Was there an “aha” moment in this great discovery about receptors?
Robert Lefkowitz: There were many. But probably the single biggest was, “Aha! It looks like rhodopsin.” How crazy is that? None of us expected that. So that was a true “Eureka!” Unpredicted, nobody knew it was coming.
How did you figure that out? Were you with students?
Robert Lefkowitz: Yes. That part was simple, because there are these data banks of sequences. The sequence of rhodopsin had been determined a couple of years before. So once we had our sequence of the beta adrenergic receptor, we just compared it with that. We realized this one evening, and we were so excited. I remember calling a collaborator in New Jersey and we couldn’t find him and it was crazy. We finally got a hold of him. But we know immediately, as soon as we saw that, we understood the significance of it and the fact that there would be much work to do to prove it. But immediately, it suggested the hypothesis that there might be a huge family of these receptors, and that by getting the first one, we’d be able to get others because they looked very similar. Did I realize in that moment how broad the implications would be for medicine? No. That would take a number of years.
When did you first realize the implications?
Robert Lefkowitz: I think that came more gradually, over a period of the next five or six years. I would say within about five years, it was clear to me that, “Wow!” because I see the drug companies. They had been adapting our technologies right from the earliest days. So to really innovate a scientific field, you almost have to develop new technology. And that’s what we were doing. There were no ways to study receptors. So at every step of the way, through the ’70s, ’80s, and ’90s, we were inventing technology to do that.
And sharing it.
Robert Lefkowitz: And sharing it. Completely. In fact, I didn’t even patent anything. Somebody was asking me today over lunch, “Did you patent the stuff?” It was Ted Olson. And he said, “Did you patent any of that?” I said, “No.” He said, “Why not?” I said it never occurred to me. Very different today. Today we patent our discoveries. But back then, things weren’t so entrepreneurial. They weren’t so commercial.
It sounds like, in order to have a successful, robust research lab, you have to be kind of a Pied Piper, bringing people with you to see your vision.
Robert Lefkowitz: Yes, very much the case. Now I was listening to the talks today — just absolutely amazing — and there were these two tech networking gurus. Apparently, they’ve collaborated a bunch and done a lot of things together. But they have totally different personalities, and they were stressing that. I would stress the same thing, that there’s no one right way to do it. I tend to be very extraverted and enthusiastic.
I am kind of a Pied Piper. I would sort of bring my students and fellows along, dream these grand dreams and schemes and this and that, and somehow get them working together with me. Because many of the techniques we invented relied on the brilliance and expertise of my students and fellows, expertise that I did not have. I had a vision and I had some expertise, but there was a lot of expertise I needed that I didn’t have. But students and fellows were excited enough by what I was doing that they wanted to join the effort. So over the years we did that. In fact, one of the fellows who worked with me in the 1980s, Brian Kobilka, who’s a professor at Stanford now, would ultimately share the Nobel Prize with me. Not for the work he did with me — although that was part of it, I think — but for work he did independently here at Stanford. And his personality and mine could not be more different. We have very different styles. So that’s another thing. You have to do it your way. General Petraeus was just now talking about leadership and leadership styles, et cetera. My leadership style is very much about being a Pied Piper. I think any leader has to be able to bring along colleagues and the people who work for them. Because if they don’t buy in, you’ve got nothing.
So you had this very original concept, a new way of looking at science and biology. But at the same time, you have to be a team player.
Robert Lefkowitz: You have to put a team together. I think the days of, you know, the isolated scientist, you know, working in his or her laboratory all by themselves, that just isn’t the way it works anymore. But it’s interesting, I’m a very social person. And I often say that if I — if you put me on a desert island with all the financial support and equipment and everything that I needed to do science, I would wither and die. Because I need the stimulation of working with my students and fellows. And in a very real sense, I’ve always kind of almost viewed that as my central activity — is mentoring the students and the science — I mean, this is a bit of an overstatement. The science almost a by-product. It’s like, you know, if you’re chopping wood, you know, you’re trying to get through the tree, but you have all this sawdust that gets generated. And to me a lot of the papers that we write is almost the sawdust. I mean, mainly what I’m trying to do is shape these young people and sort of show them how I do this — this kind of thing.
There was a beautiful line in an article in The News & Observer around the time of the Nobel Prize. The writer described you amidst all your grad students. He says, “He 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.”
Robert Lefkowitz: That’s so true. I just need that human contact. There are introverts and extraverts. Introverts are drained by social interaction. They’ve got to take a little time by themselves just to recharge their battery. I’m the opposite. My batteries get charged by interacting with my students and fellows. That is a big part of what I do.
