Nobel Laureate Robert Lefkowitz: Intuition, Loss and the Discovery That Changed Modern Medicine

Professor Robert Lefkowitz is a Nobel Prize-winning scientist whose discovery of G protein-coupled receptors underpins more than 700 of the drugs in use today, including beta blockers, antihistamines, antidepressants and GLP-1 medications like Ozempic. At 83 years young, he still runs his lab at Duke University, exercises an hour every day, and eats entirely plant-based food after quadruple bypass surgery at 51.

In this deeply personal conversation, Professor Lefkowitz takes Méline through the science that changed modern medicine, the role of intuition in research, and the father who gave him the most important piece of advice he ever received and died three weeks later, never knowing what his son would go on to achieve.

He explains:
 ◼ How G protein-coupled receptors work and why they are the foundation of modern pharmacology
 ◼ Why a third of all FDA-approved drugs work through the same system he discovered in the 1970s
 ◼ How GLP-1 drugs like Ozempic actually work and why we are only at the beginning
 ◼ Why intuition is the only thing that keeps a scientist going when experiments fail for years
 ◼ The two things he says are all that really matter in a life: love and work
 ◼ What he hopes to see breakthroughs in before he dies: cancer and dementia
 ◼ The advice his mentor gave him that he still lives by: five year packages, never more

0:00 Intro
0:47 How Winning the Nobel Prize Changed His Name and His Life
1:50 The Discovery That Underpins 700 of Today's Most Used Drugs
4:42 How Receptors Work: The Lock and Key That Runs Your Body
8:05 Why Intuition Is the Only Thing That Keeps a Scientist Going
11:35 The Vietnam War Draft That Accidentally Made Him a Scientist
17:00 Why He Missed the Lab and What That Told Him About Himself
20:35 The Science of GLP-1: How Ozempic and the New Weight Loss Drugs Actually Work
23:15 Gene Therapy and the Future of Editing the Human Body
27:50 The Chemistry vs Medicine Nobel: The Story Behind the Tug of War
33:00 The Thanksgiving Conversation With His Father That Changed Everything
38:30 Why He Still Exercises an Hour a Day at 83 and What He Eats
42:00 His Warning About AI in Medicine and Why You Cannot Trust It Blindly
44:45 The Two Breakthroughs He Is Still Waiting For: Cancer and Dementia
47:00 Love and Work: What a Nobel Laureate Says Actually Makes a Life

 ◼ Duke University Profile:
https://www.lefkowitzlab.org/ 

 ◼ Book: A Funny Thing Happened on the Way to Stockholm:
 https://www.amazon.com/Funny-Thing-Happened-Way-Stockholm/dp/1324006811

Transcript

SPEAKER_02 0:00

I've impacted the lives of millions of end of millions. Intuition is often wrong, but the fact that I won the Nobel Prize, what it tells you is the intuition was right. Today, about a third of all FDA-approved drugs work through G protein coupled receptors. Every drug has side effects. The higher the dose, the greater the side effects. That was the last conversation I ever had with my father. He died three weeks later. And he never got to see any of that. Any of that. I've been remarkably blessed in my life. I'm going to tell you something, you're not going to believe.

SPEAKER_00 0:40

Professor Robert Foy won the Nobel Prize for discovery. That's something that's the last conversation he ever had with his father.

SPEAKER_01 1:10

It's such an honor to have you today, Dr. Lefkowitz. Welcome to the Humanware Project. In the day you received the Nobel Prize Award, has that changed your life before and after?

SPEAKER_02 1:22

Yes, it changed my life in many ways. In a sense, it even changed my name because I'm no longer introduced as Robert Lefkowitz or Bob Lefkowitz. Anytime anybody introduces me, I'm introduced as Nobel laureate, Bob Lefkowitz. So it even becomes part of your name. So those are the two uh, I guess, most significant ways that it changed my life.

SPEAKER_01 2:04

Because your study on the cell receptors and how our cells behavior at the late 1960s is actually quite a niche subject to study. When you look back to a younger self, what do you would say to him?

SPEAKER_02 2:18

The first thing I would say to him is, sit down. I'm going to tell you something you're not going to believe. And he would say, What is it? And I would say, you're going to become a famous scientist. And he would have laughed out loud.

SPEAKER_03 2:34

Yeah.

