AT A GLANCE
Name: Stephen K. Burley
Age: 44
Position: Chief Scientific Officer, Structural Genomix
Prior Experience: Determined the crystal structure of the TATA binding protein, Professor of Molecular Biophysics, Rockefeller University, PI for New York Structural Genomics Research Consortium
QHow did you get involved in high-throughput protein crystallography?
AI was originally trained in physics as an undergraduate, and in my final year I made the judgment that physics applied to biology would be an interesting area of research. I looked around for how best to apply the sort of skills that a physicist has for biology and crystallography was the thing that jumped out at me. That was 1980. I did an honors thesis project that involved structure determination.
QWas there more opportunity in biology at the time?
ANot so much a question of opportunity, but perhaps a recognition that some of the interesting problems in physics had been resolved, and that there was a goldmine of interesting research programs to be pursued in biology. And I must say at the time I wasn’t thinking in terms of medical school, but after I did my D. Phil. at Oxford in structural biology I realized that I needed to learn a lot more biology to maximize my impact in the field. So I went to medical school at Harvard in 1983 and did four years of medical school. Then I went on and did my internship and residency in internal medicine at the Brigham [and Women’s Hospital] in Boston. It was a very broad training in biology ultimately, and at the end of that I concluded, although I enjoyed medicine very much, that again, thinking about impact, a combination of clinical medicine and science was not going to be as interesting or as fun as just focusing on medically relevant problems in structural biology. So I decided just do science full-time at that stage.
QSo you went back to structural biology at that time?
AActually the whole time I was a medical student, an intern, and a resident, I was working as a postdoc in a lab, first at MIT with Greg Petsko and subsequently with Bill Lipscomb at Harvard, in both cases in the chemistry departments of those institutions. At the end of 1990 I moved to Rockefeller, where I became an assistant professor. I worked my way up through the ranks, and left there [this fall] after more than 11 years on the faculty.
QWhat would you say has been your most important contribution to structural biology?
AMy work on the TATA box-binding protein. That’s a protein required for expression of every gene in every cell in our bodies. It’s an essential regulator of gene expression even in archaebacteria. It’s a very primitive, essential piece of the transcription machinery. I would say that’s the project I got the most notoriety for.
QWhat about contributing to making protein structure determination faster?
AMany, many people contributed to this area and I would rate my contribution as being less important than those of people like Wayne Hendrickson who established the multi-wavelength phasing technique that sped up structure determination. We’ve done a number of things in terms of speeding up crystallization and we actually started taking a genomics approach to the problem of understanding the TATA box-binding protein in 1991. We worked on genes from yeast, from plants, from humans, and from the fly. It was that protein-family-based approach that was critical for our success in that area, and I think that was an early signpost that the genomics approach to protein structure determination was going to be very efficient in the long run.
QBy finding a protein that’s easier to crystallize?
AYes. We bought a number of lottery tickets. By working on essentially the same protein from different organisms you become quite expert at working with the protein, and after we determined the first structure, it was relatively easy for us to go back and determine the structure of the human [form of the protein]. The first [TATA box-binding protein] we got was the plant protein, and armed with the knowledge that we got from determining the structure of the plant protein, we went back and were able to solve the structure of the human protein very rapidly. That’s one of the themes of structural genomics: you can get information about human biology by studying other organisms.
QHow did you get involved with the New York Structural Genomics Research Consortium?
AIn 1998, there was a meeting held at the Argonne National Lab to talk about trying to evaluate the feasibility of high-throughput protein crystallization, knowing that the Advanced Photon Source was going to come online shortly. There was a very clear consensus among the participants that the time was right, and that it was important to get moving and start trying to do proof-of-concept experiments. We began in collaboration with a number of crystallographers at Brookhaven National Lab and Albert Einstein Medical College to work on a cooperative attempt to show that it could be done. That collaboration broadened out to include people at Weill Medical College and Mt. Sinai. The grant was awarded in September of 2001.
QWhat was your role?
AI was the organizer. The grant was a collective effort but in the end there has to be one person who accepts responsibility for the management of the grant. That’s what I did. But it would have been impossible without the cooperation of everyone involved.
QWhat’s happening to the consortium now?
AThe plan is to transfer a portion of the New York Structural Genomics project to [SGX] to take advantage of the infrastructure that’s available here. I will be overseeing that. This is a complicated process that involves the Rockefeller formally relinquishing the grant, which they have done, and then the NIH formally evaluating a new proposal from SGX to receive the grant, and then the NIH actually approving that. We’re at the stage where we’re working on the approvals process. At the moment the grant is still resident at Rockefeller University and I have daily meetings with the team back in New York to administer the grant. I will be flying to New York City once a month to conduct our monthly meeting with the participants from the other institutions. So I’m still very much involved, just by remote.
QWhat does SGX get out of it?
AThe company will receive money from NIH for providing access to the infrastructure. It allows the company to continue building the technology platform here at SGX for high-throughput protein expression, purification, crystallization, and structure determination. We view it as a public-private partnership. The company is of course committed to honoring all of the requirements for public access to the information produced with NIH money. All of the structures that are produced with NIH money are going to be put into the public domain, and the company will not enjoy any special intellectual property access.