General Petraeus talks about affirmative leadership. That’s what some of his subordinates really required. Your grad students have said you make every one of them feel like theirs is the most important research.
Robert Lefkowitz: That’s very important. I didn’t know I did that, until they had a big 60th birthday party for me. That would have been 11 years ago at Duke. And about half of my trainees returned from around the world. I’ve trained almost 250 people in my lab. At the time it was about 200, and about 100 of them came back. And we had this — they had this — all kinds of activities. And they had this big scientific festschrift for me. They gave talks and they all told vignettes. And one of them told that story where he basically said that one of the things that kept him going, when he was in my lab, was no matter how dark things got, I would always convince him that his was the most important project in the lab and he had to keep going because this was it. And he said it was only after he had left the lab and he was at something with one of the other guys in the lab — and this was years later — and he was telling him that story, and this other fellow said, “Well, he always told me mine was the most important project.” And then they talked to several others. It turned out, apparently, I’d given everybody the same message. But you know, I believed it. They were all the most important projects.
How do you get through those times when there is frustration and disappointment in the lab? And how do you mentor your students to get through that?
Robert Lefkowitz: That’s a very important question. That’s one of the most difficult things that there is. Once one is established and has his own laboratory, it’s much easier for you, as the lab chief, because there’s so many things going on in the lab, something’s working all the time. Most isn’t, but at least there’s the one thing you can hang your hat on. But for that student, that’s all they’ve got. I use humor a lot. Humor’s very important to me. There are basically two kinds of people: funny people and not funny people. Most people think I’m pretty funny. I don’t tell jokes, but I have an offbeat perspective on things. So I try to use humor a lot.
Often, for example, somebody’s experiments aren’t working, a graduate student. They’ll tell me and we’ll talk about it. And I’ll look at him and I’ll say something along the lines of, “Now look, I know it doesn’t look good right now. But here’s what we’re going to do. I want you to put your best people on this. Your whole team.” And he’ll say, “But I don’t have a team. I’m just a graduate student.” But then they’ll laugh. They’ll realize how totally absurd that is. And I play all kinds of games with them. And, yeah, I use humor a lot. That helps the suffering. For example, something I’ve been doing the last few years that I got into totally spontaneously. We were collaborating with a pharmaceutical company. And the culture in pharma is totally different than the culture in academia in many ways. So we were having the first of several teleconferences with this company, and we get on the phone and I have them on speaker and they have me on speaker. I’ve got four or five of my students and post-docs with me who are going to be involved in the project. And the guy at the other end of the phone who’s like, who knows, the Executive Vice President for God-knows-what, says, “Well, before we get started, I’d like to introduce my team. I have Dr. So-and-So who’s head of Synthetic Chemistry, Dr. So-and-So who’s head of Medicinal Chemistry, and So-and-So is head of Pharmacology, and whatever.” I say, “Well, let me introduce my team.” Just off the top of my head, I point to my first guy over here who’s a graduate student. I said, “I’d like to introduce Dr. So-and-So, who’s head of computational biology in my group.” Now the only thing that was true is that this guy is doing a project that had something to do with computational biology. And then I introduced the next guy, who’s a post-doc who just started, who did have a Ph.D. in chemistry anyway. And I said, “The head of my synthetic chemistry division is So-and-So.” And of course, the people in the lab are trying to stifle their laughter. Meanwhile, these guys are none the wiser. So we had a lot of fun with that. Two weeks later, we were starting another collaboration with another company. I had some of the same people in my office. We went through the same drill, only I changed the titles. The guy who was head of computational biology last week was now a head of pharmacology. You know, you sort of have fun with it.
I think the humor helps a lot. Plus, very important, even when I myself am really frustrated and down, I never let them see it. Because I feel it’s my job to sort of keep things upbeat, et cetera. But it is very, very difficult because failure is our constant companion. I often repeat to them something that — not my mentor, but a senior scientist at the NIH — said to me once. We were having lunch together. I was despondent, despondent because nothing had worked. I had been there a year. And this guy said to me, “Look,” he said, “do you know the difference, Bob, between an average scientist and a world class scientist?” I said no. He said, “Here’s what it is.” He said, “For the average scientist, maybe one percent of their experiments work. But for the world class guy, the world beater, it could be as high as one-and-a-half or two percent.” And then that really stuck with me because it’s really true. It’s that little difference. But still 98 percent doesn’t work, even if you’re winning the Nobel Prize.
So patience is really a big deal.
Robert Lefkowitz: It is, and I’m not a patient person. We all have certain gifts and we all have certain deficiencies. Patience is not a gift that comes naturally to me.
You have high expectations of your grad students.
