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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998

Director's Overview

Julius Rebek, Jr., Ph.D.

In 1996, Aline and Sam Skaggs founded, through an extraordinarily generous gift, The Skaggs Institute for Chemical Biology. The Institute fosters research at the interface of chemistry and biology and has as its ultimate goals the cure for diseases and the improvement of human health. Now at full strength with 25 principal investigators, the Institute supports research in 5 departments: Chemistry, Molecular Biology, Cell Biology, Neurobiology, and Molecular and Experimental Medicine. The specific areas of concentrated effort and broad expertise include nucleic acid dynamics, protein structure, antibody catalysis, and organic synthesis.

These subjects are highlighted in the separate reports that follow and include for the first time contributions from the latest recruits: Professors Martha Fedor, Jeff Kelly, Paul Schimmel, and Jamie Williamson. These investigators are at the forefront of research in nucleic acids, especially RNA, and proteins. Martha Fedor examines the assembly and catalysis of hairpin ribozymes. Paul Schimmel endeavors to understand the origins of the genetic code through the enzymes that act as a bridge between nucleic acids and amino acids. Jamie Williamson studies the dynamics of RNA folding and structure. These investigators' results, along with Albert Eschenmoser's studies of the etiology of nucleic acids and Jerry Joyce's discoveries of the catalytic action of nucleic acids, place the Institute at the leading edge of research on "the RNA world."

On the protein front, Peter Wright, chairman of the Department of Molecular Biology, applies nuclear magnetic resonance to problems in macromolecular recognition, and Phil Dawson devises methods for synthetic protein chemistry aimed at the folding problem. Jeff Kelly defines the role of proteins in neurodegenerative diseases and new therapeutic strategies for intervention. Ben Cravatt explores the chemical physiology of amide hydrolases with the newly discovered lipid hormones. Elizabeth Getzoff illuminates mechanisms of enzyme catalysis, and John Tainer explores proteins that regulate the stability of the genome. Ian Wilson continues to elucidate the structures of cell-surface proteins. Gerry Edelman, director of the Neurosciences Institute and chairman of the Department of Neurobiology, describes advances in the characteristics of cell adhesion molecules. Ernest Beutler, chairman of the Department of Molecular and Experimental Medicine, investigates receptors on prostate cancer cells and signaling mechanisms.

The research groups involved with the antibody initiative include those of Stephen Mayfield, who studies the expression of antibodies in algae, and of Carlos Barbas, who applies antibodies to reactions crucial to organic synthesis and adapts combinatorial strategies to recognize DNA sequences. Catalytic uses of antibodies continue to be developed by Udi Keinan for organometallic reactions and by Kim Janda for the evolution of phosphodiesterases capable of recognizing RNA.

On the chemistry front, tremendous successes in the synthesis of natural products have been scored. Members of the research group of K.C. Nicolaou, chairman of the Department of Chemistry, have synthesized the powerful antitumor agents epothilones and eleutherobins and are currently targeting vancomycin antibiotics. Dale Boger synthesized duocarmycins and bleomycin hybrids, molecules that alter DNA. Chi-Huey Wong applies enzymes to the synthesis of biologically active molecules, particularly aminoglycoside antibiotics. Broadly applicable synthetic strategies define the focus of Erik Sorensen's research, and catalysis invention and the exploration of molecular diversity are the goals of Barry Sharpless. Reza Ghadiri introduced synthetic peptides capable of self-replication and even more complex interactive behavior. Finally, my own research group is involved with various aspects of molecular recognition--how molecules fit together--and the weak interactions that lie at the heart of most biological phenomena. Everywhere in chemistry, combinatorial methods pervade the atmosphere.

As this brief summary indicates, some research is immediately applicable to the goals of the Institute, whereas other efforts are more basic, concerned with providing scientific underpinnings for the next generation of molecules targeted against disease. But whether the research is practical or abstract, the support of the Skaggs Institute gives us all the opportunity to take on long-term projects. This level of commitment and the sheer concentration of research activity define the spirit of the Institute; they create a unique environment for the practice of chemical biology.



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