A master practitioner initiates young scientists into the arcane craft of crystallography

A crystal is a thing of beauty, but to a protein scientist it is that and much more. The crystal form of a material embodies its essence—the unique framework of atoms and chemical bonds that determines the molecule's function and how it interacts with other molecules.

But growing the crystal from a protein involves an uncommon blend of science, art, and tenacity—qualities that HHMI investigator and protein biochemist David Eisenberg strives to convey in his course on x-ray crystallography at the University of California, Los Angeles.

“At any of several steps, you can get stuck for months at a time,” says Howard Chang, a student in the course. “All you can do is continue to screen the hundreds or thousands of different conditions that influence crystallization in hopes that one will work. Even under optimum conditions, a crystal can take years to grow.”

But the payoff is huge, Chang adds, both in scientific terms and as a kind of pure wonder. “Seeing the molecules in the greatest detail possible, it's beautiful how these intricate atomic-level `machines' evolved by nature operate.”

Atoms are too small to see with visible-light microscopes. Instead, scientists infer the positions and orientations of atoms indirectly by using x-ray diffraction. They fire x-ray beams into the crystal, which are scattered in different directions by the atoms and captured on a detector surface. An experienced researcher can then devise a structural model of the protein from the resulting pattern. Knowing the structure gives insights, for example, into how amyloid proteins cause neurological disease (see “Chasing Amyloid”). And structure-based drugs, such as the protease inhibitors created to treat HIV/AIDS, are becoming more common.

Eisenberg, whose career has witnessed—and contributed to—many milestones of protein crystallography over the last three decades, puts a great deal of thought, personal experience, and enthusiasm into his course, which is taken by about 20 researchers—mostly graduate students—each year.

“We feel that x-ray crystallography is an extremely important tool for young scientists to acquire—it is no longer the province of specialists,” says Eisenberg, who is director of UCLA's Institute for Genomics & Proteomics. The multi-instructor course includes the history of x-ray diffraction techniques, their theoretical underpinnings, hands-on practice in crystallizing a protein, “shooting” it with x-rays, and interpreting the data.

Illustration: Drew Beckmeyer

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