Robert Lefkowitz: Yes, I do. I guess that comes from my mother. She had very high expectations of me. I have very high expectations of me. And I have very high expectations of anybody who works for me. But — and this is a big but — I don’t have the same expectations of everyone. So when somebody comes to work with me, I don’t really know what I’m getting as a student or fellow. How can I? It’s like, can you really know somebody when you marry them what they’ll be like ten years later? You don’t know until you live with somebody. But you can’t live with them to hire them. They come for an interview, right? You spend a few hours. You’ve got some letters of recommendation and you make your decision. Then you got ’em, and you don’t really know. But I get to know them very, very well, and that happens very quickly. Now once I understand what I got, then I begin to form expectations. I mean, you can’t take somebody — I’m much like a coach in that regard. You know, basketball is big at Duke University. We’ve got Coach K., a fabulous basketball team. So in a certain sense, part of my work is as a coach. So let’s say — I don’t know if you know anything about basketball — let’s say I got a guy who’s 5’3″ who’s really quick. I don’t make him a center, okay? Let’s say I got a guy who’s 7’1″, got a great hook shot, can dunk, but very slow afoot. I don’t make him a shooting guard, okay. So you got to work with what you got. And, you know, some people are brilliant, some are less gifted. Some people are beautiful experimentalists, but they’re not very good at synthesizing things. Some people are the opposite. So you’ve got to learn to put people in positions where they can succeed by playing to their strengths. So I have different levels of expectations. And if I realize in the fullness of time that I have somebody who maybe isn’t all that gifted, I can’t have the same expectations. It’s not fair to them and it’ll frustrate the hell out of me. So it’s very important that I learn to really understand each of my trainees.
When you gave your Nobel speech, a journalist counted that you used the words “we” or “us” more than 50 times, mentioning other scientists by name. You’re very generous in this, but you truly believe that your students and your peers help you accomplish what you’ve accomplished.
Robert Lefkowitz: Not just help, but were an integral part of it. For the most part, prizes like the Nobel Prize are, in my mind — what’s the word? — symbolic. You give it to an individual, but it’s really a team effort. The extreme case was probably the physics prize last year for the Higgs boson, where they gave it to three guys. But, as I understand it, the discovery that proved this thing existed involved two teams, each with 3,000 physicists. So that’s sort of, to me, the limit case. But you can’t give it to 3,000 people. So yes, I mentioned 50 people, and I probably should have mentioned another 50. But I was trying to distribute the credit as widely as I could. I had a very touching experience that relates to just that thing. Remarkably, many of my alumni came to the Nobel. They came on their own nickel. They had to pay for themselves to get there. These are people who were alumni of the lab from around the world. They could not come to the ceremony or the banquet, because you only get 14 tickets and I have a big family. You know, I have hundreds of alumni. But they came just to be there and be part of it. And of course, I shared the prize with one of them. So we had a big reception, Brian and I, for about 70 or 80 who were there, amazingly. Most of whom, of course, were from my lab.
Flying to Europe.
Robert Lefkowitz: They flew to Stockholm just to be there. They came to the lecture. The Nobel lectures are open to the public. And then they watched the ceremonies from various sports bars and the hotel and various people’s rooms, et cetera. Well, at the ceremony — at the lecture rather — was one of my fellows from the ’80s who had actually been a collaborator in the lab with Brian Kobilka, had done very important work. And he’s gone on to a nice career in academia, not a stellar one. He’s had a difficult personal journey, in that his wife died of breast cancer along the way and he was left to raise their two daughters alone. I had not seen him for probably 15 years before the Nobel. But he was there with his two daughters — now I think 18 and 16, or 20 and 18 — one of whom wants to be a scientist. And he took me — and I didn’t even know they were in the audience until afterwards. And I had called — he was one of the 50 I called out by name and showed one of the things he had done back 30 years ago. And he came over to me afterwards and he said — he says, “I just want to thank you for that,” he says. “If you knew what it meant to my daughters to hear my name mentioned.” And yeah. So they understood what their father had done for the very first time. And that meant a lot to me.
It’s an amazing image. Practically a whole plane full of your former students and fans. It’s remarkable.
