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Peter G. Schultz

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Peter G. Schultz
Born (1956-06-23) June 23, 1956 (age 68)
Cincinnati, Ohio
Alma materCalifornia Institute of Technology (BS, PhD)
AwardsACS Award in Pure Chemistry (1990)
Wolf Prize (1994)
Scientific career
FieldsChemical biology
InstitutionsThe Scripps Research Institute,
Doctoral advisorPeter Dervan
Other academic advisorsChristopher Walsh
Notable studentsDavid Liu
Sara Cherry
Nathanael Gray
Kevan M. Shokat
Lei Wang
Virginia Cornish
Alice Y. Ting
Young-Tae Chang

Peter G. Schultz (born June 23, 1956) is an American chemist, entrepreneur, and nonprofit leader. He is the CEO and President and Professor of Chemistry at Scripps Research,[1] the founder and former director of GNF,[2] and the founding director of the California-Skaggs Institute for Innovative Medicines,[3] established in 2012. In August 2014, Nature Biotechnology ranked Schultz the #1 top translational researcher in 2013.[4] Schultz's contributions to the field of chemistry have included the development and application of methods to expand the genetic code of living organisms, the discovery of catalytic antibodies, and the development and application of molecular diversity technologies to address problems in chemistry, biology, and medicine.

Academic career

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Schultz completed his undergraduate degree at Caltech in 1979 and continued there for his doctoral degree in chemistry (in 1984) with 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 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.[5] In 1999, Schultz moved to Scripps Research 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 nonprofit sector and, in March 2012, founded the California Institute for Biomedical Research (Calibr), later renamed the Calibr-Skaggs Institute for Innovative Medicines.[6][7][8][9][10] Schultz was named CEO of Scripps Research in 2015 and President the following year.[11] He has trained over 300 graduate students and postdoctoral fellows, many of whom are on the faculties of major research universities.[12]

Research

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Combinatorial chemistry and molecular evolution

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Much of 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 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 metalation 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 a large community of different molecules, plus a method for fishing out and identifying the ones that do 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.[13]

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.

Expanding the genetic code

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Schultz has 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. Normally, the unnatural amino acid itself must be synthesized in the lab and supplied to the organism by adding it to the organism's growth medium. The unnatural amino acid must also be able to pass through the organism's cell membrane into the interior of the organism.

More than 70 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.

A bacterial organism has been generated which biosynthesizes a novel, previously unnatural amino acid (p-aminophenylalanine) from basic carbon sources and includes this amino acid in its genetic code.[14][15] This is the first example of the creation of an autonomous twenty-one-amino-acid organism.

Unnatural genetic information

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Schultz's group has recently created bacteria whose chromosomes include unnatural DNA-bases, and bacteria whose chromosomes are hybrids which include both RNA and DNA.[16][17]

Origins of mitochondria

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In order to probe details of the traditionally accepted hypothesis that mitochondria originated when independent bacteria capable of respiratory (oxygen-dependent) metabolism took up residence inside host cells which had previously only been capable of fermentation (metabolism without using oxygen), and evolved to establish a symbiotic relationship with them,[18] Schultz's group has created bacteria capable of surviving inside yeast cells and maintaining a symbiotic relationship with the host yeast cells by carrying out reactions which the yeast cells cannot catalyze without the bacteria.[19] One goal of this work is to culture the yeast-bacteria hybrids and see whether the bacterial genome evolves to increase the mutual benefits of its chemical interactions with the host cells, as has happened with mitochondria over time.[20]

ReFRAME drug repurposing library

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Schultz and his team at the Calibr-Skaggs Institute for Innovative Medicines recognized that the chemical diversity and known safety profiles of drugs that had previously been tested in humans make them valuable to further explore for other potential therapeutic targets aside from originally intended use. This idea of "drug repurposing" is an appealing strategy for advancing a given drug with less time and resources from a candidate and into clinical application, and led to the creation of the ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) drug repurposing library. ReFRAME offers open-access drug repositioning screening of around 13,000 compounds, nearly all of which are small molecules that have reached clinical development or seen significant preclinical profiling.

The library was created by combining three widely used commercial drug databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects) along with patent mining of small molecules dosed in humans. One of the library's first major successes screened its collection against Cryptosporidium spp., a major cause of childhood diarrhea in developing countries.[21] The library found two compounds (VB-201 and a structurally related analog of ASP-7962) previously tested in humans for other therapeutic uses that subsequently showed to be effective in animal models of the infection, providing novel candidates.[22]

Commercial activities

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Schultz is a founder of several biotechnology startups, including Affymax Research Institute, Symyx Technologies, Syrrx, Kalypsys, Phenomix, Ilypsa, Ambrx, Ardelyx, and Wildcat Discovery Technologies.[23][24][25][26][27][28][29]

Flywheel for scientific investment

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At Scripps Research, Schultz has pioneered a "bench-to-bedside" model that is uncommon in the nonprofit research space. Through the establishment of the Calibr-Skaggs Institute for Innovative Medicines and a merger with the Scripps Research Translational Institute, as well as the formation of partnerships with pharmaceutical companies during his time as CEO and President of Scripps Research, Schultz has worked to accelerate fundamental scientific research into drug discovery and real-world medical advances. This model, based on the flywheel effect, has created a self-renewing revenue stream in which novel medicines that arise from the institute's scientific findings lead to revenue that is then reinvested in institute research programs and used to further expand research capabilities. The strategy has helped Scripps Research to overcome the funding challenges typically faced by scientific research institutions.

