Meet Discovery Maker: Robert “Bob” Lefkowitz

DODI: Today, we're going to meet a scientist of extraordinary accomplishment and humility. You may have heard this name before. It is Bob Lefkowitz.

CONOR: No way, that's amazing. The Nobel Prize Laureate!

DODI: That is the one! For the past 50 years, Bob's work has had a tremendous impact on medicine. His work centered around identifying and understanding receptors - those are the parts of cells that interact with molecules. And this has led to the creation of many drugs that saved countless lives. And this is why he and his colleague, Brian Kobilka, were awarded the Nobel Prize in Chemistry in 2012. For the studies of G protein coupled receptors.

CONOR: And the man is a legend. And this like success after success after success, remarkable, right?

DODI: Not exactly, he's actually failed more than he has succeeded.

CONOR: Okay, what do you mean?

DODI: In 1968, Bob was working as a physician at the NIH Clinical Center, he was bummed out because he was failing for 18 straight months. And I mean, who doesn't recognize that feeling of nothing going your way? Right?

CONOR: Yeah, I know the feeling.

ROBERT "BOB" LEFKOWITZ: And this was a new experience for me, I had never failed, especially in a prolonged way at anything I had tried in my life to that point.

DODI: So one day, Bob had lunch with a senior scientist, and the older man had a really good question for Bob:

BOB: What percentage of all experiments an average scientist has, do you think work? I said, I don't know. He says, well, it's probably about 1%. I said, really? It's that low? He said, yeah. He says, well, now let's take a world class scientist, Nobel laureate, what percentage of their experiments do you think work? I said, I don't know. He says, well, it could be as high as 2%. And that was a real eye opener. He's saying that for the top scientist in the world 98% of what they do is failure.

DODI: Right? 98% of what they do is failure. The number seems pretty high, doesn't it?

CONOR: And then we're just going to be even higher up there in the 99.9%, because we're mere mortals! But that's that trope, right? Failure is how we learn. This is not a revelation. That's what I'm trying to say, Dodi. It may have been a revelation in 1968 for Bob, but it's not a revelation to us now. Right? That failure is how we learn.

DODI: Exactly. Even the inventor Thomas Edison really believed in failure.

BOB: He said he came up with something like 300 ideas every year. He says maybe only one of them works. And so somebody said to him, well, isn't that a horrible thing? He said, oh, absolutely not. He says I have 299 things that I know don't work.

CONOR: So through failure, success. And that's what matters on today's episode of Discovery Matters.

DODI: Today we're going to talk about Bob's journey as both a physician and a scientist.

BOB: I am a professor of medicine and biochemistry and chemistry at the Duke University Medical Center in Durham, North Carolina.

DODI: It's what he calls a tale of two callings.

BOB: I'm a physician, and I'm a scientist.

CONOR: So he started off as which one? Was it a doctor or a scientist?

DODI: It was a doctor and that, he felt was his calling since he was eight years old.

BOB: I worship my family physician, a man named Dr. Joseph Fibersh, who practiced internal medicine and family practice in the Bronx. He made house calls when you were sick, if you had a stomachache, Dr. Fibersh came to the house, he let me play with a stethoscope. And so by eight or nine, I was absolutely convinced he was my role model, my ideal.

CONOR: That lucky man. So he knew exactly what he wanted to do from like age eight, brilliant.

DODI: And like many other people in life. I mean, when you were eight years old, did you think you'd become the CMO of a life sciences company?

CONOR: I've been dead on track since I was five, since I pivoted from wanting to be a milkman driving a milkfloat. Yeah, nevermind.

DODI: Anyway, back to Bob, his adoration of the family doctor became a straight path to his career. He knew which schools to go to, what was needed to get there. And working as a physician was really fulfilling for him.

BOB: To me working directly with patients as a physician, is a remarkable privilege in the sense that it's an absolutely unique relationship. You can have people who were essentially strangers, confide their deepest concerns to you, the kinds of things they would not tell anybody, sometimes even their spouses, their closest friends or children, things they would confide only to a clergy person or to a physician. The idea that somebody would trust you with their deepest confidences, and sometimes with their very life is an awesome responsibility. And one not to be taken lightly.

DODI: How often do we need to remind ourselves about that? That is an awesome responsibility and think about the kind of trust and confidence we put in our doctors.

CONOR: Yeah, it's not just going to the doctor and saying, you know what, biology is broken. Fix me. There's, there's the deep psychological bond between, you know, an individual and their medicine and their physician. We forget that often.

