Five years after sharing the 2012 Nobel Prize in Chemistry with his former student, Stanford’s Brian Kobilka, Robert Lefkowitz of the Duke University Medical Center continues lab work. At age 75, he’s still building on the groundbreaking discoveries that reveal the functions of G protein-coupled receptors which drive the effects of half of all medications. He also contemplates issues as timeless and conventional as the importance of mentors and as topical and controversial as the danger of the anti-science attitudes of the current presidential administration. At the fifth anniversary of his becoming a Nobel laureate,, Lefkowitz sat with Emilia Chiscop-Head, an internationally awarded journalist now working at Duke University Initiative for Science & Society, for a wide-ranging discussion.
ECH: In your autobiography, you call yourself a “serendipitous scientist.” Could you explain what you meant by this title and the magic role of serendipity in your life?
Robert Lefkowitz: I was thinking of two aspects of my career. One, that the whole fact that I had a career In science was pure serendipity because that was not the direction that I was going; and the second meaning I had was just that I think, frankly, that most successful scientific careers -- and certainly most Nobel prize winning careers -- are filled with serendipity. The serendipity of my career had to do with the fact that I was planning to be a physician, and it was only because of the Vietnam War and the fact that there was a draft of physicians that I was looking for a way out of serving in a very, very unpopular war. And I was able to do that by joining the United States Public Health Service as a commissioned officer, which counted for my draft service, and then being assigned to the National Institutes of Health to learn how to do research. And after a very -- shall we say -- checkered start there filled with failure, I eventually met with some success. That's a whole long story. But, as I say, ultimately it was because of that experience that I wound up gravitating to science. So that was pure serendipity, circumstances way beyond my control. I never would have dreamed up such a career. And then, of course, on a day-to-day basis in science, every once in a long while serendipity just sort of drops in and gives you a remarkable gift because you've got a chance. Chance favors the prepared mind. It's true. You've got to be ready for it.
But of course beyond serendipity there is a huge amount of work. I was just curious. If you were to quantify the number of hours invested in your research on protein receptors what would that look like?
What would the numbers be? Well, you know what? It really is such a huge number, because I have been pursuing this line of research for just under 50 years -- 49, but who's counting? I've never viewed it as work, OK? So when I'm in it and you say, "Well how many hours a week have I worked?" even that's almost unanswerable because I couldn't tell you when I'm working or playing. Certainly, you know 10-hour days in the lab and office, etcetera. Maybe somewhat less now at age almost 75. But then at home in the evenings and on weekends, much of the time I'm working. I'm not really working. I'm just doing what I do. And it will be work and reading papers planning experiments e-mailing with my students and fellows at all hours. So it all runs together. I don't have a clean separation between work and recreation.
This anticipates one of my questions: In your autobiography, you list those key factors for success, and play and humor are perhaps the most unusual, in a way, that you list there. How do you see play and humor in terms of important factors in your life?
You know, having a childlike curiosity in what you're doing and childlike wonder about what you're doing I find really stimulates creativity. Just think of it -- when we are most creative? When we're children, right? Especially when we are young kids. I have six grandkids and I raised five children of my own. So I've had a lot of experience with kids. And, yeah, I mean kids are so creative. I love playing with my grandkids because my approach is that I just go with whatever is going on. So you know we can be having a conversation and all of a sudden they're off in some crazy tangent. That's fine. I go right with it. No problem at all. So, having a playful attitude, I think, enhances creativity, because, what is play? Play is sheer imagination. I mean one of my favorite quotes is from Albert Einstein, who said, "Imagination is more important than knowledge." That certainly has been my experience. But humor is also part of this. You may have gathered that I have a pretty good sense of humor and I see most things in a humorous perspective. I find that with my trainees. I'm always challenging them with humor, and part of humor is timing and surprise. So they never quite know what's coming, and right in the middle of a discussion or something I'll throw something in. In my lab meetings I use a lot of humor, because 1) it's fun and 2) it's just me and 3) most importantly, I feel it encourages creativity. When you're using humor-- and this is a problem for some of my foreign trainees, especially the Asians, I realized they don't get a lot of my humor, and I can tell as I look around the room who gets it and who doesn't. Part of that is cultural, part of that is language. A lot of humor uses nuance and double entendre. But, every time you make a humorous remark, you are basically putting things together which would not ordinarily be together, or you're presenting a perspective which is different than the usual one. But that's what scientific discovery is all about, it's about putting things together that maybe you wouldn't ordinarily put together. So I find that a humorous and playful perspective is really -- for the way I do science -- very important… Most of the really great scientists that I have respected in my career are pretty funny. Not all of them. There are a couple of dry ones and they obviously have a different system, but a lot of them are really fun.
