As the home of three academic high-throughput screening facilities and several of the nation’s experts in chemical biology, Boston makes it easy for biologists to try out the tools of industrial chemistry.
Constanza Villalba
Until about a year ago, Charles Hoffman, professor of biology at Boston College, thought the term “vehicle” was just another word for car. Unaccustomed to drug discovery work, he didn’t know that it refers to the experimental control group that does not receive the drug being tested. “I’m a yeast guy,” he explains. “You normally don’t give drugs to yeast.”
Still, with the help of Nicola Tolliday, head of screening in the chemical biology program at the Broad Institute, Hoffman has been doing just that–giving would-be drugs to yeast.
Trained as a classical geneticist, Hoffman has spent much of his career looking for genetic mutations that change the levels of a cellular messenger called cyclic AMP (cAMP). Among the mutations he has studied are ones affecting the gene for cAMP phosphodiesterase, the enzyme that destroys cAMP.
Because compounds that inhibit phosphodiesterase could be used to treat a variety of human diseases, Hoffman became interested in finding small molecules–drug-like compounds–that could produce effects similar to those of the mutations he studied. Until that point, all Hoffman needed for his research was, as he put it, “a Petri dish and some yeast.” With his newfound interest in drug discovery, he needed access to small molecule libraries and a way to test whether any of the compounds in these libraries could alter phosphodiesterase function.
Lucky for Hoffman, he is just a 20-minute drive from not one but three academic high-throughput screening facilities, all of which offer some degree of open access and could fulfill his needs.
He and Tolliday are optimizing a cell-based assay to detect compounds that alter cAMP levels. Soon they’ll be able to screen tens of thousands of molecules with miniaturized experiments running in parallel.
The work is preliminary but has already earned him an invitation to speak at a prestigious Gordon conference on phosphodiesterases. A year ago, he wasn’t sure he’d even be allowed to attend the conference.
Hoffman’s story is not unusual. Increasingly, academic scientists, particularly cell biologists, are searching for and using small molecules to perturb and probe biological processes.
Junying Yuan, professor of cell biology at Harvard Medical School, turned to chemical biology eight years ago when she grew frustrated with the limitations of her genetics-based research. She is now hot on the trail of several small molecules dubbed necrostatins. Necrostatin-1, the only one of these molecules to have been tested so far, inhibits a form of cell death that accompanies stroke.
Yuan says that being in Boston “has everything to do with” her decision to turn to the tools of chemical biology. She credits local chemical biology leaders Tim Mitchison and Stuart Schreiber, both of Harvard, with her success.
In 1998, Mitchison and Schreiber established the Institute of Chemistry and Cell Biology (ICCB) at Harvard, one of the first high-throughput screening facilities in an academic setting. Yuan, whose necrostatin research began at ICCB, says that without Mitchison and Schreiber, her work in chemical biology would not have been possible.
Other academic scientists using small molecules as research tools share Yuan’s gratitude. They agree that chemical biology has come into vogue but don’t necessarily think they are doing anything new. Chemical biology is simply a term referring to pharmaceutical research done in academia. The difference is that academic scientists are interested in small molecules even if they can never become drugs, so long as they help explore biological questions. In Yuan’s case, for example, necrostatin-1 has proven an invaluable tool in figuring out the signaling pathway involved in one form of cell death.
Last year, ICCB split off into two centers, ICCB-Longwood and the Broad Institute facility. In 2001, the Harvard Center for Neurodegeneration and Repair started up another screening facility, the Laboratory for Drug Discovery in Neurodegeneration (LDDN). According to Yuan, this third center offers more than just another place to screen.
“One of the bottlenecks in chemical biology is medicinal chemistry,” she says. When you do a screen, you get hits, but you have to do chemistry follow-up to make the active compound more stable, more active, less toxic, and, in her case, available to the brain.
That follow-up, she says, often can’t be done in academia because it requires medicinal chemists with small-molecule expertise: personnel usually found in the pharmaceutical industry. So the LDDN brought in people like Greg Cuny, a medicinal chemist with years of industry experience. Now when Yuan gets a hit, she can ask Cuny and the LDDN to help her iron out the chemical wrinkles.
Indeed, these academic screening centers are modeled on their industrial counterparts. Ross Stein, an industry veteran who directs the LDDN, says that he set up the center to function like a small biotech company, where people with deep knowledge of their own fields work together as a team.
Chemical biology is, at its core, interdisciplinary, but Stein fears that the popularization of the field may cause people to rush into it with a superficial understanding. “It gives students the impression that they all have to become renaissance people…that to be successful they all have to do chemistry and cell biology and genetics,” he says.
“Most people can’t do interdisciplinary work on their own and make truly substantive contributions to science,” says Stein. In his view, universities would do better to continue training good biologists and good chemists, and then teach them to work together.