February 10, 2003 | Stuart Schreiber has a knack for getting scientists from different disciplines to work together. In 1997, Schreiber and cell biologist Tim Mitchison co-founded the Institute for Chemistry and Cell Biology (ICCB), based at the Harvard Medical School, an institute devoted to Schreiber's passion for chemical genetics and the related field of diversity-oriented chemistry.
Poles apart: Treating cells with monastrol replaces the normal bipolar spindle (A) with a rosette-like array of microtubules surrounded by a ring of chromosomes (B) stained blue.
Here, chemists are devising new ways to make libraries of the more natural-like compounds Schreiber is now so interested in, and biologists are designing better tests to reveal the effects of those compounds. "[Schreiber and Mitchison] are both trained in one area and reaching toward the other," says Rebecca Ward, director of research affairs at ICCB. "The fact that they have complementary visions is what makes the institute possible."
Bringing together chemistry and biology in academia wasn't any easier than in industry. "From the beginning, we had situations where the chemists thought the problem was solved, but the biologists didn't. There has been a lot of retooling," Ward says. For example, the traditional setup for combinatorial chemistry — using tiny 80-micron beads that hold a single compound — didn't leave any material to play with after the initial screening. The chemists had to increase the diameter of the beads to 500 microns. "We worked extremely hard to come up with a compromise that provided more compound, but still in small enough amounts that we could still get a lot of diversity," she says.
A priority at ICCB is to establish rules linking structure to biological effect by creating a vast compound database, and thus guide the development of the next generation of chemical libraries. "If [Schreiber] could wave a magic wand, my guess is he would want a small- molecule partner for every protein in the human proteome," Ward says. "He'd want a way to manipulate every protein and for those small molecules to be reasonably selective." Lacking such wizardry, Ward concedes they are probably "less than 1 percent of the way toward 100 percent coverage of the proteome."
ICCB researchers aren't constrained by the pharmaceutical properties of their compounds, so they tend to study many molecules that pharma companies avoid. However, as Ward points out, maybe the dogmas are wrong — perhaps ICCB will find completely new kinds of molecules that do make good drugs.
"One suspicion we have is that there is a certain self- fulfilling prophecy in the kinds of compounds that the pharmaceutical industry goes after," says Ward, who worked in HIV research at Genentech Inc. in the early 1990s. "They know the kinds of compounds that have produced the drugs of the past, and those are the kinds they go after." An early success story at ICCB was the discovery of a small molecule, monastrol, which inhibits a member (Eg5) of the kinesin family, a type of protein never before targeted by small molecules — and an attractive drug target.
Besides the ICCB, Schreiber co-founded the Bauer Center for Genomics Research with fellow professor Doug Melton. The center houses about a dozen researchers and theorists in genomics, proteomics, mathematics, and computer modeling, as well as providing technology training (see "Harvard's Bauer Center: A Broad View of Genomics," July 2002 Bio·IT World.)
Schreiber is also the director of Harvard's new Molecular Target Laboratory. Funded by a $40-million grant from the National Cancer Institute, the MTL work focuses on generating libraries of ICCB-designed compounds. MTL researchers, many of whom also work at ICCB, will investigate the biological effects of those compounds, depositing that information into the public ChemBank database. They already have about 200,000 compounds, with data on about 50,000 of those. The aim is to stock ChemBank with hundreds of thousands of data points over the next five years.
Schreiber has trained a generation of chemical biologists who are carrying chemical genetics forward in their own laboratories. "Stuart is willing to come up with a larger vision and go for it in a way that most people aren't," Ward says. "And his generosity with credit makes people eager to follow any trail he blazes."
IMAGES REPRINTED WITH PERMISSION FROM SCIENCE, VOL. 286, PAGE 971 (1999). COPYRIGHT 1999 AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE.
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