When did you start your research on the protein receptors and how was this research question born?
For me, the question was born when I went to the NIH and I had two mentors. Both of them are still alive. Both of whom are still professionally active in their mid-80s -- one in New York and one at NIH. They were molecular endocrinologists. And they actually, amongst some other scientists, had the idea that there might be such a thing as a receptor. It was a very controversial idea. Most people didn't really believe in it. So they assigned me a project to try to develop a certain assay for a certain kind of receptor. As it turns out, it was the same family of receptors that I would ultimately study my whole career, but it was not the same receptor. It was a receptor for a hormone called ACTH -- Adrenocorticotropic hormone. And at the time there were no direct means of studying receptors by direct assays, and they just assigned to this total novice the idea of trying to develop such an assay. And they did not micromanage me at all, and I was really a lot on my own and I made many, many errors and, you know, for 18 months got nowhere. So, that's where the question was born. Then, after I went off to continue my clinical training and found that I missed the laboratory, I wanted to start up again, but I didn't want to work on that research. I wanted to work on something with more direct relation to cardiovascular medicine which was the clinical field I was pursuing. That's when I selected something called the beta adrenergic receptor, which is the target of beta blockers, to study. And that became, not the sole model I used throughout my career, but by far the most important. But the concept was born at the NIH.
When asked what was the best thing about winning the Nobel Prize, you respond like the Nobel Prize winner Alfred Gilman who said, "The best thing about winning the Nobel Prize is Never again having to answer this question, “When are you going to win the Nobel Prize?” Could you tell me when you heard that question for the first time?
About 20 years before I won the prize, people began touting me for it… I give a humorous presentation, sort of an after dinner talk, called, "A Funny Thing Happened on the Way to Stockholm," in which I take delight in reviewing this long 20-year history of not being a Nobel laureate. It definitely started a good 20 years before. People would ask me, "When would I win the prize?" "Why hadn't I won the prize?" "Isn't it about time I won the prize?" and went on and on and on. I even made the front page of the Durham paper one year. I think it was in 2003. They had me on the front page of the paper as not winning the Nobel Prize but being Duke's best candidate. Now I laugh about it. There were times when I was not so thrilled.
So you and other young physicians started to do the research in order to avoid serving in Vietnam and nine of these young scientists went on to win the Nobel Prize. What I was thinking was this: The Vietnam War is responsible for about 2 million fatalities among civilians and about 58,000 American military. And I find the scientific discoveries of these nine Nobel laureates as a great war compensation, and I thought about the impact of your research. If you were asked to estimate how many lives were saved through treatment from your discoveries, what would that be?
Well let me let me make the following point. In terms of my own research, by far the commonest target for drugs that are used in the clinic are the G-protein coupled receptors that my lab discovered and which I have worked on my whole career -- everything from anti-histamines to beta blockers to serotoninergic to dopaminergic drugs. The list goes on and on and on. Who's to say how many millions of lives have been at least affected by it… My friend Harold Varmus – who was a classmate in medical school, is one of the nine and was with me at NIH -- discovered oncogenes, the genes that cause cancer. Untold things have come from that in terms of all the new anti-cancer medicines; Brown and Goldstein -- and I'm picking this group because the four of us were not just there during the Vietnam War, we were there for the same two years, '68 to '70. Brown and Goldstein's work was responsible for the development of statins for cholesterol. So now you’ve got the commonest drug targets, you've got cancer, you've got heart disease.
This is just four. I'm not going to the other five.
I found the stunning statistic in your autobiographical essay that all nine laureates had a Nobel winner as their mentor or their mentor's mentor. I find this very powerful. I know you value mentoring and you won the Nobel Prize with one of your mentees. What is the biggest ethical challenge of mentorship? Is this about establishing professional boundaries that would allow the mentee to thrive and be equally recognized? I find this is a challenging relationship.
