Stuart Schreiber

Stuart L. Schreiber (born 6 February 1956) is a scientist at Harvard University and co-Founder of the Broad Institute. He has been active in chemical biology, especially the use of small molecules as probes of biology and medicine. Small molecules are the molecules of life most associated with dynamic information flow; these work in concert with the macromolecules (DNA, RNA, proteins) that are the basis for inherited information flow.

Stuart L. Schreiber
Born (1956-02-06) February 6, 1956
Alma materUniversity of Virginia
Harvard University
Known forOrganic Synthesis
Chemical Biology
Human Biology
Therapeutics Discovery
AwardsArthur C. Cope Award (2015)
Wolf Prize (2016)
Scientific career
FieldsChemical Biology
InstitutionsYale University
Harvard University
Broad Institute
Doctoral advisorRobert Burns Woodward
Yoshito Kishi

Education and training

Schreiber obtained a Bachelor of Science degree in chemistry from the University of Virginia in 1977, after which he entered Harvard University as a graduate student in Chemistry. He joined the research group of Robert B. Woodward and after Woodward's death continued his studies under the supervision of Yoshito Kishi. In 1980, he joined the faculty of Yale University as an assistant professor in Chemistry, and in 1988 he moved to Harvard University as the Morris Loeb Professor.

Work in 1980s and 1990s

Schreiber started his research work in organic synthesis, focusing on concepts such as the use of [2 + 2] photocycloadditions to establish stereochemistry in complex molecules, the fragmentation of hydroperoxides to produce macrolides, ancillary stereocontrol, group selectivity and two-directional synthesis. Notable accomplishments include the total syntheses of complex natural products such as talaromycin B, asteltoxin, avenaciolide, gloeosporone, hikizimicin, mycoticin A, epoxydictymene[1] and the immunosuppressant FK-506.

Following his work on the FK506-binding protein FKBP12 in 1988, Schreiber reported that the small molecules FK506 and cyclosporin inhibit the activity of the phosphatase calcineurin by forming the ternary complexes FKBP12-FK506-calcineurin and cyclophilin-ciclosporin-calcineurin.[2] This work, together with work by Gerald Crabtree at Stanford University concerning the NFAT proteins, led to the elucidation of the calcium-calcineurin-NFAT signaling pathway.[3] The Ras-Raf-MAPK pathway was not elucidated for another year.

In 1993, Schreiber and Crabtree developed "small-molecule dimerizers", which provide small-molecule activation over numerous signaling molecules and pathways (e.g., the Fas, insulin, TGFβ and T-cell receptors[4][5]) through proximity effects. Schreiber and Crabtree demonstrated that small molecules could activate a signaling pathway in an animal with temporal and spatial control.[6] Dimerizer kits have been distributed freely resulting in many peer-reviewed publications. Its promise in gene therapy has been highlighted by the ability of a small molecule to activate a small-molecule regulated EPO receptor and to induce erythropoiesis (Ariad Pharmaceuticals, Inc.), and more recently in human clinical trials for treatment of graft-vs-host disease.[7]

In 1994, Schreiber and co-workers investigated (independently with David Sabitini) the master regulator of nutrient sensing, mTOR. They found that the small molecule rapamycin simultaneously binds FKBP12 and mTOR (originally named FKBP12-rapamycin binding protein, FRAP).[8] Using diversity-oriented synthesis and small-molecule screening, Schreiber illuminate the nutrient-response signaling network involving TOR proteins in yeast and mTOR in mammalian cells. Small molecules such as uretupamine[9] and rapamycin were shown to be particularly effective in revealing the ability of proteins such as mTOR, Tor1p, Tor2p, and Ure2p to receive multiple inputs and to process them appropriately towards multiple outputs (in analogy to multi-channel processors). Several pharmaceutical companies are now targeting the nutrient-signaling network for the treatment of several forms of cancer, including solid tumors.[10]

In 1995, Schreiber and co-workers found that the small molecule lactacystin binds and inhibits specific catalytic subunits of the proteasome,[11] a protein complex responsible for the bulk of proteolysis in the cell, as well as proteolytic activation of certain protein substrates. As a non-peptidic proteasome inhibitor lactacysin has proven useful in the study of proteasome function. Lactacystin modifies the amino-terminal threonine of specific proteasome subunits. This work helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal threonine protease. The work led to the use of bortezomib to treat multiple myeloma.

In 1996, Schreiber and co-workers used the small molecules trapoxin and depudecin to investigate the histone deacetylases (HDACs).[12] Prior to Schreiber's work in this area, the HDAC proteins had not been isolated. Coincident with the HDAC work, David Allis and colleagues reported work on the histone acetyltransferases (HATs). These two contributions catalyzed much research in this area, eventually leading to the characterization of numerous histone-modifying enzymes, their resulting histone “marks”, and numerous proteins that bind to these marks. By taking a global approach to understanding chromatin function, Schreiber proposed a “signaling network model” of chromatin and compared it to an alternative view, the “histone code hypothesis” presented by Strahl and Allis.[13] These studies shined a bright light on chromatin as a key gene expression regulatory element rather than simply a structural element used for DNA compaction.

