Peter G. Schultz

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Peter G. Schultz (born June 23, 1956 in Cincinnati, Ohio) is currently a Professor of Chemistry at The Scripps Research Institute,[1] the founder and former director of GNF,[2] and the founding director of the California Institute for Biomedical Research (Calibr), established in 2012.

Biography[edit]

Schultz’s work spans the interface of chemistry, biology and materials science, and includes: the discovery of catalytic antibodies and their use to study fundamental mechanisms of biological catalysis and the evolution of binding and catalytic function, the systematic expansion of the genetic codes of living organisms to include unnatural amino acids, and the application of combinatorial methods to a large array of problems in chemistry, biology, and materials science. He has trained over 300 graduate students and postdoctoral fellows, many of whom are on the faculties of major research universities.[3]

Academic career[edit]

Schultz completed his undergraduate degree from Caltech in 1979 and continued there for his doctoral degree (in 1984) with Professor Peter Dervan. His thesis work focused on the generation and characterization of 1,1-diazenes and the generation of sequence-selective polypyrrole DNA binding/cleaving molecules. He then spent a year at the Massachusetts Institute of Technology with Professor Christopher Walsh before joining the chemistry faculty at the University of California, Berkeley. He became a Principal Investigator of Lawrence Berkeley National Laboratory in 1985 and an investigator of the Howard Hughes Medical Institute in 1994. In 1999 Schultz moved to The Scripps Research Institute and also became founding Director of the Genomics Institute of the Novartis Research Foundation(GNF), which was initiated purely as a genomic research outlet of Novartis, but which grew during Schultz's tenure to include a significant drug discovery effort and more than triple the number of intended employees (currently over 500 people). In March 2010, he left GNF to return to the non-profit sector and founded the California Institute for Biomedical Research (Calibr) in March 2012.[4][5][6][7]

Work[edit]

Combinatorial chemistry & molecular evolution[edit]

Schultz's work consists of finding ways to do a great many similar experiments at the same time, on many different compounds. He is one of the leading pioneers in combinatorial chemistry, screenable molecular libraries, and "high-throughput" chemistry. His interests are extremely wide-ranging, with applications in such diverse areas as catalytic mechanisms, cell-specialization and other complex biological processes (normally studied by biologists, not chemists), basic photochemistry, biophysical probes of all stripes from NMR through positron-emission, and solid-state materials science.

Early in his career Schultz showed that the natural molecular diversity of the immune system could be directed to generate catalytic antibodies. This method enabled the subsequent development of many new selective enzyme-like catalysts for reactions ranging from acyl transfer and redox reactions to pericyclic and metallation reactions. Although their catalytic activities are only rarely strong enough to be of practical use, catalytic antibodies have provided important new insights in our understanding of biocatalysis, structural plasticity of proteins, evolution of biochemical function, and the immune system itself.

Schultz then applied molecular diversity—the strategy of creating large communities of different molecules, plus a method for fishing out the one that does what you want—to a range of problems in chemistry, biology and materials science. Along with Richard Lerner, he was one of the critical players in the development of phage-display libraries, and surface-library chips. For high-throughput bioassays which require freely soluble test-compounds, he uses microrobotic fluid-manipulation systems, adapted for 1,536-microwell cell-culture plates, to separately treat very small cell colonies with large numbers (hundreds of thousands) of different compounds.[8]

Using these various high-throughput and combinatorial experimental approaches, Schultz has identified materials with novel optical, electronic, and catalytic properties; also, proteins and small molecules which control important biological processes such as aging, cancer, autoimmunity, and stem-cell differentiation and de-specialization back to pluripotency.

Unnatural amino acids[edit]

Schultz has also pioneered a method for adding new building blocks, beyond the common twenty amino acids, to the genetic codes of prokaryotic and eukaryotic organisms. This is accomplished by screening libraries of mutant amino acyl tRNA synthetases for mutants which charge nonsense-codon tRNAs with the desired unnatural amino acid. The organism which expresses such a synthetase can then be genetically programmed to incorporate the unnatural amino acid into a desired protein in the usual way, with the nonsense codon now coding for the unnatural amino acid.

More than fifty unnatural amino acids have been genetically encoded in bacteria, yeast and mammalian cells, including photoreactive, chemically reactive, fluorescent, spin-active, sulfated, pre-phosphorylated, and metal-binding amino acids. This technology allows chemists to probe, and change, the properties of proteins, in vitro or in vivo, by directing novel, lab-synthesized chemical moieties specifically into any chosen site of any protein of interest. It may ultimately make possible the creation of new organisms with expanded amino-acid vocabularies, beyond those possible with the twenty-amino acid code.

Chemistry & cell biology[edit]

A significant effort of the Schultz laboratory in recent years has been to screen small molecule libraries in a diversity of cell based assays to identify compounds that control cell fate. Examples of such compounds identified include:

  • reversine,[9]
  • stauprimide,[10] a molecule priming stem cells for differentiation
  • stemregenin 1 (SR1),[11] an AhR antagonist that expands hematopoietic stem cells ex vivo.
  • kartogenin,[12] a CBFβ activator that induces cartilage differentiation in vivo.
  • TCA1,[13] a dual DprE1-MoeW inhibitor capable of killing both drug-resistant and persistent tuberculosis, now in the TB Alliance pipeline.[14]

Awards[edit]

Schultz has received numerous awards including the NSF Alan T. Waterman Award (1988), the ACS Award in Pure Chemistry (1990), the UC Berkeley College of Chemistry Teaching Award (1992), the Wolf Prize in Chemistry (1994), the ACS Alfred Bader Award in Bioorganic Chemistry (2000), the Paul Erhlich and Ludwig Darmstaedter Award (2002), and the ACS Arthur C. Cope Award (2006). Professor Schultz is a member of the National Academy of Sciences, USA (1993), the Institute of Medicine of the National Academy of Sciences (1998), and many editorial and scientific advisory boards. He is a founder of Affymax Research Institute, Symyx Technologies, Syrrx, Kalypsys, Phenomix, Ilypsa, Ambrx, and Wildcat Discovery Technologies, pioneers in the application of high throughput technologies to chemistry, biology, medicine, and materials science.

References[edit]

External links[edit]