SPEAKER_02 2:35

And he would have said, But I don't want to be a famous scientist or any scientist at all. Really? Yes. I have no interest in being a scientist. I want to be a doctor. And I would say, well, uh, you'll get to do that, but you're also uh be gonna become a successful scientist. And if that isn't crazy enough, here's something else for you. You're gonna win the Nobel Prize. Uh at which point I think I would have been speechless.

SPEAKER_01 3:05

So what intriguing you from being a physician or from being a doctor into, you know, pursued science?

SPEAKER_02 3:14

So I graduated medical school, Columbia, in 1966. The Vietnam War was raging. There was, in addition to the lottery draft for all men over 18, there was a doctor draft. But this was not a lottery. Everybody was drafted upon graduation from medical school. You were deferred till you graduated medical school, then you were given two additional years to pursue postdoctoral training, an internship, a medical residency for a year or two. And then you went into either the Army, the Navy, the Air Force, or the United States Public Health Service. Yeah. If you were drafted into one of the first three, Army, Navy, Air Force, you were pretty much guaranteed of spending a year or more in Vietnam. Nobody wanted to do that. It was a very unpopular war. Many of us thought it was uh at least immoral, if not illegal. Uh, and so everybody was trying to find a way out. Uh, one way out of serving in Vietnam in support of the war was to be drafted into the public health service. If you were able to get a commission in the public health service, you stood a chance of being assigned stateside.

SPEAKER_05 4:35

Okay.

SPEAKER_02 4:35

And better yet, if you were really fortunate, being assigned stateside to one of their research institutions, like the NIH or the CDC.

SPEAKER_05 4:44

Yeah.

SPEAKER_02 4:45

So it was extraordinarily competitive to get those commissions. Because I always was a very good student and had gone to good schools. I was able to get the commission in the public health service and was assigned to the NIH for two years. There, I spent about 20% of my time taking care of patients in the what was called the clinical center. These were research patients, and 80% of my time doing mentored research. I was there doing that research, not because I was particularly interested in becoming scientist, becoming a scientist. I was there because it was the best of several options open to me at the height of the Vietnam War. And initially things went very poorly. Okay. Uh for the first year or year and a half of my two-year stint, uh I met with no success.

SPEAKER_04 5:38

Yeah.

SPEAKER_02 5:38

This was a new experience for me. I had never failed in a prolonged way at anything I had ever tried in my life to that point. But now I failed over and over again. So I made arrangements that at the end of my two years I would leave the NIH, finish my clinical training at the Massachusetts General Hospital in Boston, and then I thought either go into practice or have some kind of clinical professorship at a medical school.

unknown 6:09

Yeah.

SPEAKER_02 6:11

But during the last six months at the NIH, my work started to yield some fruit. I actually published a couple of papers and was starting to enjoy it. Uh my mentors uh importuned me to stay uh and continue the work, but I wasn't enjoying it that much. So off I went uh to the Massachusetts General Hospital in 1970. And for the first six months, I threw myself into full-time clinical work again, no research. But at the end of those six months, I realized I missed the lab. That uh not that I would want to do that full-time, but I really I missed it. Which part of it do you aren't me say? What I was missing was the day-to-day challenge of forming hypotheses, devising experiments, trying to answer a question that nobody else had ever answered before. I missed the creative aspect of it. I guess increasingly, even though medicine was my first love, less and less did I see it as a really creative enterprise.

SPEAKER_04 7:19

Yeah.

SPEAKER_02 7:20

It was a humane enterprise. It was about as humane uh an enterprise as I could imagine. Uh and it was what I had dreamed of doing uh from the time I was seven or eight years old, when my role model and my idol was my family physician. Uh but now these creative stirrings seemed to me pulling me in a different direction. And so after six months out of the lab at the Mass General, uh in 1970, 71, I decided, you know, I need to start working in the lab again, even while doing clinical work. And then in 1973, I came to Duke, set up my lab, uh, and uh, as they say, the rest is history.

SPEAKER_01 8:07

But when you were first starting to set up your lab, is there any challenge at the time?

SPEAKER_02 8:12

I had decided the research problem that I would work on, okay, uh, which has to do, as you know, with cellular molecules that we call receptors to drugs and hormones. At the time, there was no general consensus that such molecules even existed.

SPEAKER_01 8:31

Can you tell us, because this technology and this discovery not only win you a Nobel Prize, but it also helps millions of people with our everyday life. So if we bring those signs into our everyday life, what are those receptors doing? Why that matters to us?

