By Dan Hogan, NIGMS
Dr. Jeremy M. Berg became director of the National Institute of General Medical Sciences (NIGMS) in November 2003, after serving most recently as director of the Institute for Basic Biomedical Sciences and professor and director of the Department of Biophysics and Biophysical Chemistry at The Johns Hopkins University School of Medicine in Baltimore. The following excerpts have been adapted from an interview with him after his first month on the job. (A shorter version appears in the Jan. 6, 2004 issue of the NIH Record.)
NIGMS director Dr. Jeremy M. Berg holds a wire model of a nucleosome core particle, one of many models he has made since becoming fascinated with molecular structures at a young age.
(Photo by Alisa Machalek, NIGMS)
What were your motivations for accepting the offer to become NIGMS director at this point in your career?
On a personal level, it seemed like a whole new set of challenges. Every day there's something new to learn and think about. That's what I hoped would be true, and it's surpassed my expectations.
Second, I'm a strong believer in the importance of basic research. NIGMS has done more than any other organization to foster basic research in biomedical fields. Having a chance to participate in decisions about how to make the Institute as effective as possible and figuring out which directions are exciting is what I thought would be fun. And it is.
And the third reason is public service. I feel that if people benefit from the system, they have to give back. There are some significant challenges, though. There are so many things that could be done, you have to pick carefully what you decide to do. And you have to balance the long view of basic research that's relatively untargeted—that is, figuring out fundamental mechanisms of biological processes—with more directed efforts where you know what you want to know.
In addition to serving as director of NIGMS, you'll be continuing your own research here at NIH. Tell us about this part of your work.
My lab will be within the Laboratory of Molecular Biology in the National Institute of Diabetes and Digestive and Kidney Diseases. Both this lab and NIDDK's Laboratory of Chemical Physics have had a strong basic science bent over their entire existence. It seemed like the natural place, and I'm delighted that they were pleased to have me on board.
In terms of research areas, the overarching theme of my research is molecular recognition—that is, how do molecules recognize specific binding partners, where does this specificity come from on a biophysical level, and can you understand those things well enough that you can predict what binds to what or design things for particular targets?
For me, this started off with zinc finger proteins. My training is as an inorganic chemist. But I decided as a post-doc to change direction completely and work on DNA binding proteins. I was trying to figure out how to combine inorganic chemistry and DNA binding proteins at just about the right moment, to within a week of when zinc-containing DNA binding proteins were discovered. And I thought, "Cool." That was in 1985, when that paper got things going.
I was a post-doc at Hopkins working on lambda repressor, a DNA-binding protein, bound to DNA, and doing structural biology. I had a position in the chemistry department at Hopkins and I was trying to decide whether I was going to go back to inorganic chemistry, where I actually had significant amounts of training, or stay in the DNA binding protein area, which is what I had been working on for a year. At that point, it was a field that was just beginning to open up and was incredibly exciting. But I didn't feel particularly competent. So when this paper appeared about zinc-containing DNA binding proteins, it took 10 picoseconds to decide this was the perfect combination.
The other nice thing was that the protein I was studying was from Xenopus—from frogs—which seemed to me to be pretty obscure. So I thought I would have this whole area to myself for a while. And it turned out that these zinc finger motifs are the most abundant motifs encoded in the human genome. There are 700 or 800 zinc finger genes, and literally thousands of zinc finger domains, in the human genome and other eukaryotic genomes. So it's been the tip of a very big iceberg, which has been stimulating in all sorts of ways.
NIH director Dr. Elias Zerhouni recently unveiled the NIH Roadmap for Medical Research. How do you see NIGMS' role in the Roadmap?
The Roadmap is an attempt to find areas that cut across all of NIH and aren't disease-specific, but where techniques or technologies or other sorts of infrastructure are needed to address problems in a broad sense. In a lot of ways, the Roadmap overlaps substantially with the NIGMS mission of supporting fundamental biological processes that are not specific to a particular disease.
NIGMS has clearly been ahead of the curve in several Roadmap areas. For example, NIGMS has been doing more and more interdisciplinary training programs—molecular biophysics, the chemistry-biology interface, and so on. Also, the Institute has supported interdisciplinary research teams—through its "glue grants," for example—that are right along the lines of what Dr. Zerhouni was thinking about in the Roadmap.
