HHMI: WHAT SOLD YOU ON CRYSTALLOGRAPHY IN THE FIRST PLACE?

DR: As a graduate student, I was excited by what I saw in [current HHMI investigator] Stephen C. Harrison’s lab—the power of x-ray crystallography to provide structural insights into important biological questions. My thesis adviser, William Lipscomb, used crystallographic methods to address systems ranging from small, inorganic molecules to the mechanisms of enzymes that I studied. At that time, it was just becoming easier to use x-ray crystallography to study macromolecules, but it was still not trivial—a lot of practical problems needed to be solved each day. Many of these issues have since become routine, so now the primary focus in our lab is on preparative biochemistry—how to generate and trap the samples we need for the study of molecular assemblies, the large groups of molecules that carry out the chemical processes of life. If we want to understand the structure of these molecular machines, we need a large supply of proteins. And that can be a big obstacle.

Things are starting to change, however. New crystallization techniques, such as the microfluidics methods now being developed by Stephen R. Quake of Stanford [recently tapped to be an HHMI investigator], and others, require only one-hundredth of the material needed with older methods. In fact, every aspect of crystallography is changing rapidly.

HHMI: WHAT WOULD YOU SAY IS THE BIGGEST CHANGE?

DR: At the present time, automation. Beam lines, for instance, are going to almost-complete automation. And software programs developed by Stanford’s Axel T. Brunger [an HHMI investigator] and others are making it easier to decipher structures from the x-ray data. The technology is advancing really fast, to the extent that trying to capitalize on it is a real challenge. Cloning, protein purification, and crystallization are all becoming automated, which ultimately will save us both time and effort.

HHMI: WHERE IS ALL THIS LEADING US?

DR: We may be embarking on another industrial revolution—this one based on molecular-scale artificial devices and powered through the types of energetic mechanisms utilized by biological systems. That would be very exciting.

Photo: ©Paul Fetters

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