Publications and retractions

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Schultz has authored around 790 papers. [12][30]

One of his papers in 2013 PNAS about making more stable antibodies was retracted, due to suspect data from co-author Shiladitya Sen:

  • Wang, F; Sen, S; Zhang, Y; Ahmad, I; Zhu, X; Wilson, IA; Smider, VV; Magliery, TJ; Schultz, PG (12 March 2013). "Somatic hypermutation maintains antibody thermodynamic stability during affinity maturation". Proceedings of the National Academy of Sciences of the United States of America. 110 (11): 4261–6. Bibcode:2013PNAS..110.4261W. doi:10.1073/pnas.1301810110. PMC 3600448. PMID 23440204. (Retracted, see doi:10.1073/pnas.1712805114, PMID 28874538,  Retraction Watch)

Two papers from his lab published in 2004, one in Science and one in Journal of the American Chemical Society, were retracted in 2009, related to work in the Shultz lab by a postdoc, Zhiwen Zhang, on incorporating non-native glycosylated amino acids into proteins. Had it succeeded, this method could have become an essential tool for investigating the functions of carbohydrate attachments to proteins; however, the work could not be replicated, and when the lab went to find the relevant notebooks, they were missing. In the course of the investigation, Zhang received emails and phone calls blackmailing him, and at one point the person doing this wrote to several institutions and Science saying that he or she was going to commit suicide. The lab eventually identified the problem as a misunderstanding of the function of a key enzyme used in the experiments.[31] The papers were:

Awards

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Schultz is a member of the American National Academy of Sciences (1993), and the Institute of Medicine of the National Academy of Sciences (1998).[5]

