WEBVTT
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I've impacted the lives of millions of end of millions.
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Intuition is often wrong, but the fact that I won the Nobel Prize, what it tells you is the intuition was right.
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Today, about a third of all FDA-approved drugs work through G protein coupled receptors.
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Every drug has side effects.
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The higher the dose, the greater the side effects.
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That was the last conversation I ever had with my father.
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He died three weeks later.
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And he never got to see any of that.
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Any of that.
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I've been remarkably blessed in my life.
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I'm going to tell you something, you're not going to believe.
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Professor Robert Foy won the Nobel Prize for discovery.
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That's something that's the last conversation he ever had with his father.
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It's such an honor to have you today, Dr.
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Lefkowitz.
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Welcome to the Humanware Project.
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In the day you received the Nobel Prize Award, has that changed your life before and after?
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Yes, it changed my life in many ways.
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In a sense, it even changed my name because I'm no longer introduced as Robert Lefkowitz or Bob Lefkowitz.
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Anytime anybody introduces me, I'm introduced as Nobel laureate, Bob Lefkowitz.
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So it even becomes part of your name.
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So those are the two uh, I guess, most significant ways that it changed my life.
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Because your study on the cell receptors and how our cells behavior at the late 1960s is actually quite a niche subject to study.
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When you look back to a younger self, what do you would say to him?
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The first thing I would say to him is, sit down.
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I'm going to tell you something you're not going to believe.
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And he would say, What is it?
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And I would say, you're going to become a famous scientist.
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And he would have laughed out loud.
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Yeah.
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And he would have said, But I don't want to be a famous scientist or any scientist at all.
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Really?
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Yes.
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I have no interest in being a scientist.
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I want to be a doctor.
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And I would say, well, uh, you'll get to do that, but you're also uh be gonna become a successful scientist.
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And if that isn't crazy enough, here's something else for you.
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You're gonna win the Nobel Prize.
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Uh at which point I think I would have been speechless.
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So what intriguing you from being a physician or from being a doctor into, you know, pursued science?
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So I graduated medical school, Columbia, in 1966.
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The Vietnam War was raging.
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There was, in addition to the lottery draft for all men over 18, there was a doctor draft.
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But this was not a lottery.
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Everybody was drafted upon graduation from medical school.
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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.
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And then you went into either the Army, the Navy, the Air Force, or the United States Public Health Service.
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Yeah.
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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.
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Nobody wanted to do that.
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It was a very unpopular war.
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Many of us thought it was uh at least immoral, if not illegal.
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Uh, and so everybody was trying to find a way out.
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Uh, one way out of serving in Vietnam in support of the war was to be drafted into the public health service.
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If you were able to get a commission in the public health service, you stood a chance of being assigned stateside.
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Okay.
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And better yet, if you were really fortunate, being assigned stateside to one of their research institutions, like the NIH or the CDC.
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Yeah.
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So it was extraordinarily competitive to get those commissions.
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Because I always was a very good student and had gone to good schools.
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I was able to get the commission in the public health service and was assigned to the NIH for two years.
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There, I spent about 20% of my time taking care of patients in the what was called the clinical center.
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These were research patients, and 80% of my time doing mentored research.
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I was there doing that research, not because I was particularly interested in becoming scientist, becoming a scientist.
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I was there because it was the best of several options open to me at the height of the Vietnam War.
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And initially things went very poorly.
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Okay.
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Uh for the first year or year and a half of my two-year stint, uh I met with no success.
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Yeah.
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This was a new experience for me.
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I had never failed in a prolonged way at anything I had ever tried in my life to that point.
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But now I failed over and over again.
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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.
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Yeah.
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But during the last six months at the NIH, my work started to yield some fruit.
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I actually published a couple of papers and was starting to enjoy it.
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Uh my mentors uh importuned me to stay uh and continue the work, but I wasn't enjoying it that much.
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So off I went uh to the Massachusetts General Hospital in 1970.
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And for the first six months, I threw myself into full-time clinical work again, no research.
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But at the end of those six months, I realized I missed the lab.
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That uh not that I would want to do that full-time, but I really I missed it.
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Which part of it do you aren't me say?
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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.
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I missed the creative aspect of it.
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I guess increasingly, even though medicine was my first love, less and less did I see it as a really creative enterprise.
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Yeah.
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It was a humane enterprise.
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It was about as humane uh an enterprise as I could imagine.
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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.
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Uh but now these creative stirrings seemed to me pulling me in a different direction.
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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.
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And then in 1973, I came to Duke, set up my lab, uh, and uh, as they say, the rest is history.
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But when you were first starting to set up your lab, is there any challenge at the time?
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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.
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At the time, there was no general consensus that such molecules even existed.
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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.
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So if we bring those signs into our everyday life, what are those receptors doing?
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Why that matters to us?
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So receptors are sites on cells with which drugs and hormones interact or combine to initiate their actions.
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Okay.
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Think about it as a lock and a key.
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So the lock is the receptor.
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Okay.
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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.
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Let's take a specific example: adrenaline, epinephrine.
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Okay.
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Uh I chose that as my model system.
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Epinephrine, everybody knows, stimulates the heart, makes it beat stronger, faster, uh, dilates the airways, et cetera.
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But in order to start those actions, it has to fit into a specific site on the cell that recognizes it.
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That site is called a receptor, and it's called an adrenergic receptor from adrenaline.
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Okay.
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Uh so I set out to prove there was such a thing.
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But of course, there was no way to measure.
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But uh there must be a lot of voice that says otherwise, right?
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There must be not a lot of evidence.
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How do you know it was right to study?
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Well, intuition plays a very big role.
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Okay.
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There were uh pieces of evidence that suggested that there must be such receptors.
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Not conclusive at all, or people would have believed in them.
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What what were some of these pieces of evidence?
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Well, one, drugs like adrenaline, they work at very low concentrations.
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Very low concentrations.
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A few molecules can have an effect.
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That means there must be something on the cell for which that adrenaline has a very high, what we call affinity.
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It likes to bind to it.
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The other thing uh is that there's tremendous specificity in the actions.
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In other words, the only things which can imitate adrenaline are molecules which chemically look very, very similar to adrenaline.
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Again, suggesting you've got to have a key that that fits very, very specifically.
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But beyond that, you've already hit the key, intuition.
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Uh, and nobody can really explain intuition.
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Uh, but intuition is a real thing.
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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.
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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.
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Even though I can't prove it yet, it's gotta be true.
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It's a real process, I believe.
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It's just we don't understand it.
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What it is, is basically, you know, you have all these circuits in your brain, uh, and they're all kind of spinning.
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Uh, and sometimes it's like a slot machine, and you get three oranges or three apples.
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Uh anyway, uh that's the way I picture uh intuition.
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It's just something below the surface that's just telling you this.
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Now, intuition is often wrong, uh, but sometimes it's right.
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And uh, you know, the fact that I won the Nobel Prize, uh what it tells you is the intuition was right.
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For those young scientists right now, they're pursuing science and they're pursuing their own subject of study.
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What are your advice for them?
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For the younger scientists who are still in training, my most significant piece of advice is choose your mentors very carefully.
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Your mentors are much more important than where you go to school, uh, et cetera.
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I mean, young people think that, oh, I gotta go to school here, I've got to go train at this place.
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Much more important is who is the specific mentor that you select?
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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?
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What am I gonna work on?
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Uh and you you've got to find something which is challenging, not easy, and which is important.
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Well, how do you know what's important?
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Okay.
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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.
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The only way you learn that kind of judgment is by watching your mentor.
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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?
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When do they decide to pursue something?
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When do they brush it off?
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How do they make those decisions?
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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.
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Uh so it's an experiential process.
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Um, if I have the number up to date, you have mentored more than 250.
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More than 250, that's right.
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Also, both of them have winning a Nobel Prize with you.
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Right.
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So could you tell us how do we find good mentors?
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When you're in the process of choosing a mentor, very important to visit the laboratory.
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Talk to the trainees.
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What's the esprit de corps?
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What's the mood?
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Are these happy people?
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What do they say about the mentor?
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Do they enjoy working with him or her?
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Uh is he positive, supportive, inspirational?
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All of these things.
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So those are some of the things.
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There is one caveat, though.
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The caveat is supposing you have a potential mentor uh who's just starting out.
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He has no track record.
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He may be great, but there's no way to tell yet, because he's just started.
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So when I started my laboratory here in 1973, I was all of 30 years old.
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I had many postdocs that are much older than that.
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Okay, so I'm 30 years old.
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I've never trained anybody.
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I published some interesting work, but you know, nothing fabulous yet.
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Uh so how do they know?
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That's the one caveat.
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Uh so they have to trust me and I have to trust them.
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Uh, interestingly, some of the most very talented trainees uh I uh have had came at the very beginning.
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Do you think your daily routine changed much, let's say 30, 40 years ago compared with today?
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If you talk to any of the people in my lab, they'd say, yeah, I'm filled with energy and this and that.
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Uh but it's changed.
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How?
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Well, none of us are the same at 83 years of age as we are at 33.
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If we were, we'd be a total freak of nature.
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Uh so uh I spend less hours here than I did.
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Uh so just think, when I was 33, that's 50 years ago.
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That's a half a century ago.
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Okay.
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Uh so now I spend more time taking care of myself.
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I sleep more, uh, I exercise more, uh, I meditate more.
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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.
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So I come from a family with a lot of family history of premature heart disease.
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My father died of his fourth heart attack at age 63.
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My mother lived to a pretty good age, just shy of her 89th birthday.
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But she had a heart attack when she was 56.
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Uh, and her mother died of a heart attack at 60.
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So I had a lot of heart disease coming at me.
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Uh, and I always knew this.
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And I suspect it is no coincidence that for my medical specialty I chose cardiology.
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So I was always trying to run away from that family history in a very literal sense.
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Uh, if you look around my office, you'll see several pictures of me running.
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Okay.
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Uh there's one, I think, behind me up here.
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Uh I spent all my years between late 20s and maybe 15 or 20 years ago, doing long distance running.
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Uh, in a very real sense, trying to run away uh from my history of heart disease.
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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.
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Yeah.
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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.
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Since that time, I have tried my best to control every possible risk factor.
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Uh I eat no meat, chicken, fish.
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I do take uh uh a fish oil supplement.
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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.
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Uh, but that's all I eat.
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Uh I maintain my weight at ideal body weight.
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So I I exercise on average an hour uh seven days a week.
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Uh and I sleep about eight hours a night.
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So the days when I could be in by 8 a.m.
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Yeah are long gone because, well, I'm busy in the morning for several hours with all this.
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But hey, I never expected to be here uh at age 83.
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Uh, but here I am.
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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?
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Completely.
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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.
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But then I was, to my amazement, I was drawn more and more deeply into the science, which surprised me.
