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The Skaggs Institute
for Chemical Biology


Scientific Report 2007




President's Introduction


It is my pleasure to report on another extraordinary year at the Skaggs Institute for Chemical Biology, which is so vital to The Scripps Research Institute as a whole. In 2007, scientists at the Skaggs Institute continued to push the boundaries of discovery, producing innovations at the intersection of chemistry and biology to advance our shared goal of improving human health.

Research Highlights

Investigators at the Skaggs Institutes had many significant accomplishments in 2007, including the following:

  • In hopes of combating the growing scourge of antibiotic-resistant bacteria, in particular, drug-resistant staphylococci, Professor Kim Janda and colleagues designed a new type of vaccine that could one day be used in humans to block the onset of infection. The vaccine would not only work on currently resistant bacterial strains but also avoid the potential of inducing bacterial resistance. Rather than killing bacterial cells as antibiotics do, the vaccine blocks the cells' communication system, preventing the shift from harmless to virulent and allowing the body's natural defenses to combat the pathogen.
  • Dr. Janda and his group also developed a new monoclonal antibody that destroys the highly addictive drug methamphetamine. The new antibody, YX1-40H10, converts methamphetamine to a benign substance, pointing to an entirely new way to treat the global epidemic of substance abuse. In a separate study, the scientists found that chronic abuse of methamphetamine may be an unrecognized risk factor for potentially serious cardiovascular disorders that often occur in methamphetamine abusers.
  • With Sydney Brenner, Tobin J. Dickerson, and other colleagues, I developed a breakthrough method that can be used to rapidly predict how viruses such as avian influenza H5N1, a dangerous strain that causes "bird flu," will mutate in response to attacks by the immune system. The new approach, dubbed "checkmate analysis," may also be useful in predicting which antibodies or small-molecule therapeutic agents will best neutralize these viral mutations before the viruses can result in global epidemics. Because of its simplicity and low cost, this innovative approach will be accessible to scientists around the world.
  • Professor Jeffery Kelly, dean of graduate and postgraduate studies and vice president for academic affairs, Professor William Balch, and colleagues, came up with a simple but comprehensive way of probing the biological machinery in humans that controls folding, packaging, and export of proteins from cells. The new model, called folding for export (FoldEx), integrates the chemistry and biology of protein folding and provides a framework for understanding the causes of diseases such as cystic fibrosis and Alzheimer's disease that arise when the protein homeostasis machinery malfunctions. FoldEx may also be useful in designing treatment strategies for protein misfolding disorders.
  • Professor Ulrich Müller and coworkers shed light on how vibrations entering the ear are converted to electrical signals that can be interpreted by the brain. The scientists showed that 2 key proteins join at the precise location where energy of motion is turned into electrical impulses. These proteins, cadherin 23 and protocadherin 15, are part of a complex of proteins called "tip links" on hair cells in the inner ear.
  • Professor Julius Rebek, director of the Skaggs Institute, and colleagues described a new chemical tool that effectively pauses the formation of certain intermediate products never before seen, allowing the products to be identified and studied. The illumination of elusive chemical intermediates will improve basic understanding of chemical processes and may aid in biosynthesis studies, drug development, and detection of pollutants.
  • Assistant Professor Lisa Stowers and colleagues discovered specific pheromone compounds responsible for eliciting aggressive behavior in mice. The researchers have also identified the first step in the neurologic pathway that triggers the aggressive response. These findings further the broad and important goal of elucidating how the neurologic system can detect and respond to specific cues in of a sea of potential triggers.
  • Professor Paul Wentworth and coworkers furthered the ongoing search for better treatments for devastating parasitic diseases such as Chagas' disease and African sleeping sickness. The group now understands better a critical DNA-protein binding event that if blocked can kill the parasites that cause the diseases. The researchers are already working to screen drugs that will block this mechanism.
  • Peter Wright, chair of Scripps Research Department of Molecular Biology, Professor Jane Dyson, and colleagues uncovered a process by which disordered or unstructured proteins become bound to specific cellular sites. The findings offer valuable insights into how proteins carry out their genetically encoded functions and may provide new targets for drug development.

Faculty News

In 2007, Skaggs Institute investigators were again the recipients of numerous awards.

  • Benjamin Cravatt, professor and chair of the Department of Chemical Physiology, Scripps Research, was elected a fellow of the American Association for the Advancement of Science for the development of innovative chemical proteomic technologies to annotate enzymatic pathways in mammalian systems. Dr. Cravatt also won the 2007 Young Investigator Award from the Linda and Jack Gill Center for Biomolecular Science at Indiana University, Bloomington, in recognition of his work, including the discovery and structural identification of several biomolecules involved in processes as diverse as sleep, thermal sensation, and pain, and the identification of a key enzyme that metabolizes a substance produced by the body that resembles marijuana in its actions.
  • Professor Chi-Huey Wong was the recipient of a Humboldt Research Award in recognition of lifetime achievements in research. The award, conferred by the Alexander von Humboldt Foundation, honors outstanding scientists and scholars from all disciplines whose fundamental discoveries, new theories, or insights have had a significant impact on the scientists' own discipline and who are expected to continue producing cutting-edge achievements. In addition, in 2007 Dr. Wong received the F.A. Cotton Medal from Texas A&M, which recognizes excellence in chemistry research; an honorary degree from Technion-Israel Institute of Technology in recognition of his original and prolific research in bioorganic chemistry ; and an honorary fellowship from the Chemical Research Society of India, bestowed every year to eminent chemists from around the world for outstanding contributions to chemical science.
  • Professor Dale Boger won the Ernest Guenther Award in the Chemistry of Natural Products from the American Chemical Society. The award, sponsored by Givaudan, was given in recognition of contributions to the total synthesis of complex biologically active natural products and key analogs used to define their mode of action.
  • Professor Paul Schimmel won the prestigious Stein and Moore Award from the Protein Society for contributions to the highest level of the study of proteins. The award, sponsored by the Merck Company Foundation and named for Nobel laureates William Stein and Stanford Moore, venerates their contribution to understanding the connection between chemical structure and catalytic activity of the active center of the ribonuclease molecule.
  • In June, I received an honorary doctor of science degree from the University of Oxford for my research on catalytic antibodies. The studies indicate that antibodies can be used as enzymes and are relevant for such conditions as atherosclerosis and Alzheimer's disease.

Extraordinary Generosity

I extend my congratulations to my Skaggs Institute colleagues on another successful year, made possible by the extraordinary generosity of the Skaggs family and the ALSAM/Skaggs Institute for Research.

 



Richard A. Lerner, M.D.
President, Scripps Research

Lita Annenberg Hazen Professor of Immunochemistry

Cecil H. and Ida M. Green Chair in Chemistry