SPEAKER_02 8:48

So receptors are sites on cells with which drugs and hormones interact or combine to initiate their actions. Okay. Think about it as a lock and a key. So the lock is the receptor. Okay. To fit that lock, a drug or a hormone needs to have a complementarity in its structure to fit into the lock, just like a key. Let's take a specific example: adrenaline, epinephrine. Okay. Uh I chose that as my model system. Epinephrine, everybody knows, stimulates the heart, makes it beat stronger, faster, uh, dilates the airways, et cetera. But in order to start those actions, it has to fit into a specific site on the cell that recognizes it. That site is called a receptor, and it's called an adrenergic receptor from adrenaline. Okay. Uh so I set out to prove there was such a thing. But of course, there was no way to measure.

SPEAKER_01 9:58

But uh there must be a lot of voice that says otherwise, right? There must be not a lot of evidence. How do you know it was right to study?

SPEAKER_02 10:07

Well, intuition plays a very big role. Okay. There were uh pieces of evidence that suggested that there must be such receptors. Not conclusive at all, or people would have believed in them. What what were some of these pieces of evidence? Well, one, drugs like adrenaline, they work at very low concentrations. Very low concentrations. A few molecules can have an effect. That means there must be something on the cell for which that adrenaline has a very high, what we call affinity. It likes to bind to it. The other thing uh is that there's tremendous specificity in the actions. In other words, the only things which can imitate adrenaline are molecules which chemically look very, very similar to adrenaline. Again, suggesting you've got to have a key that that fits very, very specifically. But beyond that, you've already hit the key, intuition. Uh, and nobody can really explain intuition. Uh, but intuition is a real thing.

SPEAKER_01 11:17

I imagine it would be harder to do the research based on your core belief that there's a thing and we can't see it by eyes.

SPEAKER_02 11:25

This intuition is very important because when things are failing and you are working on something over not just days, weeks, or months, but years, the only thing that keeps you going is intuition, which is a feeling, this has got to be true. Even though I can't prove it yet, it's gotta be true. It's a real process, I believe. It's just we don't understand it. What it is, is basically, you know, you have all these circuits in your brain, uh, and they're all kind of spinning. Uh, and sometimes it's like a slot machine, and you get three oranges or three apples. Uh anyway, uh that's the way I picture uh intuition. It's just something below the surface that's just telling you this. Now, intuition is often wrong, uh, but sometimes it's right. And uh, you know, the fact that I won the Nobel Prize, uh what it tells you is the intuition was right.

SPEAKER_01 12:27

For those young scientists right now, they're pursuing science and they're pursuing their own subject of study. What are your advice for them?

SPEAKER_02 12:37

For the younger scientists who are still in training, my most significant piece of advice is choose your mentors very carefully. Your mentors are much more important than where you go to school, uh, et cetera. I mean, young people think that, oh, I gotta go to school here, I've got to go train at this place. Much more important is who is the specific mentor that you select? Now, for young scientists, you know, who are beyond the training uh stage, the single most important decisions they will ever make are what's my problem? What am I gonna work on? Uh and you you've got to find something which is challenging, not easy, and which is important. Well, how do you know what's important? Okay. Well, it's like a lot of other things in science, nobody can tell you criteria uh for what's important, what you should work on. The only way you learn that kind of judgment is by watching your mentor. If you've chosen a good mentor and sort of lived in their laboratory for a few years, over and over again, you'll have the opportunity or the privilege to see what do they choose to work on? When do they decide to pursue something? When do they brush it off? How do they make those decisions? They themselves wouldn't be able to explain it to you, but they can demonstrate it to you, and they do on a day-to-day basis if you pay attention. Uh so it's an experiential process.

SPEAKER_01 14:15

Um, if I have the number up to date, you have mentored more than 250.

SPEAKER_02 14:20

More than 250, that's right.

SPEAKER_01 14:21

Also, both of them have winning a Nobel Prize with you. Right. So could you tell us how do we find good mentors?

