Molecular engineers
How chemical biologists explore the workings of cells
By Robert Levy
A mini-protein locked into shape by a hydrocarbon "staple" represents a new approach to understanding and treating cancer. (Courtesy of Peter Kutchukian and Eric Smith)
For every job, there is a tool — except, it might be said, in the field of cancer research. Despite galloping advances in biological knowledge, scientists have had no means of grappling with most of the malfunctioning machinery in cancer cells.
An estimated 80 percent of the abnormal proteins involved in cancer are unreachable with existing classes of compounds, either because such compounds cannot get inside the cell or because "pits" on the surface of target proteins can't accommodate them. As a result, researchers find themselves knowing very well which proteins they'd like to block with drug molecules, but lacking the means to do so.
Enter the field of chemical biology, a relatively young discipline in which investigators use very small molecules to construct compounds of precise size and shape. The diminutive dimensions and key-like structure of such compounds give them an extraordinary versatility. They enable scientists to turn cell machinery on and off with almost pinpoint control. They provide a novel way of interrogating "suspect" genes to see if they're involved in disease. And they vastly expand the pool of diseased genes and proteins — known as "druggable targets" in medical parlance — that can be attacked with therapies.
"The beauty of small molecules, from the standpoint of cancer, is that they allow us to alter the natural history of the disease process."
Chemical biology has "cancer relevance" written all over it, which explains why it is part of Dana-Farber's Strategic Plan. "The beauty of small molecules, from the standpoint of cancer, is that they allow us to alter the natural history of the disease process," says Greg Verdine, PhD, who directs the Chemical Biology Initiative at Dana-Farber and is the Erving Professor of Chemistry in Harvard University's Faculty of Arts and Sciences. Because cancer arises from a series of incorrect or incoherent messages between genes, the field is uniquely capable of interrupting those messages, decoding them, and showing where they've gone astray.
Chemical biology's rise to prominence, Verdine notes, results from the growing "democratization" of biology and chemistry — the advent of technology that enables chemists to easily perform certain biological procedures, and biologists to do some chemistry.
Greg Verdine
The partnership between Dana-Farber and Harvard's Department of Chemistry and Chemical Biology grew out of that same sense of lowered barriers. "By associating with Harvard, Dana-Farber is connected to one of the foremost centers for synthetic chemistry [the construction of new chemical compounds] in the world," says Verdine, who now splits his time between his Cambridge laboratory and the Institute. "When I get on the elevator in the Smith laboratories at Dana-Farber, I find myself riding with patients confronting their disease. That doesn't happen at my lab in Cambridge. It makes the sense of urgency palpable."
The next pages offer a look at the work of the members of Dana-Farber's Chemical Biology Initiative.
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