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Robert Lefkowitz
 
Robert Lefkowitz
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Robert Lefkowitz Interview

Nobel Prize in Chemistry

September 13, 2014
San Francisco, California

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  Robert Lefkowitz

You received the Nobel Prize for your work in receptor biology. When did you first become involved in this area of research?


Robert Lefkowitz: In 1968, when I went to the NIH, there was no receptor biology. And in fact, there was no consensus that these receptor molecules even existed. But my two mentors there thought they might, and I was given the project of trying to develop techniques to study a particular kind of receptor for a hormone. And I didn't realize just how challenging -- since I had no perspective -- I didn't realize just how challenging and daunting that assignment was. Nobody had ever done anything like that. And, as I said, for 18 months, I flailed and failed. But I did eventually meet with a modicum of success, and started to like it and saw the value in studying receptors. I could see a vision of where that might go, although in retrospect, I had no idea just how far it could go. So when I set up my own laboratory at Duke, I decided to study receptors. But since I was now a cardiovascular physician, I chose very deliberately to study something called adrenergic receptors, which means receptors for adrenaline. These are the targets of beta blockers, which are commonly used drugs. In retrospect, that turned out to be a very felicitous choice. Of course, I had no way of knowing that then. So that's how I got interested in it in the first place, and then I just kind of ran with it.


So at the time, there wasn't even evidence that these receptors existed?

Robert Lefkowitz: Correct.

That's a remarkably courageous act, but also a very creative one, to try and open up a whole new area of biology.

Robert Lefkowitz: Exactly. In retrospect, yes. At that moment, I didn't see it that way. I often tell people that if I knew then what I know now, there's no way I would have done this, because it was so difficult as it turned out.


I can say this in all honesty. It never crossed my mind that I would fail. And I don't know why that is. It almost seems delusional. Because there was no proof that these things even existed. And yet it was raw intuition. It just seemed to me, of course they exist. How else could it all work? And you know, I didn't have a Ph.D. I was not a biochemist. I wasn't anything. I was a physician. So I was kind of self-taught over the next few years. I gathered students and post-docs together and off we rode into the night to try to figure it all out. I talk about sometimes the chutzpah of youth. It was totally chutzpahdich, as we say in Yiddish. It was just filled with chutzpah -- brazen gall that you would think you could do that. But you know, in the end it worked. And exactly why, I can't say. I guess it was meant to be.

[ Key to Success ] Courage


You had to trust that instinct.

Robert Lefkowitz: Yes. It's not only that I was not filled with self-doubt. And it was not that I was an arrogant person. Even with all the failure that I had had, and with all the failure that would come my way over the next 15-20 years, it just seemed to me, it was always a question of when -- not if -- things would work.

You have to be very patient as a research scientist.

Robert Lefkowitz: You have to have a huge tolerance for frustration and failure, which I do not innately have. Just ask my wife. I have no patience with failure. So how I survived it all, I don't really know.

How did you go about proving the existence of this receptor, and why is it so important in physiology?


Robert Lefkowitz: Receptors are molecules, we now know, on cells, with which hormones and drugs interact to begin their biological actions. To give you a specific example, consider adrenaline, also known as epinephrine. Let's say we have a patient with asthma and their airways are constricted. They can't breathe. We give them adrenaline and the airways relax because of the smooth muscle in their airways relaxes when the adrenaline works on it. How does the adrenaline know to work on that, and to stimulate the heart, rather than to work on your nose or your retina or something like that? Well, the answer is, and what seemed obvious to me, is there must be molecules on the cells that the adrenaline would bind to, much like a key interacts with a lock, where the key would be the adrenaline, but it could be any hormone by extension. And this mystical receptor I was looking for would be like a lock on the cell, and it would fit in, and the adrenaline would then do something to that lock, open it, and things would happen in the cell. That was the idea. So how to prove this? Well, at first, there was no way to even study it.

