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The Skaggs Institute For Chemical Biology
Scientific Report 2002-2003


President's Introduction


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

As is the norm, members of The Skaggs Institute for Chemical Biology at The Scripps Research Institute 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 the knowledge they created and the importance of their discoveries.

Research Activities

Work in the laboratory of Peter Schultz 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 that occur naturally. 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 scientists 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 antibody 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 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 fibrillar 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 folding 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 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 research 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 F. Barbas and his group designed a hybrid anticancer compound that combines the efficacy of a cancer cell­targeting agent with the long-lasting dose of an antibody. This potent combination has a profound effect on the size of tumors in animal models; in preclinical studies, the compound shrank both Kaposi sarcomas and colon cancers. 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.

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

In a related 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 that could interact in a similar fashion, preventing the aggregation of amyloid-ß protein and perhaps Alzheimer's disease.

A group of scientists including John Tainer of the Skaggs Institute and Lisa Craig, Mark Yeager, and Mike Pique at The Scripps Research Institute 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 sometimes deadly 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 of the Skaggs Institute and Dennis Burton of The Scripps Research Institute 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 had 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.

Faculty Honors and Awards

Many of our scientists, at various stages of their careers, were honored by their peers this past year with awards for achievement in numerous areas of scientific endeavor. Members of the Skaggs Institute who received recognition include Ernest Beutler, who was awarded the E. Donnall Thomas Lecture and Prize of the American Society of Hematology, and Ben Cravatt, who won the Eli Lilly Award in Biological Chemistry from the American Chemical Society.

A Look At the Future

The Skaggs Institute for Chemical Biology is an organization that exceeds expectations on multiple levels; its faculty and staff remain at the leading edge of science in an era in which the pace of discovery accelerates on a continual basis. Its new developments and discoveries, all of which were made possible by the vision and remarkable generosity of the Skaggs family and The Skaggs Institute for Research, will provide greater impetus for the Skaggs Institute for Chemical Biology to play an even larger role on the international stage of scientific discovery.

 

 







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