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The Skaggs Institute For Chemical Biology
Scientific Report 2001-2002

President's Introduction

Richard A. Lerner, M.D.

As I reflect on the year's accomplishments of members of The Skaggs Institute for Chemical Biology at The Scripps Research Institute, I am struck anew by the scope, depth, and extraordinary quality of scientific inquiry here. Most impressive is the eclectic yet synergistic nature of the faculty; although the members vary greatly in age, background, research interests, and scientific sensibility, their bond as part of the Skaggs Institute has created a unique opportunity for scientific collaboration and achievement.

Of course, we were delighted to share in the celebration for Kurt Wüthrich, member of the Skaggs Institute, Cecil H. and Ida M. Green Visiting Professor of Structural Biology at TSRI, and professor of biophysics at Eidgenössische Technische Hochschule Zürich, when he was awarded the 2002 Nobel Prize in Chemistry for applying the technique of nuclear magnetic resonance (NMR) to solving the structures of biological macromolecules. Dr. Wüthrich's recognition followed that of K. Barry Sharpless, member of the Skaggs Institute and W.M. Keck Professor of Chemistry at TSRI, who was awarded the 2001 Nobel Prize in Chemistry for the development of catalytic asymmetric synthesis. We are proud of the accomplishments of these eminent scientists and are humbled by their unwavering commitment to the scientific enterprise.

Dr. Wüthrich is at the forefront of his field as he continues to push the boundaries of structural biology in new and important ways. He pioneered using NMR to determine the structure of biological macromolecules, allowing scientists to "see" what the molecules look like, study and probe their structures, and design drugs to inhibit them. Specifically, Dr. Wüthrich was cited for his work in the development of NMR spectroscopy for determining the 3-dimensional structure of biological macromolecules in solution.

In 1982, Dr. Wüthrich's group published a series of articles that outlined a framework for NMR determination of protein structure. In 1984, he published the first protein structure determined by using NMR: that of the protein bull seminal protease inhibitor. He is the author of the definitive book on the method: NMR of Proteins and Nucleic Acids.

Dr. Wüthrich has solved more than 50 novel NMR structures of proteins and nucleic acids, including those of the immunosuppression system cyclophilin A­cyclosporin A, the homeodomain operator DNA transcriptional regulation system, and murine, human, and bovine prion proteins. He has also solved the structures of numerous pheromones from Mediterranean sea creatures and pheromone-binding proteins from other organisms. In addition, he has been examining ways to solve the structures of membrane proteins, which are some of the least solved of all the relevant structures in biology.

Most recently, Dr. Wüthrich pioneered the new technique of transverse relaxation-optimized spectroscopy NMR (TROSY), which extends several-fold the size limit of structures that can be solved with NMR. With this technique, scientists can elucidate many important biological structures, such as large proteins and protein-protein, protein-DNA, and protein-lipid complexes, that are impossible to investigate by using conventional NMR.

He has also developed other techniques, such as cross-correlated relaxation-enhanced polarization transfer. Using this technique in combination with TROSY, scientists can examine very large structures, including ones with molecular mass as large as 1 million daltons.

Since his affiliation with TSRI in 2001, Dr. Wüthrich has been collaborating with the Joint Center for Structural Genomics, a $30-million effort to develop high-throughput technology that could someday support efforts to catalog the structures of all proteins in the human body. The center is a multi-institution consortium funded by the National Institutes of Health and led by TSRI professor Ian Wilson. Dr. Wüthrich is using NMR as a screening tool to evaluate the quality of protein preparations produced by the automatic procedures. This research could have a major impact on the quality of the overall effort.

Many other members of the Skaggs Institute were also recognized by their peers for scientific excellence. In a list from ISI Essential Science Indicators, 5 investigators were ranked among the top 100 most-cited researchers in the field of chemistry for the past decade: K.C. Nicolaou, Chi-Huey Wong, K. Barry Sharpless, Dale Boger, and Julius Rebek, Jr. On an organizational level, TSRI was ranked second in the world among high-impact institutions in chemistry. Dr. Wong was elected to membership in the National Academy of Sciences, Dr. Nicolaou received the Tetrahedron Award, Kim D. Janda was elected a fellow of the American Association for the Advancement of Science, Albert Eschenmoser received the Oparin Medal, Dr. Rebek won the Chemical Pioneer Award, and Dr. Wilson was elected to the American Academy of Arts and Sciences. In addition, Ben Cravatt was named one of the country's top 100 young innovators by Technology Review, the magazine of the Massachusetts Institute of Technology; Dale Boger received the Janssen Award; and I was given the Presidential Medal from the University of California and an honorary degree from Northwestern University.

Once again, we had another extraordinary year of research accomplishments, all of which were made possible by the vision and outstanding generosity of the Skaggs family and The Skaggs Institute for Research. Few institutions in the world are blessed with friends such as the Skaggs family, who understand the value of the often painstaking, deliberate, complex, and exciting work of early-stage biomedical research. Only by reaching a profound understanding of the basic mechanisms that underlie human health and disease can we discover new ways to alleviate human suffering. To alleviate human suffering is the goal and mission of The Skaggs Institute for Chemical Biology, and I am secure in the knowledge that we are making great strides forward.