[ Key to Success ] Vision



The first thing we had to do was find some way to study these things. So I used -- again, it's a relatively simple idea. The idea is simple. In practice, it's very difficult. Which was to take molecules that I had reason to believe could interact with this receptor, like beta blockers, which had just been developed, and radioactively label them and use that radioactivity as a way of following the binding, the sticking interaction of that molecule to the receptor. And then with this radioactive probe stuck to it, now I could try to isolate it, following the radioactivity as a marker. And over a period of years, we got that to work for several receptors. Then we dissolved the cell membranes, plucked the receptors out. The receptors are very rare. So for example, for every two- or 300,000 protein molecules in the cell membrane, one of them would be this receptor. So the next job was to isolate this receptor, to get rid of the 199,999 that aren't the receptor and just get receptor. Okay, yeah, exactly. Extraordinarily difficult work, but we succeeded in doing that and showed that this one isolated molecule could do the two things that a receptor would do. First, it could bind or interact with drugs that were known to interact with that receptor. And in a way that would be predicted by the physiology. That is, if I had three things that could work on that receptor and we knew from physiological experiments that, say, drug one was better than drug two was better than drug three, then my protein should bind drug one better than two better than three. Only there weren't just three, there were dozens. So we could test that very rigorously. So that was the first criterion. The second criterion is that binding of a drug like adrenaline to this receptor, that that receptor could now do something -- stimulate the cell to do stuff. Now that was even tougher. So we came up with methods where we found cells that didn't have adrenaline receptors. How did we know they didn't have them? Because they couldn't bind these radioactive probes. But they did have the response machinery, okay. Because they had receptors for other things. And then we took these receptors and by techniques that we worked out, we were able to plug them back into the outside of these cells. And now the cells responded to adrenaline. So now I knew that this pure receptor molecule that I had could do both things that you'd expect a receptor to do, interact with something like adrenaline and do something to the cell.

[ Key to Success ] Perseverance



The next series of discoveries, after we had purified this receptor, was to do what's called "cloning the gene." Okay. That allows us, because of the work on DNA, which we'd been hearing a bit about at this meeting. And of course, by the '80s this was the era when recombinant DNA was picking up steam. All based on Jim Watson and (Francis) Crick's original discovery -- from, I guess, the '60s -- about DNA. So we were able to ultimately clone the gene for this one particular receptor and thereby deduce its complete amino acid sequence. And when we did that, we made a remarkable discovery. And the discovery was it looked just like another molecule. And that molecule is called rhodopsin, and rhodopsin is the molecule in the eye that allows you to see. And when we saw that -- this was in 1986 -- we realized immediately that, you know, I'll bet there's a huge family of receptors that all look like this. In a sense, rhodopsin is a light receptor, and it looked just like what's called a beta adrenergic receptor, which was one of these adrenaline receptors that I was studying. I said, "If these two, so disparate in their function, look alike, what about receptors for histamine, serotonin, dopamine? You name it. I bet they all look alike." So using the techniques that we had developed, very quickly over the next few years, we were able to get the genes for about 10 or 12 of these different receptors. And they all looked the same. I mean, they had distinct sequences, very close though. I mean, you might have 60 to 70 percent of all the amino acids would be the same. But enough were different that they did different things.

[ Key to Success ] Preparation



Meanwhile, all these technologies were being adapted by the drug companies. So the pace of drug discovery increased dramatically, because they went from testing drugs in animals to being able to use the isolated genes that we had and they could now find. And then it turned out that there were about 1,000 different members of this family, not just rhodopsin and the beta receptor and the others I mentioned, but the smell receptors. It turned out the way we smell is by substances binding to receptors in our nose that look just like these. And then it turned out the way we taste bitter and sweet looks like that. So now, you had three of the five senses working that way. Well, it turns out this family of receptors regulate virtually all processes in animals. And today about half of all the drugs used clinically around the world target one or another of these receptors. I mean, things like beta blockers or antihistamines or opiates or you name it. So the work in the end had an impact far beyond what I could have imagined in 1970, when I was just beginning to do this.


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