On the record with this year's Rosenstiel Award winner

Harvard professor Stephen C. Harrison talks about his groundbreaking research on protein structure, his work on the HIV virus and his passion for science.

On March 25, Harvard structural biologist Stephen C. Harrison will receive the Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research. He will deliver a public lecture on his accomplishments followed by a ceremony in his honor.

Harrison, the Giovanni Armenise­ Harvard Professor of Basic Medical Sciences, was recognized for his fundamental and far-­reaching studies of protein structure using X-­ray crystallography.

His work has ranged from the elucidation of the structure of viruses to understanding the recognition of DNA sequences by transcription factors, to the regulation of protein kinases implicated in cancer.

Harrison, who is also an investigator of the Howard Hughes Medical Institute, is the 48th Rosenstiel recipient. The award has a distinguished record of identifying and honoring pioneering scientists who subsequently have been honored with the Lasker and Nobel Prizes.

BrandeisNOW asked Harrison about his career and research.

BNOW: What drew you to a career in the sciences?

Harrison: Both my parents were scientists. If you grow up with evidence­-based analysis of everything around you — the traffic jam you're in or the way that an egg cooks when it boils — then science becomes the natural language you use to interpret your own personal experiences and observations.

BNOW: Early on you became fascinated by proteins.

Harrison: I can spend hours staring at a protein's structure and looking at its details. I think part of my fascination is an underlying appreciation of the complexity but also the orderliness and neatness of the protein molecule. Those properties are ultimately what genes and genetic mutations determine — in other words, how human beings evolve.

BNOW: In the late 1970s, you and several colleagues used X­-ray crystallography to produce the first-­ever three-­dimensional images of a virus, a landmark breakthrough that greatly enhanced our understanding of viral structure. How did this come about?

Harrison: After college, I spent a year at the MRC Laboratory of Molecular Biology in Cambridge [England]. We all went to hear a lecture by [University of Oxford structural biologist] David Phillips, in which he described the structure of the enzyme lysozyme.

That was a watershed moment for me because I rather naively thought, "Well, now we understand all that we need to understand about proteins. We'd better go and work on big things like viruses."

A few people said I was silly — it was going to take 30 years to solve virus structure. But I figured that there wasn't anything about the laws of physics that said you couldn't do it and therefore just plunged ahead.

Of course, at the time, we could only work on a very simple virus like the tomato bushy stunt virus. But beginning to understand its structure helped me and others realize that ultimately many fundamental questions in virology and indeed in cell biology could be answered by understanding structures of viruses and other large macromolecular complexes.

A quick illustration: How a virus gets into a cell is a critical question for infectious disease. When we make antibodies to a virus, antibodies almost always bind to the virus particle and block this first step.

Understanding how the virus interacts with whatever it binds to on the surface of the cell, how an antibody prevents that, and how we can mimic that blockade with antiviral drugs — all those are reasons for understanding virus structure.

BNOW: In the 1990s, you turned your attention to the HIV virus.

Harrison: Don Wiley and I were experts on the structure of viruses and proteins, and we felt we were obligated to give at least some of our attention to the HIV problem. The whole idea was to make headway but without being competitive about it — simply trying to contribute to more knowledge on that subject.

I worked on the cellular receptor for HIV-1, called CD4. A little later I worked on the enzyme reverse transcriptase, which was the target of the earliest HIV drugs.

With the reverse transcriptase, I wanted to understand the enzyme mechanism and how the protease inhibitors that had been developed work. And equally important, why do certain HIV mutations confer resistance to those inhibitors?

The bit of it that I was most proud of was being able to actually capture a catalytic complex and therefore understand in more detail how the enzyme wraps around its substrate and how some of the resistance mutations block that wrapping.

BNOW: How do you decide when it's time to shift your focus to a new subject?

Harrison:  When I have made it possible for others to do what I have been doing, I begin to think about moving on. I like trying to do things that are hard enough that others avoid them.

Choosing what to do then comes from extended thinking about the important questions and what particular experimental system you can use to tackle those questions. And it's important to recognize when those questions are answerable because it's not very useful to work on a problem that can't be solved for another 30 years.

It's also not useful to tackle questions that several other people are already busy answering and are going to figure out before you do. You've got to find something that's adventurous enough, perhaps even crazy enough, that other people aren't already working on it.

BNOW: Tell us about some of the current research you're doing on kinetochores, which are the protein complexes assembled on the centromeric region of DNA.

Harrison: What we're looking at is the three-­dimensional structure of large subcomponents of kinetochores. And we're getting close to being able to put together a picture of the entire linkage between the chromosome and the microtubules of the mitotic spindles.

By knowing the three­-dimensional structures of three parts of it, we can already draw a very reasonable, complete picture of what the whole thing is likely to look like.

Now, that just raises the key questions, namely, how do the various signaling inputs and outputs trigger assembly at the right time? And how do they tell the cell when the kinetochore is properly assembled and the chromosome is indeed attached to a microtubule?

But one's got to begin with the three­-dimensional architecture of the whole thing and also the three­-dimensional architecture of it at different stages of cell division — because there are some important changes as cell division proceeds.

The field has suddenly become a bit more crowded than it was when I started, so one now has to pick and choose questions to answer because other people are busy answering several of the questions that were there for the picking a while ago.

BNOW: What advice do you have for aspiring scientists?

Harrison: I tend to think of science as a calling (or perhaps a compulsion), rather than just a profession. It’s a passion for understanding what's "out there" in terms that can reconcile my experiences and observations with yours, and hence lead both of us forward to better understanding — the opposite of an inward-looking artistic experience and very much the opposite of an introspection-based opinion.

So you'd better have that in you or doing science won't be much fun. It is also important to find a scientific territory that you really enjoy, so that a long series of nights in the laboratory or an intense period of developing an idea or a theory is ultimately fun as well as productive — or perhaps fun even when it proves unproductive.