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Published On February 18, 2021

INTERVIEW

One Thing Leads to the Next

Robert Lefkowitz is best known for revealing the mechanism behind hundreds of drugs in use today. But he thinks of himself as a storyteller first and has a new book out to make his case.

What guides a scientist’s trajectory, from the first twinge of a research interest to the apex of a career? Occasionally it’s a sense of story, says Robert J. Lefkowitz, a professor of biochemistry and chemistry at the Duke University Medical Center. For Lefkowitz, that story began in the 1970s with an interest in the behavior of hormones and led, in 2012, to the Nobel Prize in Chemistry.

Lefkowitz has recently channeled his memories into a book, A Funny Thing Happened on the Way to Stockholm. In it he explores his work on the study of G-protein-coupled receptors, which are found on hormones in the body and responsible for how these hormones function. He’s grateful, he says, that the story hasn’t stopped yet; these receptors are targets of hundreds of drugs used today, and part of his work continues to refine how they may be targeted. The rest of his work involved helping young researchers find the “story” their careers will follow.

Q: You’ve said that your career has been driven by a sense of story. What do you mean by that?

A: There aren’t many research careers like mine, and by that I mean my work has had a very long and connected arc. You could take any experiment going on in my laboratory and trace it back to an experiment going on yesterday or the day before, and then trace that experiment back, and so on, back to the very beginning of my research. So I’ve essentially been following one thread—writing one story, you could say—for about 50 years.

I first became interested in the interactions between hormones and the drugs that targeted them, including adrenaline and beta blockers or insulin and glucagon. I was a practicing cardiologist, and we know that adrenaline—a hormone that can do a lot of damage to the heart—can be subdued by beta-blockers. It suggested to me that there must be very specific sites on cells to which these drugs and hormones bind with great specificity, fitting like a key into a lock.

So, I set out to demonstrate that in fact such locks and keys actually existed on cells. Little did I know it would be a decades-long project.

Q: Why was that work important?

A: Well, together with my students and fellows, we proved that these structures, known as receptors, existed in the plasma membrane of cells and each specific type activates a specific protein in the cell that leads to various downstream effects. So in the case of adrenaline, the receptor we identified makes the heart beat stronger and faster.

Then we made the shocking discovery that the receptor we were working on looked similar to rhodopsin, a receptor in the retina. This receptor interacts with light and allows us to see. Then we found other receptors that allow us to taste and smell. And it turned out that the structure of the receptor we identified turned out to be a very general structure for a huge family of receptors known as G-protein-coupled receptors. There are currently about 1000 known types of these.

It turns out that about a third of all FDA-approved drugs—about 700 —work because they target this family of receptors. So the impact of our work on clinical medicine has been tremendous.

We never intended to cure a disease or create a drug. But it was a perfect example of a basic research discovery that led to important clinical developments.

Q: You’ve spoken about the importance of mentors—those who can help younger researchers nurture their research “stories.”

A: Yes, the importance of mentoring in science—and I suspect most careers—can’t be overestimated. I advise your researchers to look at someone’s track record. The best predictor of future success is past success. But maybe more importantly, find someone whose work you find interesting. It doesn’t have to be the type of work you want to do forever, but it should intrigue you.

Q: For the researchers you mentor yourself, what advice do you give?

A: The most important lessons for a young scientist is to learn how to deal with failure. In my first year or so of research, everything I tried failed. I was failing every day. I was getting really upset. I relayed this to a senior scientist who told me something that really stuck with me: for an average scientist, experiments work about 1 percent of the time. For a really successful scientist that success rate might reach 2 percent.

He was telling me that most of what we do in science fails. And it’s true. If you want to do important things and make big discoveries, you have to be willing to challenge yourself—and eat a lot of failure.

Other than that, be curious. Even though there is the drive to make a difference in clinical medicine, don’t underestimate the power of raw, unvarnished curiosity.

Q: Is your own research ongoing?

A: Oh yes. We now have technology, through cryo-electron microscopy and other techniques to actually see the atoms in these receptors. We can watch how their structures and shapes change when they interact with different types of drugs. That can lead to better targeting the function we want.

For example, opioids interact with a specific G-protein-coupled receptor to relieve pain. But stimulating that receptor can also trigger constipation or suppress breathing. Our research shows that it might be possible to emphasize one or more of these responses—so when you’re creating a drug, you can pick which of these responses you want to trigger.

I’m excited for the future of my work, and excited to share my journey in the book that just came out. They’re both good “stories,” and thank goodness, neither is over yet.