The Skaggs Institute
for Chemical Biology

Scientific Report 2005

Director’s Overview

The Skaggs Institute for Chemical Biology is entering its 10th year. The generous endowment of the Skaggs family currently supports the research of 31 principal investigators, 85 graduate students, and more than 140 postdoctoral fellows. These researchers produced 334 publications during the past year in the areas of chemistry, chemical biology, molecular biology, and immunology. The individual reports of the principal investigators are presented elsewhere in this volume, but a few of the highlights are given here.

Albert Eschenmoser and members of his group are studying the minimal requirements for a self-replicating, informational biopolymer. Using a “bottom down” approach and starting from the structure of current nucleic acids, they are simplifying backbones and recognition elements that are consistent with prebiotic molecules. The target structures must pair not only to themselves but also to RNA, and thereby provide the bridge that may have led to the RNA world.

K. Barry Sharpless and his group have developed ingeniously simple reactions “on water.” They find that such reactions proceed optimally in contact with water, particularly when the organic reactants are insoluble in the aqueous phase. The origins of the rate accelerations are being pursued here and worldwide.

Dale Boger and colleagues have developed second-generation syntheses of antibiotics related to vancomycin. They have pinpointed the molecular details of vancomycin resistance and have now completed synthesis of a vancomycin derivative that can overcome this resistance. This type of reengineering could be a model for the medicines of the future.

Scientists in Ian Wilson’s group have solved the first structure of a human Toll-like receptor. These spectacular molecules are members of signaling compounds that activate the innate immune response. The horseshoe-shaped structure recognizes RNA from microorganisms and activates the immune cascade. The researchers have reconstructed and analyzed the hemagglutinin from the 1918 Spanish flu virus. Their structural studies also target the avian influenza viruses that are currently prevalent in Asia.

Kim Janda and members of his laboratory have shown that a simple metabolite of nicotine alters the balance of retinoids in living systems. Specifically, nornicotine was implicated in the underlying molecular mechanism of age-related macular degeneration. Elizabeth Getzoff and her group have sequenced a new gene for cryptochrome, a flavoprotein that is a component of circadian clocks in animals and humans. The scientists determined the first crystal structure of the flavoprotein and found that the molecule has an unusual shape, consistent with its function of surrounding DNA. The ultimate goal is to find the chemical basis for biological responses to light.

M.G. Finn and his colleagues have taken a novel view of viruses and use them as molecular building blocks. The proteins of virus particles can be modified by synthetic reactions to attach, for example, carbohydrates that are selective markers for various cancer cells. These particles are intended to have advantageous properties for pharmacokinetics and for targeting cells in vivo. Kurt Wüthrich and his group use nuclear magnetic resonance to solve the structures of proteins in solution and study the motions of the proteins. The self-splicing protein elements, the inteins, are the current target. The proteins adopt a horseshoe-shaped fold and undergo unusually slow changes in shape as they are processed into the fully active substances.

Researchers in the laboratory of Peter Schultz continue to expand the number of building blocks for proteins beyond those involved in the genetic code. The researchers have prepared autonomous organisms capable of incorporating 21 amino acids, and they hope to optimize unnatural amino acid incorporation to even mammalian cells.

Stephen Mayfield and his group have developed a system for synthesizing proteins in algae. The molecules can be generated in a short time and on a large scale. The goal of the research is the production of monoclonal antibodies; antibodies represent a large fraction of newly approved drugs but are some of the most expensive agents on the market. The research group of Richard Lerner is expanding the application of catalytic antibodies to problems of drug delivery. Specifically, activation of prodrugs can be catalyzed by these antibodies; the intent is to target the prodrug and antibody specifically to cells of interest.

A number of the Skaggs investigators have received national and international recognition, and the graduate program at Scripps Research continues to be at the top in national surveys. The support of the Skaggs family has enabled the emergence of The Skaggs Institute for Chemical Biology as one of the best research environments in the United States. We continue moving our basic research discoveries toward applications of cures for diseases.