Peter G. Schultz

Last updated
Peter G. Schultz
Born (1956-06-23) June 23, 1956 (age 66)
Cincinnati, Ohio
Alma mater Caltech
Known for Chemical Biology
Awards ACS Award in Pure Chemistry (1990)
Wolf Prize (1994)
Scientific career
Fields Chemistry
Institutions The Scripps Research Institute,
Doctoral advisor Peter Dervan
Other academic advisors Christopher Walsh
Notable students David Liu
Sara Cherry
Nathanael Gray
Kevan M. Shokat
Virginia Cornish
Alice Y. Ting
Young-Tae Chang

Peter G. Schultz (born June 23, 1956) is an American chemist. He is the CEO and 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. In August 2014, Nature Biotechnology ranked Schultz the #1 top translational researcher in 2013. [3]

Contents

Academic career

Schultz completed his undergraduate degree at Caltech in 1979 and continued there for his doctoral degree (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. [4] 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. [5] [6] [7] [8] He has trained over 300 graduate students and postdoctoral fellows, many of whom are on the faculties of major research universities. [9]

Research

Combinatorial chemistry and molecular evolution

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 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 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. [10]

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

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 seventy 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. [11] [12] [13] This is the first example of the creation of an autonomous twenty-one-amino-acid organism.

Unnatural genetic information

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. [14] [15]

Origins of mitochondria

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, [16] 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. [17] 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. [18]

Commercial activities

He is a founder of Affymax Research Institute, Symyx Technologies, Syrrx, Kalypsys, Phenomix, Ilypsa, Ambrx, and Wildcat Discovery Technologies.[ citation needed ]

Publications and retractions

Schultz has authored around 500 papers. [9]

One of his papers in 2013 PNAS about making more stable antibodies was retracted, due to suspect data from co-author Shiladitya Sen:

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. [19] The papers were:

Awards

Schultz is a member of the National Academy of Sciences, USA (1993), the Institute of Medicine of the National Academy of Sciences (1998). [4]

Related Research Articles

<span class="mw-page-title-main">Genetic code</span> Rules by which information encoded within genetic material is translated into proteins

The genetic code is the set of rules used by living cells to translate information encoded within genetic material into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries.

<span class="mw-page-title-main">Metabolism</span> Set of chemical reactions in organisms

Metabolism is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the conversion of food to building blocks for proteins, lipids, nucleic acids, and some carbohydrates; and the elimination of metabolic wastes. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, and respond to their environments. The word metabolism can also refer to the sum of all chemical reactions that occur in living organisms, including digestion and the transportation of substances into and between different cells, in which case the above described set of reactions within the cells is called intermediary metabolism.

<span class="mw-page-title-main">Protein</span> Biomolecule consisting of chains of amino acid residues

Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific 3D structure that determines its activity.

<span class="mw-page-title-main">Selenocysteine</span> Chemical compound

Selenocysteine is the 21st proteinogenic amino acid. Selenoproteins contain selenocysteine residues. Selenocysteine is an analogue of the more common cysteine with selenium in place of the sulfur.

<span class="mw-page-title-main">Pyrrolysine</span> Chemical compound

Pyrrolysine is an α-amino acid that is used in the biosynthesis of proteins in some methanogenic archaea and bacteria; it is not present in humans. It contains an α-amino group, a carboxylic acid group. Its pyrroline side-chain is similar to that of lysine in being basic and positively charged at neutral pH.

<span class="mw-page-title-main">Coenzyme A</span> Coenzyme, notable for its synthesis and oxidation role

Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it (or a thioester) as a substrate. In humans, CoA biosynthesis requires cysteine, pantothenate (vitamin B5), and adenosine triphosphate (ATP).

