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Stanford Report, October 15, 2003

Molecular pharmacology department strikes new, interdisciplinary approach Faculty additions allow shift in research directions


By KATE RAMSAYER

Over the past 30 years, pharmacology has shifted from the study of drug metabolism and action to investigations of signaling networks the drugs affect. To obtain new perspectives in this changing field, the School of Medicine’s molecular pharmacology department has assembled a group of researchers from varied scientific backgrounds under one roof.

"I believe that breakthroughs come from the mergers of fields," said Daria Mochly-Rosen, PhD, chair of the Department of Molecular Pharmacology and the George D. Smith Professor of Translational Medicine. "They rarely come by looking at the same thing in the same way."

After 15 years of cloning and characterizing genes, and with huge amounts of data from endeavors like the human genome project, many researchers are now investigating quantitative, rather than just qualitative, questions, said James Ferrell, MD, PhD, professor of molecular pharmacology. One way to do this is by importing methods from the physical sciences.

Although the department housed faculty trained in chemistry, mathematics and biophysics, when the opportunity arose to hire three new faculty members, it decided to strengthen the chemical biology aspect of molecular pharmacology by hiring two chemists and a neuroscientist.

James Chen, PhD, who started at Stanford in June, earned his PhD in organic chemistry but was curious about developmental biology. He read about a naturally occurring plant toxin that caused sheep in the mountains of Idaho to give birth to lambs with one eye and looked at the toxin’s effects on cells in his postdoctoral training.

Chen found that the aptly named cyclopamine interfered with a component of the Hedgehog pathway, which plays a role in development and cancer. He currently studies how other molecules interact with the pathway and is developing chemical methods of controlling gene expression in zebrafish to examine how pathways collectively regulate the formation of embryos.

"Chemistry is a useful tool," said Chen. "It allows you to make things that nature can’t." In molecular pharmacology, he can use these tools to answer biological questions. "In this department there are few boundaries and limitations," he said. "I can pursue synthetic organic chemistry and study embryonic development without getting raised eyebrows from colleagues."

Tom Wandless, PhD, has been on the faculty at Stanford for eight years and moved from chemistry to molecular pharmacology in July. As a synthetic organic chemist, he is trained in transforming molecules.

"I love making new things," said Wandless. "It’s fun, but it’s also fascinating to put them with applications." With Gerald Crabtree, MD, PhD, professor of pathology and developmental biology, Wandless developed a system to turn mouse genes on and off based on a toxic compound called rapamycin. Wandless added a "synthetic bump" to rapamycin that renders it nontoxic and allows it to stabilize any protein the researchers are studying.

His lab works on ways to control the binding strength between small molecules and proteins in order to regulate their activity. Wandless has also synthesized possible anti-malarial compounds that are harmless to mammals but toxic to malarial parasites.

"Some of the most exciting things are happening at interfaces between different fields," said Wandless. "We’re not going to take away the core of pharmacology, but we’re just broadening the interface."

Ricardo Dolmetsch, PhD, is interested in molecular messengers in neurons, a topic intertwined with the department’s core focus on cell signaling networks. Dolmetsch, who was trained in neuroscience and immunology, is developing ways of creating cell circuits by shooting neurons onto thin glass slides using a technology similar to inkjet printing. With these defined cell patterns, he hopes to study how links between cells form and how groups of neurons process and store information.

"We are developing new technologies to study signaling between cells and within cells," said Dolmetsch. "We hope to open new scientific frontiers by observing signaling pathways in ways that people have not thought of before."

He is also interested in calcium channels, proteins that convert electrical signals in neurons and are often drug targets for diseases like hypertension. By identifying and cataloging the proteins that bind to each channel, Dolmetsch hopes to understand how channels influence the number and connectivity of neurons — information that could be useful in drug development.

With new perspectives from new hires adding to an already diverse background, the molecular pharmacology department will investigate questions outside its traditional field. Different interests and skills could also add to collaborations within the department, said Mochly-Rosen. "My hope is that, in this new interdisciplinary and scientifically diverse environment, we will be able to carry out research that otherwise would not have been done."



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