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The Skaggs Institute
for Chemical Biology


Scientific Report 2008




President's Introduction


I am proud to report on some of the many accomplishments at The Skaggs Institute for Chemical Biology at The Scripps Research Institute during the past year.

Scientific Breakthroughs

This past year's scientific findings from scientists at the Skaggs Institute are, as in earlier years, extraordinary.

  • Professor Chi-Huey Wong and colleagues developed a new 2-punch strategy against HIV and successfully tested aspects of the strategy in the laboratory. The investigators created devices they call glycodendrons that are designed to do 2 things at once: (1) inhibit the transport of HIV from where it traditionally enters the body, preventing the virus from moving deeper inside where it can infect immune cells, and (2) set up an immune antibody response to a unique carbohydrate structure on the surface of the virus.
  • Professor Kim Janda, Associate Professor Eric Zorrilla (Scripps Research), and colleagues discovered a catalytic antibody that degrades a known appetite stimulant. The antibody works against the gastric hormone ghrelin, which has been linked to weight gain and fat storage. These findings may lead to a potentially novel treatment for obesity.
  • Using samples from survivors of the 2005–2006 "bird flu" outbreak in Turkey, an international team, including researchers at Sea Lane Biotechnologies, L.L.C., Atherton, California, and me, created the first comprehensive libraries of monoclonal antibodies against avian influenza virus (type H5N1). These antibody libraries may be useful in developing a therapy that could stop an influenza pandemic and provide treatment to the people infected and in pointing the way to the development of a universal flu vaccine.
  • Paul Schimmel, Ernest and Jean Hahn Professor and Chair in Molecular Biology and Chemistry, and colleagues uncovered 2 surprising new methods for correcting mistakes in protein production. This editing system is important because even small mistakes in protein production can have profound disease effects.
  • Jeffery Kelly, chair of the Department of Molecular and Experimental Medicine and Lita Annenberg Hazen Professor of Chemistry, and colleagues discovered that 2 widely available prescription drugs restore partial cellular folding, trafficking, and function to a variety of mutant enzymes responsible for 3 distinct lysosomal storage diseases, maladies involving failure of multiple organ systems. The team found that the calcium channel blockers diltiazem and verapamil, which are used to treat hypertension, increased the overall function of mutant lysosomal enzymes associated with Gaucher disease, α-mannosidosis, and type IIIA mucopolysaccharidosis in cell lines derived from tissues from patients with these diseases.
  • Professor John Tainer and colleagues revealed how tiny mutations in a single gene can produce 3 strikingly different childhood diseases. The scientists solved a crystal structure of the enzyme XPD helicase, which unwinds DNA to fix damage that regularly occurs. This research sheds light on 3 different inherited syndromes: xeroderma pigmentosum, which increases the risk for skin cancer by several thousandfold, and Cockayne syndrome and trichothiodystrophy, which are premature aging and developmental disorders.
  • Professor Elizabeth Getzoff and colleagues developed a new method for chemically targeting a single enzyme to block production of nitric oxide without limiting the beneficial production of this oxide by other closely related enzymes. The technique provides a general solution that should enable development of new drugs to treat medical problems linked to nitric oxide overproduction, such as arthritis, and may aid in the discovery of treatments for other conditions such as HIV disease and AIDS.
  • Professor Gerald Joyce, dean of the faculty, and colleagues demonstrated genetic adaptation to selective pressure in real time. Under the control of a computer, a population of billions of genes went through 500 cycles of forced adaptation to emerge as molecules that could grow faster and faster on a continually dwindling source of chemical fuel.
  • Professor Peter Schultz, who holds the Scripps Family Chair, and colleagues produced a powerful immune response in mice by incorporating an unnatural amino acid into a target protein. This novel >approach could be useful in developing new vaccines for cancer, infectious diseases, and other disorders.
  • Professor Benjamin Cravatt, chair of the Department of Chemical Physiology and director of the Helen L. Dorris Child and Adolescent Neuro-Psychiatric Disorder Institute, and colleagues did a protein survey that nearly tripled the number of proteins known to be involved in programmed cell death and refuted a long-held idea about the life cycle of proteins. The findings may open doors for the discovery of new drugs.

People News

It is with great sadness that I report the death, on October 5, 2008, of Professor Ernie Beutler, chair of the Department of Molecular and Experimental Medicine since 1978. His passing is a great loss to science, to the Skaggs Institute and Scripps Research, and to all who knew and worked with him over his long, brilliant career. It is difficult to adequately acknowledge his host of significant discoveries—among them X-inactivation and novel treatments for Gaucher disease and several forms of leukemia, including hairy cell leukemia—or to fully recognize his authorship of more than 1000 scientific articles in all the leading journals in his field, his numerous monographs and book chapters, and his editing of the widely used textbook Williams Hematology. He was an extraordinary man who led an exceptional life, and I am most thankful that he crossed our path and stayed with us for so long.

Filling the position of chair of the Department of Molecular and Experimental Medicine is Jeffery Kelly, who also recently became chair of the Board of Trustees of the Skaggs Institute for Research.

Assuming the deanship of the Kellogg School from Dr. Kelly is Professor Jamie Williamson. Dr. Williamson will build on his 7 years as associate dean to lead this top-ranked graduate program into the future.

Faculty Honors

In 2008, members of the Skaggs Institute again received many honors and awards.

  • Professor Peter Wright, chair of the Department of Molecular Biology and Cecil H. and Ida M. Green Investigator in Biomedical Research, was acknowledged for his outstanding research achievements by election to the National Academy of Sciences.
  • Professor Albert Eschenmoser won the Benjamin Franklin Medal in Chemistry. Franklin Institute Awards are given for outstanding achievements that have enhanced the quality of human life and deepened our understanding of the universe. Dr. Eschenmoser was recognized for his research on the structure of nucleic acids, leading to the understanding of why RNA and DNA have the structures they do.
  • Professor Ian Wilson was showered with honors, including an honorary degree from the University of St. Andrews in Scotland in recognition of achievements "at the forefront of research to understand the immune system and influenza"; election as a Corresponding Fellow to the Royal Society of Edinburgh, Scotland's National Academy of Science and Letters; and election to the Board of Directors of the Keystone Symposia.
  • Professor Carlos Barbas III received the 2009 Tetrahedron Young Investigator Award, Bioorganic and Medicinal Chemistry, an award for scientists less than 45 years old who have exhibited "exceptional creativity and dedication" in their fields. In addition, Dr. Barbas was chosen for the American Chemical Society Arthur C. Cope Scholar Award, which recognizes excellence in organic chemistry.
  • Jeffery Kelly won the American Peptide Society's Vincent du Vigneaud Award, sponsored by Bachem, Inc., Torrance, California, for "fundamental, visionary research on folding and aggregation processes in peptides and proteins, and for courageous, insightful exploration of the biological and medical implications of his discoveries."
  • I am delighted to take this moment to appreciate the many, significant accomplishments that have brought us this far, through the extraordinary generosity and continuing support of the Skaggs family. Thank you also to the many members of the Scripps Research community, including donors, trustees, friends, faculty, staff, postdoctoral fellows, and students, for your dedication, hard work, and vision.

 



Richard A. Lerner, M.D.
President, Scripps Research

Lita Annenberg Hazen Professor of Immunochemistry

Cecil H. and Ida M. Green Chair in Chemistry