Dr. Robert Lefkowitz, Nobel in hand, still shapes young researchers

jprice@newsobserver.comDecember 30, 2012 

  • Robert Joseph Lefkowitz Born: April 15, 1943, the Bronx, New York City. Family: Wife, Lynn Lefkowitz; five grown children, David Lefkowitz, Noah Jordan, Cheryl Herbsman, Mara Lefkowitz and Joshua Lefkowitz; five grandchildren. Education: B.A., chemistry, Columbia University, 1962; M.D., Columbia University College of Physicians and Surgeons, 1966. Area of research: Exploring the nature of certain cell surface “receptors”; made key discoveries, including proof that these receptors exist as distinct structures; and that they are similar in nature to other receptors, and therefore had implications for the human body’s response to everything from smell and taste to dangerous germs. Titles: Howard Hughes Medical Institute investigator. James B. Duke Professor of Medicine and Professor of Biochemistry, Duke University Medical Center. Member of National Academy of Sciences, Institute of Medicine of the National Academies and the American Academy of Arts and Sciences. Reading table: “Don Quixote” by Miguel de Cervantes; “The Age of Insight: The Quest to Understand the Unconscious in Art, Mind, and Brain, from Vienna 1900 to the Present” by Eric Kandel; “Thinking, Fast and Slow” by Daniel Kahneman. Air miles this year: 46,696.
  • More information What did he do? Dr. Robert Lefkowitz’s discoveries on cell receptors are revolutionizing drug development. His findings about how the body’s cells sense outside signals opened the door to medicines that are more effective and less likely to cause side effects. For this work over the past 40 years, Lefkowitz and one of his former postdoctoral researchers, Brian K. Kobilka, shared the 2012 Nobel Prize in Chemistry.

Not long before jetting off to Sweden for more than a week of ceremonies, speeches, formal dinners, informal schmoozing and the medal that he swore would not change him, Dr. Robert J. Lefkowitz, winner of this year’s Nobel Prize in Chemistry, leaned back so far in his office chair that he was nearly facing the ceiling, clasped his hands over his stomach and grinned as the force that powers his soul and his science washed over him: human contact.

The young, ambitious researchers who work in his lab jammed nearly every square foot of his small office for their twice-monthly meeting. They were culled from hundreds of applicants every year who clamor for a chance to work with a scientist whose work explained how perhaps half of all prescription drugs work. Lefkowitz has fundamentally changed drug development and our understanding of how the human body responds to everything from light to smell and taste.

He recruits and trains them – more than 200 over the years – for stints in his nearly four-decade quest to understand as much as possible about a tiny cell part called G protein-coupled receptors.

Eventually 16 researchers plopped into stackable chairs covering nearly the entire floor, filled an L-shaped couch and perched on shelves.

The gregarious Lefkowitz just basked in it, occasionally wondering aloud about the research, ribbing in a way meant to make someone feel a part of things – “You are the queen of reluctance!” – or waxing on about good data the way a wine connoisseur speaks of a great vintage.

In turn, his charges seemed lifted by his energy as they made progress reports on various projects, the energy passing back and forth. Even though the room was packed, it held a fraction of the sprawling web of people he trained, or who were trained by people he trained.

In a sense, Robert Lefkowitz is a larger creature made up of many, many people. Indeed, his co-Nobel winner, Brian Kobilka, trained with Lefkowitz before going off to start his own lab at Stanford. About 70 friends, family members and researchers whom he had trained came with him to Stockholm for “Nobel Week,” even though most couldn’t get into the lectures or the prize ceremony.

It was his world-class mentoring, along with Lefkowitz’s unwavering focus and intuitive picks of which high-risk questions to pursue, that brought Duke University its long-awaited first Nobel Prize, began an entire field of science, and enabled a new approach to designing innumerable better drugs.

‘The secret stuff’

Lefkowitz, 69, was born in New York City in 1943, and lived a Jewish immigrant-neighborhood childhood in the Bronx that could have been the back story for a Woody Allen protagonist. He played stickball, argued passionately on behalf of his beloved Yankees on street corners, and labored at the impossible: satisfying his demanding, perfectionist mother, Rose, who was an elementary school teacher.

“She would check my homework and make sure everything was perfect,” he said. “If I was handing in an essay in grade school and I had written it in pencil and smudged where I had erased, she made me write it all over.”

Lefkowitz’s childhood sweetheart and ex-wife, Arna Brandel, says his mother was picky in other ways as well.

“His whole life, he won many, many prizes, but each and every time, his mother would say ‘It’s very nice, but it’s not the Nobel,’ ” she said. “To her dying day, she’d say to him, ‘When are you going to win the Nobel Prize?’ ”

He absorbed the expectations, but not the hard edge. From his gentle, easy-going father, Max, a bookkeeper in the garment industry, Lefkowitz acquired something else: a belief that you should treat people well.