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Okay, but it just happened.
00:20:22.880 --> 00:20:38.319
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.
00:20:38.960 --> 00:20:47.200
But ultimately it became millions, tens of millions, through all these medicines that have been uh developed based on our work.
00:20:47.359 --> 00:20:50.160
And that's extremely gratifying to me.
00:20:50.480 --> 00:20:55.599
As we know it, the amazing discovery and study have win you the Nobel Prize.
00:20:55.759 --> 00:20:58.880
We are thinking it should be the Nobel Prize of Medicine.
00:20:59.039 --> 00:21:02.000
In the end, it became the Nobel Prize of Chemistry.
00:21:02.240 --> 00:21:04.160
Was that title matters for you?
00:21:04.559 --> 00:21:09.359
Well, the first thing is it was a tremendous surprise to me that we won in chemistry.
00:21:09.839 --> 00:21:18.720
In retrospect, it shouldn't have been, because if you look at the prizes in medicine and chemistry, there's a lot of overlap.
00:21:19.119 --> 00:21:22.559
And it's sort of arbitrary, I think, in terms of what they do.
00:21:22.799 --> 00:21:33.599
If I had to choose a single scientific discipline that was responsible for most of the big discoveries we made, it was biochemistry.
00:21:34.000 --> 00:21:36.079
I used the techniques of the biochemist.
00:21:36.240 --> 00:21:39.039
So in that sense, it shouldn't have been such a big surprise.
00:21:39.279 --> 00:21:58.960
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.
00:22:00.160 --> 00:22:06.720
And I was discussing this issue with him that how surprising it was to me uh to be the laureate in chemistry.
00:22:06.880 --> 00:22:10.240
He said, Well, you were also nominated in medicine.
00:22:10.400 --> 00:22:15.119
Uh, he said, and the two committees often communicate.
00:22:15.279 --> 00:22:21.839
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.
00:22:22.079 --> 00:22:24.559
Uh so I felt good about that.
00:22:25.119 --> 00:22:29.519
So yeah, I'm, you know, whether it was medicine, chemistry, so fine.
00:22:29.680 --> 00:22:38.240
And there are many other examples uh of chemistry Nobel really could have just as well been in medicine.
00:22:38.400 --> 00:22:42.799
And many medicine Nobel's really were pieces of biochemistry.
00:22:43.200 --> 00:22:51.119
What is GPCR and also what is like that part of cell's receptor function like in our day-to-day life?
00:22:51.599 --> 00:23:00.400
G protein coupled receptors are a particular type of receptor uh which have a number of things in common.
00:23:00.720 --> 00:23:10.559
Now, we basically uh discovered uh or or realized that there was a family of these receptors.
00:23:10.799 --> 00:23:17.359
Well, today we know that the G protein-coupled receptors are by far the largest family of receptors.
00:23:17.519 --> 00:23:22.240
In fact, they are the largest gene family in the entire human genome.
00:23:22.319 --> 00:23:26.000
There are about 800 or more of these receptors.
00:23:26.160 --> 00:23:31.759
They regulate virtually every physiological process in humans.
00:23:32.000 --> 00:23:33.039
You can name something.
00:23:33.119 --> 00:23:34.319
I mean, it doesn't matter what.
00:23:34.559 --> 00:23:43.519
Breathing, uh, digestion, uh, genital urinary function, reproduction, everything is through that.
00:23:43.759 --> 00:23:52.240
Today, about a third, a third of all FDA-approved drugs work through G protein coupled receptors.
00:23:52.400 --> 00:23:55.359
That's more than 700 drugs, okay?
00:23:55.599 --> 00:24:08.000
Everything from adrenaline to antihistamines, to beta blockers, to antidepressants, and of course, all anybody talks about today, GLIP 1.
00:24:08.640 --> 00:24:15.519
All of these drugs, terzepatide, wagovy, all of them work through G protein coupled receptors.
00:24:15.680 --> 00:24:21.359
And there are certain principles that basically apply broadly to all the receptors.
00:24:21.440 --> 00:24:34.480
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.
00:24:34.880 --> 00:24:39.119
When we think about, we said that two people have chemistry, right?
00:24:39.279 --> 00:24:40.799
Or the chemistry of love.
00:24:41.039 --> 00:24:44.480
Is that also go through the G protein receptors?
00:24:44.799 --> 00:24:46.559
Undoubtedly, undoubtedly.
00:24:46.720 --> 00:24:52.319
Uh there have been uh there are certain uh receptors.
00:24:52.480 --> 00:25:05.279
I mean, prolactin is one, uh dopamine uh is always talked about dopamine and dopamine receptors in reward uh, you know, good feelings, etc.
00:25:05.680 --> 00:25:15.839
You know, most human behaviors uh and even diseases are regulated not by a single gene, but by hundreds of genes.
00:25:16.000 --> 00:25:16.319
Yeah.
00:25:16.480 --> 00:25:16.799
Okay.
00:25:17.279 --> 00:25:32.319
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?
00:25:32.480 --> 00:25:34.079
No, it wouldn't surprise me at all.
00:25:34.400 --> 00:25:46.240
Even the commonest of diseases, for the most part, are caused by not one or two or three genetic abnormalities, but hundreds.
00:25:46.559 --> 00:25:49.599
So if you say, what's the genetic cause of diabetes?
00:25:49.759 --> 00:25:50.960
We have no idea.
00:25:51.200 --> 00:25:54.079
What's the genetic cause of coronary disease?
00:25:54.240 --> 00:25:55.200
We have no idea.
00:25:55.359 --> 00:26:05.119
Now, there are individual cases where, for example, somebody has a single mutation that makes their cholesterol go sky high.
00:26:05.359 --> 00:26:06.720
That's not what I'm talking about.
00:26:06.960 --> 00:26:10.960
But something like personality, uh, just think how complex that is.
00:26:11.279 --> 00:26:13.039
What do you think about gene therapy?
00:26:13.200 --> 00:26:18.400
Like, can we as a human really edit it our gene to have, let's say, better genes?
00:26:18.799 --> 00:26:19.359
Definitely.
00:26:19.440 --> 00:26:22.319
Uh, this is certainly not a field I have any expertise.
00:26:22.799 --> 00:26:25.119
Techniques are just becoming available now.
00:26:25.359 --> 00:26:35.759
Scientific discoveries led to a gene editing uh treatment, uh, which has now been used, where they can basically uh edit a gene.
00:26:35.920 --> 00:26:40.400
This gene editing technology for sickle cell disease has been approved by the FDA.
00:26:40.720 --> 00:26:44.400
And when we talk about GLP1, how does GLP1 work?
00:26:44.640 --> 00:26:48.880
Why some people, it just seems very difficult for them to lose weight.
00:26:49.039 --> 00:26:53.519
For some people, maybe they also eat a lot, but they don't put on the weight so easily.
00:26:53.920 --> 00:26:54.720
How do they work?
00:26:54.880 --> 00:26:56.720
I'm not sure that anybody knows.
00:26:56.960 --> 00:27:00.160
Uh it started off as a very simple story.
00:27:00.400 --> 00:27:04.079
These hormones are referred to as incrementins, okay?
00:27:04.400 --> 00:27:33.039
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.
00:27:33.279 --> 00:27:39.039
Okay, and that's why they were originally developed and used in diabetes.
00:27:39.200 --> 00:27:41.359
I mean, they seem to be working.
00:27:41.599 --> 00:27:45.279
Uh I know somebody who's trying it for long COVID.
00:27:45.680 --> 00:27:49.680
Uh it's being used for in heart disease.
00:27:49.920 --> 00:28:03.119
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.
00:28:03.279 --> 00:28:04.079
Unbelievable.
00:28:04.160 --> 00:28:09.599
So it and it's turning out that there are receptors for these molecules all over the body.
00:28:09.759 --> 00:28:09.920
Yeah.
00:28:10.079 --> 00:28:10.400
Okay.
00:28:10.640 --> 00:28:15.119
So we're just in the infancy of understanding uh how that works.
00:28:15.440 --> 00:28:15.680
Yeah.
00:28:15.839 --> 00:28:21.680
What about the histamine resistance and also people slowly develop the allergies?
00:28:21.839 --> 00:28:23.920
For example, I'm living in London.
00:28:24.079 --> 00:28:27.359
I have a lot of friends who developed the hay fever.
00:28:27.599 --> 00:28:32.480
So they probably first a few years into the UK, they're fine.
00:28:32.640 --> 00:28:38.000
But maybe the year 10, year 11, they start to have this hay fever every spring.
00:28:38.079 --> 00:28:39.759
Uh, what happened to them?
00:28:40.319 --> 00:28:49.039
Well, you know, there have been huge uh advances in the treatment of allergy and eczema and things like that.
00:28:49.279 --> 00:29:01.440
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.
00:29:01.519 --> 00:29:02.880
They're called cytokines.
00:29:03.519 --> 00:29:20.880
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.
00:29:21.119 --> 00:29:29.119
Uh we don't need to go into but IgE and other kinds of antibodies, which stimulate things like histamine release, et cetera.
00:29:29.200 --> 00:29:38.640
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.
00:29:38.880 --> 00:29:44.160
An important concept in uh clinical therapeutics is the following.
00:29:44.400 --> 00:29:46.640
Every drug has side effects.
00:29:46.880 --> 00:29:47.759
Every drug.
00:29:48.160 --> 00:29:52.319
Uh the higher the dose, the greater the side effects.
00:29:52.480 --> 00:29:54.640
Some drugs have more side effects than others.
00:29:54.799 --> 00:29:59.599
There are two types of side effects, uh off-target and on-target.
00:29:59.920 --> 00:30:03.039
Off-target are almost impossible to predict.
00:30:03.200 --> 00:30:07.200
But the more common thing are on-target side effects.
00:30:07.839 --> 00:30:16.160
And it brings up an interesting thing is even though we call them side effects, they're not really side effects.
00:30:16.480 --> 00:30:19.920
They are, another term that's used is adverse effects.
00:30:20.480 --> 00:30:27.440
Because in general, when we give a drug, we're giving it because it has an effect that we want.
00:30:28.000 --> 00:30:30.000
But it also has lots of other effects.
00:30:30.319 --> 00:30:35.839
One of the biggest complications with antihistamines is they made you very sleepy.
00:30:36.240 --> 00:30:44.319
Uh, and this was, you know, things like Benadryl and uh pyrobenzamine, the uh first generation antihistamine.
00:30:44.640 --> 00:30:54.319
This is because they cross-reacted with other GPCRs, like what we call cholinergic receptors and other receptors in the brain.
00:30:54.559 --> 00:31:07.759
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.
00:31:08.079 --> 00:31:14.000
Let's talk about your book, because it was so fun, and I it really reminds me of Mr.