DODI: Absolutely. So this was really important to Bob. He graduated from medical school in 1966. He was at the top of his class. But that year was also pivotal for United States history, for Southeast Asian history, the world - it was, of course, the Vietnam War.

CONOR: Oh my, yeah.

BOB: Most people were drafted into the Army, the Navy or the Air Force. It was a two-year assignment. It guaranteed you one year in Vietnam. That was a very unpopular war, many of us demonstrated against the war, it was felt to many of us, immoral, illegal, and we didn't want to serve in Vietnam, but there were very few legal ways to get around it.

DODI: And one of the ways for physicians to avoid serving on the front lines of Vietnam was to get drafted into the US public health services. And this crew came to be called The Yellow Berets.

CONOR: Okay, that's cute. Why yellow?

DODI: Well, unfortunately, you know, the Green Berets have this reputation for being macho, terribly enough. The yellow term was derogatory. They were labeled as cowards for not serving on the front line. Oh, that's not fair. But Bob kept his North Star, that awesome responsibility of being a physician. And then he went to the NIH, the National Institutes of Health, where top physicians were gathered.

BOB: 20% of our time was spent taking care of patients who were undergoing research studies at the NIH, but the other 80%, you were assigned to a laboratory. And that's where I began to experience my second calling.

CONOR: And it's science.

DODI: Yes, his second calling is science. He isn't the only one from his time at NIH that succeeded as researchers like, check this out. It was a who's who of scientists in his class.

BOB: A total of 10 of us who trained in this program, 10 went on to win the Nobel Prize later in our careers. My class, and by that I mean, the group of us who went to the NIH as yellow berets in 1968 to 1970, because it was a two year hitch and then we all left, that group contained 4 future Nobel laureates: myself, Mike Brown and Joe Goldstein, who discovered the LDL receptor, which laid the basis for the development of statins. And Harold Varmus, who discovered onco-genes, the cancer causing genes. And oh, by the way, there was one other guy you may have heard of that class, he didn't win a Nobel Prize. But you may have heard of him, his name is Tony Fauci.

CONOR: Like Tony Fauci, the Tony Fauci?

DODI: The one and the same!

CONOR: This is insane.

DODI: They were classmates!

CONOR: How much genius in one place all at once.

BOB: He is the consummate physician scientist, an indicator of the importance of physician scientists to society. And in fact, many of the experts that we hear, talking on all the TV stations these days, during the pandemic, almost all of these are physician scientists, many of them are people well known to me for my professional associations. So the question is, where's the next Tony Fauci coming from?

DODI: After his two years at NIH, Bob felt he wanted to go back to clinical medicine. Are you starting to get the sense that Bob is a restless creature?

CONOR: Yeah, curious people just wanting to move on from new thing to new thing, right? So what direction did his research go after that?

DODI: Back in the 60s, researchers knew that drugs like adrenaline or morphine had very specific actions, and they worked on very specific tissues, but they also knew that they could be blocked or antagonized by other drugs. The only thing is researchers and physicians didn't know exactly why.

BOB: We were a number of us at the time who thought there must be specific sites on cells, which would generally refer to as receptors into which these drugs must fit, much like a key fits into a lock. But I became convinced either through insight or obsession, or whatever you want to call it, that they must exist. And so I set out to develop techniques, technologies that would enable me to first identify such receptors, if they existed, to then actually purify them, and find out what they looked like and how they worked. And my entire 50-year career has been dedicated to those interrelated aims.

DODI: Here's how he proved the existence of those receptors and went a bit further.

BOB: I used specific models, the receptors for adrenaline, which are called adrenergic receptors. One phase of the work came to a head in 1986, when after having isolated the receptors, and proven that they existed, I was able to clone the gene and cDNA for one particular receptor called the beta-adrenergic receptor.

DODI: Bob realized there might be a whole family of receptors that would be able to recognize all sorts of things.

BOB: And we learned that receptors through which we taste, receptors through which we smell, receptors for all manner of hormones and drugs like dopamine and serotonin and glucagon, and on and on, they were all members of the same family of receptors that I had discovered in 1986.

CONOR: Okay, and so today, we know these as G protein coupled receptors, right?

DODI: Exactly. And this discovery had a huge impact on the medical field.