SPEAKER_02 14:29

When you're in the process of choosing a mentor, very important to visit the laboratory. Talk to the trainees. What's the esprit de corps? What's the mood? Are these happy people? What do they say about the mentor? Do they enjoy working with him or her? Uh is he positive, supportive, inspirational? All of these things. So those are some of the things. There is one caveat, though. The caveat is supposing you have a potential mentor uh who's just starting out. He has no track record. He may be great, but there's no way to tell yet, because he's just started. So when I started my laboratory here in 1973, I was all of 30 years old. I had many postdocs that are much older than that. Okay, so I'm 30 years old. I've never trained anybody. I published some interesting work, but you know, nothing fabulous yet. Uh so how do they know? That's the one caveat. Uh so they have to trust me and I have to trust them. Uh, interestingly, some of the most very talented trainees uh I uh have had came at the very beginning.

SPEAKER_01 15:45

Do you think your daily routine changed much, let's say 30, 40 years ago compared with today?

SPEAKER_02 15:52

If you talk to any of the people in my lab, they'd say, yeah, I'm filled with energy and this and that. Uh but it's changed. How? Well, none of us are the same at 83 years of age as we are at 33. If we were, we'd be a total freak of nature. Uh so uh I spend less hours here than I did. Uh so just think, when I was 33, that's 50 years ago. That's a half a century ago. Okay. Uh so now I spend more time taking care of myself. I sleep more, uh, I exercise more, uh, I meditate more. I come from a family with premature heart disease, and I have coronary artery disease and had quad quadruple bypass surgery uh 32 years ago. So I come from a family with a lot of family history of premature heart disease. My father died of his fourth heart attack at age 63. My mother lived to a pretty good age, just shy of her 89th birthday. But she had a heart attack when she was 56. Uh, and her mother died of a heart attack at 60. So I had a lot of heart disease coming at me. Uh, and I always knew this. And I suspect it is no coincidence that for my medical specialty I chose cardiology. So I was always trying to run away from that family history in a very literal sense. Uh, if you look around my office, you'll see several pictures of me running. Okay. Uh there's one, I think, behind me up here. Uh I spent all my years between late 20s and maybe 15 or 20 years ago, doing long distance running. Uh, in a very real sense, trying to run away uh from my history of heart disease. Uh it helped in the sense I never had a heart attack, but I developed angina at about age 50, just which was the same age my father had his first heart attack. Yeah. Uh and uh so I I was evaluated and found to have advanced coronary artery disease, and at age uh 51 basically had quadruple uh coronary artery bypass surgery. Since that time, I have tried my best to control every possible risk factor. Uh I eat no meat, chicken, fish. I do take uh uh a fish oil supplement. Uh so it's all plant-based, uh protein derived from beans, peas, lentils, legumes, and various nuts, lots of nuts, whole grains, uh, lots of fresh fruit and vegetables. Uh, but that's all I eat. Uh I maintain my weight at ideal body weight. So I I exercise on average an hour uh seven days a week. Uh and I sleep about eight hours a night. So the days when I could be in by 8 a.m. Yeah are long gone because, well, I'm busy in the morning for several hours with all this. But hey, I never expected to be here uh at age 83. Uh, but here I am.

SPEAKER_01 19:36

Do you think this sense of family history of cardiovascular disease have somehow become also a force for you to pursue the truth of science or to finding out why?

SPEAKER_02 19:49

Completely. Uh, I never worked on coronary artery disease myself, but the idea that science, which I always loved science, the idea that science could provide uh relief of human suffering through ultimately leading to new treatments, uh, was always a very strong motivating force for me. But then I was, to my amazement, I was drawn more and more deeply into the science, which surprised me. Okay, but it just happened. Uh but at some point I realized that whereas if I had practiced medicine uh for a long time, maybe I could have impacted the lives of thousands of patients, maybe 10,000 if I had a long career. But ultimately it became millions, tens of millions, through all these medicines that have been uh developed based on our work. And that's extremely gratifying to me.

SPEAKER_01 20:50

As we know it, the amazing discovery and study have win you the Nobel Prize. We are thinking it should be the Nobel Prize of Medicine. In the end, it became the Nobel Prize of Chemistry. Was that title matters for you?