Absolutely, and not every great scientist is a great mentor. Not every great mentor is a great scientist. To me the greatest challenge is the following -- and you hinted at it. It is that you can fail in different ways. On the one side, you could fail by, counter-intuitively, being too close to the mentee and micromanaging their work. If you do that, I think, what happens is that the student or fellow never develops true intellectual ownership of what they're doing, and confidence that this is really their work. In consequence, even when it works, they can't fully embrace it, because they kind of know deep in their heart, "You know, without the boss . . . well." At the other extreme you can fail by being so distant that they never learn the things that you need to teach them. So, for me, the greatest challenge has always been walking that line and finding that balance… But it's even more complex than that because the lines are in a different place for every single trainee. There are some who are very, very naturally gifted, and they often seek out the best scientists to train with because they have the intuitive sense of who's doing the best stuff. So for them I might set the line in one place. And sometimes you have a much less talented trainee, and you've got to set the line in a very different place. So that's the biggest challenge. The key to it, though is, really being a good psychologist -- really taking the time to get to know everybody one-on-one, because if you don't do that you have no idea. And believe me, a lot of colleagues I have don't know the first thing about it, to be quite honest.
What is the next major breakthrough you hope to see building on your work with cell receptors?
I think the next major breakthrough for me has to do with some ideas we have in my laboratory which build on work that we're doing right now which will allow us to, by virtue of understanding in greater detail than we ever did before, how the different drugs fit into the receptors… We hope that this will allow us to develop new classes of drugs that are much more specific than ones that have existed before. And it's not for any one particular receptor or disease. We have ideas that are, we believe, generally applicable to this whole family of receptors. Now, in order to achieve that goal, it's going to be necessary to take some of the work out of the academic laboratory and into the commercial sector. Once before, I was a founder of a biotech company, just a decade ago. It's doing quite well, it's a publicly traded company now. They have a couple of drugs that are very close to being approved. But I'm on the verge of doing this again. In general, that's not what I like to do, but if it's necessary to achieve a certain end, then, 10 years ago we did something similar. We had ideas which we really felt could kind of revolutionize the way certain drugs were developed, but you can't do that in academia. That's not our goal. Our goal was to develop new ideas and new knowledge and then the actual translation of that best goes on the commercial side.
It seems gene therapy is the field that is rising today. Can you foresee a day when genetic treatments will make the lifesaving drugs we rely on now obsolete?
Probably not obsolete. You know, it's interesting. I have a long enough perspective on medicine now, I've been a physician since 1966, so, more than 50 years, and my research career is also almost 50 years. And, you know, a lot of stuff gets hyped in the press. Gene therapy as it's called has been hyped for probably at least 30 years -- at least 30 years. And, we are making some modest progress. I do think that some of the recent developments that you read about in the paper do have the potential -- underscore potential -- to revolutionize the way a number of diseases are treated. But it's a hard-=fought battle and this could be some tiny steps. So I wouldn't expect any revolution in the next decade. In the next 50 to 100 years? Yes. Did you ever watch, back in the day, a TV series called Star Trek? Anyway, there was a doctor on the show, they called him “Bones”, and he would just touch people and they'd get better and he would talk about how barbaric it was the way they used to treat whatever the particular condition was. I can relate to that. For example, twenty-three years ago I had quadruple bypass surgery for coronary artery disease. I really do think that 50 years from now people will look back and say what barbarism that was. They cut people's chests open when now we can do… whatever. Already we do stents… So I think there'll be big changes, but I don't think there's going to be a revolution that we can see in either of our lifetimes. I think it's going to take many, many decades.
As the Obama administration ended, it advocated a "moon shot" approach for curing cancer. In other words, devoting government resources to cancer research the way we did to land men on the moon. Do you believe America has still the will to do this and if we do, would that work?
