Paul Schimmel, Ph.D.
Paul Schimmel is Ernest and Jean Hahn Professor at The Skaggs Institute for Chemical Biology at The Scripps Research Institute. He formerly was the John D. and Catherine T. MacArthur Professor of Biochemistry and Biophysics in the Department of Biology at MIT. His major research activities have concentrated on the decoding of genetic information, with emphasis on the rules of the universal genetic code which are established through aminoacylation reactions catalyzed by a group of enzymes known as aminoacyl tRNA synthetases. The latter are believed by many to be among the first enzymes to arise on this planet in the early stages of the evolution of life.
His laboratory uncovered what has been referred to as an early, “second genetic code” that relates specific sequences/structures in small RNA oligonucleotides to specific aminoacylations. The work at the time (1988) was widely discussed and described in various commentaries. This second genetic code is generally considered to give critical insights into the development of the modern genetic code and protein synthesis.
He and his coworkers were also among the first to use genetic methods to establish the modular design of aminoacyl tRNA synthetases, with distinct functional units for amino acid activation, for specific tRNA binding, and for the assembly of quaternary structures. He later showed how this design relates to the operational RNA code and its relationship to the genetic code. In recent work he combined these concepts with a rationale for the two structural classes of the 20 synthetases. These two classes have long been known but the reason for them has been unclear. In his investigations, structural information was used to show how the simultaneous binding of two synthetases on one tRNA could lead to two distinct classes that, in turn, could also explain much of the table of codons that make up the genetic code.
In other work he showed that a novel module in certain synthetases acts in concert with transfer RNA to enhance the accuracy of the genetic code by an error correction mechanism. This work led to the discovery that, by disruption of this error correction mechanism, living cells can incorporate into proteins substantial amounts of a noncanonical amino acid. Recent experiments in collaboration with investigators at Jackson Laboratories have connected editing defects with errors of protein synthesis. These errors, in turn, lead to the unfolded protein response and neurological disorders.
Other recent work in the Schimmel laboratory forged a link between protein synthesis and signal transduction pathways in human cells. In particular, they demonstrated that a human tRNA synthetase could be split into two distinct cytokines. In subsequent studies, they established a role for specific human tRNA synthetases in pathways for angiogenesis. This work has led to efforts to commercialize applications of human synthetases to treat diseases such as macular degeneration and cancer.
Finally, in a separate line of research published back in 1983, Schimmel developed the concept of what are now known as ESTs (expressed sequence tags) and the strategy of shotgun sequencing, approaches that several years later were adopted for the human genome project. The ESTs provide a way to identify all genes that are expressed in a specific tissue, such as muscle among others. Nature magazine listed Schimmel’s work on the development of ESTs as one of the four key developments that launched the human genome project (Nature volume 409, p. 862 (2001).
Author or co-author of more than 450 scientific papers and of a widely used three volume textbook on biophysical chemistry, he was named to the American Chemical Society's Pfizer Award in Enzyme Chemistry, as co-recipient of the Biophysical Society’s Emily M. Gray Award for significant contributions to education in biophysics, and as recipient of the Chinese Brilliant Achievement Award. He was also elected to membership in the American Academy of Arts and Sciences, the National Academy of Sciences, the American Philosophical Society, and the Institute of Medicine. In addition to these honors and awards, Ohio Wesleyan University (his undergraduate alma mater) conferred on him an honorary Doctor of Science Degree. He has given many honorary name lectures including among others the Peter Debye Lectures (Cornell University), the Sherman Beychok Lecture (Columbia University), the Reilly Lectures (University of Notre Dame), the Mildred Cohn Lecture (University of Pennsylvania School of Medicine), the University Lecture Series (University of Texas Health Sciences Center (Dallas)), the Stanley Gill Memorial Lecture (University of Colorado), the Sir Hans Krebs Lecture (Sheffield, UK), the Nucleic Acids Award Lecture (Biochemical Society and Royal Society of Chemistry, UK), Henry Kamin Lecture (Duke University), the Perlman Lecture Award (American Chemical Society), and the Marker Lecture Series (Pennsylvania State University). He has been active in many scientific and academic organizations and committees, including service as Chairman of the Division of Biological Chemistry of the American Chemical Society and as an editorial board member of ten different scientific journals. Having a longstanding interest in the applications of basic biomedical research to human health, Schimmel holds several patents and is a cofounder or founding director of eleven biotechnology companies, of which six(Alkermes, Inc., Alnylam Pharmaceuticals, Inc., Avicena Group, Cubist Pharmaceuticals, Inc., Momenta Pharmaceuticals, Inc., Repligen Corporation) are publicly traded. These companies are developing new therapies for human diseases and disorders.
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