SPEAKER_02 21:04

Well, the first thing is it was a tremendous surprise to me that we won in chemistry. In retrospect, it shouldn't have been, because if you look at the prizes in medicine and chemistry, there's a lot of overlap. And it's sort of arbitrary, I think, in terms of what they do. If I had to choose a single scientific discipline that was responsible for most of the big discoveries we made, it was biochemistry. I used the techniques of the biochemist. So in that sense, it shouldn't have been such a big surprise. Uh interestingly, the first night that I was in Stockholm uh for the Nobel ceremonies, and you're there for a week or I think 10 days, uh, we're at dinner, and uh I was sitting next to the chairman of the uh Nobel Prize Committee in Chemistry. And I was discussing this issue with him that how surprising it was to me uh to be the laureate in chemistry. He said, Well, you were also nominated in medicine. Uh, he said, and the two committees often communicate. And he said, there was kind of a tug of war going on as to who would get to give you the prize, he said, and we won. Uh so I felt good about that. So yeah, I'm, you know, whether it was medicine, chemistry, so fine. And there are many other examples uh of chemistry Nobel really could have just as well been in medicine. And many medicine Nobel's really were pieces of biochemistry.

SPEAKER_01 22:43

What is GPCR and also what is like that part of cell's receptor function like in our day-to-day life?

SPEAKER_02 22:51

G protein coupled receptors are a particular type of receptor uh which have a number of things in common. Now, we basically uh discovered uh or or realized that there was a family of these receptors. Well, today we know that the G protein-coupled receptors are by far the largest family of receptors. In fact, they are the largest gene family in the entire human genome. There are about 800 or more of these receptors. They regulate virtually every physiological process in humans. You can name something. I mean, it doesn't matter what. Breathing, uh, digestion, uh, genital urinary function, reproduction, everything is through that. Today, about a third, a third of all FDA-approved drugs work through G protein coupled receptors. That's more than 700 drugs, okay? Everything from adrenaline to antihistamines, to beta blockers, to antidepressants, and of course, all anybody talks about today, GLIP 1. All of these drugs, terzepatide, wagovy, all of them work through G protein coupled receptors. And there are certain principles that basically apply broadly to all the receptors. So that helps in developing new drugs, because even though each receptor is different and specific, yeah, there are common principles uh that can be uh leveraged to develop these drugs.

SPEAKER_01 24:34

When we think about, we said that two people have chemistry, right? Or the chemistry of love. Is that also go through the G protein receptors?

SPEAKER_02 24:44

Undoubtedly, undoubtedly. Uh there have been uh there are certain uh receptors. I mean, prolactin is one, uh dopamine uh is always talked about dopamine and dopamine receptors in reward uh, you know, good feelings, etc. You know, most human behaviors uh and even diseases are regulated not by a single gene, but by hundreds of genes.

SPEAKER_04 25:16

Yeah.

SPEAKER_02 25:16

Okay. And so, yeah, would it not surprise me if uh basically a whole series of single mutations in genes put together would lead to changes in morality and behavior? No, it wouldn't surprise me at all. Even the commonest of diseases, for the most part, are caused by not one or two or three genetic abnormalities, but hundreds. So if you say, what's the genetic cause of diabetes? We have no idea. What's the genetic cause of coronary disease? We have no idea. Now, there are individual cases where, for example, somebody has a single mutation that makes their cholesterol go sky high. That's not what I'm talking about. But something like personality, uh, just think how complex that is.

SPEAKER_01 26:11

What do you think about gene therapy? Like, can we as a human really edit it our gene to have, let's say, better genes?

SPEAKER_02 26:18

Definitely. Uh, this is certainly not a field I have any expertise. Techniques are just becoming available now. Scientific discoveries led to a gene editing uh treatment, uh, which has now been used, where they can basically uh edit a gene. This gene editing technology for sickle cell disease has been approved by the FDA.

SPEAKER_01 26:40

And when we talk about GLP1, how does GLP1 work? Why some people, it just seems very difficult for them to lose weight. For some people, maybe they also eat a lot, but they don't put on the weight so easily.

SPEAKER_02 26:53

How do they work? I'm not sure that anybody knows. Uh it started off as a very simple story. These hormones are referred to as incrementins, okay? Uh and they basically uh were secreted by the uh GI tract, uh, and they so they're hormones in that sense, and they uh basically bind to receptors in the pancreatic uh cells, the islands of Langerhands, which make insulin, and they basically work together with insulin to uh promote insulin secretion. Okay, and that's why they were originally developed and used in diabetes. I mean, they seem to be working. Uh I know somebody who's trying it for long COVID. Uh it's being used for in heart disease. Uh they're even even talking about the fact that it may have amazing effects to uh interdict uh alcoholism and other substance abuse things. Unbelievable. So it and it's turning out that there are receptors for these molecules all over the body.

