeons; he was led to cardiology in part because of his father’s heart attack. His first research experience was in 1968, as a young physician. He had just finished his two years of clinical training and had gone to the National Institutes of Health for a two-year stint. (At the height of the Vietnam War, he had applied to the NIH for a clinical associate position and a commission in the Public Health Service.) Lefkowitz and a medical-school classmate named Harold Varmus shared a mentor, molecular biologist and cancer researcher Ira Pastan. As Lefkowitz recalls, Pastan told them, “I’ve got two interests. One is receptors, but we have no way to study them. And the other has to do with this new molecular biology stuff.”

"I like people who think they're lucky, because I believe luck is more a state of mind than anything else."

Varmus wound up with the molecular biology project; Lefkokwitz, with the receptor project. “It was clear to me that the future would be the era of receptors,” Lefkowitz says, “that these molecules had to be crucially important—crucially important—for biology and medicine.”

Varmus, now director of the National Cancer Institute, would win the 1989 Nobel Prize in Physiology or Medicine for discovering oncogenes, or genes with the potential to cause cancer.

Lefkowitz was recruited to Duke in the fall of 1972. By then he was a cardiology fellow at Massachusetts General Hospital, which had offered him a chief residency. Duke’s recruiting efforts were led by cardiology chief Andy Wallace and James Wyngaarden Hon. ’06, chair of medicine. Lefkowitz turned down Duke’s starting offer. But Duke persisted, and eventually agreed to conditions— including a starting salary of $32,000—that Lefkowitz thought would register as “outrageously” demanding.

For his part, Wallace (who later became dean of Dartmouth’s medical school) recalls, “I had pretty much determined that cardiology needed a couple of people who would foster insights into the molecular-biology side of cardiovascular disease.” He had been impressed with Lefkowitz’s presentations to the American Heart Association. Lefkowitz, in turn, was ultimately drawn to the idea of starting a new lab and running it independently. “I remember the key recruitment visit was around the Duke-North Carolina football game in November of 1972,” Wallace says. “It was a beautiful day. You couldn’t have asked for better conditions to recruit someone who was going to face the New England winter.”

At Duke, Lefkowitz’s very first graduate student was Lewis T. “Rusty” Williams Ph.D. ’77, M.D. ’78, now executive chairman of Five Prime Therapeutics Inc., a biotech company that he founded. At Wallace’s urging, Williams was led to Lefkowitz just as Lefkowitz was preparing to come to Duke. Williams watched the lab take shape, even before Lefkowitz had landed on the scene.

Williams has strong memories of Lefkowitz’s passion for data; to Williams, a classic image from his lab days would be Lefkowitz standing over him and his fellow students as they all watched data spill out in real time. Williams “learned from the master,” in his words, about crafting the compelling argument—whether the context is a scientific peer review or a business deal. He has one particularly vivid memory of Lefkowitz guiding him to speak about research findings, in front of hundreds, at a combined meeting of several academic-science societies. “From that I learned two things,” he says. “First, that our work together was interesting to scientists, that we were really at the forefront of something. And second, that Bob had confidence in me. Of course, he had me rehearse that presentation a hundred times.”

Early on, research was hardly an obvious course for Lefkowitz. “When I came to the NIH, I had never failed at anything in my life. I mean, in general, I was a top student. Now, for the first time in my life, I didn’t know what the hell I was doing. And so, the first six to nine months to a year—total failure. Total failure. Making no progress. I was given, in retrospect, a very difficult project, which might not have worked at all. And I just wasn’t used to that. And I concluded, erroneously, that I had no talent for this at all. But in the second year, things began to really work. And by the time I left at the end of two years, things were in high gear.

“What I subsequently came to realize is that a year’s failure is nothing—nothing. I remember one prominent scientist telling me, ‘The difference between a really successful scientist and an average scientist is that for the average scientist, maybe 0.5 to 1 percent of his experiments work. For an absolutely fabulous scientist, it could be as high as 2 percent.’ At the time, I kind of discounted that. But it’s almost all failure, and accepting that didn’t come naturally to me. So I try to teach my students and fellows that they are going to encounter almost nothing but failure. But the thing about failure is that each failure teaches you a little something, and you build on it. Success is, in a very real sense, just the product of repeated failure.”

One of Lefkowitz’s closest scientific collaborators is Howard Rockman, a Duke professor in the areas of medicine, cell biology, molecular genetics, and microbiology. A few years after arriving at Duke in 1999, Rockman was doing an informal yearlong research retrospective with Lefkowitz. Rockman had pointed proudly to something like 75 or 80 percent of his lab’s projects coming to fruition. As he recalls, Lefkowitz’s reaction was that it sounded like “terrible science.” Rockman asked him to elaborate, and Lefkowitz told him, “You’re doing derivative science. If 80 percent of the stuff that you dream of comes to fruition, that means it’s all derivative. You know the answers. Where are your bold ideas?”

Rockman says, “I walked out of there almost breaking down in tears. But it was an important lesson. He knew I could do better.”