Robert Lefkowitz: It was amazing to me. In fact, I have a slide of that that I show all the time. And Brian is next to me. The last slide that I showed in my Nobel lecture, which you can see online, was a slide from my 60th birthday party, where there are about 100 of my former trainees there. The photographer took a picture of us. I’m standing in the middle. And then, just spur of the moment, he says, “Let’s do something different,” he says. He didn’t even suggest anything. All of a sudden, they lifted me up and body surfed me to the back. And I have that picture. Okay? A hundred of my trainees and I’m held up in the air like this. Okay? And to me it’s symbolic because, yeah, they held me aloft. I showed that for the last slide of my Nobel lecture, which is published. And then in the back row, I pulled out a face, which you can see in the picture, and pulled it to the side. And I said, “And now,” I said, “I want to point out one of these individuals. The slide comes out. I said, “This is Brian Kobilka. He’s your next speaker.” And I sat down. That’s how I introduced him, ’cause he lectured right after me.
Could you tell us about getting the phone call, notifying you that you’d won the Nobel Prize?
Robert Lefkowitz: Everybody loves to hear about the call and it is everything they say. It’s an amazing, life-changing experience. So the first question is, “Did I expect it?” Okay, that’s what everyone wants to know. The answer’s yes and no. Okay. Why might it be yes? Well, for 20 years people have been telling me, “You’re going to get the Prize. Why haven’t you gotten the Prize already? Are you ever going to get the Prize?” It was a constant drumbeat. In fact, I have an honor that — or distinction, I should say, that I suspect — there are a lot of Nobel Laureates here, but I’ll bet none of them, I don’t think, have this one. In 2003, almost a full decade before I won the Nobel Prize, in the Durham Morning Herald — and I have a slide of this, which I show in kind of a funny talk I give sometimes called, “A Funny Thing Happened on the Way to Stockholm.” In 2003, in mid-October, after Nobel week had passed, and once again I had not won the Nobel Prize, my picture appears on the front page of the Durham Herald, which is the local paper in Durham, North Carolina. The headline is “Stockholm Calling? Not This Year.” And then the sub thing is, “Robert J. Lefkowitz is Duke’s best hope for the Nobel Prize.” And then a lengthy article with my picture on the front page about how once again I have failed to win the Nobel Prize.
It’s like your mom.
Robert Lefkowitz: Exactly. In fact. In this talk, I talk about her and her pestering. And then I show this article. And then, of course, the punch line is, “How many people do you know who are on the front page of the paper for not winning the Nobel Prize?” And I don’t know anybody. Then the next slide in this talk is a picture from something called The Independent, I think, which is one of these throwaway newspapers that you get at the Whole Foods Market. You know, you pick them up for free. So The Independent was in the food markets the next week with a big smiling picture of me. And the headline on the front — on the front of the paper — is “Why Is This Man Smiling?” And then it says, “He Finally Won the Nobel Prize.” Finally. Not “He Won the Nobel Prize!” He finally won the Nobel Prize. Okay, so that’s the yes part. The no part, in other words, no, I — part of me wasn’t surprised that it finally happened. But the yes part is just as dramatic. First of all, I’m a physician scientist. If I was going to win the Nobel Prize, I would have thought it would have been in medicine. It never occurred to me that I might win the Nobel Prize in Chemistry. Second of all, their secrecy, which is much vaunted, is the real deal. There were no rumors: this year, that year. There was nothing. You know, sometimes somebody gives you a clue. “Oh, I heard them talking. You’re on the short…” Nothing, zero, nada. Now the Nobel Prizes, as you probably know, are announced in a set order every year. There’s Nobel Week. Monday is medicine, Tuesday is physics, Wednesday is chemistry, Thursday is economics, Friday is literature, Monday is peace. Monday came and went. Medicine, no call. I no longer waited for it. There was a period of time for a number of years, probably in my 50s and 60s, where I can’t say I was waiting for the call, but it wouldn’t have surprised me. But I had pretty much abandoned that. I had let go of it. For sure, I wasn’t waiting by the phone on Wednesday, which is chemistry day. But Wednesday the phone rings at 5:00 a.m. I sleep with earplugs, so I don’t hear the phone. My wife fortunately, does not. She picks it up, so she knows before I do. She hears a Swedish voice say, “Is Professor Lefkowitz there?” She gives me an elbow, which she denies, but I’m quite sure she did. She gives me the elbow and she says, “There’s somebody calling from Stockholm.” So immediately, you know right there. But my mind is racing, what the hell is this? This is Wednesday, why would they be calling me? And very quickly, this woman says, “Dr. Lefkowitz, I’d like to put on Dr. So-and-So, the Chairman of the Chemistry Nobel Prize Committee from the Royal Swedish Academy. He has some good news for you.” Well, so there you know. And the interesting thing was, I think if you were taking an EKG, I have a very slow pulse. I work out a lot, plus I take beta blockers, interesting enough. So my resting pulse is 50. It did not shoot to 100, maybe it went to 55. I did not have this amazing, you know, surge of, “Oh, my God.” It was more like this very quiet feeling of satisfaction. “Wow, it finally happened.” And the very first question I asked was, “Am I sharing this with anybody?” Because you never know what they’re going to do. And when they told me Kobilka, then I teared up. I was just — to know that I would get it with one of my students.