SPEAKER_03 28:09

Yeah.

SPEAKER_02 28:10

Okay. So we're just in the infancy of understanding uh how that works.

SPEAKER_01 28:15

Yeah. What about the histamine resistance and also people slowly develop the allergies? For example, I'm living in London. I have a lot of friends who developed the hay fever. So they probably first a few years into the UK, they're fine. But maybe the year 10, year 11, they start to have this hay fever every spring. Uh, what happened to them?

SPEAKER_02 28:40

Well, you know, there have been huge uh advances in the treatment of allergy and eczema and things like that. Uh these work, interestingly, not through so much through G protein coupled receptors, but through a whole other class of what, in a sense, are hormones. They're called cytokines. Uh, these are uh molecules that are made by uh lymphocytes, for example, or other kinds of white blood cells uh that uh basically lead to the production of certain kinds of antibodies. Uh we don't need to go into but IgE and other kinds of antibodies, which stimulate things like histamine release, et cetera. Uh so yeah, I would say that uh there's reason for optimism for people suffering with allergies, but they they need to talk to the right doctors, they need to see allergists. An important concept in uh clinical therapeutics is the following. Every drug has side effects. Every drug. Uh the higher the dose, the greater the side effects. Some drugs have more side effects than others. There are two types of side effects, uh off-target and on-target. Off-target are almost impossible to predict. But the more common thing are on-target side effects. And it brings up an interesting thing is even though we call them side effects, they're not really side effects. They are, another term that's used is adverse effects. Because in general, when we give a drug, we're giving it because it has an effect that we want. But it also has lots of other effects. One of the biggest complications with antihistamines is they made you very sleepy. Uh, and this was, you know, things like Benadryl and uh pyrobenzamine, the uh first generation antihistamine. This is because they cross-reacted with other GPCRs, like what we call cholinergic receptors and other receptors in the brain. But now there's a whole new generation of non-sedating antihistamines, which are uh more specific, uh, and some of them don't even cross the blood brain barrier.

SPEAKER_01 31:08

Let's talk about your book, because it was so fun, and I it really reminds me of Mr. Feynman. And uh, could you tell us why your name A Funny Thing Happened on the Way to Stockholm?

SPEAKER_02 31:20

First of all, uh a comment or two about Feynman, who was also one of my many heroes. Uh I've read some of his books and lectures. And uh like Feynman, uh, I guess I'm kind of a racon tour. I like stories, I like to tell stories, I like to hear stories. And for the past more than 50 years, I've been telling my stories to uh uh all my fellows and students, etc., and they often take them away. Uh and so over the years there was a growing chorus of voices saying, Bob, you need to write up your stories. Why don't you write a book with all your stories in it? I never would have done it. But then uh one year, about five or six years ago, one of my former trainees, now a well-known professor at Emory, professor of pharmacology, uh Randy Hall, uh propositioned me. He said, Look, why don't we imitate what Feynman did? You remember? He got one of his former students, now a professor, uh, to work with him. He told his stories uh to this guy, and then the guy helped him write them up. So I said, Well, if you're willing to do some of the heavy lifting, I'll tell you the stories. And so we started. Uh, and so every week for about a year, uh, we would talk for about two hours. Uh, he would record my stories, uh, and I tried to tell them uh chronologically in terms of my life. Uh he would then try to shape them into a narrative. For a year or more, year and a half, we worked on it. Uh, and the book is what we came up with. As I guess you've already gathered, one of the defining characteristics of my personality is humor. Uh right. Uh I like making people laugh, and I like seeing the humor in situations where other people might not see the humor. Uh, and so we said, okay, let's call her a funny thing happened on the way to Stockholm.

SPEAKER_01 33:22

Could you share with us one story in the book?

