AT A GLANCE
Name: Stephen K. Burley
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
This is part two of a two-part interview. The first part was published in last week’s edition of ProteoMonitor.
QWhy did you decide to enter the private sector?
AIt’s an interesting story. I was put on the scientific advisory board of SGX at its inception in the summer of 1999, and while I was advising SGX, I was also involved in the founding of a bioinformatics company in San Francisco called Prospect Genomics. If you looked at SGX and Prospect Genomics at that time you would have seen that the two companies were entirely complementary. By the end of January of 2001 we had concluded a merger agreement which built a much stronger company. The opportunity for me became very interesting once the two companies had merged.
The thing that most interested me intellectually was the molecular recognition problem, and the way I wanted to pursue that was to work on the problem of identifying and perfecting small molecule inhibitors of medically relevant targets — proteins. I concluded that the best place to do that was in the private sector, and the best company in which to do it was SGX.
QIs it much different than working in academia?
AThe management challenges are more substantial — there are 135 employees here at the company. The science is essentially the same, and the management challenges are eased by the fact that there are some very talented middle managers already on board at SGX — people with a lot of experience in the pharmaceutical industry, who are very good at running teams of people.
The issue is largely a strategic one: to establish what we’re going to be working on, what the general experimental philosophy is going to be, making sure we have the right alliances in place, making sure we stay ahead of the competition.
QWhat about the competition?
AIf you think about this sector, there are three companies within this sector that are reasonably mature. Those are Astex in the UK, and Syrrx and SGX, both based in San Diego. Each company has identified a slightly different technological solution to a common set of problems. The primary distinguishing features between us and Syrrx would be our commitment to a modular automation strategy as opposed to the emphasis at Syrrx as I understand it, which is more on a single technological solution, with a lot of in-house engineering. We’re taking the position that we would rather integrate components that are already commercially available and already very well supported.
QSo the module approach does more than just come up with different conditions?
AThe number of combinations you have to try doesn’t just include the solution conditions that are used for the purification. Our experience has been that there’s a lot of benefit in taking a protein-engineering approach where we would change the N- or C-terminus of the protein, or make a point mutant in the protein — something that would make it more soluble, more likely to crystallize. We pioneered a lot of these approaches using mass spectrometry, and combining that with proteolysis to map domains within larger protein structures. You know, a lot of eukaryotic proteins actually look like beads on a string — well-defined domains separated by extended polypeptide chains. We frequently find that the extended polypeptide chain segments actually interfere with crystallization, and you can identify those because they’re susceptible to protease digestion. Then you can go back and try to express and purify just the domain itself. The biochemistry tends to be supported by the domain.
QHow will SGX integrate this into drug discovery?
AWe’re trying to combine high-throughput protein crystallography with medicinal chemistry. The big difference between this business strategy and the history of attempts to do rational drug design is that our data measurement capabilities, our crystallization capabilities, are such that we can now keep up with the typical medicinal chemistry cycle in a pharmaceutical company. The reason that structural biology has not been as substantial a contributor to drug discovery in the past has been the speed. It’s just been too slow historically.