The Long Shot

by Douglas Quenqua Published Winter 2011-12
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Drowning in the synthetic sea

Stockwell is a slight, fastidious man with neatly parted black hair and thin-rimmed eyeglasses. His office in Columbia’s new Northwest Corner Building, a science and engineering tower at Broadway and 120th Street, is a study in organization, from the tidy rows of water bottles on his shelf to the precisely angled family pictures on his desk.

Stockwell, a forty-year-old Queens native, did his doctoral work in chemistry at Harvard in the late 1990s, an exciting time for drug discovery. After centuries of deriving medicines mainly from natural compounds, chemists were making great progress in synthesizing molecules that might be used as drugs. Companies were manufacturing huge collections of these synthetic molecules, which they sold to drug researchers. The researchers would essentially hurl these molecules at the protein they wanted to target, in hopes that one of the molecules would stick to it.

While working in the lab of the Harvard biochemist Stuart Schreiber, Stockwell started to look for a molecule that could shut down a squiggly, tapeworm-shaped protein named TGF-beta, which causes some tumors. Over the course of eighteen months, he tested sixteen thousand synthetic molecules assembled by commercial labs, but didn’t find a single molecule that showed any promise of affecting TGF-beta.

“So then I thought, OK, it’s probably not something that we can really find a compound to do,” he says. “It’s just an impossible, undruggable target.”

However, to make sure that he had exhausted all possibilities, Stockwell conducted one last experiment. This time, instead of relying on synthetic products, he used a small library of naturally occurring molecules, some two hundred extracts taken from hard-to-find marine sponges. To his amazement, one of these extracts showed a striking capacity to block the effects of TGF-beta. This taught Stockwell something that many other drug researchers were realizing around the same time: the synthetic molecules being churned out by commercial vendors were, for the most part, lousy drug candidates.

“There had been a lot of excitement about synthetic molecules initially because you could get your hands on huge numbers of them, which seemed to improve your odds of finding one that could act as a drug,” he says. “However, they tended to be flat, architecturally simple products. Natural molecules, in comparison, tend to be larger and more complex. Their structural richness, scientists came to realize, makes them better able to attach to other biological entities.”

As thrilling as the discovery was, Stockwell quickly found that natural molecules had their own drawbacks. Most notably, because they cannot be manufactured, there are limited quantities available. The world’s supply of the sponge extract he had identified was exhausted before Stockwell could finish his experiment. To this day, it remains a mystery whether that extract might have helped treat cancer.

“This is one of the reasons that few scientists today are chasing the most elusive proteins,” Stockwell says. “If you don’t find a drug candidate among the cheaply available synthetic molecules, you’re faced with looking at naturally occurring molecules that are much more expensive and in short supply. It’s a pragmatic challenge that has serious repercussions for our ability to develop new cancer treatments.”


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