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TSRI Scientific Report 2003

President's Introduction

lerner/Photo Richard A. Lerner, M.D.

Like many things in life, science is a serendipitous enterprise. Although we conduct experiments according to well-prescribed methods, the surprises that come to the diligent and the prepared are often those moments that yield the most unexpected and exceptional insights. And so it is this year in the life of The Scripps Research Institute that we find ourselves, somewhat serendipitously, in collaborations with 2 unique partners in what will be truly exciting and profoundly meaningful experiments.

After months of discussions with Florida Governor Jeb Bush, TSRI recently began negotiations that will lead to the establishment of a new Scripps research science center in Palm Beach County, with an emphasis on biomedical research, advanced technology, and drug discovery. I fully expect that the extension of TSRI’s activities in this new scientific arena will increase the scope and depth of scientific inquiry in the biomedical sciences; the synergy between the 2 research centers most likely will lead to major new developments to improve human health.

This enterprise is expected to serve as a stimulus to Florida’s economic development in biotechnology, because TSRI and other academic institutions have been the engine driving the burgeoning biosciences industry in San Diego County. Further, TSRI will be involved with the business community, the university system, and school districts in the Palm Beach area.

We are particularly grateful to Governor Bush for his foresight, his confidence in TSRI, and this unprecedented opportunity to play an important part in creating and transforming the scientific landscape in South Florida. I have every hope that this initiative will contribute not only to economic development, job creation, and educational enrichment but also to the overall growth of biomedical knowledge.

In another development that simultaneously acknowledges the reputation of TSRI in the international scientific community and elevates it to the next level, TSRI and the University of Oxford Department of Biochemistry have announced the establishment of a joint graduate program to train young doctoral candidates at both acclaimed institutions. Named for supermarket and drugstore magnate L.S. Skaggs and his wife Aline, the Skaggs Oxford Scholarships Program will support the enrollment of 10 graduate students during the next 5 years. This collaboration is the first time in Oxford’s 800-year history that the university has offered a degree jointly with another academic institution, and the new program is the first such venture for TSRI. Indeed, it is a distinct honor to be associated with Oxford University and to share a commonality in the pursuit of education at the highest level for the chemical biologists of the future.

Changes in Board of Trustees

A change in board leadership in any organization is a double-edged sword. Although the change brings with it the opportunity for new ideas, a new perspective, and innovative thinking, it also acknowledges the closing of a chapter in the history of an institution. And so it is that we welcome the Honorable Alice D. Sullivan, a former Alameda County superior court judge, as chair of the TSRI Board of Trustees and thank John Diekman, former chairman of the board of Affymetrix and Bay City Capital, for his many years of extraordinary leadership. Judge Sullivan has served with distinction as a member of our board for the past several years and for the past decade has worked in private practice in the resolution of business disputes, particularly in the life sciences and technology fields.

In addition, this year we welcomed the following new members to the Board of Trustees: Rod Dammeyer, president of CAC, L.L.C., a private company offering capital investment and management advisory services; Thomas Insley, former managing partner of the San Diego office of PricewaterhouseCoopers L.L.P., and current vice president and chief financial officer of SkinMedica, Inc., a privately held health specialty pharmaceutical company; Richard J. Elkus, Jr., an executive and entrepreneur whose career has been closely connected with the development and evolution of Silicon Valley; Warren Beatty, Academy Award-winning film actor, director, screenwriter, and producer; and Mervin Morris, founder of Mervyn’s chain of retail stores.

Major Research Grants

TSRI continues to attract large-scale consortia grants from the National Institutes of Health, an accomplishment that reflects its leadership position in numerous fields of study in the biomedical sciences and its collaborative relationships with centers of scientific excellence throughout the United States. Early in 2003, the National Institute of Allergy and Infectious Diseases awarded a multiyear, $24 million grant to a group of researchers at TSRI, the Institute for Systems Biology in Seattle, and Rockefeller University in New York City. The group’s charge is to create an “encyclopedia” of innate immunity, a comprehensive picture of this ancient, essential first line of defense against bacterial and fungal diseases that is mustered by all living creatures. The knowledge generated could help scientists develop treatments for septic shock, certain autoimmune disorders, and diseases caused by potential agents of bioterrorism.