But there was a downside. You missed a haircut.
Robert Lefkowitz: I missed a haircut. I was getting a haircut that day and it went by the boards. That was quoted widely. In fact, about three days later, I finally went for that haircut. I was on my way across campus. Of course, everybody by then knew who I was. I ran into a colleague who I didn’t know well. And he wanted to chat. And I said, “I’m sorry, but I’m late. I’m going to get a haircut.” He said, “Ah, you’re finally getting that haircut.” Because everybody knew about that haircut. Golly!
Could you tell us about your childhood, growing up in the Bronx? That was kind of a turbulent time for the world.
Robert Lefkowitz: It didn’t seem very turbulent to me. I guess I was in kind of a protected environment.
I was born in 1943, and so my earliest memories date to, I guess, the late ’40s. One of my earliest is television. The very first television set in my neighborhood appeared in 1948 when I was five. And we would all gather in the apartment. Of course, I lived in a tall apartment building. And we would all gather in a friend’s apartment to watch something called The Howdy Doody Show, which became a real classic. Of course, in those days, there was programming on only three stations — the three major networks. And it was only from about 5:00 p.m. to 10:00 p.m. each day. The rest of the time there was a test pattern on the TV. So the programming would begin at 5:00 pm. So we would gather about ten of 5:00 and sit around, six or eight of us little kids. And we’d watch the test pattern with the tone in the background until 5:00, when a program would start. Those are the kind of memories I have. It was a totally idyllic existence. It was just fun playing with my friends. Never saw grass at all. It was all pavement. There was one park, as I recall, with a few blades of grass. But it was wonderful. I remember it as a very peaceful and happy time.
A test pattern was just a black and white image. It didn’t move.
Robert Lefkowitz: That is correct. And the TV set was about this big. In fact, subsequently, a year or two later, they started selling what were basically giant magnifying glasses. So it looked like a music stand. There was a base and a pole and on the top of it was just a big magnifier. You put that in front of your tiny little TV set so now the image was a little bigger.
Now we’re going back to little TV sets again with iPhones.
Robert Lefkowitz: Exactly. What things change?
Tell us about your folks. What did they do when you were growing up?
Robert Lefkowitz: My father was an accountant and my mother was a schoolteacher. I grew up in a fairly traditional, Conservative to Orthodox Jewish home. It was a kosher home, which means I learned a lot about discipline. And it was a home that was filled with books. I learned to read very early and was somewhat precocious in my reading, loved to read. I would fake illness, particularly a stomach ache, so that I could stay home and just read books rather than go to class when I was in elementary school.
What books did you like to read?
Robert Lefkowitz: As I say, I was rather precocious.
Mostly I liked non-fiction. I read two types of books actually. I did read some fiction. But one of the recollections I have — this would have been when I was maybe 10, 12 at the most — is in The New York Times book section, book review section, which would come out on Sundays. There would be advertisements for book clubs. One was called Literary Guild and the other was called Book of the Month Club. And there would be coupons that you could clip out to join the book club. And in return for joining the book club, you could pick out either a set of books or several free books, in return for which you agreed to buy some number of titles — usually three or four — in the next year. So I would clip these coupons without my parents’ knowledge, send them off, choosing sets of books that I wanted to read, which would arrive. My parents would then ask, “What’s going on here?” I would explain and then they, of course, since I was a little kid, they were stuck holding the bag to buy three or four more books, which, of course, further increased our library, which was great.
I remember, at a very young age — I look back on this now, how ridiculous this was — I bought Winston Churchill’s six-volume set History of the Second World War, read every book. I was probably 10 or 12 years old. And then the other one I bought was Sandburg’s four-volume biography of Abraham Lincoln, and I read all of those. So I liked that kind of stuff. The other thing that I was obsessed with was anything to do with medicine, in particular medical fiction. So I had decided by the third grade that I was to be a practicing physician. It was my only goal in terms of professional life. So I must have been like eight years old when I conceived that goal. And it was based entirely on a single role model, my family physician, Dr. Feibush, who was a general practice physician in the Bronx who made house calls. I was totally taken by it. I mean, nothing seemed — I mean, it seemed to me, what could be better than to be like Dr. Feibush? He was a guy who knew all this stuff that other people didn’t know and fancy words. And he could come to the house and take the stethoscope and listen to you, and then, in an illegible hand, write these prescriptions for medicine. And then you’d feel better. What else could you want to do? So I read books, which nobody’s ever heard of anymore like — Arrowsmith by Sinclair Lewis, which was about a physician. There’s another one called The Citadel by, I think, A.J. Cronin. There was another classic. Then one that was a non-fiction title was Microbe Hunters by Paul De Kruif, which told the story of people like Pasteur and how they tracked down bacteria. I just loved it.