I think the Roadmap initiatives are very exciting. The science will be good. It will help the image of NIH, in terms of making people realize how much already goes on between institutes. But it will also help the institutes work together better than they ever have.
In what directions would you like to steer NIGMS over the next 5 to 10 years? Are there any research areas in particular that need more support?
A lot of things in the Roadmap or pre-existing programs at NIGMS are pointed in the right direction. But from the broadest perspective, I think the key—although it's getting to be an overused term today—is systems biology. We spent the last few decades effectively looking at all the little pieces that make up biology, from identifying 35,000 or so genes to trying to determine 3-D structures of as many proteins as we can.
But biology takes place in a lot of interacting components—proteins bind to DNA, proteins form simple or complicated complexes where the function is really not the sum of the parts but is much bigger. By working both directions—from individual molecules to complexes to macromolecular machines to organelles, on up, as well as from organisms to cells to structures within cells, organelles, and so on—you can start seeing individual molecules inside cells doing things.
Everything is ripe to meet in the middle. It's sort of like the transcontinental railroad, where the two directions are going to start meeting pretty soon. And you have to make sure that the necessary technologies are being fostered, and that the human resources—the people—are being trained well enough to understand how things work.
Do you think there's a culture shock for the quantitative and qualitative disciplines to come together?
Oh yes, there are real cultural issues. They're not at all insurmountable, but they're not trivial either. There's a molecular biophysics training program at Hopkins. In its first few years, we got a lot of students who came from physics backgrounds, for example. And they were entirely convinced that there were master equations for biology that we weren't telling them about. They were very used to having Maxwell's equations or the Schrödinger equation, where you could always sit down and from first principles figure how something had to work. And it took us a long time to realize that as part of the training, we had to hit them up front and say biological systems mostly evolved by reusing pre-existing parts and re-tasking them for new functions. Even though a lot of the solutions are incredibly elegant, they're not optimized in any sense. And you can't derive those solutions from first principles. You have to know what the building blocks are. And there is a lot of factual information that you need to know that you can't figure out from scratch.
And the other direction is equally important—that is, biologists have to realize that the question is not just "Does molecule A bind to molecule B?" but "How tightly does molecule A bind to molecule B?" and "Do kinetics of the processes matter, or is it just thermodynamics?"—all the sorts of things that chemists and physicists like to think about.
NIGMS Director Dr. Jeremy M. Berg uses wire models he constructed to show how a zinc finger protein fits into the major groove of double-helical DNA.
(Photo by Alisa Machalek, NIGMS)
How did you end up where you are today, and who were the people who were the most influential in guiding you along the way?
Certainly my parents were very influential. My father [Paul Berg] was a mathematician and a math professor at Stanford, and my mother [Judy Nadell] was an hematologist. I grew up literally on the Stanford campus. And it wasn't until some time in high school that I realized the question "What does your father do?" did not mean "In what field is your father's doctorate?" So academics was an easy direction to go for me. Faculty kids tend to go in sort of one of two directions: they either follow approximately in the academic direction of their parents, or they run the other way as fast as they can. [laughs]
I always liked three-dimensional shapes. For my 12 th birthday, my dad gave me this book by Linus Pauling called The Architecture of Molecules, which is very simple—nice pictures with one- or two-paragraph descriptions. So I got very interested in chemistry because of this. Well, the amazing thing about this book is that it's really intended for a very broad audience. When I read it when I was 12, I understood 10 percent of it, but it was enough to get me excited. I still re-read it every couple of years, and I keep learning something new.
Then I got interested in chemistry and read Watson's The Double Helix when I was in high school, and I learned a little bit about crystallography. You know, one advantage about being a faculty brat is that you're not particularly intimidated by professors. So when I was in my first week as a freshmen, I went over to the chemistry department and found there was this young new faculty member who was setting up a crystallography lab. And I said, "If you're interested in an undergraduate research student, here's my number, give me a call." A few weeks later, he did, and I started working. His name is Keith Hodgson, and he's now the director of the synchrotron radiation lab at Stanford.