He scored well enough on an entrance test to be admitted to the famed Bronx High School of Science, a hothouse for high achievers that counts among its alumni eight Nobel Prize winners, more than most countries.

His big passion as a kid was the Yankees. He still can recite player numbers, batting orders and cost of tickets in each section at Yankee Stadium.

A more permanent passion was ignited by a stethoscope-brandishing family doctor, Joseph Feibush, whose house calls were an even longer-lasting inspiration than Mickey Mantle’s long homers.

“I just loved the idea of you put that stethoscope on and somehow you would know stuff that other people didn’t know,” Lefkowitz said. “And better yet, the secret stuff that these guys knew, they could use to make people better, and to a kid, what more did you need?”

He wanted to be a cardiologist in a major teaching hospital, not a researcher. But the draft was on for the Vietnam War, and one way to avoid it after medical school was volunteering for the Public Health Service, which would allow him to do his two years of service as a researcher for the National Institutes of Health.

For the first year of research, Lefkowitz struggled. In his second, though, he began to see some success and he was hooked. After the NIH and residency, Duke administrators tried to recruit him, but Lefkowitz first said no, then was asked what it would take, and made a counteroffer that he thought was so outrageous he’d never hear from Duke again.

Duke wanted him badly, though, and he and Arna brought their four – soon to be five – children south for a $33,000 salary and his own lab.

Producing great scientists

Good research, Lefkowitz often says, requires four things: focus, focus, focus and focus. Which is what he had done for nearly 40 years, hunting information about the same small group of cell components because his intuition said they were important. Never mind that in the beginning, many prominent scientists didn’t believe they existed.

Even before arriving in Durham, he began recruiting young researchers to help him study G protein-coupled receptors. These receptors, which are laced through a cell’s surface membrane, convey information from outside the cell about chemical changes in the body to inside the cell, giving them a middleman role in triggering the cell’s response to the presence of substances such as adrenaline or drugs.

Focusing on receptors for adrenaline, his lab made a series of major advances in understanding their nature and how to clone them for study. The findings made it clear that the receptors responded to the presence of adrenaline in the same way that receptors elsewhere in the body allow cells to detect smells, taste and light, opening doors to research on those. Also, about half of all prescription drugs act on such receptors.

Before the discoveries by Lefkowitz and Kobilka, the way drugs acted on receptors wasn’t fully understood. Now new versions can be engineered to have desired responses from cells but trigger fewer side effects. Commercial implications related to food, scent and light aside, those for drugs seem almost limitless.

Indeed, Lefkowitz and a colleague at Duke started a company, Trevena, five years ago that has two drugs in clinical trials already, and major drug companies are also using similar approaches.

The lab at Duke has become known not just for its discoveries but as a prolific finishing school for extraordinary young scientists. At first, Lefkowitz had just a couple of apprentice scientists, later a revolving cast of up to 30. And no matter how many there were, each somehow was convinced that Lefkowitz had assigned him or her the project he considered the most important.

“Obviously you can’t have eight projects at the same time that are most important, but in a sense they were because each one was incredibly important to Bob, and he transmitted the feeling to each one of them that they were the most important, and for a young researcher, that is incredibly powerful,” said Ralph Snyderman, a longtime friend and Duke’s former chancellor of medicine.

Kobilka says it’s impossible to fully explain Lefkowitz’ technique for training young researchers.

“He sees their different strengths and weaknesses and I’m sure adjusts his approach to fit each person,” he said. “He was never heavy-handed. Frequent, informal discussions with Bob helped you focus your research efforts, and he let you do what you were most interested in, and supported you.”

Part of it, said several of his former researchers, is simply that Lefkowitz is always approachable and often funny, and newcomers to the lab quickly sense that he is exactly what he seems to be.

The researchers are much younger than their boss and come from a host of countries and cultures, but somehow that doesn’t matter. When Sudha K. Shenoy came to the lab in 1999 from India via Oklahoma State University, she was quiet and so reserved that she was afraid to approach the ever-genial Lefkowitz with her data.

“Once he realized my potential he came looking for me, and he’d say, ‘Sudha, what’s going on?’ And eventually I felt easy with him and gained confidence so that I was able to speak up in meetings,” she said. “He raised my confidence level as a scientist and transformed me. He made me into a better person.”

Soon her work appeared in a major journal. Now she is an assistant professor of medicine with her own lab at Duke, and she trains researchers herself.

A crucial goal, Lefkowitz said, is that everyone who comes to the lab gets a taste of what it’s like to perform at his or her highest level.

