By David N. Leff
MIAMI - "Tropoxin is a natural product," chemical biologist Stuart Schreiber told his Sunday morning audience at the Miami/Nature Biotechnology Winter Symposium here. "It's a small molecule produced by a soil bacterium. It's very likely to help that organism engage in competition with other single-cell organisms for foodstuffs - competing [to land] on the same orange peel."
Schreiber, a professor of chemistry and chemical biology at Harvard University, spoke on "Specificity and Generality in Chemical Genetic Research." Tropoxin paved Schreiber's way from an oddment of evolution to a therapeutic handle on leukemia.
"Our first observation about it," he recounted, "was that tropoxin changed the shape of cells that were receiving the compound. That's very analagous to a genetic screen where you may screen for many mutations, and ultimately find one that causes cells to modify their morphology. From there, we were able to explore the function of the many classic forward genetic experiments to isolate the actual mutation, and the gene harboring the mutation, which is responsible for the change in cell shape.
"That would teach you," he continued, "that that gene product is somehow involved in cell shape. Rather than track down a mutation, we used the small molecule to track down the gene product protein, that it binds directly to and alters its function. And the protein, we discovered, that it binds to we named histone deacetylase [HD]. That enzyme removed acetyl groups from histone proteins, which are components of chromatin - the protein DNA complex in chromosomes that come out from the nucleus.
"From there," Schreiber said, "we were able to explore the function of not only the HD target - the small molecule - but of the many proteins that the HD itself binds to. These we now know are proteins involved in regulating the structure of the chromatin, and regulating which genes are active at any point in time in vivo."
Schreiber recalled that "there was a very interesting in vivo outcome of these in vitro studies. It was discovered that a chromosome translocation leading to promyelocytic leukemia (PML) involves the inappropriate fusion of a DNA-binding protein and an HD enzyme. Once that was recognized, it became clear that a therapeutic consequence would be to treat PML patients with an HD blocker, thereby inhibiting the chromosomal translocation product that causes their cancer. The treatment of patients with those inhibitors had a very favorable outcome."
In conclusion, Schreiber told BioWorld Today: "For me, the next 10 years will focus on realizing the potential of chemical genetics as a means not only to explore biology, but to do so in a way that makes a direct connection to medicine." Schreiber has a research collaboration with Merck & Co. Inc., which sponsors his work. The symposium concludes today.