00:31:14.160 --> 00:31:14.799
Feynman.
00:31:14.960 --> 00:31:20.160
And uh, could you tell us why your name A Funny Thing Happened on the Way to Stockholm?
00:31:20.559 --> 00:31:25.519
First of all, uh a comment or two about Feynman, who was also one of my many heroes.
00:31:25.839 --> 00:31:29.200
Uh I've read some of his books and lectures.
00:31:29.359 --> 00:31:35.119
And uh like Feynman, uh, I guess I'm kind of a racon tour.
00:31:35.279 --> 00:31:38.799
I like stories, I like to tell stories, I like to hear stories.
00:31:39.200 --> 00:31:48.880
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.
00:31:49.440 --> 00:31:57.039
Uh and so over the years there was a growing chorus of voices saying, Bob, you need to write up your stories.
00:31:57.440 --> 00:31:59.839
Why don't you write a book with all your stories in it?
00:32:00.079 --> 00:32:01.440
I never would have done it.
00:32:01.599 --> 00:32:15.759
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.
00:32:15.920 --> 00:32:18.880
He said, Look, why don't we imitate what Feynman did?
00:32:19.039 --> 00:32:19.759
You remember?
00:32:20.079 --> 00:32:25.119
He got one of his former students, now a professor, uh, to work with him.
00:32:25.200 --> 00:32:31.039
He told his stories uh to this guy, and then the guy helped him write them up.
00:32:31.759 --> 00:32:35.920
So I said, Well, if you're willing to do some of the heavy lifting, I'll tell you the stories.
00:32:36.079 --> 00:32:37.039
And so we started.
00:32:37.440 --> 00:32:42.400
Uh, and so every week for about a year, uh, we would talk for about two hours.
00:32:42.480 --> 00:32:52.160
Uh, he would record my stories, uh, and I tried to tell them uh chronologically in terms of my life.
00:32:52.400 --> 00:32:56.000
Uh he would then try to shape them into a narrative.
00:32:56.240 --> 00:32:59.039
For a year or more, year and a half, we worked on it.
00:32:59.119 --> 00:33:00.960
Uh, and the book is what we came up with.
00:33:01.119 --> 00:33:08.559
As I guess you've already gathered, one of the defining characteristics of my personality is humor.
00:33:09.119 --> 00:33:09.839
Uh right.
00:33:10.240 --> 00:33:18.640
Uh I like making people laugh, and I like seeing the humor in situations where other people might not see the humor.
00:33:18.720 --> 00:33:22.400
Uh, and so we said, okay, let's call her a funny thing happened on the way to Stockholm.
00:33:22.720 --> 00:33:25.200
Could you share with us one story in the book?
00:33:25.680 --> 00:33:38.000
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.
00:33:38.160 --> 00:33:42.240
Uh and it was not that I wanted to be a scientist and I was being disappointed.
00:33:42.319 --> 00:33:46.559
I just I never failed before in a long way like that.
00:33:47.680 --> 00:33:54.799
Uh so I went home uh over the Thanksgiving holiday, and by then I was married and had some young children.
00:33:54.960 --> 00:34:04.240
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.
00:34:04.480 --> 00:34:07.279
Uh and uh I talked with my dad.
00:34:07.440 --> 00:34:10.239
I was an only child and I was very close to my dad.
00:34:10.400 --> 00:34:15.199
I went home, he was always my advisor on anything that came up.
00:34:15.440 --> 00:34:17.840
He just had good common sense.
00:34:17.920 --> 00:34:20.480
Uh so I told him how unhappy I was.
00:34:20.719 --> 00:34:25.679
Uh and he said to me, Look, no need for that.
00:34:25.840 --> 00:34:28.480
He says, You never wanted to be a scientist.
00:34:28.719 --> 00:34:31.039
You just wanted to be a doctor and a cardiologist.
00:34:31.199 --> 00:34:33.440
So look, it's two years.
00:34:33.760 --> 00:34:37.280
Half one quarter of that is over already.
00:34:37.760 --> 00:34:50.000
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.
00:34:50.320 --> 00:34:54.079
Well, it was like a weight lift from my shoulder.
00:34:54.239 --> 00:34:59.199
Uh, and I went back uh to the NIH uh and I was really happy with that.
00:34:59.440 --> 00:35:03.679
Uh and that was the last conversation I ever had with my father.
00:35:03.840 --> 00:35:06.239
He died three weeks later, he dropped it.
00:35:06.800 --> 00:35:10.320
Uh and so that stuck with me.
00:35:10.559 --> 00:35:35.280
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.
00:35:35.599 --> 00:35:40.559
We would pursue a career as a physician, uh, etc.
00:35:40.960 --> 00:35:50.880
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?
00:35:51.039 --> 00:35:57.599
I mean, we we agreed in our very last conversation that I would become the doctor that we both dreamed of.
00:35:57.840 --> 00:36:00.320
Now, he died in 1968, okay?
00:36:00.480 --> 00:36:12.960
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.
00:36:13.199 --> 00:36:25.599
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?
00:36:26.239 --> 00:36:27.920
Uh I can't imagine.
00:36:28.079 --> 00:36:33.199
Uh do you feel regret or do you feel kind of sad that you couldn't share that joy with your dad?
00:36:33.519 --> 00:36:34.159
The latter, yeah.
00:36:34.239 --> 00:36:34.400
Yeah.
00:36:34.639 --> 00:36:37.360
I wish he could have seen some of it.
00:36:37.440 --> 00:36:41.280
Uh but I mean, he died before any of it happened.
00:36:41.519 --> 00:36:42.960
Before any of it happened.
00:36:43.119 --> 00:36:51.920
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.
00:36:52.400 --> 00:36:54.480
And then the way it played out.
00:36:54.559 --> 00:36:56.480
And he never got to see any of that.
00:36:56.719 --> 00:36:57.360
Any of that.
00:36:57.599 --> 00:36:59.599
That's really sad.
00:36:59.840 --> 00:37:03.760
I wish I think in in a certain way, maybe that or these things.
00:37:04.000 --> 00:37:05.599
Can you have a t-shirt, please?
00:37:05.760 --> 00:37:06.960
You just feel a bit sad.
00:37:07.039 --> 00:37:07.360
Yeah.
00:37:07.920 --> 00:37:09.760
I feel he must be very, very proud.
00:37:09.920 --> 00:37:10.719
That's how I feel.
00:37:10.960 --> 00:37:15.039
Because it seems like uh he's a very happy and a supportive character.
00:37:15.519 --> 00:37:16.079
My father?
00:37:16.480 --> 00:37:17.280
Oh, God, yeah.
00:37:17.440 --> 00:37:18.239
It's interesting.
00:37:18.559 --> 00:37:21.920
My mother, for lack of a better term, a real hard ass.
00:37:22.239 --> 00:37:22.559
Okay.
00:37:22.880 --> 00:37:27.840
Uh she was the one driving me to get the top grades uh to always bring home.
00:37:28.000 --> 00:37:31.599
If I brought home an A-, she'd want to know why wasn't it an A?
00:37:32.320 --> 00:37:35.199
Uh, why wasn't I studying more, et cetera?
00:37:35.440 --> 00:37:41.199
He was much softer uh and just always there for me if I had a problem.
00:37:41.360 --> 00:37:45.199
And I was an only child, so what kind of father are you to your kid?
00:37:45.280 --> 00:37:47.119
Are you the tough one or the sweet one?
00:37:47.440 --> 00:37:48.639
Well, it's really interesting.
00:37:48.800 --> 00:37:54.320
In both my professional and personal lives, I see both my parents in me.
00:37:54.559 --> 00:37:56.000
I missed having siblings.
00:37:56.159 --> 00:38:00.320
I always regretted as a little kid that I was alone a lot.
00:38:00.480 --> 00:38:03.760
Uh I had no brothers or sisters, like my friends do.
00:38:03.920 --> 00:38:10.320
Uh so maybe that impelled me to go in the opposite direction to have five kids in my own.
00:38:10.639 --> 00:38:13.840
Uh, but I like to think that I'm a blend of both parents.
00:38:14.000 --> 00:38:21.599
On the one hand, uh I I was always the disciplinarian in the family, more so than my uh my wife.
00:38:21.760 --> 00:38:25.920
Uh on the other hand, uh I was always kind of a soft touch as well.
00:38:26.320 --> 00:38:39.360
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.
00:38:39.519 --> 00:38:44.400
And our idea of longevity is not really about you living forever.
00:38:44.559 --> 00:38:49.679
It's about can we be happy in the days here on earth?
00:38:49.920 --> 00:38:57.679
So, when someone achieved so much, how did you see the humanity and the character placed in the happiness?
00:38:57.920 --> 00:39:03.119
Because I see many successful people, but they kind of live an unhappy life.
00:39:03.280 --> 00:39:12.320
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?
00:39:12.719 --> 00:39:15.039
Well, that's that's a very deep question.
00:39:15.280 --> 00:39:20.880
Uh I've been remarkably blessed, remarkably blessed in my life.
00:39:21.119 --> 00:39:25.840
Uh nobody deserves to be to be that blessed, but I have been.
00:39:26.159 --> 00:39:29.199
I've had remarkably gratifying work.
00:39:29.440 --> 00:39:29.760
Okay.
00:39:30.239 --> 00:39:41.840
So I I would say uh the two biggest things in my life are love and work.
00:39:42.639 --> 00:39:49.920
Uh the work in turn, for me, I mean who could be more fortunate?
00:39:50.239 --> 00:39:53.840
To be a physician scientist, which is what you I am.
00:39:53.920 --> 00:39:55.280
I'm a physician scientist.
00:39:55.360 --> 00:39:57.599
I I practice medicine as part of my career.
00:39:57.760 --> 00:40:00.320
I did clinical teaching for 35 years.
00:40:00.559 --> 00:40:03.119
Uh I don't do that anymore.
00:40:03.199 --> 00:40:05.119
Uh now I just do research.
00:40:05.440 --> 00:40:19.280
But I had the remarkable privilege of relieving suffering, curing disease from time to time, and on a rare occasion saving a life.
00:40:19.920 --> 00:40:24.559
There is no greater fulfillment uh for a human being than that.
00:40:25.440 --> 00:40:31.360
Uh but then I got to make these discoveries which impact people's lives.
00:40:31.679 --> 00:40:42.960
Uh and that alone would have been the ultimate uh reward for the work, but instead they get prizes and recognition, etc.
00:40:43.679 --> 00:40:44.800
And then the love.
00:40:45.199 --> 00:40:47.440
Uh I've been married twice.
00:40:47.519 --> 00:40:53.360
Uh my wife Lynn uh and I have been together, just had our 35th wedding anniversary.
00:40:53.679 --> 00:40:54.480
Congratulations.