That book, Microbe Hunters, has been mentioned by many of the scientists we’ve interviewed.
Robert Lefkowitz: Interesting.
It must have been very powerful.
Robert Lefkowitz: Oh, very powerful. Those three books. Speaking of The Microbe Hunters, there’s something I learned years later.
When I won the Nobel Prize a couple of years ago, I had to write an autobiography, which appears on the Nobel website. And I was trying to come up with some memories and this and that. I was thinking about those books. And so I started going back for the first time since I was a child to look up something about those books. And I learned the interesting piece of trivia that Paul De Kruif, who was himself, I forget, a microbiologist or a scientist, and who had written Microbe Hunters, had actually collaborated with the author of Arrowsmith, Sinclair Lewis, who was a novelist. I think he maybe won the Nobel Prize for Fiction. But Paul De Kruif had actually helped him with some of the medical aspects of his classic Arrowsmith, which was about a physician and this and that. But yeah, that book was very powerful — Microbe Hunters — for many of my generation. Introduced us to the idea of science.
Did your parents push you academically?
Robert Lefkowitz: My mother did. She was never satisfied.
She was an elementary school teacher and very strict. And so, as I recall, she would review my homework and if I had — in those days we wrote with pencils — and I was kind of a sloppy kid and made a lot of mistakes, so I would make erasures all the time. And of course, the more I erased, the more I smudged it. She wouldn’t let it through. She’d say, “You got to write the whole thing.” And I’d say, “Mom, it’s five pages.” “No. Sorry. You got to rewrite the whole thing.” If I brought home an A minus, she wanted to know why it wasn’t an A. If I brought home an A, why wasn’t it an A plus? This never stopped. So fast-forward 40, 50 years. I’m at mid-career and I’m starting to win a number of prizes, significant prizes for my research. So whenever I would win a prize, I would call my mother up and say, “Mom, good news.” And she called me Bobby right ’til the end. She’d say, “What is it, Bobby?” And I’d say, “Well, I won a big prize.” “What is it?” And I would tell her. And she’d always say the same thing, “It’s nice, but it’s not the Nobel.” So she wasn’t happy even then. And when I finally won the Nobel, she was long gone.
On some level, she probably knew.
Robert Lefkowitz: Hopefully, hopefully.
So you had to go out and win the Nobel.
Robert Lefkowitz: Right. Although it was not her goal for me to win the Nobel. Her goal was for me to come to my senses and come back to the practice of clinical medicine.
I started to become a doctor and I did become a doctor. And I went to medical school. And I did full training. I was board certified in internal medicine and cardiology. The research came later. We can talk about that. But the research came later. And she wasn’t so happy about that because she saw practicing medicine as sort of my true destiny, as in fact I had for many years. So the way she seemed to understand things is that somehow along the way, I had been seduced intellectually by some kind of research problem. And the hope was that someday I would figure that out. And with that done, I would come back to my senses and start practicing medicine again. And so whenever I would talk to her about my research, which wasn’t that often because she wasn’t all that interested in it, she would say, “Have you figured it out yet, Bobby?” The idea being that someday I would answer this damn problem and come back and start practicing medicine again. But it never happened. I tried to explain to her, “You never figure it out, Mom, because every answer raises five new questions.” But she never got that, bless her soul.
Some kids would have rebelled against that kind of pressure.
Robert Lefkowitz: I did not. I guess I was docile in that regard. It’s funny, I didn’t have the sense that they pressured me to go into medicine. You know, “My son, the doctor.” I didn’t get that. That seemed to me to come from me. Where she pressured me was just to perform at the very top level. Fortunately, my dad gave me no pressure at all. He was sort of the opposite. He was, “Whatever, as long as you’re happy.”
You went to a high school that has produced a remarkable number of Nobel Prize winners. Can you tell us about Bronx Science High School?
Robert Lefkowitz: First of all, the remarkable number is eight. I am the eighth Nobel Laureate to graduate from the Bronx High School of Science. I don’t know if I have it exactly right, but if the Bronx High School of Science was a country, that would place us about 12th on the all-time list of most Nobel Prizes by a country. I may be off on that, but it’s pretty high.
You’ve surpassed Australia and tied with Norway.