I think that we don't have the will to do it. I think the current political administration is an anti-science administration -- very shortsighted. They want to cut the NIH budget. Fortunately, Congress won't let them do it. But they also will not give the expansion that is really necessary. And I think a lot of people -- the man or woman in the street -- don't understand just how important original scientific investigation is. And so that's not what they're voting on. So I don't think we have the will. Let's say, for the sake of argument, we did have the will. Do I think a moon shot approach would work? No, I really don't. The reason is the following: What we need is strong support for basic scientific discovery research, which is what's going to lead to the major advances. It always has been that way. You can't dial that up, OK. It's got to bubble up naturally. It's not like ordering a hamburger. You can't order a cure for cancer. You can't order a cure for heart disease or anything else. So what you've got to do is just have solid support. Also invest in training and selecting the best scientists and most creative scientists and then supporting them not just adequately but generously. Let 'em rip and hope for the best. These moon shot things to me don't work.
In your biography you say that one of the missed points was not having an interest in a management position. Would you have ever been interested in politics?
It's a fascinating question. You know, my good friend Harold Varmus, who won the Nobel Prize for oncogenes, went from being a lab scientist, like me, at UCSF [University of California, San Francisco] back in the ‘90s, and had never even held an administrative position in academia, he went from that, after he won the Nobel Prize, to being the director of the National Institutes of Health. He had no administrative experience whatsoever. At multiple points in my career, I considered taking on administrative types of responsibility. I could have put myself on that track. I've been able to predict nothing about my career, which in retrospect, is nice. It makes life fun and exciting. But when I was a resident in medicine, I really excelled. I was an excellent physician if I do say so myself. And so both institutions that I trained at asked me eventually to be the chief medical resident, which is like a big honor. Now, if you had asked me when I was in medical school, what would I conceive the biggest honor that could ever come to me, I would have said to be chief medical resident. Nonetheless, both Columbia and Harvard asked me to be the chief medical resident, and I turned them both down, because by the time that came along, my interests were elsewhere. I came to Duke in '73. If you would have asked me, "In the next few years, what do you think is the next step in your career?" I would have said to be chief of cardiology somewhere, maybe here. I can't tell you how many offers I got to be chief of cardiology. Never took one. I wasn't interested in it by that time. So if you would have asked me by 1980, "What do you think is next?" I think it would have been being chairman of medicine that would have seemed to me the ultimate thing that I could do in my career. I was offered chairs of medicine, including here at Duke. I had no interest in it by the time that came around. And on and on and on. Why didn't I do it? Do I think I could have done a good job of those? Yeah, I think I could have done an excellent job. So why didn't I do it? I guess the best way I can put it is although I think I could have done a good job, I think I would have done a lousy job because I was so focused on the discoveries and the research that I wouldn't be giving it my best. And so, at least I was honest enough with myself to say if I'm not going to give it my very best and 100 percent, I'm not going to do it. And so here I am now in my seventy-fifth year, and I still haven't done any of those jobs...
How do you see the relationship between science and divinity?
Oh, wow. That's very interesting. So I guess some of Einstein's views which I'm just reading about are in accord very much with my own, which is that when you discover how things work . . . you can’t help -- at least I can't, and apparently Einstein couldn't either -- but be in awe of the complexity and yet order of everything. I don't like to think of myself as a creationist. On the other hand, I just don't know how this all got organized, and it just leaves me wondering sometimes. Yes, evolution can explain how things in the realm of life developed. But that it started at all, leaves me wondering. And the complexity of the systems puts me in a very spiritual frame, rather than the opposite.
Yeah. I personally don't know much about science or divinity. But I intuitively think there's no contradiction between them.
Yes. That's exactly the way I feel. I've actually read several books on that subject…A very good one is “The Language of God.” It's a very interesting book. If you haven't read it, you might look it up, the author is Francis Collins. He is a good friend of mine, and he is the director of the NIH. He's a very well-known scientist and he's is a member of the National Academy of Sciences. He's a geneticist. But he's also an evangelical Christian. He began as an atheist, and after he was already a very successful scientist, he became an evangelical Christian. And he wrote a book about it.
You also say that in order to succeed, you need to be able to tell a good story. I love that. My last question is if you were asked to tell your story in three sentences, what would those be?
Jewish boy from the Bronx, loves to read. Dreams of being a doctor. And somehow turns out to be a scientist who wins the Nobel Prize.
Interview by Emilia Chiscop Head (recorded on September 21, 2017)