00:40:54.880 --> 00:41:02.000
Uh I have five very loving children and six grandchildren and great relationships with them.
00:41:02.159 --> 00:41:05.920
Uh so I would say love and work is what it's all about.
00:41:06.239 --> 00:41:10.559
And uh, what are the best at the voice that you have been given by your mentors?
00:41:11.039 --> 00:41:15.039
My main mentor at the NIH was a guy named Jesse Roth.
00:41:15.360 --> 00:41:15.599
Okay.
00:41:16.159 --> 00:41:22.800
He believed in receptors uh at a time when there were no proof that they existed.
00:41:22.960 --> 00:41:26.480
And he kind of got me thinking about receptors.
00:41:26.719 --> 00:41:33.519
So Jesse passed away about six weeks ago, eight weeks ago, at age 92.
00:41:33.760 --> 00:41:34.000
Yeah.
00:41:34.159 --> 00:41:37.440
But Jesse had all these crazy pieces of advice.
00:41:37.599 --> 00:41:52.159
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.
00:41:52.400 --> 00:41:56.559
Because I remember when I was interviewing with him, he said, What do you want to do in life?
00:41:56.880 --> 00:42:09.280
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.
00:42:09.840 --> 00:42:12.079
He says, You can't be super great at all of those.
00:42:12.159 --> 00:42:15.039
You're gonna have to find one thing to sort of focus on.
00:42:15.199 --> 00:42:27.760
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.
00:42:27.920 --> 00:42:30.400
He says, five-year packages.
00:42:30.559 --> 00:42:32.719
Don't think more than five years ahead.
00:42:32.960 --> 00:42:37.679
Figure out what you think you want to do for the next five years, and then you can reevaluate it.
00:42:37.760 --> 00:42:39.119
But don't try to plan your whole life.
00:42:39.280 --> 00:42:42.159
I thought that was a a pretty apt piece of advice.
00:42:42.559 --> 00:42:46.000
Today AI seems like an unavoidable topic.
00:42:46.239 --> 00:42:51.840
What's what's your thought in AI and also our advancements in science in biochemistry?
00:42:52.159 --> 00:42:56.159
I find for the most part they're pretty good.
00:42:56.239 --> 00:43:05.039
Uh and I can seek out information and even sophisticated analyses of problems.
00:43:05.679 --> 00:43:14.079
But the big caveat I have, and I've others have you know found this, is the hallucination thing.
00:43:14.719 --> 00:43:17.679
They uh they they just make stuff up.
00:43:17.760 --> 00:43:18.079
Yeah.
00:43:18.239 --> 00:43:28.960
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.
00:43:29.039 --> 00:43:41.360
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.
00:43:42.480 --> 00:43:51.519
And one of his former postdocs, now a professor here at Duke, was called upon to introduce him for his lecture.
00:43:52.480 --> 00:43:59.119
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.
00:43:59.280 --> 00:44:05.599
He said, And so I asked ChatGPT to write an introduction, and I'm gonna read that introduction.
00:44:05.760 --> 00:44:11.119
And he read it, and it was great, and sat down, and the professor gave up.
00:44:11.360 --> 00:44:15.039
He says, Well, that was an absolutely wonderful introduction, he says.
00:44:15.280 --> 00:44:18.880
However, there were three egregious errors in it.
00:44:19.119 --> 00:44:26.320
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.
00:44:26.559 --> 00:44:28.559
So again, you gotta be suspicious.
00:44:29.039 --> 00:44:34.559
But I do think it it's gonna uh change so many things.
00:44:34.719 --> 00:44:45.920
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.
00:44:46.079 --> 00:44:54.239
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.
00:44:54.320 --> 00:44:56.400
I mean, it it it's a whole new world.
00:44:56.559 --> 00:45:03.119
I I really wonder what the uh occupation of being a physician will be like in 20 years.
00:45:03.199 --> 00:45:04.079
I I can't imagine.
00:45:04.480 --> 00:45:11.440
In the five years package, what are the things you're most exciting about in the world of medicine and the biochemistry?
00:45:11.840 --> 00:45:18.559
The things I'm most hopeful about uh is breakthroughs in two areas.
00:45:18.880 --> 00:45:20.400
Uh one is cancer.
00:45:20.559 --> 00:45:35.760
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.
00:45:35.840 --> 00:45:38.000
It's all very much case by case.
00:45:38.159 --> 00:45:40.239
And the other is dementia.
00:45:40.559 --> 00:45:48.239
I see so many friends and colleagues my age, I'm 83, uh, already suffering with dementia or having died with dementia.
00:45:48.400 --> 00:45:50.960
We know a lot, and there are many different kinds of dementia.
00:45:51.039 --> 00:45:53.440
We know a lot more about it than we used to.
00:45:53.599 --> 00:46:00.480
And there have been real scientific advances, but we need we need some breakthroughs.
00:46:00.639 --> 00:46:13.440
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.
00:46:13.599 --> 00:46:17.679
And then they can be translated and moved further down the line.
00:46:17.840 --> 00:46:25.760
But the true breakthroughs that are going to influence the maximum number of lives occur back here at the most fundamental level of understanding.
00:46:26.000 --> 00:46:27.519
Thank you for your time today, though.
00:46:27.760 --> 00:46:28.880
My pleasure indeed.
00:46:29.199 --> 00:46:32.719
Thank you for watching this new episode of Humanware Project.
00:46:32.880 --> 00:46:37.280
So that we can bring out more amazing content like this one to you.
00:46:37.440 --> 00:46:39.199
Please like and subscribe.
00:46:39.280 --> 00:46:41.679
Your support means the world to us.
00:00:00.080 --> 00:00:03.120
I've impacted the lives of millions of end of millions.
00:00:03.439 --> 00:00:10.160
Intuition is often wrong, but the fact that I won the Nobel Prize, what it tells you is the intuition was right.
00:00:10.400 --> 00:00:17.440
Today, about a third of all FDA-approved drugs work through G protein coupled receptors.
00:00:17.600 --> 00:00:19.600
Every drug has side effects.
00:00:19.760 --> 00:00:23.199
The higher the dose, the greater the side effects.
00:00:23.440 --> 00:00:25.839
That was the last conversation I ever had with my father.
00:00:25.920 --> 00:00:27.359
He died three weeks later.
00:00:27.440 --> 00:00:29.280
And he never got to see any of that.
00:00:29.519 --> 00:00:30.239
Any of that.
00:00:34.000 --> 00:00:37.039
I've been remarkably blessed in my life.
00:00:37.200 --> 00:00:40.079
I'm going to tell you something, you're not going to believe.
00:00:40.640 --> 00:00:44.799
Professor Robert Foy won the Nobel Prize for discovery.
00:00:55.280 --> 00:01:04.000
That's something that's the last conversation he ever had with his father.
00:01:10.640 --> 00:01:12.719
It's such an honor to have you today, Dr.
00:01:12.799 --> 00:01:13.840
Lefkowitz.
00:01:13.920 --> 00:01:15.760
Welcome to the Humanware Project.
00:01:15.920 --> 00:01:22.319
In the day you received the Nobel Prize Award, has that changed your life before and after?
00:01:22.719 --> 00:01:26.000
Yes, it changed my life in many ways.
00:01:26.239 --> 00:01:34.159
In a sense, it even changed my name because I'm no longer introduced as Robert Lefkowitz or Bob Lefkowitz.
00:01:34.239 --> 00:01:40.000
Anytime anybody introduces me, I'm introduced as Nobel laureate, Bob Lefkowitz.
00:01:40.079 --> 00:01:42.000
So it even becomes part of your name.
00:01:58.560 --> 00:02:03.920
So those are the two uh, I guess, most significant ways that it changed my life.
00:02:04.239 --> 00:02:13.680
Because your study on the cell receptors and how our cells behavior at the late 1960s is actually quite a niche subject to study.
00:02:13.919 --> 00:02:18.400
When you look back to a younger self, what do you would say to him?
00:02:18.800 --> 00:02:22.319
The first thing I would say to him is, sit down.
00:02:22.560 --> 00:02:25.919
I'm going to tell you something you're not going to believe.
00:02:26.159 --> 00:02:27.919
And he would say, What is it?
00:02:28.080 --> 00:02:32.479
And I would say, you're going to become a famous scientist.
00:02:32.719 --> 00:02:34.800
And he would have laughed out loud.
00:02:34.879 --> 00:02:35.120
Yeah.
00:02:35.280 --> 00:02:42.159
And he would have said, But I don't want to be a famous scientist or any scientist at all.
00:02:42.479 --> 00:02:42.879
Really?
00:02:43.120 --> 00:02:43.599
Yes.
00:02:43.759 --> 00:02:45.680
I have no interest in being a scientist.
00:02:45.759 --> 00:02:47.039
I want to be a doctor.
00:02:47.599 --> 00:02:55.680
And I would say, well, uh, you'll get to do that, but you're also uh be gonna become a successful scientist.
00:02:55.840 --> 00:02:59.520
And if that isn't crazy enough, here's something else for you.
00:02:59.680 --> 00:03:01.599
You're gonna win the Nobel Prize.
00:03:01.759 --> 00:03:04.879
Uh at which point I think I would have been speechless.
00:03:05.280 --> 00:03:13.599
So what intriguing you from being a physician or from being a doctor into, you know, pursued science?
00:03:14.000 --> 00:03:18.479
So I graduated medical school, Columbia, in 1966.
00:03:18.960 --> 00:03:21.199
The Vietnam War was raging.
00:03:22.080 --> 00:03:30.560
There was, in addition to the lottery draft for all men over 18, there was a doctor draft.
00:03:31.199 --> 00:03:32.800
But this was not a lottery.
00:03:33.520 --> 00:03:37.919
Everybody was drafted upon graduation from medical school.
00:03:38.000 --> 00:03:51.919
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.
00:03:52.159 --> 00:03:57.840
And then you went into either the Army, the Navy, the Air Force, or the United States Public Health Service.
00:03:58.000 --> 00:03:58.240
Yeah.
00:03:58.400 --> 00:04:07.520
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.
00:04:07.680 --> 00:04:09.039
Nobody wanted to do that.
00:04:09.120 --> 00:04:11.039
It was a very unpopular war.
00:04:11.199 --> 00:04:15.360
Many of us thought it was uh at least immoral, if not illegal.
00:04:15.520 --> 00:04:18.399
Uh, and so everybody was trying to find a way out.
00:04:18.879 --> 00:04:26.639
Uh, one way out of serving in Vietnam in support of the war was to be drafted into the public health service.
00:04:27.199 --> 00:04:34.879
If you were able to get a commission in the public health service, you stood a chance of being assigned stateside.
00:04:35.120 --> 00:04:35.439
Okay.
00:04:35.680 --> 00:04:44.399
And better yet, if you were really fortunate, being assigned stateside to one of their research institutions, like the NIH or the CDC.