Chemical biology

Schreiber applied small molecules to biology through the development of diversity-oriented synthesis (DOS),[14] chemical genetics,[15] and ChemBank.[16] Schreiber has shown that DOS can produce small molecules distributed in defined ways in chemical space by virtue of their different skeletons and stereochemistry, and that it can provide chemical handles on products anticipating the need for follow-up chemistry using, for example, combinatorial synthesis and the so-called Build/Couple/Pair strategy of modular chemical synthesis. DOS pathways and new techniques for small-molecule screening [17][18][19] provided many new, potentially disruptive insights into biology. Small-molecule probes of histone and tubulin deacetylases, transcription factors, cytoplasmic anchoring proteins, developmental signaling proteins (e.g., histacin, tubacin, haptamide, uretupamine, concentramide, and calmodulophilin), among many others, have been uncovered in the Schreiber lab using diversity-oriented synthesis and chemical genetics. Multidimensional screening was introduced in 2002 and has provided insights into tumorigenesis, cell polarity, and chemical space, among others.[20]

Schreiber also contributed to more conventional small molecule discovery projects. He collaborated with Tim Mitchison to discover monastrol – the first small-molecule inhibitor of mitosis that does not target tubulin.[21] Monastrol was shown to inhibit kinesin-5, a motor protein and was used to gain new insights into the functions of kinesin-5. This work led pharmaceutical company Merck, among others, to pursue anti-cancer drugs that target human kinesin-5.

Schreiber has used small molecules to study three specific areas of biology, and then through the more general application of small molecules in biomedical research. Academic screening centers have been created that emulate the Harvard Institute of Chemistry and Cell Biology and the Broad Institute; in the U.S., there has been a nationwide effort to expand this capability via the government-sponsored NIH Road Map. Chemistry departments have changed their names to include the term chemical biology and new journals have been introduced (Cell Chemical Biology, ChemBioChem, Nature Chemical Biology, ACS Chemical Biology]) to cover the field. Schreiber has been involved in the founding of numerous biopharmaceutical companies whose research relies on chemical biology: Vertex Pharmaceuticals, Inc. (VRTX), Ariad Pharmaceuticals, Inc. (ARIA), Infinity Pharmaceuticals, Inc (INFI), Forma Therapeutics, H3 Biomedicine and Jnana Therapeutics. These companies have produced new therapeutics in several disease areas, including cystic fibrosis and cancer.[22]

Other research

Schreiber has collaborated with the pharmaceutical company Eisai.[23] Other work focused on targeting the cancer therapy-resistant states.[24]

Selected awards
  • ACS Award in Pure Chemistry (1989) "For pioneering investigations into the synthesis and mode of action of natural products."
  • Ciba-Geigy Drew Award for Biomedical Research: Molecular Basis for Immune Regulation (1992). "For the discovery of immunophilins and for his role in elucidating the calcium-calcineurin-NFAT signaling pathway."
  • Leo Hendrik Baekeland Award, North Jersey Section of ACS (1993). "For outstanding achievement in creative chemistry."
  • Eli Lilly Award in Biological Chemistry, ACS (1993). "For fundamental research in biological chemistry."
  • American Chemical Society Award in Synthetic Organic Chemistry (1994). "For creative accomplishments at the interface of organic synthesis, molecular biology, and cell biology as exemplified by landmark discoveries in the immunophilin area."
  • George Ledlie Prize (Harvard University) (1994). "For his research which has profoundly influenced out understanding of the chemistry of cell biology and illuminated fundamental processes of molecular recognition and signaling in cell biology."
  • Paul Karrer Gold Medal (1994) at the University of Zurich.
  • Harrison Howe Award (1995). "In recognition of accomplishments in the synthesis of complex organic molecules, progress in understanding the immunosuppressant action of FK506, and innovation in molecular recognition and its role in intracellular signaling."
  • Warren Triennial Award (shared with Leland Hartwell) (1995). "For creating a new field in organic chemistry, what Phil Sharp has coined 'chemical cell biology.' In these studies, small molecules have been synthesized and used to understand and control signal transduction pathways. Schreiber has made it possible to generalize the use of small molecules to study protein function in analogy to the use of mutations in genetics. This approach has illuminated fundamental processes in cell biology and has great promise in medicine."
  • Tetrahedron Prize for Creativity in Organic Chemistry (1997). "For his fundamental contributions to chemical synthesis with biological and medicinal implications."
  • ACS Award for Bioorganic Chemistry (2000). "For his development of the field of chemical genetics, where small molecules are used to dissect the circuitry of cells using genetic-like screens."
  • William H. Nichols Medal (2001). "For contributions toward understanding the chemistry of intracellular signaling."
  • Chiron Corporation Biotechnology Research Award, American Academy of Microbiology (2001). "For the development of systematic approaches to biology using small molecules."
  • Society for Biomolecular Screening Achievement Award (2004). "In recognition of the advances made in the field of chemical biology through the development and application of tools that enable the systematic use of small molecules to elucidate fundamental biological pathways."
  • American Association of Cancer Institutes (2004). "For his development of the field of chemical biology, which has resulted in a new approach to the treatment of cancer."
  • Arthur C. Cope Award (2014)
  • Nagoya Gold Medal (2015)
  • Wolf Prize (2016). "For pioneering chemical insights into the logic of signal transduction and gene regulation that led to important, new therapeutics and for advancing chemical biology and medicine through the discovery of small-molecule probes."
  • National Academy of Medicine, elected 2018[25]
gollark: Oh, have you seen Basilisk?
gollark: What if I wish for proof that it works?
gollark: Just give everyone neural implants allowing thought broadcasting‽
gollark: > I love how that'd push implementation difficulty from "completely infeasible" to "physically impossible"WRONG!
gollark: Real men just attach jumper cables to the RAM.

