The Long Shot

by Douglas Quenqua Published Winter 2011-12
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Aiming at cancer’s source

From the nearly floor-to-ceiling windows in his new twelfth-floor office, Stockwell can look out on both Chandler Hall and the Sherman Fairchild Center, where he previously maintained separate chemistry and biology labs. The University conceived of the Northwest Corner Building precisely for researchers like Stockwell: those who work outside the normal confines of academic disciplines, at the nexus of chemistry, engineering, biology, and physics. 

“Real-world problems are not simply biology problems or chemistry problems,” Stockwell says. “If you want to understand the physical forces that act upon molecules within human cells, or the electrical properties of single molecules, you need to bring together different types of researchers. Targeting an undruggable protein is this type of complex problem.”

Stockwell’s new laboratory is a bright, open space that is designed for collaboration. On one side, the room connects with the laboratory of Virginia Cornish ’91CC, a chemistry professor who creates artificial cellular pathways as a means of studying disease mechanisms.

“Virginia is also at the chemistry-biology interface,” Stockwell says. “So we put in a shared space between our labs.” 

In his laboratory, Stockwell is now trying to find a drug to bind to the Ras protein, which is implicated in about 90 percent of all pancreatic cancers and 50 percent of colon and lung cancers. Its job is to regulate cell growth in the body, which it does by toggling between “on” and “off” positions. When Ras is on, it’s instructing cells to divide; when it’s off, it’s telling them to stop. When Ras is healthy, it’s constantly fluctuating between these two positions. But when Ras breaks down — often as a result of a genetic mutation triggered by carcinogens — it tends to get stuck in the “on” position. The result is runaway cell growth, leading to tumors.

If researchers could find a way to shut down mutant Ras proteins, they might prevent some types of cancer. Scientists have long focused on the Ras protein, and many have tried to find a molecule to dismantle it, but, so far, they have produced nothing. To many scientists, Ras is just one more undruggable protein.

Stockwell isn’t so sure. As in his experience with TGF-beta in graduate school, he believes that finding the right molecule to bind with Ras is primarily a matter of working with better molecules. And he has devised a way to design his own high-quality molecular candidates: he uses sophisticated computer models to synthesize molecules that are physically similar to natural molecules previously shown to have cancer-fighting qualities.

“The molecules we’re designing are based on the physical architectures of two naturally occurring molecules, one of which is found in chocolate and soy beans, the other in certain types of fungi,” Stockwell says. “A few years ago, my laboratory discovered that these two molecules will sometimes kill cancer cells that contain mutant Ras. So we’ve been synthesizing millions of compounds that are slight variations of these natural molecules, with the goal of creating a new molecule that’s perfect for latching onto the mutant Ras and disrupting it. This could enable us to treat many types of cancer, with few side effects.”

Although Stockwell’s approach is more strategic than the conventional method of throwing countless low-quality molecules at proteins to see if any will stick, he still believes that finding the right molecule requires testing many of them. The result is an emphasis on both quality and quantity.

“Our initial results are exciting,” says Stockwell. “We’ve identified some drug candidates that have real potential for locking into Ras. We need to do further experiments, but I’m optimistic we’re going to solve this.”


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