BOB: And today, about 1/3 of all drugs approved for use in the United States anyway, by the FDA, that's about 700 drugs, target this family of receptors. So that even though the research was always very basic in concept, it wasn't aimed at developing any drugs or curing any disease, it was just aimed at trying to figure out how these various molecules work. In the end, it's had a profound impact on the practice of medicine.

DODI: This is why Bob finds so much gratification in his work as a scientist.

BOB: When I look back over my career, and I think of the number of patients whose lives I could have influenced, if I had been a full-time practitioner of medicine, maybe it would be a few 1000 over a long career. But the work that I've done, which created as I said, underlies, you know, a third of all drugs that are used today, I mean, I've reached millions, tens, hundreds of millions of patients in one way or another. So that makes it as I say, gratifying, at a whole additional level.

CONOR: So that's extraordinary. This is one of those accidental things again, isn't it. So he didn't set out to create new drugs for medicine specifically, did he?

DODI: No, their focus has been on the fundamental aspects of science. And as you're saying, Bob thinks that most scientific discoveries are actually made by looking for something else but finding something different: serendipity.

BOB: You know the old story of Fleming discovering penicillin, when the bacteria on his plate, he found that, in certain parts of his plate, the bacteria weren't growing, which on the one hand, was an annoyance. On the other hand, it turned out it was due to some microbes. The yeast, I think that was secreting an antibiotic, which was killing his bacteria. That was a serendipitous finding, he never would have discovered penicillin were it not for that serendipitous finding. On the other hand, he might have looked at that plate as a pain in the neck that has bacteria growing, and then thrown out the plate and gone on with his business. 

DODI: And Bob says that he has been blessed in his career to have serendipitous findings over and over again.

BOB: I mean, take the receptors that I worked on, I was not specifically trying to develop a drug or cure a disease, I was simply trying to understand why it was that there was this great specificity and drug action and how how drugs, in a sense, knew which cells to work on which cellular processes to turn on. I just wanted to understand why.

CONOR: So it's just down to kind of like Bob's rabid curiosity.

DODI: And his personality, that optimism, he says, you really have to have faith in what you do. Because if you're going to make a big discovery, you have to have a big hypothesis and stick by it.

BOB: I think if you're gonna make a big discovery, you have to have a big hypothesis. Big hypotheses are often very controversial. And a lot of people don't believe them. And so requires a certain obsessive personality to just persist. I have a rather obsessive personality. And if I believe in something, I believe in it strongly. Now, that's good and bad, because I'm wrong as often as I'm right. Maybe, maybe more so. I always tell people, if you believe in something, it feels the same whether you're right or wrong until you find out. In this particular case, thank goodness I was right. And I'm glad that I persisted.

CONOR: So I get how being completely obsessive and just pushing really makes a difference here.

DODI: Yeah. And you know what's kind of fun, you and I, well, everybody is getting older. And even Bob is getting older and he says that that personality has changed slightly as he's gotten older.

BOB: I don't know if you know the word chutzpah. Chutzpah is sort of brazen goal. People like to define it as that quality of an individual who having murdered both his parents rose himself on the mercy of the court because he's now an orphan. That's chutzpah. But well, there´s a certain chutzpah when you're young, that many of us don't quite have at the same level when we're older, From the vantage point that I have now, 50 years on, I look back, and you know, I don't think I have the guts now. I look back on what I did, the odds of succeeding and what we took on, I don't know I would have had the chutzpah today to take on something like that.

CONOR: It's kind of interesting. So we always talk about the recklessness and foolhardiness of youth just pushing through and daring more than you know how ...

DODI: And we idolize that, right. We idolize the daring youth.

CONOR: Yes. If only I could do the things that I thought I could do when I was young.

DODI: Exactly.

CONOR: Bob tells a story in an amazing way.

DODI: Yes, he does. You could listen to him talking for hours. And his talent for storytelling started when he went to med school at Columbia. He's got this great story. He was doing his clinical clerkship at the Mount Sinai Hospital on Fifth Avenue in New York.

