Skaggs Institute for Chemical Biology

Some major accomplishments have included the determination of the crystal structure of the T-cell receptor, the synthesis of antitumor agents, the discovery of multipurpose antibodies, the characterization of lipid-like hormones, the regulation of cell adhesion molecules and the invention of self-replicating peptides. A more subtle accomplishment has been the synergy that the Skaggs Institute has made possible between research groups.

For example, an initiative in RNA chemistry and biology is focused on understanding the structure and function of these key molecules of life that will ultimately lead to new therapeutic agents. As another example, four groups now work in molecular evolution. The depth of this effort has made the Skaggs Institute the leading edge for research in this field. A third cohesive effort is in drug design, which brings the Institute's structural and computational facilities for proteins and nucleic acids together with the expertise in organic synthesis and combinatorial chemistry.

The capability of the Skaggs Institute to assume broad, long-term projects makes it unique, and its leadership is evaluating strategic opportunities in newly emerging fields that blend chemistry with biology. Nowhere does this seem more likely than in the opportunities expected to emerge from the sequencing of the genomes of living organisms and from the conversion of biological information pouring out of such projects to a science at the molecular level. This conversion will involve determining the genes that encode the specific proteins, receptors or nucleic acids associated with a particular state; unraveling the interactions of those genes; and controlling the interactions by means of appropriate synthetic agents. Because an enormous array of small molecules is already available through combinatorial chemical synthesis, it seems inevitable that the disciplines of genomics and combinatorial chemistry will meet at the biological macromoleculesthe therapeutic targetsof the disease.

The goal of the Skaggs Institute is to maintain itself as a model for research in chemical biology and to provide a nurturing environment for the next generation of scientists. The ultimate research identity of the Skaggs Institute will be the scientists it produces. As a measure of progress, a list of publications from our first twenty years (19962015) is now available on this site. It contains some 3,600 articles acknowledging support of the Skaggs Institute. More than 1,000 postdoctoral researchers and graduate studentsthe Skaggs Fellowswere involved in the work; their lives have been forever enriched by the generosity of the Skaggs family.

Julius Rebek, Jr., PhD

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. 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 diseasesthe ultimate mission of the Institutewill 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.

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 that includes Dale Boger, chairman of the Department of Chemistry, 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 Jeffery Kelly's research group promises to bring medicinal chemistry at Scripps Research 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. 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 rely on the continued support of the Skaggs Institute for Chemical Biology.



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