In that and other episodes, Lefkowitz came across as “a student of human nature.” Rockman says. “What really makes him unique as a role model, a mentor, is that he really loves to understand the innate qualities that determine someone’s potential. And then he gets you to realize what your potential is—it’s essentially self-discovery. It’s interesting. His love for research is all about curiosity and discovery. It’s the same principles that lead him to be a fantastic mentor.”

While Lefkowitz talks about reckoning with failure in science, his longtime friend Ralph Snyderman HS ’67 sees Lefkowitz’s career as driven by a form of scientific courage. Snyderman joined Duke’s faculty in 1972, a year before Lefkowitz; after a stint at the biotech firm Genentech, Snyderman returned to Duke as dean of the medical school and chancellor for health affairs. “I think the issue of courage is what differentiates the really outstanding from even the very good and the good,” Snyderman says. “By courage, I mean having a willingness to take risks, to spend time, effort, money, energy on pursuing a research or an experimental direction that is not proven and may be very difficult to prove.”

When he and Lefkowitz became nearneighbors in their labs, “I would hear people shrieking with delight as they found some experimental data,” Snyderman recalls. “It was a certain culture and level of activity and frenzy of energy—really, an optimistic feeling that everything happening there was the greatest thing in the world.”

For decades, beginning in 1977, Snyderman and Lefkowitz were running partners, with avid conversations all the way—including the subject of the Genentech offer to Snyderman and the competing lure of academic medicine. Snyderman estimates that they ran more than 60,000 miles together. “His personality is one of intense engagement with his friends, and if he believes in something— well, I don’t know if you’ve ever heard the word Nudzh. It’s a Yiddish word. And Bob nudges you until he kind of wears down your resistance. He nudged me for a long time until I started running.”

When new trainees come into his lab, Lefkowitz nudges them toward big thinking. He tells them, “Look, I could give you any number of projects to work on that have a 100 percent chance of succeeding. They will be publishable in decent journals. But they won’t be of any great significance. Or we can work on something together that has a much lower chance of succeeding but that, if it does succeed, will really make a difference. And what do you want to do?”

"It's not my intention to develop a drug or a treatment. But it's an inextricable part of what I'm doing. I'm a physician."

Virtually everybody chooses the latter course, he says. Part of the reason is that he works to weed out those who are “too safe.” As he considers potential trainees, he looks not just for smart and motivated individuals with fabulous recommendations, but also for “a sense of adventurousness,” as he puts it. “I’m looking for a sense of optimism. Confidence, but not overconfidence or arrogance. And, at some point in the conversation, I’ll say to them, ‘So tell me, are you lucky?’ I get some very interesting answers. I like people who think they’re lucky, because I believe luck is more a state of mind than anything else.”

Among Lefkowitz’s early trainees was R. Sanders “Sandy” Williams M.D. ’74, who—fresh from Duke Medical School— worked in his lab for about three years, beginning in 1977. “He taught me what science at the highest level really is about,”Williams says, “and what one needs to do and needs to think about that creates the opportunity for scientific discoveries that really matter. The other thing I’d say about Bob is, as much as anyone on the planet, he’s been a champion for physicians doing science. By his own example, he shows that physicians can do science at the very highest level.”

Trained, like Lefkowitz, as a cardiologist, Williams served six years as dean of Duke’s medical school. He’s now president of the J. David Gladstone Institutes, an independent nonprofit biomedical research institute. Williams says lessons from Lefkowitz’s lab have informed his career. “The first lesson is, fall in love with a problem or a question. Bob’s own career has been to understand how information moves from the outside to the inside of the cell. And he has relentlessly pursued that understanding from the start.”

There were other Lefkowitz-derived lessons: “Scientists can often go wrong by accepting a result that seems to prove your pet hypothesis. You need to be your own harshest critic.” And this: “You should understand that the work you do in medical science is important, that it’s serious business, but you should have fun while doing it. Make the hard work not seem like hard work because you’re having such a good time.” According to Williams, “I’ve never seen anyone who showed the joy of discovery more than Bob.”

One of Lefkowitz’s enjoyable involvements is judging a student essay contest for the Bronx High School of Science, his alma mater. The students are asked to reflect on the scientist they most admire. Who would be his choice?

“I guess it’s not a terribly original answer, but somebody who always fascinated me was Albert Einstein. With all his mathematics, his core insights came out of sheer intuition. Lay people have this image of scientists as being these dry individuals—you follow the scientific method, and it’s all very logical. That’s one aspect of it. But the other, most interesting aspect is that the real flashes of insight are almost always intuitive. One of my favorite quotes from Einstein is that ‘Imagination is more important than knowledge.’ That’s why he’s so fascinating to me.”

In describing his theories, Einstein embraced metaphorical pictures— trains, elevators, beams of light. And Lefkowitz is an avid storyteller. One of his favorite stories resides in the fact that in medical school, he and his fellow students were obliged to provide their own microscopes. Those microscopes were typically purchased from older students. His was pretty beaten up; the coarse and fine focusing knobs didn’t work well together. But he learned to apply just the right amount of pressure to hold the focus. From that memory he produced his own guiding principle in science.

“So there you have my famous line: Focus. Focus. Focus. Focus. Lefkowitz’s four keys to success.”