Robert Lefkowitz: There you go. The other seven were all in physics. So I’m the first one in chemistry. So far there’s been nobody in medicine. So it’s an amazing school. It exists to this day. I was class of ’59.
I had not been back to the Bronx High School of Science until March of this year, when at their invitation I paid a visit and spent the whole day. And it was a marvelous, marvelous day. It was the same building. My class was the first class to graduate from what at the time we called “the new building.” And that’s where they are to this day. I had a marvelous day there. I spoke to the students, and of course, at a place like Bronx High School of Science, a Nobel Laureate is like a rock star. That’s their idea of the quarterback with the most touchdowns, or whatever the analogy is. So they were really over the moon to see me. And in a very happy turn of circumstances, about half a dozen of my classmates who still live in the city, several of whom I’ve kept up with, were able to come and spend the day with me as well. It’s an amazing school. There was only one criterion for admission: how you did on a competitive examination. Nothing else. No letters of recommendation, no teachers’ recommendations, not what your average was of studies in junior high, just that exam. That’s become somewhat controversial these days since it doesn’t necessarily support the idea of diversity. But the demographics are totally different. In my day, I’d say 90 percent of my class were Jewish, immigrant Jewish descent. Today almost everybody is of Asian descent. So a totally different demographic.
What is that about?
Robert Lefkowitz: Well, I think it’s about several things. One, I think a lot of the group that my classmates and I represented — I think a lot of them have moved out of the city. Those families are no longer in New York City. You have to be in New York City to qualify. And I think that the Asian-American culture is much like the immigrant Jewish culture was back in the ’40s and ’50s, namely very striving, trying to better themselves, and very much aware of how important education was in that regard.
Were there teachers in high school you remember that were particularly important to you?
Robert Lefkowitz: One in particular, Mrs. Gordon. I hated her. I took AP English. The AP courses were just starting in the ’50s. And you could take a maximum of two. I took Chemistry and AP English. Today, the kids come into Duke, they have ten, 12, 15 AP courses. They start taking AP courses in their first year of high school. It’s absolutely amazing.
Mrs. Gordon taught AP English. And she took a disliking to me for some reason early on, and she didn’t like the way I wrote, so she gave me very bad grades on all my essays. She pounded into me about how to write clear, effective, succinct English. And I learned those lessons well. But what I remember — and I pay her a tremendous tribute for that because there’s no more important skill, certainly for a scientist, but really for almost any profession, than to be able to express yourself clearly and succinctly. And I think she really taught me that. She actually did the following, I think, ridiculous thing. She went around the class the day before we were to take the AP exam and predicted, and wrote on the board what she thought each of us would get. I don’t know if you know anything about that scoring system. But five is the highest grade you can get, then four, and three, and two. And depending on what score you got, when you went to college the next year, you might either — if you got a top grade, you might get not just placed out of that course, but you might actually get credit for it. If you got a four, somewhere, three, less. And if you got below a three, it was like you didn’t take the course. So for many in the class, she predicted a five and some a four. And for me she predicted a three and one other kid. And then she said she would write the scores on the board in a few weeks when they came in. P.S., I got a five. And I still remember looking at her when she wrote that up there. And I could see she was not happy about it. Oh, I’m sure she was happy, but she didn’t like the idea that she had been that off the mark. Anyway, that was Mrs. Gordon.
Did Mrs. Gordon live to see your Nobel Prize, by any chance?
Robert Lefkowitz: I do not know. She was not there when I came back to Bronx Science. Although, interestingly, my tenth grade math teacher was. Now in her 80s. She doesn’t teach anymore, but she had heard I was coming back. She keeps up with things. She actually was there. She’s amazing. At first, I didn’t remember her, because when I had her it was her first year of teaching, so she was probably like 23, 24. Now she’s like 85. So there wasn’t much resemblance.
So you ended up at Columbia, thinking pre-med.
Robert Lefkowitz: Straight pre-med. Absolutely, nothing else on my mind.
How did you become involved in research? Was that already your interest as an undergraduate?
Well, that’s an interesting story. That came much later.
