News and Publications
The Skaggs Institute For Chemical Biology
Scientific Report 1999-2000
Richard A. Lerner, M.D.
This past year was one of significant transition at The Scripps Research Institute. Nevertheless, through all the changes, we maintained our impressive array of scientific accomplishments, expanded facilities to accommodate new initiatives, and made important new faculty appointments. Sadly, this year marked the passing of TSRI's dean of graduate studies, vice president for scientific affairs, and chairman of the Department of Cell Biology, Norton B. Gilula, after a valiant struggle with cancer. Dr. Gilula made an indelible imprint on the quality and character of TSRI, and we all miss his keen insights, sound scientific judgment, generosity of spirit, leadership ability, and friendship. His death is a great loss to the scientific community.
Taking over many of Dr. Gilula's responsibilities, Jeffery Kelly, Lita Annenberg-Hazen Professor, Department of Chemistry, and The Skaggs Institute for Chemical Biology, is now acting dean of the graduate studies program and acting vice president, academic affairs. While maintaining an ongoing program of laboratory studies, Jeff will assist me with policy issues related to the direction of scientific activities at TSRI. In addition, Sandra L. Schmid is the new chairman of the Department of Cell Biology. She has been a member of the TSRI faculty for more than 10 years and has distinguished herself as an outstanding scientist whose work is widely respected in the international scientific community.
At TSRI, we are indeed fortunate to count a number of remarkable philanthropists as true partners in the scientific endeavor. The effects of the extraordinary generosity of the Skaggs family in establishing The Skaggs Institute for Chemical Biology have already been felt in a significant way. With a full complement of 25 principal investigators, the Skaggs Institute supports research in 5 departments; the specific areas of concentrated effort and broad expertise include pharmaceutical chemistry, protein structure, antibody catalysis, organic synthesis, and nucleic acid chemistry. The ultimate goals for research at the interface of chemistry and biology are cures for diseases and the improvement of human health. In many instances, important progress has been made toward this end. In addition, many of the researchers' efforts focus on basic science, providing the underpinnings for the next generation of molecules targeted against disease.
Training predoctoral and postdoctoral fellows is an integral part of developing novel therapeutic strategies and approaches. These fellows will educate others and will ultimately themselves be the innovators of the future for the pharmaceutical relief of human abnormalities. The Skaggs Clinical Scholars Program, conceived to closely integrate clinical and basic science, is now 2 years old and has been successful in instilling a renewed sense of camaraderie between clinicians and scientists.
Hundreds of published manuscripts describe research made possible by the generous support of the Skaggs family. Consequently, singling out only a few of the scientists whose studies have benefited from this support is difficult. However, the following descriptions of a small number of these studies connote the breadth of achievements made thus far.
Chi-Huey Wong has developed new strategies to tackle the problem of drug-resistant bacterial infections. Members of his group have developed bifunctional aminoglycosides that target bacterial RNA. One of these compounds is 1000-fold more potent than the antibiotic neamine used now.
Although most drugs currently on the market target proteins and alter the activity of RNA, both the Wong group and Jamie Williamson's group are providing the knowledge required to discover molecules other than aminoglycosides that can enter cells, bind RNA, and change the course of a pathologic process.
Jeff Kelly and coworkers in his laboratory have developed small molecules that interfere with the formation of amyloid fibrils, a process whereby a protein undergoes a change in shape and self-assembles into a structure implicated as a cause of the neurodegeneration associated with amyloid diseases such as Alzheimer's disease. As a prelude to studies in humans, the efficacy of these compounds is being tested in a mouse model of Alzheimer's disease.
The overproliferation of blood vessels in the eye is a common cause of vision impairment or loss. Paul Schimmel showed that a fragment of a specific human protein is active against the abnormal proliferation of these blood vessels, suggesting a new therapeutic strategy.
Members of Ian Wilson's laboratory have been instrumental in developing novel peptide mimics for erythropoietin, a hormone that stimulates the production of red blood cells and is useful for treating anemia. The hope is that these small molecules can be given orally rather than being injected, because administration of the injectable form often requires a hospital visit.
The extraordinary ability to make novel small molecules is highlighted by the work of K.C. Nicolaou and Dale Boger. Their findings have made it possible to create new structures with both anticancer and anti-infectious properties. Members of these groups are collaborating with other scientists at TSRI to find clinically useful compounds. In the meantime, their investigations provide the infrastructure for making larger numbers of compounds more efficiently, a situation that facilitates the discovery of new drugs.
Results from the laboratory of Peter Schultz and from my laboratory reveal that gradual genetic changes may be the source of many, if not all, illnesses of aging, including breast cancer, osteoporosis, Alzheimer's disease, and arthritis. Aging and its associated diseases can be traced to a gradual increase in errors in all division in tissues throughout the body. This functional change begins slowly in middle age and increases gradually. Although scientists previously thought that aging is a disease in which cells stop dividing, our work suggests that aging is a disease of quality control. With advancing age, altered gene expression results in cells with diminished function. Errors in cell division lead to the altered expression of a collection of key genes in the cells. Altered gene expression gradually causes the loss of tissue function, a condition that results in aging.
Finally, Ben Cravatt and coworkers discovered that specific fatty acid amides modulate pain sensation in vertebrates. This finding should be a major advance in our approach to chronic pain management in humans. Importantly, a combination of chemical, biological, and physiologic studies were used to identify a new enzyme and receptor that can now be targeted with small molecules to alleviate chronic pain, a significant clinical problem.
Clearly, the scope of research activities in the Skaggs Institute reflects the multidisciplinary nature of the work and the creativity and innovative spirit of its scientists. The important collaboration between science and philanthropy has already yielded significant results, and we are well positioned to make even greater strides in the future.