In their introductions of Heidi Hamm, Ph.D., prior to her Flexner Discovery Lecture last week, Susan Wente, Ph.D., and P. Jeffrey Conn, Ph.D., recounted how early encounters with her influenced their careers.
For Wente, associate vice chancellor for Research, senior associate dean of Biomedical Science and soon-to-be University Provost, it was a lecture that Hamm gave in the late 1990s when Wente was at Washington University.
Conn, who directs the Vanderbilt Center for Neuroscience Drug Discovery, recalled a conversation with Hamm 14 years ago while he was working for Merck, when she suggested that drug discovery could be done by universities — not just pharmaceutical companies.
“She just challenged that widely held belief,” he said. “… that planted a seed in my mind and ultimately culminated in me coming to Vanderbilt … to really take hold of that dream.”
As an internationally known expert on G protein-coupled receptors (GPCRs), which are targeted by more than half of all drugs, and as long-time chair of Pharmacology, Hamm was always “pushing the envelope,” Conn said. “I’ve never seen a greater champion of Vanderbilt.”
Hamm who stepped down as chair in January to return to the laboratory full-time, said her Vanderbilt collaborations invigorated her science and enabled her “to ask very different questions.”
“There is really so much we don’t know,” she said. About 300 GPCRs are known to be pharmacologically relevant, yet “only about 10 percent of those are targeted with drugs. There are another 200 GPCRs … just waiting for us to understand.”
Hamm chose two examples: the search for better anti-platelet drugs to prevent strokes and heart attacks, and understanding how an inhibitory G protein controls the release of neurotransmitters and hormones.
The enzyme thrombin is one of the triggers for the “coagulation cascade” that is essential for stopping bleeds but which also can create damaging blood clots. It activates a family of GPCRs in platelets called protease activated receptors (PARs) by chopping them in half.
Last month the FDA approved a new drug that blocks one of these receptors, PAR1. But because it can cause bleeding complications like other anti-platelet drugs, its use is limited.
For several years, Hamm and her colleagues have investigated another receptor, PAR4, which causes much stronger and more sustained platelet activation than PAR1, and which sheds more “microparticles,” known to play roles in coagulation and platelet “stickiness.”
The scientists recently have found small molecule inhibitors of PAR4, and are conducting screens for “negative allosteric modulators,” compounds that can “tune down” receptor activity like the dimmer switch in an electrical circuit.
Another active area of research builds on the discovery Hamm and her colleagues made several years ago, that the beta-gamma subunit of an inhibitory G protein can block neurotransmitter release by preventing vesicles from fusing with the nerve cell membrane.
This snarling of the cell’s “fusion machinery,” the SNARE protein complex, may be a way the body regulates release of a chemical messengers, including hormones. Hamm’s team is now looking for small molecules that can block the beta-gamma-SNARE interaction to better understand its physiological role and implications for disease.
For archived video of previous Flexner Discovery Lectures, go to www.mc.vanderbilt.edu/discoveryseries.