So I started working in a collaboration between his lab and Lubert Stryer's lab, working on the structure of a peptide antibiotic which forms ion channels called gramicidin A. And my first job was tracing electron density maps from computer printouts on to Plexiglas sheets using a Sharpie. Before plotters and printers were available, that was the state of the art. But it was great fun. I got very involved in undergraduate research. And fortunately for me, Keith Hodgson's lab went in a fairly different direction shortly after I got there. There was all this wonderful crystallography equipment, and no one who was particularly interested in using it. So I became the de facto crystallographer, and got to participate in all sorts of projects. I published about 15 papers as an undergraduate. It was just like being a kid in a candy store.
Then I got interested in inorganic chemistry, because I was involved in determining structures of interesting inorganic molecules. I went to Harvard and ended up working with Richard Holm, who is a synthetic inorganic chemist working on bio-inorganic chemistry but with a capital I: the things he's doing are trying to synthesize compounds that look like metal centers found in biological systems. So, I actually never worked on any proteins or organisms but was making compounds and trying to compare them structurally and spectroscopically and so on.
After a few years in graduate school, I realized that I had started off interested in actually looking at protein structures and had gotten side-tracked. So I decided to go back and redirect my career more in that direction.
Meanwhile, I had gotten back together with my lab partner from quantitative analysis [Wendie Anderson], who was in the M.D.-Ph.D. program at Hopkins. We decided to get married. And, after having various plans to do a post-doc, I went to Hopkins to work in Carl Pabo's lab in the biophysics department working on lambda repressor, a DNA-binding protein, bound to DNA. I was starting to think about what his big interest was, which was protein design—that is, can we really get enough elements to design proteins that have particular properties? So, I had a wonderful solution both to career and to personal life.
Then I had a faculty position in the chemistry department at Hopkins. I actually had that lined up. Once Wendie and I got back together, I had applied for the chemistry department position, and then decided I definitely wanted to do a post-doc. So, I withdrew my application. However, they had done their search and hadn't found anybody they were happy with or could attract. So they said, "We understand you want to do a post-doc, but do you want to come interview anyway?" So, I had a faculty position with a commitment before I started my post-doc, which was scientific heaven. Being a post-doc with a job already lined up is as good as it gets; so you can do research and worry about the science and not worry about whether you're publishing enough or whether you have to get a job ready to go.
Then zinc fingers came along, and the main issue then was I was getting ready to write my first NIH proposal. Zinc fingers seemed like a perfect way to combine what I was doing in Carl's lab and my background in inorganic chemistry. So, I wrote my first NIH proposal back in the mid-1980s, and got the best priority score I ever received.
And was that with NIGMS?
Absolutely, the only NIH institute that's ever funded my research.
That got me started, and a lot of things progressed. When zinc fingers took off, we were in on the ground floor, so things had gone well. After I'd been in the chemistry department for about 4 years, I got a phone call asking if I wanted to be considered for the directorship of the biophysics department in the medical school where I had been a post-doc. And I was stunned. I think I literally said something like, "Why would I want to ruin my career at such an early stage?" But it became clear that it was a great opportunity, and it was, and I had a great time during my 13 years there.
A year or so ago, I got a phone call from Michael Gottesman [NIH Deputy Director for Intramural Research], asking me if I wanted to be considered for the directorship of NIGMS. And I said, "Why would I want to ruin my career at this particular stage?" [laughs]
If you could write your own job review, how would you like it to read a year from now, or a decade from now?
I guess, "good listener, creative problem-solver." With NIGMS, it's not too different from how I felt when I was working on the fifth edition of Lubert Stryer's Biochemistry textbook. You know, it was so effective at what it does that I didn't want to be known as "the person who ruined Stryer's Biochemistry book." So, likewise, I don't want to be known as "the guy who ruined NIGMS." [ laughs]
I've been incredibly impressed with how wise the leadership of NIGMS has been in the past. And the fact that NIGMS is well positioned for the Roadmap initiatives is reflective of that. So, I'd also like my job performance review to read: "continued in the fine tradition of NIGMS leaders, from Ruth Kirschstein through Marvin Cassman to Judith Greenberg as acting director in the last couple of years."
Ten years from now, hopefully it would read something like: "charted new directions, integrating basic research and practical applications." To some extent, I think it's a case of "If I knew, I'd been working on it now." There are going to be discoveries that we can't anticipate that will give us ideas about what directions to go.