Later in 2003, the National Institute of Allergy and Infectious Diseases awarded a $9.2 million, multicenter program project grant to a team of scientists at TSRI, Harvard Medical School, and the Salk Institute for Biological Studies to discover and develop novel anthrax antitoxins and ways of delivering them. The overall goal of the program is to design antianthrax nanosponges, antitoxin particles that could be administered to someone who has been exposed to anthrax. In addition, another government agency, the U.S. Centers for Disease Control and Prevention, awarded a group of TSRI investigators a multiyear, $11.4 million grant to study the interaction of the human immune system with toxins of the microorganism that causes anthrax. The goal is to understand how these toxins suppress immune responses in humans, circumventing the usual mechanisms by which the body would destroy the bacterium.

Significant Scientific Discoveries

As is the norm, TSRI researchers this year contributed a prodigious volume of work to the body of scientific knowledge in a broad range of disciplines, work that changes the way we think about biological mechanisms and the course of human disease. The following merely skims the surface of knowledge they created and the importance of their discoveries.

Work in the laboratory of Peter Schultz, professor of chemistry and Scripps Family Chair of The Skaggs Institute for Chemical Biology, effectively removed a billion-year constraint on the ability to manipulate the structure and function of proteins. Dr. Schultz and his research group completed the synthesis of a form of the bacterium Escherichia coli with a genetic code that uses 21 basic amino acid building blocks to synthesize proteins, instead of the 20 found in Nature. This creation was the first one of an autonomous organism that uses 21 amino acids and has the metabolic machinery to build those amino acids. Further, the group introduced revolutionary changes into the genetic code of organisms such as yeast that allow the mass production of proteins with unnatural amino acids. By so doing, Dr. Schultz and his team set the stage for an entirely new approach to applying the same technology to other eukaryotic cells, and even to multicellular organisms. Simply stated, these scientiests have opened up the whole pathway to higher organisms.

Researchers in the laboratory of Stephen Mayfield and in my laboratory used algae to express an antibody that targets herpesvirus. The usefulness of the anitbody lies not only in the potential production of an antiherpes topical cream or treatment but also in the development of technology that could facilitate the production of multiple human antibodies and other proteins on a massive scale. This technology enables the generation of antibodies, soluble receptors, and other proteins so much more cheaply than previous technology that an entire new class of therapeutic agents may become available.

Jeffery Kelly and his colleagues in the Department of Chemistry and The Skaggs Institute for Chemical Biology, discovered a new approach for treating amyloid diseases, particularly transthyretin amyloid diseases, which are similar to Parkinson’s and Alzheimer’s diseases. Amyloid diseases are caused by misfolding of proteins into a structure that leads the proteins to cluster, forming microscopic fibril plaques that are deposited in internal organs and interfere with normal function. Dr. Kelly and his team showed the efficacy of using small molecules to stabilize the normal fold of transthyretin, preventing this protein from misfolding. By so doing, they were able to inhibit the formation of fibrils by a mechanism that can ameliorate disease.

In what was a first for biology, researchers in my laboratory, including Paul Wentworth in collaboration with Bernard Babior, reported that the human body makes ozone. Ozone appears to be produced in a process involving human immune cells known as neutrophils and human antibodies. The presence of ozone in the body may be linked to inflammation, and the reserach may have important ramifications for treating inflammatory diseases. In addition to killing bacteria, the neutrophils feed singlet oxygen to the antibodies, which convert it into ozone.

Carlos Barbas, Janet and W. Keith Kellogg II Chair in Molecular Biology, designed a hybrid anticancer compound that combines the efficacy of a cancer cell-targeting agent with the long-lasting dose of an antibody. This potent combination has a profound effect on the size of tumors in animal models, shrinking both Kaposi sarcomas and colon cancers in preclinical studies. The approach is general enough to be used to design hybrids against numerous different cancers; a single antibody can be mixed with multiple small molecules, resulting in a multiplicity of therapeutic agents.

A group of researchers led by immunology professor Bruce Beutler discovered rare genetic mutations in a subset of patients who have a severe form of sepsis, an acute and often deadly disease. These mutations, in gene called Tlr4, predispose persons to susceptibility to meningococcal sepsis, which strikes more than 2500 persons each year in the United States and has an overall fatality rate of 12%. Besides indicating the increased risk of severe sepsis in patients with these mutations, the results suggest that protection of patients at risk may be possible. Eventually, persons with these mutations might be given prophylactic treatment, for example, before undergoing surgery or traveling to a location where exposure to meningococcal bacteria is likely.

Scientists led by Kim D. Janda, Ely Callaway, Jr., Chair in Chemistry and an investigator in the Skaggs Institute, designed a new way to make a vaccine against nicotine that could become a valuable tool for treating addiction by helping the body clear the drug from the bloodstream. The vaccine, which eventually would be given to persons in smoking cessation programs, greatly suppresses the reinforcing aspect of nicotine. The researchers used an “immunopharmacotherapy” approach, by designing a drug that stimulates the immune system to clear the nicotine from the body.