Robert Lefkowitz: I was a chemistry major at Columbia College, but I had no interest in doing research, since I was pre-med. And I loved science. Loved science. Always did — biology, chemistry, all of it. But I didn’t want to do research. I went off to medical school at Columbia and we had several opportunities to do research in medical school. I passed them all up. I always did clinical electives. I never did a research elective because I had no interest in doing research and I couldn’t wait to get to the clinical stuff. So then I did two years of residency at Columbia after I graduated. So that brings us to 1968. The Vietnam War is raging. There’s a doctor draft. There’s a general draft, which is on a lottery basis. There’s also a doctor draft, which means everybody goes in for two years. So you got two years of training, internship and one year of residency and then you went in. It was a very unpopular war. Many of us did not want to go to Vietnam to serve. There were very few ways around it. One way is if you could win a commission in the United States Public Health Service, you could get assigned to something like the CDC in Atlanta or the NIH or one or two other installations and do research for two years. So I was able — because I was at the top of my class — I was able to get that commission and go to the NIH. And there I started doing research with no success whatsoever. And so for the first 18 months of my two-year assignment there, nothing I touched worked. I hated it, could not have been more miserable. My father died during that time, which was a further blow. But I had never failed at anything. I’d always been top of my class. Things tended to come easily for me and now this didn’t work at all. So the only thing that was clear to me was I would not be a scientist, which was no great loss, because I had never aspired to be one anyway. So I made arrangements to continue my clinical training at the Massachusetts General Hospital, which is one of the Harvard affiliated hospitals, at the end of the two years. But during the last six months, things started to work, and I got my first taste of what it feels like to make some scientific discoveries and write a paper and get the attention that was involved in that. It was fun. But it was time to go off to my residency. And then I had what was one of the defining experiences of my career, which was, interestingly, sort of an anti-experience. And that was the experience over the next six months of doing full-time clinical work again, which I enjoyed, but doing no research. And I really missed it. That was the key.
What was this clinical work?
Robert Lefkowitz: The clinical work was intensive, acute medicine. I was a senior resident in medicine. I spent about half the time as the senior resident in the emergency room.
An emergency room of a big city hospital like the Mass General is a wild place. And it’s all comers — medicine, surgery — whatever is coming through the door, you’re responsible for triaging it or taking care of it yourself. And it’s 12 hours on, 12 hours off. And after seven cycles of that, one 24-period off — 24-hour! And it was really intense. And you know, I loved clinical medicine. I was good at it. I enjoyed it, but boy did I miss the lab. And it wasn’t so much doing the experiments with my own hands that I missed. It was the idea of having data, having something to really chew on and analyze. This was just boom, boom, boom, boom. Almost like on a battlefield. And I really missed the research. And so ironically, the entire second six months of the residency year was elective. And you have to do clinical work, because you were paid with hospital dollars. So, in contravention of the rules, I actually went into somebody’s laboratory. The irony there was, all through medical school, I turned down research electives. And now in a situation where I couldn’t legally do them, I did it anyway. I really had to get back to the laboratory. That’s really when my research career really began to take shape. Although I was at that point by no means committed to a research career at all. In fact, several years later, when I took up my first — and as it turns out, only — faculty position at Duke in 1973, I would say at the beginning, I was probably spending about 50 percent of my time doing clinical work, doctoring, and 50 percent of the time setting up a laboratory. But that changed quickly over the next few years.
What are you most proud of looking back?
Robert Lefkowitz: That’s easy, my trainees. In my field, receptor biology, the field is dominated by people that I trained. Kobilka is one example. I would say I have, for years — in all due modesty — I led the field. I passed that mantle to Kobilka. He has the newest technologies and this and that. But he’s just the limit case. There are dozens and dozens of people who trained with me that, if you go to any meeting on receptor biology and you look at the program, I don’t know, 30 to 40 percent of all the speakers will have either trained with me or trained with people who trained with me. They’re in the lineage. So that’s what I’m most proud of. That would be the most proud. Second most proud? Well you know, we really changed the whole — we created a field and that field has changed drug development and led to dozens of drugs, which really impact people’s lives. I really should think about that more. I don’t. Yeah.
You enabled drugs to be more precise in what they did.
Robert Lefkowitz: More specifically targeted, and developed infinitely more rapidly because of these technologies. Drug development was so cumbersome, because the only way to have any sense of what a drug might do would be to inject it into a living animal and make all kinds of detailed physiological recordings. Now, because we can isolate the receptors and work with them either in isolation or in cells, I mean, you can screen thousands — hundreds of thousands — of compounds very quickly with these methods that we developed over the years. Now did I develop the methods so that drugs could be developed like this? No. I just wanted to know what the receptors were. And to do that, I had to develop these technologies. Which is a very interesting thing about basic research, versus what’s called translational research. I mean, the impetus to my research in the first instance was never to cure a specific disease, to change the way drugs were developed, any of it. I just wanted to know about these receptors. Do they really exist? If so, what are they like? It was just curiosity about a specific problem. But if you choose a problem well and you’re lucky, sometimes it can have big implications.
Thank you so much for talking with us today.
Robert Lefkowitz: My pleasure. That hour went by very quickly for me.
Yes, it did.