SPEAKER_02 33:25

When I was failing during the first six months uh at the NIH, uh I became kind of depressed uh because I had never failed before. Uh and it was not that I wanted to be a scientist and I was being disappointed. I just I never failed before in a long way like that. Uh so I went home uh over the Thanksgiving holiday, and by then I was married and had some young children. We went home from Washington, where I was at the NIH, to New York City, and we spent Thanksgiving uh with my parents and my in-laws. Uh and uh I talked with my dad. I was an only child and I was very close to my dad. I went home, he was always my advisor on anything that came up. He just had good common sense. Uh so I told him how unhappy I was. Uh and he said to me, Look, no need for that. He says, You never wanted to be a scientist. You just wanted to be a doctor and a cardiologist. So look, it's two years. Half one quarter of that is over already. Stick with it, enjoy your life with your family, do your two years, then you'll go and you'll finish your clinical work and become the doctor that you and I uh, you know, always dreamed you would be. Well, it was like a weight lift from my shoulder. Uh, and I went back uh to the NIH uh and I was really happy with that. Uh and that was the last conversation I ever had with my father. He died three weeks later, he dropped it. Uh and so that stuck with me. And so now, as I began to now fast-forwarding a year, two years, as I began to be drawn back into the laboratory, and it became clear over the next five years, increasingly clear, that science would play a big part in my life, I felt guilty because I had kind of made this deal with my father that we'd forget about the lab. We would pursue a career as a physician, uh, etc. And so, in a sense, that kind of held me back for a few years from fully committing myself to the science because it's what would dad think? I mean, we we agreed in our very last conversation that I would become the doctor that we both dreamed of. Now, he died in 1968, okay? That was six months into my tour at the NIH, years before it became clear that I would become a scientist, much less a Nobel laureate. And many times over the years, I've said to myself, if my graduating from medical school was the proudest day of his life, what the hell would he have thought if I if he lived to see me win the Nobel Prize? Uh I can't imagine.

SPEAKER_01 36:28

Uh do you feel regret or do you feel kind of sad that you couldn't share that joy with your dad?

SPEAKER_02 36:33

The latter, yeah. Yeah. I wish he could have seen some of it. Uh but I mean, he died before any of it happened. Before any of it happened. Uh and it's it's like my life had this first phase, which from the time I was a little boy was dreaming of being a doctor. And then the way it played out. And he never got to see any of that. Any of that.

SPEAKER_01 36:57

That's really sad. I wish I think in in a certain way, maybe that or these things. Can you have a t-shirt, please? You just feel a bit sad. Yeah. I feel he must be very, very proud. That's how I feel. Because it seems like uh he's a very happy and a supportive character.

SPEAKER_02 37:15

My father? Oh, God, yeah. It's interesting. My mother, for lack of a better term, a real hard ass. Okay. Uh she was the one driving me to get the top grades uh to always bring home. If I brought home an A-, she'd want to know why wasn't it an A? Uh, why wasn't I studying more, et cetera? He was much softer uh and just always there for me if I had a problem.

SPEAKER_01 37:41

And I was an only child, so what kind of father are you to your kid? Are you the tough one or the sweet one?

SPEAKER_02 37:47

Well, it's really interesting. In both my professional and personal lives, I see both my parents in me. I missed having siblings. I always regretted as a little kid that I was alone a lot. Uh I had no brothers or sisters, like my friends do. Uh so maybe that impelled me to go in the opposite direction to have five kids in my own. Uh, but I like to think that I'm a blend of both parents. On the one hand, uh I I was always the disciplinarian in the family, more so than my uh my wife. Uh on the other hand, uh I was always kind of a soft touch as well.

SPEAKER_01 38:26

Uh you know, the reason we started the human wear project is really wrong to answer the true question, what kind of human we will become because of those advancements in the technology, in the medicine. And our idea of longevity is not really about you living forever. It's about can we be happy in the days here on earth? So, when someone achieved so much, how did you see the humanity and the character placed in the happiness? Because I see many successful people, but they kind of live an unhappy life. So, what are the the voice that you can give to those people who are striving for, you know, doing more to have also a sense of happiness?

SPEAKER_02 39:12

Well, that's that's a very deep question. Uh I've been remarkably blessed, remarkably blessed in my life. Uh nobody deserves to be to be that blessed, but I have been. I've had remarkably gratifying work. Okay. So I I would say uh the two biggest things in my life are love and work. Uh the work in turn, for me, I mean who could be more fortunate? To be a physician scientist, which is what you I am. I'm a physician scientist. I I practice medicine as part of my career. I did clinical teaching for 35 years. Uh I don't do that anymore. Uh now I just do research. But I had the remarkable privilege of relieving suffering, curing disease from time to time, and on a rare occasion saving a life. There is no greater fulfillment uh for a human being than that. Uh but then I got to make these discoveries which impact people's lives. Uh and that alone would have been the ultimate uh reward for the work, but instead they get prizes and recognition, etc. And then the love. Uh I've been married twice. Uh my wife Lynn uh and I have been together, just had our 35th wedding anniversary. Congratulations. Uh I have five very loving children and six grandchildren and great relationships with them. Uh so I would say love and work is what it's all about.

