News and Publications

The Skaggs Institute For Chemical Biology
Scientific Report 2001-2002

Director's Overview

Julius Rebek, Jr., Ph.D.

Each year it is my pleasant duty to report the highlights of the scientific accomplishments in The Skaggs Institute for Chemical Biology. The Institute was established in 1996 by a remarkable gift from the Skaggs family. Their generosity has enabled the recruitment of 31 members as principal investigators. More than 103 postdoctoral fellows and more than 62 graduate students received direct fellowship support from the Skaggs Foundation last year. It is increasingly difficult to choose between those research accomplishments that capture the thrill of discovery in biology and the ingenuity of invention in chemistry. More than 300 publications were generated by the researchers in the past year, but which of these accomplishments will lead to cures for diseases-the ultimate mission of the Institute-will be determined only in the future. For the present, I have selected only a few of the discoveries of the principal investigators, our most valuable asset; the details are available in the individual reports that follow.

The most prominent distinctions, and there were plenty of contenders, were the awards of the Nobel Prizes in chemistry. Professor K. Barry Sharpless shared the prize in 2001 for work in catalytic asymmetric synthesis, and Professor Kurt Wüthrich, our most recently appointed investigator, shared the 2002 prize for the determination of protein structures in solution. These prizes, the numerous other awards, the elections to learned societies, and the endowed lectureships brought a collective distinction to our faculty; our graduate program in organic chemistry is now rated second in the United States by U.S. News & World Report. This program is still a fledgling, little more than a dozen years old, and we have every reason to believe that the resources made available by the Skaggs Institute will maintain this widely acknowledged status in the years to come.

Synthesis lies at the heart of organic chemistry, and the synthesis of natural products drives the discoveries of chemical biology. The flow of synthetic molecules from the team at TSRI-K.C. Nicolaou, chairman of the Department of Chemistry, Dale Boger, Erik Sorensen, and Barry Sharpless-has resulted in some remarkably active agents. During the past year, antibiotic agents targeting cancer were the focus of research: duocarmycins that strike at cancerous DNA, designed agents that inhibit growth of blood vessels to tumors, synthetic structures that stabilize microtubules reversibly, and synthetic agents that target proteins and nucleic acids irreversibly. Modified epothilones with reduced toxicity were synthesized, and an inhibitor of acetylcholinesterase with unprecedented affinity was created by a process in which the enzyme itself assembles the agent by selecting its components in the active site. The reagents "click" together in the space provided by the enzyme.

The discovery by Richard Lerner and his colleagues that antibodies can destroy antigens by chemical methods is a profound one and most likely will have its greatest impact in future years. The finding speaks for the versatility of the immune system and indicates that radical new departures can be found in basic science. Current research is directed at identifying which of the activated forms of oxygen, for example, ozone or the hydroxyl radical, is responsible for the chemistry that protects the system from toxic agents.

A third discovery, which has deep significance for biology, emerged from the work of Paul Schimmel and Peter Schultz. They have been manipulating the genetic code with the aim of engineering organisms that use a 21st amino acid. This research resulted in the discovery of a molecule that inhibits angiogenesis and may also be able to target tumors. This discovery shows such promise that a scientific consortium was able to obtain long-term support from the National Institutes of Health to pursue the findings. Again, the Skaggs gift enables amplification of future research.

Another recent development in Jeff Kelly's research group promises to bring medicinal chemistry at TSRI one step closer to clinical trials. This project involves the misfolding of proteins implicated in debilitating diseases such as Alzheimer's disease and other amyloidoses. Dr. Kelly and his colleagues found that a nonsteroidal, anti-inflammatory drug approved for other indications is effective at preventing this misfolding. The drug is orally available, and the results of human clinical studies have been so impressive that it, or a second-generation analog, will be effective in a larger population of patients.

All of us in the Institute keep an inner eye on the mission: to relieve human suffering by moving basic research to applications in medicine. We are grateful for and relying on the continued support of The Skaggs Institute for Research.