00:04:44.560 --> 00:04:45.120
Yeah.
00:04:45.360 --> 00:04:49.759
So it was extraordinarily competitive to get those commissions.
00:04:50.079 --> 00:04:54.000
Because I always was a very good student and had gone to good schools.
00:04:54.240 --> 00:05:00.000
I was able to get the commission in the public health service and was assigned to the NIH for two years.
00:05:00.160 --> 00:05:08.160
There, I spent about 20% of my time taking care of patients in the what was called the clinical center.
00:05:08.240 --> 00:05:14.240
These were research patients, and 80% of my time doing mentored research.
00:05:14.560 --> 00:05:22.480
I was there doing that research, not because I was particularly interested in becoming scientist, becoming a scientist.
00:05:22.639 --> 00:05:29.040
I was there because it was the best of several options open to me at the height of the Vietnam War.
00:05:29.279 --> 00:05:31.519
And initially things went very poorly.
00:05:31.759 --> 00:05:32.079
Okay.
00:05:32.319 --> 00:05:38.399
Uh for the first year or year and a half of my two-year stint, uh I met with no success.
00:05:38.480 --> 00:05:38.720
Yeah.
00:05:38.879 --> 00:05:40.879
This was a new experience for me.
00:05:41.040 --> 00:05:47.199
I had never failed in a prolonged way at anything I had ever tried in my life to that point.
00:05:47.360 --> 00:05:49.600
But now I failed over and over again.
00:05:50.240 --> 00:06:09.600
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.
00:06:09.680 --> 00:06:10.319
Yeah.
00:06:11.040 --> 00:06:16.800
But during the last six months at the NIH, my work started to yield some fruit.
00:06:18.079 --> 00:06:21.839
I actually published a couple of papers and was starting to enjoy it.
00:06:22.000 --> 00:06:30.879
Uh my mentors uh importuned me to stay uh and continue the work, but I wasn't enjoying it that much.
00:06:31.040 --> 00:06:35.839
So off I went uh to the Massachusetts General Hospital in 1970.
00:06:35.920 --> 00:06:41.680
And for the first six months, I threw myself into full-time clinical work again, no research.
00:06:42.000 --> 00:06:46.959
But at the end of those six months, I realized I missed the lab.
00:06:47.199 --> 00:06:51.920
That uh not that I would want to do that full-time, but I really I missed it.
00:06:52.160 --> 00:06:54.079
Which part of it do you aren't me say?
00:06:54.480 --> 00:07:06.000
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.
00:07:06.160 --> 00:07:08.879
I missed the creative aspect of it.
00:07:09.759 --> 00:07:19.519
I guess increasingly, even though medicine was my first love, less and less did I see it as a really creative enterprise.
00:07:19.680 --> 00:07:20.000
Yeah.
00:07:20.160 --> 00:07:21.759
It was a humane enterprise.
00:07:21.920 --> 00:07:27.199
It was about as humane uh an enterprise as I could imagine.
00:07:27.360 --> 00:07:39.040
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.
00:07:39.279 --> 00:07:46.480
Uh but now these creative stirrings seemed to me pulling me in a different direction.
00:07:46.639 --> 00:08:00.079
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.
00:08:00.240 --> 00:08:07.199
And then in 1973, I came to Duke, set up my lab, uh, and uh, as they say, the rest is history.
00:08:07.519 --> 00:08:11.839
But when you were first starting to set up your lab, is there any challenge at the time?
00:08:12.240 --> 00:08:26.079
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.
00:08:26.319 --> 00:08:31.600
At the time, there was no general consensus that such molecules even existed.
00:08:31.920 --> 00:08:42.399
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.
00:08:42.559 --> 00:08:47.039
So if we bring those signs into our everyday life, what are those receptors doing?
00:08:47.200 --> 00:08:48.480
Why that matters to us?
00:08:48.879 --> 00:09:01.440
So receptors are sites on cells with which drugs and hormones interact or combine to initiate their actions.
00:09:01.679 --> 00:09:01.919
Okay.
00:09:02.559 --> 00:09:05.440
Think about it as a lock and a key.
00:09:05.840 --> 00:09:07.919
So the lock is the receptor.
00:09:08.159 --> 00:09:08.399
Okay.
00:09:08.879 --> 00:09:19.200
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.
00:09:19.600 --> 00:09:23.919
Let's take a specific example: adrenaline, epinephrine.
00:09:24.240 --> 00:09:24.559
Okay.
00:09:24.960 --> 00:09:27.840
Uh I chose that as my model system.
00:09:28.159 --> 00:09:36.720
Epinephrine, everybody knows, stimulates the heart, makes it beat stronger, faster, uh, dilates the airways, et cetera.
00:09:36.879 --> 00:09:43.679
But in order to start those actions, it has to fit into a specific site on the cell that recognizes it.
00:09:43.840 --> 00:09:50.559
That site is called a receptor, and it's called an adrenergic receptor from adrenaline.
00:09:50.720 --> 00:09:51.039
Okay.
00:09:51.600 --> 00:09:55.759
Uh so I set out to prove there was such a thing.
00:09:55.919 --> 00:09:57.679
But of course, there was no way to measure.
00:09:58.240 --> 00:10:02.159
But uh there must be a lot of voice that says otherwise, right?
00:10:02.320 --> 00:10:04.720
There must be not a lot of evidence.
00:10:04.879 --> 00:10:07.519
How do you know it was right to study?
00:10:07.919 --> 00:10:10.399
Well, intuition plays a very big role.
00:10:10.559 --> 00:10:10.799
Okay.
00:10:11.440 --> 00:10:19.440
There were uh pieces of evidence that suggested that there must be such receptors.
00:10:20.080 --> 00:10:23.440
Not conclusive at all, or people would have believed in them.
00:10:23.679 --> 00:10:25.919
What what were some of these pieces of evidence?
00:10:26.159 --> 00:10:33.120
Well, one, drugs like adrenaline, they work at very low concentrations.
00:10:33.360 --> 00:10:34.960
Very low concentrations.
00:10:35.279 --> 00:10:37.759
A few molecules can have an effect.
00:10:38.080 --> 00:10:44.720
That means there must be something on the cell for which that adrenaline has a very high, what we call affinity.
00:10:44.799 --> 00:10:46.240
It likes to bind to it.
00:10:46.799 --> 00:10:52.159
The other thing uh is that there's tremendous specificity in the actions.
00:10:52.399 --> 00:11:01.360
In other words, the only things which can imitate adrenaline are molecules which chemically look very, very similar to adrenaline.
00:11:01.519 --> 00:11:06.480
Again, suggesting you've got to have a key that that fits very, very specifically.
00:11:07.120 --> 00:11:11.840
But beyond that, you've already hit the key, intuition.
00:11:12.080 --> 00:11:15.279
Uh, and nobody can really explain intuition.
00:11:15.360 --> 00:11:17.120
Uh, but intuition is a real thing.
00:11:17.360 --> 00:11:25.279
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.
00:11:25.919 --> 00:11:43.120
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.
00:11:43.279 --> 00:11:46.240
Even though I can't prove it yet, it's gotta be true.
00:11:46.480 --> 00:11:48.159
It's a real process, I believe.
00:11:48.320 --> 00:11:49.679
It's just we don't understand it.
00:11:49.840 --> 00:11:57.279
What it is, is basically, you know, you have all these circuits in your brain, uh, and they're all kind of spinning.
00:11:57.679 --> 00:12:04.000
Uh, and sometimes it's like a slot machine, and you get three oranges or three apples.
00:12:04.159 --> 00:12:08.320
Uh anyway, uh that's the way I picture uh intuition.
00:12:08.480 --> 00:12:13.120
It's just something below the surface that's just telling you this.
00:12:13.440 --> 00:12:19.919
Now, intuition is often wrong, uh, but sometimes it's right.
00:12:20.159 --> 00:12:27.279
And uh, you know, the fact that I won the Nobel Prize, uh what it tells you is the intuition was right.
00:12:27.600 --> 00:12:34.720
For those young scientists right now, they're pursuing science and they're pursuing their own subject of study.
00:12:34.960 --> 00:12:36.720
What are your advice for them?
00:12:37.120 --> 00:12:45.600
For the younger scientists who are still in training, my most significant piece of advice is choose your mentors very carefully.
00:12:45.840 --> 00:12:52.320
Your mentors are much more important than where you go to school, uh, et cetera.
00:12:52.480 --> 00:12:57.840
I mean, young people think that, oh, I gotta go to school here, I've got to go train at this place.
00:12:58.080 --> 00:13:02.639
Much more important is who is the specific mentor that you select?
00:13:02.799 --> 00:13:13.840
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?
00:13:14.000 --> 00:13:15.440
What am I gonna work on?
00:13:15.840 --> 00:13:23.679
Uh and you you've got to find something which is challenging, not easy, and which is important.
00:13:24.320 --> 00:13:26.000
Well, how do you know what's important?
00:13:26.159 --> 00:13:26.399
Okay.
00:13:26.960 --> 00:13:37.120
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.
00:13:37.440 --> 00:13:41.759
The only way you learn that kind of judgment is by watching your mentor.
00:13:41.840 --> 00:13:55.519
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?
00:13:55.840 --> 00:13:58.720
When do they decide to pursue something?
00:13:58.960 --> 00:14:00.559
When do they brush it off?
00:14:00.960 --> 00:14:02.720
How do they make those decisions?
00:14:02.879 --> 00:14:12.639
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.
00:14:12.879 --> 00:14:15.679
Uh so it's an experiential process.
00:14:15.919 --> 00:14:19.679
Um, if I have the number up to date, you have mentored more than 250.
00:14:20.000 --> 00:14:21.200
More than 250, that's right.
00:14:21.440 --> 00:14:25.039
Also, both of them have winning a Nobel Prize with you.
00:14:25.200 --> 00:14:25.360
Right.
00:14:25.600 --> 00:14:28.639
So could you tell us how do we find good mentors?
00:14:29.039 --> 00:14:34.240
When you're in the process of choosing a mentor, very important to visit the laboratory.
00:14:34.480 --> 00:14:36.159
Talk to the trainees.
00:14:36.720 --> 00:14:38.639
What's the esprit de corps?
00:14:39.120 --> 00:14:40.240
What's the mood?
00:14:40.480 --> 00:14:42.080
Are these happy people?
00:14:42.240 --> 00:14:43.840
What do they say about the mentor?
00:14:44.000 --> 00:14:46.159
Do they enjoy working with him or her?
00:14:46.559 --> 00:14:49.600
Uh is he positive, supportive, inspirational?
00:14:49.759 --> 00:14:50.799
All of these things.
00:14:51.039 --> 00:14:52.399
So those are some of the things.
