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Rebek/SRSK/Photo Director's Overview

Julius Rebek, Jr., Ph.D.

The Skaggs Institute for Chemical Biology was established in 1996 through the extraordinary generosity of Aline and Sam Skaggs. Its mission is to improve human health through cures for diseases, and to do so, it supports research at the interface of chemistry and biology. Since its inception, more than a thousand research papers have been published by scientists affiliated with it.

Each year the Institute supports more than 200 postdoctoral researchers and an average of 40 graduate students--our most important assets. During the past 6 years, more than a dozen principal investigators were recruited from leading academic institutions from around the world. One dividend of this massive recruitment is its effect on the graduate program at Scripps. Barely a decade old, the graduate program in chemistry has acquired a place among the top programs in the United States, with specialties in organic, bioorganic, and biophysical chemistry.

Specific research topics that members of the Skaggs Institute concentrate on include catalytic antibodies, nucleic acids, organic synthesis, macromolecular structure, and molecular recognition. The principal investigators' reports are presented in the 2001 scientific report of the Skaggs Institute and are highlighted here.

Peter Wright, chairman of the Department of Molecular Biology at The Scripps Research Institute (TSRI), continues to use nuclear magnetic resonance to study protein-protein and protein-nucleic acid interactions in solution. Targets for therapeutic intervention include macromolecules involved in leukemia, cancer, and mental retardation. Gerald Edelman, chairman of the Department of Neurobiology at TSRI, and his group use proteomics to distinguish the activity of brain regions during waking and after sleep deprivation. The actual connectivity of proteins (i.e., their topology) is being scrutinized by Phil Dawson, who uses chemical ligation to tie the polypeptide chain into knots. Ian Wilson continues crystallographic studies of the structure of molecules important to the immune system. He has determined the structure of molecules involved in diabetes, anemia, and HIV disease. John Tainer approaches cancer therapeutics by studying nucleic acid repair enzymes. Elizabeth Getzoff has determined the solid-state structures of human enzymes involved in the processing of nitric oxide, a biological messenger of blood pressure regulation, blood clotting, and neurotransmission.

In the catalytic antibody area, Steve Mayfield has developed efficient systems for the synthesis of antibodies in microalgae, and Kim Janda has elicited several catalytic antibodies that degrade cocaine. In collaboration with Dr. Janda, Richard Lerner and Carlos Barbas elicited new antibodies to release proven anticancer drugs from the prodrug states within living organisms. An exciting development in this collaboration involves the discovery that all antibodies can convert oxygen into hydrogen peroxide. This result may be important in understanding how antibodies evolved. Ehud Keinan studies the overall organization of the active sites of antibodies and of engineered proteins with expanded catalytic capabilities.

Nucleic acid enzymes that can cleave RNA or DNA molecules involved in multiple sclerosis have been developed by Gerald Joyce, and structural details of RNA enzymes, the ribozymes, and the folding pathways of these enzymes are pursued by Martha Fedor. Jamie Williamson has made progress on the complex machinery of the ribosome, the site where proteins are manufactured inside living cells. Elsewhere in the nucleic acid area, Albert Eschenmoser has discovered that oligonucleotides based on threose undergo informational base pairing and even cross-pairing with RNA and DNA. The origins of nucleic acid structure are the ultimate targets of this research, which lies at the interface of chemistry and biology.

In chemistry, Barry Sharpless continues to discover catalytic transformations that have practical applications in the synthesis of large libraries of molecules. M.G. Finn has devised a technique to discover new catalysts for asymmetric reactions at the nanomolar level. Reza Ghadiri has made progress on purely synthetic molecules that indicate how molecular information and nonlinear catalysis can lead to self-organization and emergent properties generally associated with living systems. Dale Boger has synthesized several of the antibiotics used to treat infections caused by drug-resistant bacteria; he is now reengineering vancomycin and teicoplanin to overcome this resistance. A combinatorial approach to these same molecules is taken by K.C. Nicolaou, chairman of the Department of Chemistry at TSRI. A number of potent antibiotics were discovered by using this approach, and the total synthesis of antitumor agents is under way. Chi-Huey Wong has devised programmable, automated syntheses of oligosaccharides, molecules involved in cell-surface recognition. In addition, members of his group are developing new antibiotics that target bacterial RNA. Erik Sorensen creates architecturally complex molecules through synthesis, and in collaboration with Benjamin Cravatt, he is inventing new methods to analyze the proteome in a functionally active way. Dr. Cravatt also follows the molecular messages of fatty acid amides in the regulation of sleep, pain sensitivity, and thermoregulation.

Paul Schimmel has discovered that enzymes involved in amino acid recognition for protein synthesis have expanded roles in cell signaling; the regulation of angiogenesis is the therapeutic goal of this research. Ernest Beutler, chairman of the Department of Molecular and Experimental Medicine at TSRI, is using combinatorial libraries of short amino acid chains to target prostate cancer cells. Peter Schultz is paving the way toward an expanded genetic code, including various avenues to the blueprint of human aging. Subhash Sinha is synthesizing cytotoxic agents that target cancer cell lines, and Jeff Kelly produces structure-based small molecules for intervention in neurodegenerative diseases, especially those involving amyloid.

In my laboratory, we are pursuing research on the fundamentals of how molecules fit together, how they recognize each other. We synthesize molecules that are self-complementary; many copies of these molecules assemble to completely surround small targets. These assemblies are used to accelerate reactions, stabilize reactive intermediates, and probe weak intermolecular forces.

Although our faculty members are our most important component, other resources of the Skaggs Institute include the world's largest nuclear magnetic resonance spectrometer, superb supercomputers, and laboratories outfitted with leading-edge equipment. These elements combine to create an environment for chemical biology that is internationally unique.



Copyright © 2004 TSRI.