References

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  1. ^ "From Bench to Bedside". Alta Online. 2019-04-22. Retrieved 2024-11-14.
  2. ^ "Xconomy: Peter Schultz Exits Top Job at Genomics Institute of the Novartis Research Foundation". 2010-07-14.
  3. ^ www.fitchratings.com https://www.fitchratings.com/research/us-public-finance/fitch-upgrades-scripps-research-ca-rev-bonds-to-a-outlook-positive-05-02-2024. Retrieved 2024-11-14. {{cite web}}: Missing or empty |title= (help)
  4. ^ Huggett, Brady; Paisner, Kathryn (7 August 2014). "Top 20 translational researchers in 2013". Nature Biotechnology. 32 (8): 720. doi:10.1038/nbt.2986. PMID 25101739.
  5. ^ a b "Carl Shipp Marvel Lecturer 2008-09 - Peter G. Schultz | Chemistry at Illinois".
  6. ^ "calibr | California Institute for Biomedical Research>". Archived from the original on 2012-03-19.
  7. ^ "Merck to create institute, hire 150 in la Jolla". 2012-03-15.
  8. ^ "Merck's New Model for Collaboration". Chemical & Engineering News.
  9. ^ Service, R. F. (15 March 2012). "New Institute Aims to Help Academics Make Medicines". Science. 335 (6074): 1288–1289. Bibcode:2012Sci...335.1288S. doi:10.1126/science.335.6074.1288. PMID 22422951.
  10. ^ www.fitchratings.com https://www.fitchratings.com/research/us-public-finance/fitch-upgrades-scripps-research-ca-rev-bonds-to-a-outlook-positive-05-02-2024. Retrieved 2024-11-14. {{cite web}}: Missing or empty |title= (help)
  11. ^ "From Bench to Bedside". Alta Online. 2019-04-22. Retrieved 2024-11-14.
  12. ^ a b Curriculum Vitae Archived 2008-03-28 at the Wayback Machine
  13. ^ Lyssiotis, Costas A.; Foreman, Ruth K.; Staerk, Judith; Garcia, Michael; Mathur, Divya; Markoulaki, Styliani; Hanna, Jacob; Lairson, Luke L.; Charette, Bradley D.; Bouchez, Laure C.; Bollong, Michael; Kunick, Conrad; Brinker, Achim; Cho, Charles Y.; Schultz, Peter G.; Jaenisch, Rudolf (2 June 2009). "Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4". Proceedings of the National Academy of Sciences of the United States of America. 106 (22): 8912–8917. Bibcode:2009PNAS..106.8912L. doi:10.1073/pnas.0903860106. PMC 2690053. PMID 19447925.
  14. ^ "The Peter G. Schultz Laboratory". Archived from the original on 2010-05-23.}
  15. ^ "Context :: 21-amino-acid bacteria: Expanding the genetic code".
  16. ^ "Research".
  17. ^ Mehta, Angad P.; Wang, Yiyang; Reed, Sean A.; Supekova, Lubica; Javahishvili, Tsotne; Chaput, John C.; Schultz, Peter G. (30 August 2018). "Bacterial Genome Containing Chimeric DNA–RNA Sequences". Journal of the American Chemical Society. 140 (36): 11464–11473. doi:10.1021/jacs.8b07046. PMID 30160955. S2CID 52132524.
  18. ^ Martin, William F.; Mentel, Marek (2010). "The Origin of Mitochondria". Nature Education. 3 (9): 58.
  19. ^ Mehta, Angad P.; Supekova, Lubica; Chen, Jian-Hua; Pestonjamasp, Kersi; Webster, Paul; Ko, Yeonjin; Henderson, Scott C.; McDermott, Gerry; Supek, Frantisek; Schultz, Peter G. (13 November 2018). "Engineering yeast endosymbionts as a step toward the evolution of mitochondria". Proceedings of the National Academy of Sciences. 115 (46): 11796–11801. Bibcode:2018PNAS..11511796M. doi:10.1073/pnas.1813143115. PMC 6243291. PMID 30373839.
  20. ^ Mehta, Angad P.; Ko, Yeonjin; Supekova, Lubica; Pestonjamasp, Kersi; Li, Jack; Schultz, Peter G. (16 August 2019). "Toward a Synthetic Yeast Endosymbiont with a Minimal Genome". Journal of the American Chemical Society. 141 (35): 13799–13802. doi:10.1021/jacs.9b08290. PMC 6999831. PMID 31419116.
  21. ^ Danish Iqbal, Mariam; Naeem, Tahir; Khurshid, Umar; Hameed, Fatima (Jan–Feb 2021). "Frequency of Cryptosporidiosis in Children Having Persistent Diarrhea". Pakistan Journal of Medical Sciences. 37 (1): 121–124. PMC 7794158. PMID 33437262.
  22. ^ Ktori, Sophia (2018-10-04). "Unique Drug Repurposing Collection Made Available as Public Resource". GEN - Genetic Engineering and Biotechnology News. Retrieved 2024-11-19.
  23. ^ "Biographies of Silicon Valley protagonists". www.scaruffi.com. Retrieved 2024-11-14.
  24. ^ Duncan, David Ewing (2004-02-22). "Biotech on brink of breakthroughs". SFGATE. Retrieved 2024-11-14.
  25. ^ "Kalypsys Patents - Insights & Stats (Updated 2023)". Insights;Gate. Retrieved 2024-11-14.
  26. ^ "Amgen Goes Chemicals". Chemical & Engineering News. Retrieved 2024-11-14.
  27. ^ "Peter Schultz, Ph.D. | Ambrx". 2021-06-09. Retrieved 2024-11-14.
  28. ^ "Ardelyx: Strong Sales Growth and Reimbursement Prospects Justify Buy Rating". markets.businessinsider.com. 2024-11-11. Retrieved 2024-11-14.
  29. ^ Technologies, Wildcat Discovery (2024-10-03). "Peter Schultz | Founder & Scientific Advisor to Wildcat". Wildcat. Retrieved 2024-11-14.
  30. ^ "Peter G. Schultz's research while affiliated with The Scripps Research Institute and other places". ResearchGate.
  31. ^ Service, Robert F. (2009). "A Dark Tale behind Two Retractions". Science. 326 (5960): 1610–1611. Bibcode:2009Sci...326.1610S. doi:10.1126/science.326.5960.1610. JSTOR 27736671. PMID 20019260.
  32. ^ "American Institute of Chemists Gold Medal". Science History Institute. Retrieved 2024-11-18.
  33. ^ Hutchins, Shana K. "Scripps Research Biochemist Peter Schultz To Receive 2022 Scott Medal". artsci.tamu.edu. Retrieved 2024-11-18.
  34. ^ "NAS Award in Chemical Sciences – NAS". www.nasonline.org/. Retrieved 2024-11-18.
  35. ^ "Peter Schultz wins Tetrahedron Prize for Creativity in Organic Chemistry".
  36. ^ "Yale awards nine honorary degrees at Commencement 2015". 2015-05-15.
  37. ^ "AAAS Council Elects 388 New AAAS Fellows | American Association for the Advancement of Science (AAAS)". www.aaas.org. Retrieved 2024-11-18.
  38. ^ "Peter Schultz to Receive Solvay Prize | Chemical & Engineering News".
  39. ^ "Honorary doctorates - Uppsala University, Sweden". 9 June 2023.
  40. ^ "NSF Award Search: Award # 8451306 - Presidential Young Investigator Award/Design and Synthesis of Biological Catalysts". www.nsf.gov. Retrieved 2024-11-18.
  41. ^ "Past Recipients". American Chemical Society. Retrieved 2024-11-18.
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