BOB: And I had a wonderful attending physician named Dr. Mortimer Bader, he was a pulmonologist. He was a pulmonary doctor, and a brilliant guy, also an identical twin. As a matter of fact, his brother did the same things. In fact, he always claimed that you didn't necessarily know whether it was him or his brother, who had come to make rounds that particular day. Anyway, on the very first day of rounds with him, a group of us students, one of my classmates presented a case and we discussed it. And then when we were done, Dr. Bader turned to me and he said, Mr. Lefkowitz, he says, you've heard all the facts of the case. You've heard the case presentation, he says, I'd like you to represent the case. He said, but tell me a different story. And I looked at him like, well, what are you talking about? I mean, the story is the story. I mean, you heard what he said. But I want a different story, he says, and the only proviso is you can't change any of the facts. But I want a different story. I was tongue tied, I couldn't come up with anything. So we turned to one of the other students: nothing. He turned to the intern and resident; they had no idea what to do. So then he showed us, he took the same facts of the case. And he presented them in a very different sequence. And with a very different emphasis, although it's the same patient, the same facts, it was a very different story. And in fact, it led us to a different diagnosis.

CONOR: Oh, wow. Okay.

DODI: I know. And he sees science this way, as well. It's about telling stories, also, what kind of art.

BOB: I mean, to create a painting, you start with certain elements. But then you can put those elements together in an infinite number of ways. And science is much the same. What we work with is data. In the case of a painter, the data are different colors, different shapes and perspective. And so the final painting, whether it's a landmark scientific paper, or a painting on canvas, I think all has to do with, in a sense how you put the elements together, and how you put the elements together as I guess what I'm calling the story.

DODI: You can understand that people have been waiting for him to write a book with all these stories. He just released his memoir, and he called it A Funny Thing Happened on the Way to Stockholm.

CONOR: Okay, for so many reasons, I can't wait to get hold of that. And ding you, Dodi, for bringing it back to the Nordics again, right?

DODI: Again, again. Bob loves making people laugh. And he has found an interesting relationship between humor and discovery.

BOB: People often ask me, well, if you were not physician scientist, is there any other career that you might have enjoyed? And definitely a stand-up comic would have been high on my list. The key to humor is often a certain irony. And the juxtaposition of things that you wouldn't ordinarily put together; or seeing things from a somewhat different angle or perspective. You know, we have the expression. Oh, I see the joke. And in a moment that you see the joke, you're making a little discovery. It's a discovery that the person who told you the story has already made, but yeah, you're seeing the link, which a second ago, you didn't see it. Now you get it, you get the joke, and now you laugh. And that's a process of discovery.

DODI: He does a joke a lot at every lab meeting he has and partly because he says it gets people to relax and makes the meeting more fun.

BOB: Once we get on a roll with that, the laughs, you know, turn into ideas that just come flying from all different directions. So for me, and I'm not saying this is the only way to do things, for me, humor and discovery are very intimately interrelated.

CONOR: Many word of truth is said in jest, and so on and so forth. So is that it for today?

DODI: No, there's one issue that Bob has not resolved yet?

BOB: Well, yes, the question of who plays Bob Lefkowitz in the movie is a very important one, and has been receiving serious discussion amongst my friends and colleagues, but largely spurred by me. Now we're trying to figure who plays the young me, and who plays the me in my current stage of life. And there have been all sorts of interesting suggestions. For the, you know, mid-career, me, I've been thinking about people like George Clooney, for example. It's got to be somebody, you know, who´s sort of true to my image, kind of swashbuckling, good looking, you know, the kind of individual who might be on the cover of a magazine is Sexiest Man Alive, something like that.

But for me, at my current stage, a guy I've always been particularly partial to is Christopher Walken. If you know him, very quirky kind of guy. And I saw a video of him not too long ago, and it took turns out he actually has some really good dance moves, which is what he's, you know, really known as an actor and sort of an offbeat comic figure, but he actually is a heck of a dancer just like me. I think those are some of the leading contenders. But I invite you to give the matter serious consideration.

CONOR: This is crazy. Why not? I mean, I would love to one day be in a position to choose who gets to play me.

DODI: These are the very important questions in science.

CONOR: Yeah. Danny DeVito.

So from what he's told us today, I don't see why not: serendipity, restlessness and curiosity. It's all in there.

DODI: I think what fun this was to get to know Bob Lefkowitz as our second super scientist in our Discovery Makers mini-series. Next time we will meet Dorraya El-Ashry, who has studied the tumor microenvironment and mechanisms of metastasis in breast cancer.

CONOR: Looking forward to that. Give us a rating if you like us, it's 5, if you don't it's 1 - tell your friends. We'll see you next time.

DODI: Our executive producer is Andrea Kilin. Discovery Matters is produced in collaboration with SoundTelling. Production, Tanvir Mansur. Our theme song was written by Thomas Henley with additional music from Epidemic Sound.

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