HHMI Investigators Reflect on 40 Years of Discovery Science

Palmiter and LefkowitzRobert Lefkowitz and Richard Palmiter at Duke University in Durham, North Carolina.

Discovery science unfolds over time, through exploration, experimentation, and rigorous debate. More than 40 years ago, Robert Lefkowitz, at Duke University, and Richard Palmiter, at the University of Washington School of Medicine, embarked on separate paths of scientific exploration as Howard Hughes Medical Institute investigators.

Lefkowitz and Palmiter have blazed trails of discovery, creating a greater understanding of the structure and function of living systems and encouraging the next generation of scientists to ask big questions.

As HHMI continues to move science forward, these two investigators share what they’ve learned along the way. Hear Lefkowitz and Palmiter discuss watershed moments in their research careers and how they approach mentorship in the lab.

TRANSCRIPT

On Discovery Science

R. Palmiter: When I joined Hughes, I was working on steroid hormone action and about 1979, I began to switch to molecular genetics and one wanted to understand the regulatory elements that allowed a gene to be controlled by environmental factors or developmental factors. Serendipitously, a veterinarian at the University of Pennsylvania by the name of Ralph Brinster, he was interested in injecting messenger RNAs into mouse eggs. I said, why don’t you inject genes instead of messenger RNA? Ralph Brinster is a developmental biologist, and he said, well, if this thing is expressed in mouse eggs, maybe it will continue to be expressed in an adult mouse. So suddenly we were developmental biologists instead of studying transcription.

These so-called transgenic mice opened up all kinds of possibilities for understanding how promoters work. So there were just hundreds of applications, once that occurred.

R. Lefkowitz: I vividly remember when you published that work, even though I was in a totally different field, because that was a true watershed: the first transgenic animals. It absolutely changed the way research was done. Everybody jumped on the bandwagon. It must have really helped your citation count, I’ll tell you.

One moment I will always remember was in 1986. I had chosen as my primary model the beta-adrenergic receptor, which is one of the receptors for adrenalin. After several very difficult years, we succeeded, in 1986, in cloning the cDNA for the beta-2 adrenergic receptor. Initially we thought that it had a completely unique structure, which didn’t surprise us because we said, hey, this is the first G protein-coupled receptor. I mean, we were expecting it wouldn’t look like anything! But then, to our amazement and delight, we found that our beta-adrenergic receptor bore a striking resemblance to a protein called rhodopsin, which is the molecule responsible for perceiving photons of light. So we immediately realized that there might be a larger family of such proteins. They shared not only amino-acid sequence similarities, but they both showed a very interesting architecture, which was that there were seven stretches of amino-acid residues, suggesting that the protein, in each case, spanned the plasma membrane seven times – sort of like a snake going this way through the plasma membrane.

R. Palmiter: Like the Loch Ness monster [laughs].

Palmiter and LefkowitzThe two investigators talked during a lunch break while at a conference held at Duke University.

R. Lefkowitz: The Loch Ness monster would be a very good analogy. And so we speculated in that first paper that there might be a much larger family of G protein-coupled receptors, all sharing this seven membrane-spanning domain architecture. Today we know there are about 1,000 different members of this family, and they’re by far the commonest target of drugs that are used. So that was kind of my watershed moment.

On Mentorship

R. Palmiter: I never thought of my job as a mentor, but I think I must have done a pretty good job. I work in the lab, just as much time in the lab as anybody, so I kind of know what’s going on. I’m not a micro-manager. If there’s a problem, pursue it as best you can, keep me informed, but you’re on your own. I think it creates independent thought. I’ve been lucky in having a lot of good people come to my lab.

R. Lefkowitz: I think there’s no one ideal way to be a mentor. I think each person has to be a mentor in a way that works with their own personality and their own personal style.

The mentoring relationship is basically an apprenticeship. And so I think one of the first characteristics – listening to Richard, he certainly exhibits it – of any good mentor is accessibility. You have to be there. What the experience, to me, is all about is that apprenticeship. They watch you, they talk to you. And in subtle ways they take on your values. I always like to tell people: if something is really important, you can’t look it up in a book or even in a paper. Of course, I’m exaggerating. But the really important things about being a successful scientist, you can’t look up.

Want to hear more? Listen to the full interview.

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