“I really do enjoy seeing what they’re like when they finally realize that they can do this,” he said. “You have to give just enough direction to get them moving in the right direction, but not so much that they don’t feel ownership of successes.”

The time and energy he spends mentoring isn’t just for the young researchers. They multiply whatever he could do, and bring skills he doesn’t have. “They’re the key to my success because I’m not at the (lab) bench myself, and I haven’t been since 1978, so it’s not all altruistic,” he said.

At home, a price

The research was consuming and it often made Lefkowitz a remote, albeit still pleasant, figure for his family.

“We all have great relationships with my dad, but the truth of the matter is, when we were growing up, he was very busy with his work,” said one of Lefkowitz’s sons, Noah Jordan, 47, an actor and artist in New York.

“Earth to Bobby Joe,” the kids would say as he sat on the couch late into the evening, his briefcase open, talking into a Dictaphone. Or they’d ignore him as they made a game of dictating their own imaginary research papers, tossing in the terms they had heard so often – “… beta adrenergic receptors blah blah blah ligand binding.” Always they signed off with their dad’s verbal shorthand to his secretary for his name and title: “… RJL etc.”

He may not have been a perfect dad, but still was an extraordinary role model and taught his kids a key lesson he teaches his researchers: to pursue work they care about.

“We’ve all pursued our passion, and he’s responsible for that,” Jordan said. “When we were young, he certainly had his work to do, but I really feel honored and fortunate to have the father I do.”

At Duke, Lefkowitz met Snyderman, a New York-born doctor with a research lab. The two were about the same age and quickly hit it off. He used the same unrelenting focus that he applies to research on Snyderman until his friend agreed to also take up running.

They jogged together nearly every day for decades, and Snyderman calculated that they logged at least 60,000 miles and 10,000 hours together. They came to know each better in some ways than they knew themselves, and running became a form of mobile psychotherapy as they talked through issues of science, kids, marriage, and Snyderman’s administrative dilemmas after he took a leadership job.

For the family, there were plenty of good times, said Brandel, his ex-wife. They went to Disney World and visited New York on holidays, singing in the car en route. And they bought a small house at Hyco Lake north of Durham. Lefkowitz would pilot their small motorboat. The kids would ski and swim, and they’d grill.

Even there, though, he needed the data version of a security blanket: a suitcase stuffed with journals, books and lab reports. He wouldn’t open it but always brought it along.

Eventually, Brandel said, she decided that she needed more from a partner than dedication to science. They were soon divorced.

In 1991, Lefkowitz married Lynn Tilley, a fellow vegetarian and lifelong Durham County resident who was raised on a small farm and had worked in his lab. They mostly have a quiet life, she said, eating most meals at home and watching movies on Netflix. He still works late into the evening, often past 10 p.m., looking away from his data only to obsessively tend his email, that instant connection to his far-flung network.

‘We,’ not ‘I’

In 2011, Snyderman was asked to write an introduction to Lefkowitz for an award ceremony, and he had to think hard about the underpinnings of Bob Lefkowitz. There were, of course the influences of his parents, and the Bronx in that era, with a peer group including many first- or second-generation immigrants, and families that cherished learning, achievement and contribution to knowledge.

“There are so many factors that go into it, and when you add them all up, most of it is still unknowable,” Snyderman said. “Part of it is this incredible focus and persistence, but part of the unknowable is genetics, and he was dealt a hand of cards that, clearly, was right for winning the Nobel Prize. But the hand of cards that leads one to be compatible, happy and content, he didn’t get that one. It’s always the striving.”

In the lab, there are many running jokes about Lefkowitz’s insatiable hunger for numbers. Someone ginned up a poem once, Shenoy said, to the effect that a researcher from the lab was sliced in two during a duel. Lefkowitz’s cheerful response, according to the verse, was, “Bring me the half with the data!”

Here’s some: In his 30-minute Nobel lecture Dec. 8 at Stockholm University, Lefkowitz laid out the history of his work, and did so while using the words “we” or “us” more than 50 times. He mentioned other scientists by name more than two dozen times. He used “I” only twice in direct reference to his work, and one of those was a reference to joint efforts with a researcher he named.

Each winner delivers such a lecture at some point in Nobel Week. And at the end of his, standing at the very pinnacle of science, Dr. Robert Joseph Lefkowitz summed up how he had won its highest prize.

“I want to acknowledge all the many, more than 200, individuals, many of whom are here, who worked with me over the past 40 years,” he said. “Just to put up a list of their names I don’t think would give the flavor of things. So instead I want to show you a photo.”

He pressed a button, and on a screen behind him it appeared: a crowd of scientists, during a kind of homecoming at Duke for Lefkowitz’s 60th birthday, hoisting the beaming Bronx kid aloft.

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