<span class="mw-page-title-main">Transfer RNA</span> RNA that facilitates the addition of amino acids to a new protein

Transfer RNA is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length, that serves as the physical link between the mRNA and the amino acid sequence of proteins. tRNAs genes from Bacteria are typically shorter than tRNAs from Archaea and eukaryotes. The mature tRNA follows an opposite pattern with tRNAs from Bacteria being usually longer than tRNAs from Archaea, with eukaryotes exhibiting the shortest mature tRNAs. Transfer RNA (tRNA) does this by carrying an amino acid to the protein synthesizing machinery of a cell called the ribosome. Complementation of a 3-nucleotide codon in a messenger RNA (mRNA) by a 3-nucleotide anticodon of the tRNA results in protein synthesis based on the mRNA code. As such, tRNAs are a necessary component of translation, the biological synthesis of new proteins in accordance with the genetic code.

<span class="mw-page-title-main">Aminoacyl tRNA synthetase</span> Class of enzymes

An aminoacyl-tRNA synthetase, also called tRNA-ligase, is an enzyme that attaches the appropriate amino acid onto its corresponding tRNA. It does so by catalyzing the transesterification of a specific cognate amino acid or its precursor to one of all its compatible cognate tRNAs to form an aminoacyl-tRNA. In humans, the 20 different types of aa-tRNA are made by the 20 different aminoacyl-tRNA synthetases, one for each amino acid of the genetic code.

<span class="mw-page-title-main">Synthetic biology</span> Interdisciplinary branch of biology and engineering

Synthetic biology (SynBio) is a multidisciplinary field of science that focuses on living systems and organisms, and it applies engineering principles to develop new biological parts, devices, and systems or to redesign existing systems found in nature.

<span class="mw-page-title-main">Auxotrophy</span> Inability to synthesize an organic compound required for growth

Auxotrophy is the inability of an organism to synthesize a particular organic compound required for its growth. An auxotroph is an organism that displays this characteristic; auxotrophic is the corresponding adjective. Auxotrophy is the opposite of prototrophy, which is characterized by the ability to synthesize all the compounds needed for growth.

Xenobiology (XB) is a subfield of synthetic biology, the study of synthesizing and manipulating biological devices and systems. The name "xenobiology" derives from the Greek word xenos, which means "stranger, alien". Xenobiology is a form of biology that is not (yet) familiar to science and is not found in nature. In practice, it describes novel biological systems and biochemistries that differ from the canonical DNA–RNA-20 amino acid system. For example, instead of DNA or RNA, XB explores nucleic acid analogues, termed xeno nucleic acid (XNA) as information carriers. It also focuses on an expanded genetic code and the incorporation of non-proteinogenic amino acids into proteins.

Chemical biology is a scientific discipline between the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. In contrast to biochemistry, which involves the study of the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology deals with chemistry applied to biology.

<span class="mw-page-title-main">Directed evolution</span> Protein engineering method

Directed evolution (DE) is a method used in protein engineering that mimics the process of natural selection to steer proteins or nucleic acids toward a user-defined goal. It consists of subjecting a gene to iterative rounds of mutagenesis, selection and amplification. It can be performed in vivo, or in vitro. Directed evolution is used both for protein engineering as an alternative to rationally designing modified proteins, as well as for experimental evolution studies of fundamental evolutionary principles in a controlled, laboratory environment.

<span class="mw-page-title-main">Fatty acid synthase</span> Class of enzymes

Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the FASN gene.

<span class="mw-page-title-main">Acetolactate synthase</span> Class of enzymes

The acetolactate synthase (ALS) enzyme is a protein found in plants and micro-organisms. ALS catalyzes the first step in the synthesis of the branched-chain amino acids.

A cell-free system is an in vitro tool widely used to study biological reactions that happen within cells apart from a full cell system, thus reducing the complex interactions typically found when working in a whole cell. Subcellular fractions can be isolated by ultracentrifugation to provide molecular machinery that can be used in reactions in the absence of many of the other cellular components. Eukaryotic and prokaryotic cell internals have been used for creation of these simplified environments. These systems have enabled cell-free synthetic biology to emerge, providing control over what reaction is being examined, as well as its yield, and lessening the considerations otherwise invoked when working with more sensitive live cells.