SPEAKER_01 41:06

And uh, what are the best at the voice that you have been given by your mentors?

SPEAKER_02 41:11

My main mentor at the NIH was a guy named Jesse Roth. Okay. He believed in receptors uh at a time when there were no proof that they existed. And he kind of got me thinking about receptors. So Jesse passed away about six weeks ago, eight weeks ago, at age 92.

SPEAKER_05 41:33

Yeah.

SPEAKER_02 41:34

But Jesse had all these crazy pieces of advice. Uh one one piece of advice he he he gave me uh was uh uh to try to focus uh in life and not to try to do everything. Because I remember when I was interviewing with him, he said, What do you want to do in life? I said, Oh, I said I want to be the great clinician and I want to be a scientist, and you know, I said I want to uh be uh chairman of a department, and he said and I still remember him saying to me, Lefkowitz, that's bull. He says, You can't be super great at all of those. You're gonna have to find one thing to sort of focus on. Another piece of advice uh he used to give me uh was uh, you know, whenever he'd hear somebody talking about what they want to do with the rest of his life, he says, Look, you can't plan the rest of your life. He says, five-year packages. Don't think more than five years ahead. Figure out what you think you want to do for the next five years, and then you can reevaluate it. But don't try to plan your whole life. I thought that was a a pretty apt piece of advice.

SPEAKER_01 42:42

Today AI seems like an unavoidable topic. What's what's your thought in AI and also our advancements in science in biochemistry?

SPEAKER_02 42:52

I find for the most part they're pretty good. Uh and I can seek out information and even sophisticated analyses of problems. But the big caveat I have, and I've others have you know found this, is the hallucination thing. They uh they they just make stuff up. Yeah. Uh and uh so you gotta be very careful because if you don't know the right answer and you're relying just on the AI, you may go down. Uh I remember the very first time that I ever heard anything to do with AI was a few years ago when a very famous scientist came here to give a lecture. And one of his former postdocs, now a professor here at Duke, was called upon to introduce him for his lecture. And and so he got up and he said, Well, I'm all excited about you know introducing my former mentor and this and that. He said, And so I asked ChatGPT to write an introduction, and I'm gonna read that introduction. And he read it, and it was great, and sat down, and the professor gave up. He says, Well, that was an absolutely wonderful introduction, he says. However, there were three egregious errors in it. One, I didn't go to school here, two, I didn't grow up in this city, and four, I didn't get my degree from this. So again, you gotta be suspicious. But I do think it it's gonna uh change so many things. I mean, in the practice of medicine, and I no longer practice medicine, but uh many of my closest friends are uh uh practicing physicians, and it's just it's amazing. It it takes the history for them, it organizes the right, it does the write-up for them, uh, it helps them with differential diagnosis. I mean, it it it's a whole new world. I I really wonder what the uh occupation of being a physician will be like in 20 years. I I can't imagine.

SPEAKER_01 45:04

In the five years package, what are the things you're most exciting about in the world of medicine and the biochemistry?

SPEAKER_02 45:11

The things I'm most hopeful about uh is breakthroughs in two areas. Uh one is cancer. There have been so many breakthroughs, but I keep hoping for some more fundamental understanding in the basic mechanisms of cancer that may lead to more generally uh applicable uh treatments, okay, which we don't have now. It's all very much case by case. And the other is dementia. I see so many friends and colleagues my age, I'm 83, uh, already suffering with dementia or having died with dementia. We know a lot, and there are many different kinds of dementia. We know a lot more about it than we used to. And there have been real scientific advances, but we need we need some breakthroughs. And of course, my bias as a physician scientist is that the true breakthroughs that have the biggest impact are those that occur at the basic science level, the fundamental level. And then they can be translated and moved further down the line. But the true breakthroughs that are going to influence the maximum number of lives occur back here at the most fundamental level of understanding.

SPEAKER_01 46:26

Thank you for your time today, though.

SPEAKER_02 46:27

My pleasure indeed.

SPEAKER_01 46:29

Thank you for watching this new episode of Humanware Project. So that we can bring out more amazing content like this one to you. Please like and subscribe. Your support means the world to us.