00:14:52.559 --> 00:14:54.320
There is one caveat, though.
00:14:54.480 --> 00:15:00.799
The caveat is supposing you have a potential mentor uh who's just starting out.
00:15:00.960 --> 00:15:02.480
He has no track record.
00:15:02.799 --> 00:15:08.559
He may be great, but there's no way to tell yet, because he's just started.
00:15:08.639 --> 00:15:14.639
So when I started my laboratory here in 1973, I was all of 30 years old.
00:15:14.799 --> 00:15:17.679
I had many postdocs that are much older than that.
00:15:17.919 --> 00:15:19.759
Okay, so I'm 30 years old.
00:15:19.919 --> 00:15:21.840
I've never trained anybody.
00:15:22.000 --> 00:15:27.039
I published some interesting work, but you know, nothing fabulous yet.
00:15:27.200 --> 00:15:28.960
Uh so how do they know?
00:15:29.120 --> 00:15:30.559
That's the one caveat.
00:15:30.960 --> 00:15:35.840
Uh so they have to trust me and I have to trust them.
00:15:35.919 --> 00:15:45.200
Uh, interestingly, some of the most very talented trainees uh I uh have had came at the very beginning.
00:15:45.600 --> 00:15:52.480
Do you think your daily routine changed much, let's say 30, 40 years ago compared with today?
00:15:52.799 --> 00:15:57.919
If you talk to any of the people in my lab, they'd say, yeah, I'm filled with energy and this and that.
00:15:58.159 --> 00:16:00.720
Uh but it's changed.
00:16:00.960 --> 00:16:01.519
How?
00:16:01.759 --> 00:16:07.120
Well, none of us are the same at 83 years of age as we are at 33.
00:16:07.600 --> 00:16:10.639
If we were, we'd be a total freak of nature.
00:16:10.879 --> 00:16:16.320
Uh so uh I spend less hours here than I did.
00:16:16.799 --> 00:16:21.759
Uh so just think, when I was 33, that's 50 years ago.
00:16:21.840 --> 00:16:23.440
That's a half a century ago.
00:16:23.919 --> 00:16:24.240
Okay.
00:16:24.799 --> 00:16:30.480
Uh so now I spend more time taking care of myself.
00:16:30.799 --> 00:16:36.799
I sleep more, uh, I exercise more, uh, I meditate more.
00:16:36.960 --> 00:16:48.720
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.
00:16:48.960 --> 00:16:55.679
So I come from a family with a lot of family history of premature heart disease.
00:16:56.000 --> 00:17:01.440
My father died of his fourth heart attack at age 63.
00:17:01.679 --> 00:17:07.119
My mother lived to a pretty good age, just shy of her 89th birthday.
00:17:07.440 --> 00:17:09.839
But she had a heart attack when she was 56.
00:17:10.400 --> 00:17:14.480
Uh, and her mother died of a heart attack at 60.
00:17:14.640 --> 00:17:18.079
So I had a lot of heart disease coming at me.
00:17:18.240 --> 00:17:20.160
Uh, and I always knew this.
00:17:20.400 --> 00:17:27.039
And I suspect it is no coincidence that for my medical specialty I chose cardiology.
00:17:27.279 --> 00:17:33.279
So I was always trying to run away from that family history in a very literal sense.
00:17:33.440 --> 00:17:37.440
Uh, if you look around my office, you'll see several pictures of me running.
00:17:37.680 --> 00:17:38.000
Okay.
00:17:38.559 --> 00:17:42.160
Uh there's one, I think, behind me up here.
00:17:42.640 --> 00:17:53.200
Uh I spent all my years between late 20s and maybe 15 or 20 years ago, doing long distance running.
00:17:53.359 --> 00:17:58.799
Uh, in a very real sense, trying to run away uh from my history of heart disease.
00:17:59.039 --> 00:18:09.839
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.
00:18:10.000 --> 00:18:10.319
Yeah.
00:18:10.720 --> 00:18:27.839
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.
00:18:28.240 --> 00:18:38.240
Since that time, I have tried my best to control every possible risk factor.
00:18:38.400 --> 00:18:41.039
Uh I eat no meat, chicken, fish.
00:18:41.279 --> 00:18:46.000
I do take uh uh a fish oil supplement.
00:18:46.319 --> 00:19:00.079
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.
00:19:00.160 --> 00:19:01.759
Uh, but that's all I eat.
00:19:02.000 --> 00:19:05.359
Uh I maintain my weight at ideal body weight.
00:19:05.920 --> 00:19:11.599
So I I exercise on average an hour uh seven days a week.
00:19:11.920 --> 00:19:16.559
Uh and I sleep about eight hours a night.
00:19:16.880 --> 00:19:20.480
So the days when I could be in by 8 a.m.
00:19:20.880 --> 00:19:28.079
Yeah are long gone because, well, I'm busy in the morning for several hours with all this.
00:19:28.640 --> 00:19:33.440
But hey, I never expected to be here uh at age 83.
00:19:33.599 --> 00:19:34.960
Uh, but here I am.
00:19:36.000 --> 00:19:49.359
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?
00:19:49.839 --> 00:19:50.480
Completely.
00:19:50.640 --> 00:20:12.880
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.
00:20:13.119 --> 00:20:20.720
But then I was, to my amazement, I was drawn more and more deeply into the science, which surprised me.
00:20:20.880 --> 00:20:22.720
Okay, but it just happened.
00:20:22.880 --> 00:20:38.319
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.
00:20:38.960 --> 00:20:47.200
But ultimately it became millions, tens of millions, through all these medicines that have been uh developed based on our work.
00:20:47.359 --> 00:20:50.160
And that's extremely gratifying to me.
00:20:50.480 --> 00:20:55.599
As we know it, the amazing discovery and study have win you the Nobel Prize.
00:20:55.759 --> 00:20:58.880
We are thinking it should be the Nobel Prize of Medicine.
00:20:59.039 --> 00:21:02.000
In the end, it became the Nobel Prize of Chemistry.
00:21:02.240 --> 00:21:04.160
Was that title matters for you?
00:21:04.559 --> 00:21:09.359
Well, the first thing is it was a tremendous surprise to me that we won in chemistry.
00:21:09.839 --> 00:21:18.720
In retrospect, it shouldn't have been, because if you look at the prizes in medicine and chemistry, there's a lot of overlap.
00:21:19.119 --> 00:21:22.559
And it's sort of arbitrary, I think, in terms of what they do.
00:21:22.799 --> 00:21:33.599
If I had to choose a single scientific discipline that was responsible for most of the big discoveries we made, it was biochemistry.
00:21:34.000 --> 00:21:36.079
I used the techniques of the biochemist.
00:21:36.240 --> 00:21:39.039
So in that sense, it shouldn't have been such a big surprise.
00:21:39.279 --> 00:21:58.960
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.
00:22:00.160 --> 00:22:06.720
And I was discussing this issue with him that how surprising it was to me uh to be the laureate in chemistry.
00:22:06.880 --> 00:22:10.240
He said, Well, you were also nominated in medicine.
00:22:10.400 --> 00:22:15.119
Uh, he said, and the two committees often communicate.
00:22:15.279 --> 00:22:21.839
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.
00:22:22.079 --> 00:22:24.559
Uh so I felt good about that.
00:22:25.119 --> 00:22:29.519
So yeah, I'm, you know, whether it was medicine, chemistry, so fine.
00:22:29.680 --> 00:22:38.240
And there are many other examples uh of chemistry Nobel really could have just as well been in medicine.
00:22:38.400 --> 00:22:42.799
And many medicine Nobel's really were pieces of biochemistry.
00:22:43.200 --> 00:22:51.119
What is GPCR and also what is like that part of cell's receptor function like in our day-to-day life?
00:22:51.599 --> 00:23:00.400
G protein coupled receptors are a particular type of receptor uh which have a number of things in common.
00:23:00.720 --> 00:23:10.559
Now, we basically uh discovered uh or or realized that there was a family of these receptors.
00:23:10.799 --> 00:23:17.359
Well, today we know that the G protein-coupled receptors are by far the largest family of receptors.
00:23:17.519 --> 00:23:22.240
In fact, they are the largest gene family in the entire human genome.
00:23:22.319 --> 00:23:26.000
There are about 800 or more of these receptors.
00:23:26.160 --> 00:23:31.759
They regulate virtually every physiological process in humans.
00:23:32.000 --> 00:23:33.039
You can name something.
00:23:33.119 --> 00:23:34.319
I mean, it doesn't matter what.
00:23:34.559 --> 00:23:43.519
Breathing, uh, digestion, uh, genital urinary function, reproduction, everything is through that.
00:23:43.759 --> 00:23:52.240
Today, about a third, a third of all FDA-approved drugs work through G protein coupled receptors.
00:23:52.400 --> 00:23:55.359
That's more than 700 drugs, okay?
00:23:55.599 --> 00:24:08.000
Everything from adrenaline to antihistamines, to beta blockers, to antidepressants, and of course, all anybody talks about today, GLIP 1.
00:24:08.640 --> 00:24:15.519
All of these drugs, terzepatide, wagovy, all of them work through G protein coupled receptors.
00:24:15.680 --> 00:24:21.359
And there are certain principles that basically apply broadly to all the receptors.
00:24:21.440 --> 00:24:34.480
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.
00:24:34.880 --> 00:24:39.119
When we think about, we said that two people have chemistry, right?
00:24:39.279 --> 00:24:40.799
Or the chemistry of love.
00:24:41.039 --> 00:24:44.480
Is that also go through the G protein receptors?
00:24:44.799 --> 00:24:46.559
Undoubtedly, undoubtedly.
00:24:46.720 --> 00:24:52.319
Uh there have been uh there are certain uh receptors.
00:24:52.480 --> 00:25:05.279
I mean, prolactin is one, uh dopamine uh is always talked about dopamine and dopamine receptors in reward uh, you know, good feelings, etc.
00:25:05.680 --> 00:25:15.839
You know, most human behaviors uh and even diseases are regulated not by a single gene, but by hundreds of genes.
00:25:16.000 --> 00:25:16.319
Yeah.
00:25:16.480 --> 00:25:16.799
Okay.
00:25:17.279 --> 00:25:32.319
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?
00:25:32.480 --> 00:25:34.079
No, it wouldn't surprise me at all.
00:25:34.400 --> 00:25:46.240
Even the commonest of diseases, for the most part, are caused by not one or two or three genetic abnormalities, but hundreds.
00:25:46.559 --> 00:25:49.599
So if you say, what's the genetic cause of diabetes?
00:25:49.759 --> 00:25:50.960
We have no idea.
00:25:51.200 --> 00:25:54.079
What's the genetic cause of coronary disease?
00:25:54.240 --> 00:25:55.200
We have no idea.
