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lerner/Photo President's Introduction

Richard A. Lerner, M.D.

In a year punctuated by significant scientific achievements and the acquisition of substantial grant funding, the quintessential event in the collective life of The Scripps Research Institute was the awarding of the 2001 Nobel Prize in Chemistry to K. Barry Sharpless, W.M. Keck Professor of Chemistry and professor, The Skaggs Institute for Chemical Biology. Coming so closely on the heels of the tragedy of September 11, this prodigious accomplishment lifted the spirits of the entire organization, as we came together in celebration of Barry's remarkable scientific career. Long recognized by the scientific community, his work has received considerable attention from the philanthropic community, most notably Sam and Aline Skaggs, whose contributions have enabled him to achieve numerous research breakthroughs.

Sharpless was lauded by the Nobel Committee "for his work on chirally catalyzed oxidation reactions." He has contributed innovations to the development of broadly useful and commercially practical catalytic oxidation chemistry for the selective production of bioactive chiral molecules with the proper right- or left-handedness. In addition to the Nobel Prize, Dr. Sharpless received the Wolf Prize and the Franklin Institute Award this year.

Late this year, a dedication ceremony was held for the new Institute for Childhood and Neglected Diseases and the Helen L. Dorris Institute for the Study of Neurological and Psychiatric Disorders of Children and Adolescents, both housed in a laboratory facility on the east side of TSRI's campus. A lead gift from John and Becky Moores created the impetus for a successful fund-raising campaign for the Institute for Childhood and Neglected Diseases, which was spearheaded by Bernie and Marc Chase. This research initiative will apply the new molecular understanding of biology to address, reduce, and treat recalcitrant illnesses in two major categories: childhood diseases and neglected diseases that effect populations primarily in developing countries. Helen Dorris's particular interest in mental health advocacy led her to provide the funding to establish the institute that bears her name, with a strong emphasis on neurologic and psychiatric disorders. The institute will be headed by Benjamin Cravatt, assistant professor, Department of Cell Biology and The Skaggs Institute for Chemical Biology.

TSRI scientists have been selected to lead 3 multiyear consortia funded by the National Institutes of Health to study important questions in basic biology. A $35 million grant has been awarded to establish The Integrative Neuroscience Initiative on Alcoholism. Headed by George F. Koob, professor, Department of Neurobiology, the program aims to combine physiologic, molecular, and cellular models to determine the genetic and environmental factors that form the basis for individual differences in the development of excessive drinking. The initiative will address the basic science of alcoholism and will establish a platform on which future treatments can be built.

James C. Paulson, professor, Department of Molecular Biology, will lead a consortium of basic scientists dedicated to studying carbohydrate function. Made possible by a $34 million grant from the National Institutes of Health, the Consortium for Functional Glycomics will bring together a large group of scientists from leading academic medical centers across the United States to identify carbohydrate molecules that collectively play important roles in cell communications. Ultimately, scientists expect that many of the findings will enhance understanding of the immune system, because immune effector cells and molecules rely heavily on sugars to travel through the blood to lymph glands and to sites of inflammation and to prompt normal immune responses to foreign invaders.

Ian Wilson, professor, Department of Molecular Biology and The Skaggs Institute for Chemical Biology, spearheads the Joint Center for Structural Genomics, an initiative funded by the National Institutes of Health. The center draws on talent from several California institutions in addition to TSRI, including the Genomics Institute of the Novartis Research Foundation; University of California, San Diego; and the Stanford Synchrontron Radiation Laboratory. The consortium has received a grant of $24 million for a 5-year period to expand on the body of knowledge made available by the completion of the human and other genome sequencing projects. Its goal is to determine the 3-dimensional structure of up to 2000 proteins by developing high-throughput technology, thereby advancing efforts to understand structure-function relationships important for diseases and treatment of diseases.

In June, the most powerful, high-resolution nuclear magnetic resonance (NMR) spectrometer, a 900-MHz machine, was delivered to TSRI. The new spectrometer became the centerpiece of one of the world's most prominent collections of NMR instruments; 10 instruments have a power of 500 MHz or greater. The new spectrometer, the first of its kind, was several years in the making by Bruker Instruments, Inc. NMR spectroscopy provides atomic coordinates of a wide range of biologically important molecules in solution. This information enables scientists to determine the structure-function relationships of molecules that lie at the heart of understanding fundamental biological processes.

As has become the norm at TSRI, scientists this year published more than 1000 articles in peer-reviewed scientific journals, bringing their knowledge and insights to bear in a significant way on the body of scientific knowledge. A collaboration between Ian A. Wilson, Chi-Huey Wong, and their colleagues in the Departments of Chemistry, Molecular Biology, and The Skaggs Institute for Chemical Biology yielded one of the best views ever of an enzyme caught in the act of catalyzing a reaction on the enzyme's substrate. This research should be valuable as a tool for drug synthesis, because it will enable scientists to engineer this enzyme to alter or improve its specificity.

