The Skaggs Institute
for Chemical Biology

Scientific Report 2007

Director's Overview

In 1996, The Skaggs Institute for Chemical Biology was established at Scripps Research through a gift from Sam and Aline Skaggs. Since then, more than $100 million has been contributed to the research efforts at the institute. This funding supports 30 principal investigators and, in 2007 alone, fellowships for 250 postdoctoral fellows and graduate students. The individual reports of the principal investigators of the institute are provided elsewhere in this report; only a few of the highlights of research from the past year are given here.

Lisa Stowers, a new member of the Skaggs Institute, studies sensory neurons that detect chemical ligands (pheromones) that govern social behaviors. Her studies provide the tools to investigate the molecular mechanisms that underlie human social behavior. Paul Wentworth, Department of Chemistry, has elucidated the universal property of antibody molecules to oxidize water to produce hydrogen peroxide. These studies point to an earlier role of antibodies in immunity as a direct means to kill foreign pathogens through oxidation. Jeff Kelly, dean of the graduate school, is using small synthetic molecules to bind to and stabilize enzymes that prevent Gaucher disease. These molecules act as chaperones and provide excellent leads for the development of therapeutic agents for treatment of the disease.

Paul Schimmel has traced the origins of Charcot-Marie-Tooth disease to mutations in genes for 2 aminoacyl tRNA synthetases. These results indicate expanded functions for tRNA synthetases in human cells that now include neurogenesis. Dale Boger and his group have synthesized molecules that inhibit fatty acid amide hydrolase. These inhibitors increase the levels of endogenous analgesics that relieve neuropathic and chronic pain. Dr. Boger and his group have also defined the structural details of vancomycin action and how resistant bacteria elude this antibiotic. Through total synthesis, they have prepared a vancomycin derivative that overcomes this resistance.

Kim Janda, the new director of the Worm Institute for Research and Medicine, has observed a startling aspect of Δ⁹-tetrahydrocannabinol, the active component of marijuana. This molecule inhibits the amyloid aggregation that leads to neurodegeneration in Alzheimer's disease and provides a new lead for development of more conventional therapeutics for treatment of the disease. Ulrich Müller, another new member of the Skaggs Institute, identifies and studies genes that control the function of hearing in mammals. His results have led to animal models for deafness and the pathogenic variance of the proteins that cause it.

Barry Sharpless continues to pursue the application of click chemistry, a reaction that has lowered the obstacles that separate chemistry from biology and is widely used by chemical biologists. He has also discovered that organic reactions that occur on water's surface offer many advantages in synthesis. M. Reza Ghadiri uses rationally designed small-molecule peptide scaffolds that present chemical functional groups in predictable 3-dimensional directions. These cyclic pseudopeptides provide a new platform for drug design. Elizabeth Getzoff has studied the 3-dimensional structures of the enzymes superoxide dismutase and nitric oxide synthase. These catalysts are involved in neuronal cell death and are key therapeutic targets for the pharmaceutical industry.

My own research in collaboration with Tamas Bartfai, Molecular and Integrative Neurosciences Department, has led to small-molecule modulators of the immune system. These modulators have excellent activity in animal models of pain and fever. In other studies, members of my laboratory are synthesizing mimics of protein surfaces to provide tools for determining how molecules fit together in biological systems.

Although this overview covers just a few of the advances made in the past year, all of us in the Skaggs Institute are dedicated to reducing human suffering by finding cures for diseases. We are grateful to the Skaggs Institute for Research for encouraging our studies at the frontiers of science and to the Skaggs family for their continued support.