00:25:55.359 --> 00:26:05.119
Now, there are individual cases where, for example, somebody has a single mutation that makes their cholesterol go sky high.
00:26:05.359 --> 00:26:06.720
That's not what I'm talking about.
00:26:06.960 --> 00:26:10.960
But something like personality, uh, just think how complex that is.
00:26:11.279 --> 00:26:13.039
What do you think about gene therapy?
00:26:13.200 --> 00:26:18.400
Like, can we as a human really edit it our gene to have, let's say, better genes?
00:26:18.799 --> 00:26:19.359
Definitely.
00:26:19.440 --> 00:26:22.319
Uh, this is certainly not a field I have any expertise.
00:26:22.799 --> 00:26:25.119
Techniques are just becoming available now.
00:26:25.359 --> 00:26:35.759
Scientific discoveries led to a gene editing uh treatment, uh, which has now been used, where they can basically uh edit a gene.
00:26:35.920 --> 00:26:40.400
This gene editing technology for sickle cell disease has been approved by the FDA.
00:26:40.720 --> 00:26:44.400
And when we talk about GLP1, how does GLP1 work?
00:26:44.640 --> 00:26:48.880
Why some people, it just seems very difficult for them to lose weight.
00:26:49.039 --> 00:26:53.519
For some people, maybe they also eat a lot, but they don't put on the weight so easily.
00:26:53.920 --> 00:26:54.720
How do they work?
00:26:54.880 --> 00:26:56.720
I'm not sure that anybody knows.
00:26:56.960 --> 00:27:00.160
Uh it started off as a very simple story.
00:27:00.400 --> 00:27:04.079
These hormones are referred to as incrementins, okay?
00:27:04.400 --> 00:27:33.039
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.
00:27:33.279 --> 00:27:39.039
Okay, and that's why they were originally developed and used in diabetes.
00:27:39.200 --> 00:27:41.359
I mean, they seem to be working.
00:27:41.599 --> 00:27:45.279
Uh I know somebody who's trying it for long COVID.
00:27:45.680 --> 00:27:49.680
Uh it's being used for in heart disease.
00:27:49.920 --> 00:28:03.119
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.
00:28:03.279 --> 00:28:04.079
Unbelievable.
00:28:04.160 --> 00:28:09.599
So it and it's turning out that there are receptors for these molecules all over the body.
00:28:09.759 --> 00:28:09.920
Yeah.
00:28:10.079 --> 00:28:10.400
Okay.
00:28:10.640 --> 00:28:15.119
So we're just in the infancy of understanding uh how that works.
00:28:15.440 --> 00:28:15.680
Yeah.
00:28:15.839 --> 00:28:21.680
What about the histamine resistance and also people slowly develop the allergies?
00:28:21.839 --> 00:28:23.920
For example, I'm living in London.
00:28:24.079 --> 00:28:27.359
I have a lot of friends who developed the hay fever.
00:28:27.599 --> 00:28:32.480
So they probably first a few years into the UK, they're fine.
00:28:32.640 --> 00:28:38.000
But maybe the year 10, year 11, they start to have this hay fever every spring.
00:28:38.079 --> 00:28:39.759
Uh, what happened to them?
00:28:40.319 --> 00:28:49.039
Well, you know, there have been huge uh advances in the treatment of allergy and eczema and things like that.
00:28:49.279 --> 00:29:01.440
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.
00:29:01.519 --> 00:29:02.880
They're called cytokines.
00:29:03.519 --> 00:29:20.880
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.
00:29:21.119 --> 00:29:29.119
Uh we don't need to go into but IgE and other kinds of antibodies, which stimulate things like histamine release, et cetera.
00:29:29.200 --> 00:29:38.640
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.
00:29:38.880 --> 00:29:44.160
An important concept in uh clinical therapeutics is the following.
00:29:44.400 --> 00:29:46.640
Every drug has side effects.
00:29:46.880 --> 00:29:47.759
Every drug.
00:29:48.160 --> 00:29:52.319
Uh the higher the dose, the greater the side effects.
00:29:52.480 --> 00:29:54.640
Some drugs have more side effects than others.
00:29:54.799 --> 00:29:59.599
There are two types of side effects, uh off-target and on-target.
00:29:59.920 --> 00:30:03.039
Off-target are almost impossible to predict.
00:30:03.200 --> 00:30:07.200
But the more common thing are on-target side effects.
00:30:07.839 --> 00:30:16.160
And it brings up an interesting thing is even though we call them side effects, they're not really side effects.
00:30:16.480 --> 00:30:19.920
They are, another term that's used is adverse effects.
00:30:20.480 --> 00:30:27.440
Because in general, when we give a drug, we're giving it because it has an effect that we want.
00:30:28.000 --> 00:30:30.000
But it also has lots of other effects.
00:30:30.319 --> 00:30:35.839
One of the biggest complications with antihistamines is they made you very sleepy.
00:30:36.240 --> 00:30:44.319
Uh, and this was, you know, things like Benadryl and uh pyrobenzamine, the uh first generation antihistamine.
00:30:44.640 --> 00:30:54.319
This is because they cross-reacted with other GPCRs, like what we call cholinergic receptors and other receptors in the brain.
00:30:54.559 --> 00:31:07.759
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.
00:31:08.079 --> 00:31:14.000
Let's talk about your book, because it was so fun, and I it really reminds me of Mr.
00:31:14.160 --> 00:31:14.799
Feynman.
00:31:14.960 --> 00:31:20.160
And uh, could you tell us why your name A Funny Thing Happened on the Way to Stockholm?
00:31:20.559 --> 00:31:25.519
First of all, uh a comment or two about Feynman, who was also one of my many heroes.
00:31:25.839 --> 00:31:29.200
Uh I've read some of his books and lectures.
00:31:29.359 --> 00:31:35.119
And uh like Feynman, uh, I guess I'm kind of a racon tour.
00:31:35.279 --> 00:31:38.799
I like stories, I like to tell stories, I like to hear stories.
00:31:39.200 --> 00:31:48.880
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.
00:31:49.440 --> 00:31:57.039
Uh and so over the years there was a growing chorus of voices saying, Bob, you need to write up your stories.
00:31:57.440 --> 00:31:59.839
Why don't you write a book with all your stories in it?
00:32:00.079 --> 00:32:01.440
I never would have done it.
00:32:01.599 --> 00:32:15.759
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.
00:32:15.920 --> 00:32:18.880
He said, Look, why don't we imitate what Feynman did?
00:32:19.039 --> 00:32:19.759
You remember?
00:32:20.079 --> 00:32:25.119
He got one of his former students, now a professor, uh, to work with him.
00:32:25.200 --> 00:32:31.039
He told his stories uh to this guy, and then the guy helped him write them up.
00:32:31.759 --> 00:32:35.920
So I said, Well, if you're willing to do some of the heavy lifting, I'll tell you the stories.
00:32:36.079 --> 00:32:37.039
And so we started.
00:32:37.440 --> 00:32:42.400
Uh, and so every week for about a year, uh, we would talk for about two hours.
00:32:42.480 --> 00:32:52.160
Uh, he would record my stories, uh, and I tried to tell them uh chronologically in terms of my life.
00:32:52.400 --> 00:32:56.000
Uh he would then try to shape them into a narrative.
00:32:56.240 --> 00:32:59.039
For a year or more, year and a half, we worked on it.
00:32:59.119 --> 00:33:00.960
Uh, and the book is what we came up with.
00:33:01.119 --> 00:33:08.559
As I guess you've already gathered, one of the defining characteristics of my personality is humor.
00:33:09.119 --> 00:33:09.839
Uh right.
00:33:10.240 --> 00:33:18.640
Uh I like making people laugh, and I like seeing the humor in situations where other people might not see the humor.
00:33:18.720 --> 00:33:22.400
Uh, and so we said, okay, let's call her a funny thing happened on the way to Stockholm.
00:33:22.720 --> 00:33:25.200
Could you share with us one story in the book?
00:33:25.680 --> 00:33:38.000
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.
00:33:38.160 --> 00:33:42.240
Uh and it was not that I wanted to be a scientist and I was being disappointed.
00:33:42.319 --> 00:33:46.559
I just I never failed before in a long way like that.
00:33:47.680 --> 00:33:54.799
Uh so I went home uh over the Thanksgiving holiday, and by then I was married and had some young children.
00:33:54.960 --> 00:34:04.240
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.
00:34:04.480 --> 00:34:07.279
Uh and uh I talked with my dad.
00:34:07.440 --> 00:34:10.239
I was an only child and I was very close to my dad.
00:34:10.400 --> 00:34:15.199
I went home, he was always my advisor on anything that came up.
00:34:15.440 --> 00:34:17.840
He just had good common sense.
00:34:17.920 --> 00:34:20.480
Uh so I told him how unhappy I was.
00:34:20.719 --> 00:34:25.679
Uh and he said to me, Look, no need for that.
00:34:25.840 --> 00:34:28.480
He says, You never wanted to be a scientist.
00:34:28.719 --> 00:34:31.039
You just wanted to be a doctor and a cardiologist.
00:34:31.199 --> 00:34:33.440
So look, it's two years.
00:34:33.760 --> 00:34:37.280
Half one quarter of that is over already.
00:34:37.760 --> 00:34:50.000
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.
00:34:50.320 --> 00:34:54.079
Well, it was like a weight lift from my shoulder.
00:34:54.239 --> 00:34:59.199
Uh, and I went back uh to the NIH uh and I was really happy with that.
00:34:59.440 --> 00:35:03.679
Uh and that was the last conversation I ever had with my father.
00:35:03.840 --> 00:35:06.239
He died three weeks later, he dropped it.
00:35:06.800 --> 00:35:10.320
Uh and so that stuck with me.
00:35:10.559 --> 00:35:35.280
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.
00:35:35.599 --> 00:35:40.559
We would pursue a career as a physician, uh, etc.
00:35:40.960 --> 00:35:50.880
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?
00:35:51.039 --> 00:35:57.599
I mean, we we agreed in our very last conversation that I would become the doctor that we both dreamed of.
00:35:57.840 --> 00:36:00.320
Now, he died in 1968, okay?
00:36:00.480 --> 00:36:12.960
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.
00:36:13.199 --> 00:36:25.599
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?
00:36:26.239 --> 00:36:27.920
Uh I can't imagine.
00:36:28.079 --> 00:36:33.199
Uh do you feel regret or do you feel kind of sad that you couldn't share that joy with your dad?
00:36:33.519 --> 00:36:34.159
The latter, yeah.
00:36:34.239 --> 00:36:34.400
Yeah.
00:36:34.639 --> 00:36:37.360
I wish he could have seen some of it.
00:36:37.440 --> 00:36:41.280
Uh but I mean, he died before any of it happened.
