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The Skaggs Institute For Chemical Biology
Scientific Report 1998-1999


Director's Overview


Rebek/SRSK/PhotoJulius Rebek, Jr., Ph.D., Director

The Skaggs Institute for Chemical Biology was established in 1996 by a gift of unprecedented generosity from Aline and Sam Skaggs. The goal of the Institute is improvement of human health through cures for diseases, and to achieve this goal, it fosters research at the interface of chemistry and biology. The Institute consists of 5 departments: Chemistry, Molecular Biology, Cell Biology, Neurobiology, and Molecular and Experimental Medicine. More than 25 principal investigators and some 200 full-time researchers are supported by funds from the Institute. With an average of more than 200 publications each year since its founding, the Institute has earned its research identity in the United States and worldwide for its accomplishments in organic synthesis, antibody catalysis, protein structure, and RNA chemistry.

Highlights of the past year in chemistry include the following: Two groups, that of K.C. Nicolaou and that of Dale Boger, independently accomplished the total synthesis of vancomycin. This achievement opens the way for second-generation vancomycins for overcoming resistant bacteria. The angiostatic natural product fumagillin was synthesized in the group of Erik Sorensen, and Barry Sharpless and colleagues parlayed practical catalytic transformations into diverse libraries of organic compounds. Elsewhere in chemistry, new materials for solid-phase synthesis were developed by Kim Janda and his group, and chemoenzymatic organic synthesis continued to flourish in the laboratory led by Chi-Huey Wong. One of our newest members, M.G. Finn, pursued chemical catalysis in solution and on solid supports, and Reza Ghadiri examined complexity through self-organized chemical networks. The dynamics of protein-protein interactions were unraveled by Jeff Kelly and his group with an eye to discovering small-molecule inhibitors for the prevention of amyloid diseases. Phil Dawson and colleagues used chemical ligation techniques to investigate the synthetic side of protein chemistry. Albert Eschenmoser and the members of his laboratory focused on the chemical etiology of nucleic acids, and my own group pursued molecular recognition phenomena in the context of "molecules within molecules."

In the Department of Molecular Biology, Peter Wright and his colleagues used multidimensional magnetic resonance techniques to understand how proteins and nucleic acids recognize each other. Jamie Williamson and his group used nuclear magnetic resonance to illuminate the events of RNA folding pathways. Jerry Joyce and members of his laboratory applied in vitro selection to obtain catalytic nucleic acids, particularly DNA enzymes that cleave RNA molecules, and Martha Fedor and her colleagues traced RNA catalytic events inside the cell. Paul Schimmel and his group continued in their efforts to define the central role of transfer RNA between the world of proteins and the world of nucleic acids and the evolutionary implications of this transfer. Three groups used crystallography to answer questions about protein structure: Elizabeth Getzoff and her colleagues studied recognition and catalysis by superoxide dismutase and nitric oxide synthase; John Tainer and the members of his laboratory pursued helicases involved in DNA repair; and Ian Wilson and his group provided an increasingly refined picture of the T-cell receptor. Gerald Edelman and his group targeted other cell-surface and adhesion molecules. Ben Cravatt and his colleagues focused on chemical physiology, particularly in the context of fatty acid amide hydrolases.

The Institute continued to build on its strengths in antibody catalysis with discoveries by Steve Mayfield and his group of the expression of antibodies in microalgae and the development by Carlos Barbas and his colleagues of recombinant strategies for designer proteins. Evolution of novel catalytic function was the target of Floyd Romesberg and his researchers, and the recent arrival of Peter Schultz, a codiscoverer of catalytic antibodies with Richard Lerner, added further luster to this sterling group. Ernest Beutler and his colleagues examined mechanisms of oncogenesis and studied hepatitis B virus and its replication.

The resources of the Skaggs Institute extend to the superb facilities for computation, analysis, and drug design offered by TSRI. These facilities maintain an environment of cutting-edge research for the Institute and augur well for success as we approach the new millennium.

 

 







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