In a related research study, Dr. Janda and his group discovered that a chemical called nornicotine, a major metabolite of nicotine, modifies proteins that misfold and form the fibril plaques found in abundance in the brains of patients who have Alzheimer’s disease. Simply stated, this process physically inhibits the formation of the fibrils. The research is promising--not because nornicotine most likely would be an effective therapeutic agent, but because it shows how a single molecule can cause a chemical interaction that may alter a mechanism important in Alzheimer’s disease. This research could lead to the development of small molecules similar to nornicotine that are not toxic but could interact in a similar fashion, preventing the aggregation of amyloid-b protein and perhaps Alzheimer’s disease.

A group of scientists including John Tainer, Lisa Craig, Mark Yeager, and Mike Pique solved 2 key structures of a bacterial protein called pilin, which is required for infection by pathogens that cause diseases such as meningitis, gonorrhea, pneumonia, and cholera. The members of the group think that the research provides essential knowledge to help scientists develop novel antibiotics and vaccines against these deadly and emerging bacterial diseases. Because the structures are too large and flexible to be solved by using the traditional techniques of structural biology, the team used both x-ray crystallography and electron microscopy to build a model of the pili that would have otherwise been impossible at that level of molecular detail.

In another structural achievement, a multi-institutional group of researchers led by Ian Wilson and Dennis Burton solved the structure of an antibody that effectively neutralizes HIV, an important step toward the goal of designing an effective vaccine against HIV and a new means by which scientists may design antibodies in general. The structure of the antibody has never been seen before, prompting the scientists to speculate on whether they can use this knowledge to engineer antibodies with higher affinity against other antigens.

In a development that could improve the prospects for designing new ways to fight malaria, a group of researchers led by Elizabeth Winzeler described a comprehensive global profile of genes in the parasite that causes malaria, associating the function of a few such known genes with the thousands that have no known function. The researchers think that these data will accelerate our understanding of the malaria parasite and its interaction with humans and should provide new avenues for more effective drugs and vaccines. In collaboration with researchers at the Genomics Institute of the Novartis Research Foundation, Dr. Winzeler created a malaria-specific gene chip with probes specific for the entire genome of the malaria parasite, enabling her to examine the expression of genes at each stage of the parasite’s life cycle. This accomplishment should accelerate the pace of research on the parasite by categorizing uncharacterized genes in functional ways.

Using a new technique known as subtractive proteomics, Larry Gerace and John Yates recently identified more than 50 previously unknown proteins, several of which are associated with rare human muscle and nerve degenerative diseases. Recognizing the proteins that may cause or contribute to diseases such as congenital muscular dystrophy and spinal muscular dystrophy is a first step in the long process of looking for ways to detect, prevent, or treat diseases. The study may clarify a significant number of the more than 300 human dystrophies for which a causative gene has not been identified. The researchers think understanding how these diseases occur requires understanding more about the network of interlinked proteins.

Faculty Honors and Awards

Many TSRI scientists, at various stages of their careers, were honored by their peers this year with awards for achievement in numerous areas of scientific endeavor. Dale L. Boger and Bernard Babior were elected to membership in the American Association for the Advancement of Science, Francis Chisari and Peter Vogt were elected to the Institute of Medicine of the National Academies, and Michael B.A. Oldstone won the Pioneer in NeuroVirology Award of the International Society for NeuroVirology. Ernest Beutler was awarded the E. Donnall Thomas Lecture and Prize of the American Society of Hematology, Tamas Bartfai received a Distinguished Investigator Award from the National Alliance for Research on Schizophrenia and Depression, Eng Tan was selected for the Japan Rheumatism Foundation/Wyeth Lederle Japan International RA Award, and Ben Cravatt won the Eli Lilly Award in Biological Chemistry from the American Chemical Society. Clare Waterman-Storer was awarded a Keith Porter Fellowship of the Porter Endowment for Cell Biologyy and Erica Ollman Saphire won the Burroughs Wellcome Fund Career Award in the Biomedical Sciences.

The events of this year have been nothing short of extraordinary, with profound and far-reaching implications for the future of TSRI. In an organization that often exceeds expectations on multiple levels and whose faculty and Staff remain at the leading edge of science in an era in which the pace of discovery accelerates on a continual basis, these new developments will provide greater impetus for TSRI to play an even larger role on the international stage of scientific discovery. I could not be more proud of our faculty, employees, trustees, donors, and friends, all of whom make me grateful to have the opportunity to work with them every day.



Copyright © 2004 TSRI.