00:36:41.519 --> 00:36:42.960
Before any of it happened.
00:36:43.119 --> 00:36:51.920
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.
00:36:52.400 --> 00:36:54.480
And then the way it played out.
00:36:54.559 --> 00:36:56.480
And he never got to see any of that.
00:36:56.719 --> 00:36:57.360
Any of that.
00:36:57.599 --> 00:36:59.599
That's really sad.
00:36:59.840 --> 00:37:03.760
I wish I think in in a certain way, maybe that or these things.
00:37:04.000 --> 00:37:05.599
Can you have a t-shirt, please?
00:37:05.760 --> 00:37:06.960
You just feel a bit sad.
00:37:07.039 --> 00:37:07.360
Yeah.
00:37:07.920 --> 00:37:09.760
I feel he must be very, very proud.
00:37:09.920 --> 00:37:10.719
That's how I feel.
00:37:10.960 --> 00:37:15.039
Because it seems like uh he's a very happy and a supportive character.
00:37:15.519 --> 00:37:16.079
My father?
00:37:16.480 --> 00:37:17.280
Oh, God, yeah.
00:37:17.440 --> 00:37:18.239
It's interesting.
00:37:18.559 --> 00:37:21.920
My mother, for lack of a better term, a real hard ass.
00:37:22.239 --> 00:37:22.559
Okay.
00:37:22.880 --> 00:37:27.840
Uh she was the one driving me to get the top grades uh to always bring home.
00:37:28.000 --> 00:37:31.599
If I brought home an A-, she'd want to know why wasn't it an A?
00:37:32.320 --> 00:37:35.199
Uh, why wasn't I studying more, et cetera?
00:37:35.440 --> 00:37:41.199
He was much softer uh and just always there for me if I had a problem.
00:37:41.360 --> 00:37:45.199
And I was an only child, so what kind of father are you to your kid?
00:37:45.280 --> 00:37:47.119
Are you the tough one or the sweet one?
00:37:47.440 --> 00:37:48.639
Well, it's really interesting.
00:37:48.800 --> 00:37:54.320
In both my professional and personal lives, I see both my parents in me.
00:37:54.559 --> 00:37:56.000
I missed having siblings.
00:37:56.159 --> 00:38:00.320
I always regretted as a little kid that I was alone a lot.
00:38:00.480 --> 00:38:03.760
Uh I had no brothers or sisters, like my friends do.
00:38:03.920 --> 00:38:10.320
Uh so maybe that impelled me to go in the opposite direction to have five kids in my own.
00:38:10.639 --> 00:38:13.840
Uh, but I like to think that I'm a blend of both parents.
00:38:14.000 --> 00:38:21.599
On the one hand, uh I I was always the disciplinarian in the family, more so than my uh my wife.
00:38:21.760 --> 00:38:25.920
Uh on the other hand, uh I was always kind of a soft touch as well.
00:38:26.320 --> 00:38:39.360
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.
00:38:39.519 --> 00:38:44.400
And our idea of longevity is not really about you living forever.
00:38:44.559 --> 00:38:49.679
It's about can we be happy in the days here on earth?
00:38:49.920 --> 00:38:57.679
So, when someone achieved so much, how did you see the humanity and the character placed in the happiness?
00:38:57.920 --> 00:39:03.119
Because I see many successful people, but they kind of live an unhappy life.
00:39:03.280 --> 00:39:12.320
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?
00:39:12.719 --> 00:39:15.039
Well, that's that's a very deep question.
00:39:15.280 --> 00:39:20.880
Uh I've been remarkably blessed, remarkably blessed in my life.
00:39:21.119 --> 00:39:25.840
Uh nobody deserves to be to be that blessed, but I have been.
00:39:26.159 --> 00:39:29.199
I've had remarkably gratifying work.
00:39:29.440 --> 00:39:29.760
Okay.
00:39:30.239 --> 00:39:41.840
So I I would say uh the two biggest things in my life are love and work.
00:39:42.639 --> 00:39:49.920
Uh the work in turn, for me, I mean who could be more fortunate?
00:39:50.239 --> 00:39:53.840
To be a physician scientist, which is what you I am.
00:39:53.920 --> 00:39:55.280
I'm a physician scientist.
00:39:55.360 --> 00:39:57.599
I I practice medicine as part of my career.
00:39:57.760 --> 00:40:00.320
I did clinical teaching for 35 years.
00:40:00.559 --> 00:40:03.119
Uh I don't do that anymore.
00:40:03.199 --> 00:40:05.119
Uh now I just do research.
00:40:05.440 --> 00:40:19.280
But I had the remarkable privilege of relieving suffering, curing disease from time to time, and on a rare occasion saving a life.
00:40:19.920 --> 00:40:24.559
There is no greater fulfillment uh for a human being than that.
00:40:25.440 --> 00:40:31.360
Uh but then I got to make these discoveries which impact people's lives.
00:40:31.679 --> 00:40:42.960
Uh and that alone would have been the ultimate uh reward for the work, but instead they get prizes and recognition, etc.
00:40:43.679 --> 00:40:44.800
And then the love.
00:40:45.199 --> 00:40:47.440
Uh I've been married twice.
00:40:47.519 --> 00:40:53.360
Uh my wife Lynn uh and I have been together, just had our 35th wedding anniversary.
00:40:53.679 --> 00:40:54.480
Congratulations.
00:40:54.880 --> 00:41:02.000
Uh I have five very loving children and six grandchildren and great relationships with them.
00:41:02.159 --> 00:41:05.920
Uh so I would say love and work is what it's all about.
00:41:06.239 --> 00:41:10.559
And uh, what are the best at the voice that you have been given by your mentors?
00:41:11.039 --> 00:41:15.039
My main mentor at the NIH was a guy named Jesse Roth.
00:41:15.360 --> 00:41:15.599
Okay.
00:41:16.159 --> 00:41:22.800
He believed in receptors uh at a time when there were no proof that they existed.
00:41:22.960 --> 00:41:26.480
And he kind of got me thinking about receptors.
00:41:26.719 --> 00:41:33.519
So Jesse passed away about six weeks ago, eight weeks ago, at age 92.
00:41:33.760 --> 00:41:34.000
Yeah.
00:41:34.159 --> 00:41:37.440
But Jesse had all these crazy pieces of advice.
00:41:37.599 --> 00:41:52.159
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.
00:41:52.400 --> 00:41:56.559
Because I remember when I was interviewing with him, he said, What do you want to do in life?
00:41:56.880 --> 00:42:09.280
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.
00:42:09.840 --> 00:42:12.079
He says, You can't be super great at all of those.
00:42:12.159 --> 00:42:15.039
You're gonna have to find one thing to sort of focus on.
00:42:15.199 --> 00:42:27.760
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.
00:42:27.920 --> 00:42:30.400
He says, five-year packages.
00:42:30.559 --> 00:42:32.719
Don't think more than five years ahead.
00:42:32.960 --> 00:42:37.679
Figure out what you think you want to do for the next five years, and then you can reevaluate it.
00:42:37.760 --> 00:42:39.119
But don't try to plan your whole life.
00:42:39.280 --> 00:42:42.159
I thought that was a a pretty apt piece of advice.
00:42:42.559 --> 00:42:46.000
Today AI seems like an unavoidable topic.
00:42:46.239 --> 00:42:51.840
What's what's your thought in AI and also our advancements in science in biochemistry?
00:42:52.159 --> 00:42:56.159
I find for the most part they're pretty good.
00:42:56.239 --> 00:43:05.039
Uh and I can seek out information and even sophisticated analyses of problems.
00:43:05.679 --> 00:43:14.079
But the big caveat I have, and I've others have you know found this, is the hallucination thing.
00:43:14.719 --> 00:43:17.679
They uh they they just make stuff up.
00:43:17.760 --> 00:43:18.079
Yeah.
00:43:18.239 --> 00:43:28.960
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.
00:43:29.039 --> 00:43:41.360
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.
00:43:42.480 --> 00:43:51.519
And one of his former postdocs, now a professor here at Duke, was called upon to introduce him for his lecture.
00:43:52.480 --> 00:43:59.119
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.
00:43:59.280 --> 00:44:05.599
He said, And so I asked ChatGPT to write an introduction, and I'm gonna read that introduction.
00:44:05.760 --> 00:44:11.119
And he read it, and it was great, and sat down, and the professor gave up.
00:44:11.360 --> 00:44:15.039
He says, Well, that was an absolutely wonderful introduction, he says.
00:44:15.280 --> 00:44:18.880
However, there were three egregious errors in it.
00:44:19.119 --> 00:44:26.320
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.
00:44:26.559 --> 00:44:28.559
So again, you gotta be suspicious.
00:44:29.039 --> 00:44:34.559
But I do think it it's gonna uh change so many things.
00:44:34.719 --> 00:44:45.920
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.
00:44:46.079 --> 00:44:54.239
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.
00:44:54.320 --> 00:44:56.400
I mean, it it it's a whole new world.
00:44:56.559 --> 00:45:03.119
I I really wonder what the uh occupation of being a physician will be like in 20 years.
00:45:03.199 --> 00:45:04.079
I I can't imagine.
00:45:04.480 --> 00:45:11.440
In the five years package, what are the things you're most exciting about in the world of medicine and the biochemistry?
00:45:11.840 --> 00:45:18.559
The things I'm most hopeful about uh is breakthroughs in two areas.
00:45:18.880 --> 00:45:20.400
Uh one is cancer.
00:45:20.559 --> 00:45:35.760
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.
00:45:35.840 --> 00:45:38.000
It's all very much case by case.
00:45:38.159 --> 00:45:40.239
And the other is dementia.
00:45:40.559 --> 00:45:48.239
I see so many friends and colleagues my age, I'm 83, uh, already suffering with dementia or having died with dementia.
00:45:48.400 --> 00:45:50.960
We know a lot, and there are many different kinds of dementia.
00:45:51.039 --> 00:45:53.440
We know a lot more about it than we used to.
00:45:53.599 --> 00:46:00.480
And there have been real scientific advances, but we need we need some breakthroughs.
00:46:00.639 --> 00:46:13.440
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.
00:46:13.599 --> 00:46:17.679
And then they can be translated and moved further down the line.
00:46:17.840 --> 00:46:25.760
But the true breakthroughs that are going to influence the maximum number of lives occur back here at the most fundamental level of understanding.
00:46:26.000 --> 00:46:27.519
Thank you for your time today, though.
00:46:27.760 --> 00:46:28.880
My pleasure indeed.
00:46:29.199 --> 00:46:32.719
Thank you for watching this new episode of Humanware Project.
00:46:32.880 --> 00:46:37.280
So that we can bring out more amazing content like this one to you.
00:46:37.440 --> 00:46:39.199
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00:46:39.280 --> 00:46:41.679
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