In addition, researchers in Dr. Wilson's laboratory, in collaboration with colleagues at Oxford University, determined the structure of an antibody that effectively neutralizes HIV. This discovery may provide a basis for the design of effective vaccines against the virus. Normally, antibodies that the body produces to fight HIV are ineffective because much of the surface of the virus is inaccessible. In addition, antibodies mostly recognize long protein loops on the outside of the virus, and in the body HIV rapidly mutates so that the loops become unrecognizable. This neutralizing antibody, however, appears to be effective against a wide variety of HIV isolates. In addition, this antibody is the first human antibody whose entire structure is known.

Jeffery W. Kelly and his colleagues in the Department of Chemistry and The Skaggs Institute for Chemical Biology uncovered a potentially useful strategy to treat the rare disease familial amyloid polyneuropathy, an approach that may be generally useful for intervention in other amyloid diseases. The team showed that it is possible to prevent the changes in protein shape that cause familial amyloid polyneuropathy, a disease similar to Alzheimer's disease. The strategy is to introduce another protein that prevents the aberrant protein from changing its shape.

Work in my laboratory this year led to the discovery that antibodies have a novel catalytic ability--unique among proteins--that could mean that they do more to protect our bodies than researchers had previously thought. My colleagues and I found that antibodies can catalyze the formation of hydrogen peroxide from singlet oxygen. Antibodies could have played a role as ancient proteins whose function was to remove singlet oxygen. In fact, before the antibody-mediated immune response evolved in vertebrates hundreds of millions of years ago, an ancient form of antibodies may have existed, molecules whose role was to catalyze singlet oxygen destruction. The work opens up possibilities for new therapies for conditions ranging from bacterial and viral infections to cancer. Further, the ability of antibodies to generate toxic compounds may be linked to a number of autoimmune diseases.

Appearing this year on the cover of Science magazine was Geoffrey Chang's elucidation of an x-ray crystal structure that provides the first detailed glimpse of a membrane transporter protein. This finding could be useful for improving cancer therapy and fighting antibiotic-resistant bacteria. One of the ways that bacteria resist antibiotic drugs is by using membrane transporters, large proteins that sit in the cell membrane and move other molecules in and out. In human cells, one of the important roles of these transporters is removal of injurious toxins. Unfortunately, harmful bacteria use transporters to nullify antiobiotics; certain cancer cells do the same thing. Dr. Chang's structure is considered a breakthrough, opening the door for scientists to design a new class of drugs that patients would take in conjunction with antibiotics or chemotherapeutic agents to keep those medications in the cells and increase their efficacy.

Dennis Burton and Anthony Williamson designed an antibody that clears prion infection in cell culture. This finding may point the way to a treatment for mad cow disease and its human equivalent. Diseases such as mad cow disease are unusual because the infectious material is not a virus or a bacterium. Rather, the material is malformed prion protein, molecules that start out with one shape that is innocuous and end up with another form that is deadly. The newly engineered antibody seems to halt the infection completely, binding to the normal form of the protein and preventing the infectious form from binding in cell culture. Potentially, a drug might be designed to bind to the same place as the antibody in humans.

Scientists at The Skaggs Institute for Chemical Biology published 2 separate articles in which they described different ways of engineering bacterial cells to encode "unnatural" proteins. These proteins differ from those produced by other living organisms because the unnatural proteins incorporate novel amino acids. The methods could provide powerful mechanisms for studying protein and cellular functions, because the results establish that bacterial strains can be made to incorporate novel amino acids into proteins. Further, the results could enable scientists to envision the possibility of engineering completely new proteins. Peter Schultz and Paul Schimmel led the 2 separate efforts.

A number of our scientists were honored this year with prestigious awards, testimony to the value that the scientific community places on their research contributions. As mentioned earlier, in addition to the Nobel Prize, Dr. Sharpless received the Wolf Prize in Chemistry and the Franklin Institute Award. Tamas Bartfai received the Ellison Medical Foundation Senior Scholar Award, and Dale L. Boger was given the Yamanouchi USA Faculty Award. Charles L. Brooks was elected a fellow of the American Association for the Advancement of Science, and Philip E. Dawson received a research fellowship in chemistry from the Alfred P. Sloan Foundation. Gerald F. Joyce was elected to membership in the National Academy of Sciences, one of the highest honors that can be conferred on a U.S. scientist or engineer. K.C. Nicolaou was awarded the Centenary Medal, Royal Society of Chemistry; Julius Rebek was named a fellow of the American Association for the Advancement of Science; and Peiqing Sun received the Ellison Medical Foundation New Scholar Award. In addition, K.C. Nicolaou, K. Barry Sharpless, and Chi-Huey Wong were named to a list of the world's most cited authors, who account for less than one half of one percent of all publishing researchers, for the past 2 decades.

I am obviously pleased with the progress of the Institute this year, and I continue to be inspired by the prodigious work, commitment, creativity, and enthusiasm of our extraordinarily talented scientists. In addition, our industrial collaboration agreement with Novartis continues to yield important research discoveries and has enabled TSRI to remain at the leading edge of scientific innovation. Also, we are most grateful to our Board of Trustees for their able guidance and to our donors for their ongoing support and strong belief in the importance of our work.

 

 







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