Biomolecular engineering is the application of engineering principles and practices to the purposeful manipulation of molecules of biological origin. Biomolecular engineers integrate knowledge of biological processes with the core knowledge of chemical engineering in order to focus on molecular level solutions to issues and problems in the life sciences related to the environment, agriculture, energy, industry, food production, biotechnology and medicine.

<span class="mw-page-title-main">Nucleic acid analogue</span> Compound analogous to naturally occurring RNA and DNA

Nucleic acid analogues are compounds which are analogous to naturally occurring RNA and DNA, used in medicine and in molecular biology research. Nucleic acids are chains of nucleotides, which are composed of three parts: a phosphate backbone, a pentose sugar, either ribose or deoxyribose, and one of four nucleobases. An analogue may have any of these altered. Typically the analogue nucleobases confer, among other things, different base pairing and base stacking properties. Examples include universal bases, which can pair with all four canonical bases, and phosphate-sugar backbone analogues such as PNA, which affect the properties of the chain . Nucleic acid analogues are also called Xeno Nucleic Acid and represent one of the main pillars of xenobiology, the design of new-to-nature forms of life based on alternative biochemistries.

<span class="mw-page-title-main">Expanded genetic code</span> Modified genetic code

An expanded genetic code is an artificially modified genetic code in which one or more specific codons have been re-allocated to encode an amino acid that is not among the 22 common naturally-encoded proteinogenic amino acids.

<span class="mw-page-title-main">Organism</span> Any individual living being or physical living system

An organism is any biological living system that functions as an individual life form. All organisms are composed of cells. The idea of organism is based on the concept of minimal functional unit of life. Three traits have been proposed to play the main role in qualification as an organism:

References

  1. ↑ "Scripps Research Institute Names Peter Schultz as CEO, Steve Kay as President".
  2. ↑ "Xconomy: Peter Schultz Exits Top Job at Genomics Institute of the Novartis Research Foundation". 2010-07-14.
  3. ↑ 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.
  4. 1 2 "Carl Shipp Marvel Lecturer 2008-09 - Peter G. Schultz | Chemistry at Illinois".
  5. ↑ "calibr | California Institute for Biomedical Research>". Archived from the original on 2012-03-19.
  6. ↑ "Merck to create institute, hire 150 in la Jolla". 2012-03-15.
  7. ↑ "Merck's New Model for Collaboration". Chemical & Engineering News.
  8. ↑ 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.
  9. 1 2 Curriculum Vitae Archived 2008-03-28 at the Wayback Machine
  10. ↑ 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.
  11. ↑ "The Peter G. Schultz Laboratory". Archived from the original on 2010-05-23.
  12. ↑ Mehl, Ryan A.; Anderson, J. Christopher; Santoro, Stephen W.; Wang, Lei; Martin, Andrew B.; King, David S.; Horn, David M.; Schultz, Peter G. (January 2003). "Generation of a Bacterium with a 21 Amino Acid Genetic Code". Journal of the American Chemical Society. 125 (4): 935–939. doi:10.1021/ja0284153. PMID   12537491.
  13. ↑ "Context :: 21-amino-acid bacteria: Expanding the genetic code".
  14. ↑ "Research".
  15. ↑ 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.
  16. ↑ Martin, William F.; Mentel, Marek (2010). "The Origin of Mitochondria". Nature Education. 3 (9): 58.
  17. ↑ 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. doi: 10.1073/pnas.1813143115 . PMC   6243291 . PMID   30373839.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ "Peter Schultz wins Tetrahedron Prize for Creativity in Organic Chemistry".
  21. ↑ "Yale awards nine honorary degrees at Commencement 2015". 2015-05-15.
  22. ↑ "Peter Schultz to Receive Solvay Prize | Chemical & Engineering News".
  23. ↑ "Honorary doctorates - Uppsala University, Sweden".
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.