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The Skaggs Institute For Chemical Biology
Scientific Report 2002-2003


Director's Overview


Rebek/SKSR/99 Julius Rebek, Jr., Ph.D.

The Skaggs Institute for Chemical Biology was established in 1996, and as it enters its 8th year, we congratulate our benefactor, L. Sam Skaggs, on his 80th birthday. His generosity, and that of the entire Skaggs family, supports the work of the Institute through its 31 principal investigators, 95 postdoctoral fellows, and some 50 graduate students. The aim of the Institute is to relieve human suffering by moving basic research to applications that lead to cures for diseases. Our researchers authored nearly 300 publications during the past year, loosely clustered in the areas of organic synthesis, antibody science, nucleic acid chemistry, and protein structure. The details of the scientific discoveries appear in the individual reports of the principal investigators, but I present a few of the highlights here.

The faculty members involved with nucleic acids, Albert Eschenmoser, Martha Fedor, Gerald Joyce, Ehud Keinan, Peter Schultz, and Jamie Williamson, showed that DNA isn't just for genes anymore. DNA can fold into a spectacular octahedral shape, visible by electron microscopy; it can do biomolecular computing; and its sequences can be selected and amplified to catalyze the cleavage of RNA. The use of RNA as a target for small-molecule medicinal agents is also growing. Synthetic alterations in either the base pairs or the sugar backbones indicate that nucleic acid structure is enormously versatile and that the information encoded can even be expanded. In the past 50 years, the seed represented by the discovery of the double helix has grown into an orchard.

The synthetic team, K.C. Nicolaou, Phil Baran, Dale Boger, Barry Sharpless, and Chi-Huey Wong, created purely synthetic molecules to regulate protein-protein interactions. These interactions emerged as targets for intervention in diseases but have not, could not, be addressed by conventional medicinal chemistry. Specific agents for blocking angiogenesis and stimulating production of blood cells were synthesized, and small molecules that arrest microtubular structures are now in clinical trials. Both plant- and marine-derived natural products were used to produce antitumor agents, and efforts to discover carbohydrate-based drugs led to the development of new HIV protease inhibitors. As a result of methods developed here last year, environmentally benign reagents are now available as building blocks for combinatorial medicinal chemistry.

Research led by Richard Lerner indicated that ozone is one of the key reactive species that antibodies can generate to destroy antigens. Steve Mayfield developed methods for large-scale, inexpensive production of antibodies in algae--good news at a time when antibodies are a sizable fraction of the new drugs approved by the Food and Drug Administration. Using x-ray crystallography, Ian Wilson and collaborators determined the structures of antibodies responsible for resistance to HIV; these antibodies, specifically, and structural biology, generally, will take greater roles in the ongoing efforts to develop an AIDS vaccine.

Peter Wright used nuclear magnetic resonance to solve protein structures as they exist in solution. Several of these proteins are transcription factors, and their interactions with other proteins are responsible for specific gene expression of tumor viruses. Elsewhere, structures of enzymes that produce nitric oxide, a ubiquitous cell-signaling molecule, were determined, and the behavior of superoxide dismutase, an enzyme involved in amyotrophic lateral sclerosis, was analyzed. The structural details offer a starting point for the development phase of small-molecule medicinal agents.

We are proud of these discoveries, for which a number of the Skaggs investigators received national and international awards, including the Paul Ehrlich Prize and, in the past 2 years, a share of the Nobel Prize in Chemistry. The Skaggs family has enabled the recruitment of more than 15 principal investigators during the Institute's short lifetime. These new faculty members have propelled our graduate programs to the top in national surveys. At the international level, recognition came through an unprecedented joint Ph.D. program with Oxford University in England. Graduate students in the program will receive Skaggs Scholarships. All of us at Scripps are grateful for the continued support of the Skaggs Institute for Research.

 

 







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