Notes and references
  1. Jamison, Timothy F.; Shambayati, Soroosh; Crowe, William E.; Schreiber, Stuart L. (1994-06-01). "Cobalt-Mediated Total Synthesis of (+)-Epoxydictymene". Journal of the American Chemical Society. 116 (12): 5505–5506. doi:10.1021/ja00091a079. ISSN 0002-7863.
  2. Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (August 1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes". Cell. 66 (4): 807–15. doi:10.1016/0092-8674(91)90124-H. PMID 1715244.
  3. Schreiber SL, Crabtree GR (1995). "Immunophilins, ligands, and the control of signal transduction". Harvey Lectures. 91: 99–114. PMID 9127988.
  4. Yang J, Symes K, Mercola M, Schreiber SL (January 1998). "Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment". Current Biology. 8 (1): 11–8. doi:10.1016/S0960-9822(98)70015-6. PMID 9427627.
  5. Stockwell BR, Schreiber SL (June 1998). "Probing the role of homomeric and heteromeric receptor interactions in TGF-beta signaling using small molecule dimerizers". Current Biology. 8 (13): 761–70. doi:10.1016/S0960-9822(98)70299-4. PMID 9651680.
  6. "Functional Analysis of Fas Signaling in vivo Using Synthetic Dimerizers" David Spencer, Pete Belshaw, Lei Chen, Steffan Ho, Filippo Randazzo, Gerald R. Crabtree, Stuart L. Schreiber Curr. Biol. 1996, 6, 839-848.
  7. Di Stasi, Antonio; Tey, Siok-Keen; Dotti, Gianpietro; Fujita, Yuriko; Kennedy-Nasser, Alana; Martinez, Caridad; Straathof, Karin; Liu, Enli; Durett, April G. (2011-11-03). "Inducible Apoptosis as a Safety Switch for Adoptive Cell Therapy". New England Journal of Medicine. 365 (18): 1673–1683. doi:10.1056/nejmoa1106152. ISSN 0028-4793. PMC 3236370. PMID 22047558.
  8. Brown EJ, Albers MW, Shin TB, et al. (June 1994). "A mammalian protein targeted by G1-arresting rapamycin-receptor complex". Nature. 369 (6483): 756–8. Bibcode:1994Natur.369..756B. doi:10.1038/369756a0. PMID 8008069.
  9. "Dissection of a glucose-sensitive pathway of the nutrient-response network using diversity-oriented synthesis and small molecule microarrays" Finny G. Kuruvilla, Alykhan F. Shamji, Scott M. Sternson, Paul J. Hergenrother, Stuart L. Schreiber, Nature, 2002, 416, 653-656.
  10. Shamji AF, Nghiem P, Schreiber SL (August 2003). "Integration of growth factor and nutrient signaling: implications for cancer biology". Molecular Cell. 12 (2): 271–80. doi:10.1016/j.molcel.2003.08.016. PMID 14536067.
  11. Fenteany G, Standaert RF, Lane WS, Choi S, Corey EJ, Schreiber SL (1995). "Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin". Science. 268 (5211): 726–31. Bibcode:1995Sci...268..726F. doi:10.1126/science.7732382. PMID 7732382.
  12. Taunton J, Hassig CA, Schreiber SL (April 1996). "A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p". Science. 272 (5260): 408–11. Bibcode:1996Sci...272..408T. doi:10.1126/science.272.5260.408. PMID 8602529.
  13. Schreiber SL, Bernstein BE (December 2002). "Signaling network model of chromatin". Cell. 111 (6): 771–8. doi:10.1016/S0092-8674(02)01196-0. PMID 12526804.
  14. (a) Schreiber SL (March 2000). "Target-oriented and diversity-oriented organic synthesis in drug discovery". Science. 287 (5460): 1964–9. Bibcode:2000Sci...287.1964S. doi:10.1126/science.287.5460.1964. PMID 10720315. (b) Burke MD, Berger EM, Schreiber SL (October 2003). "Generating diverse skeletons of small molecules combinatorially". Science. 302 (5645): 613–8. Bibcode:2003Sci...302..613B. doi:10.1126/science.1089946. PMID 14576427. (c) Burke MD, Schreiber SL (January 2004). "A planning strategy for diversity-oriented synthesis". Angewandte Chemie. 43 (1): 46–58. doi:10.1002/anie.200300626. PMID 14694470.
  15. "The small-molecule approach to biology: Chemical genetics and diversity-oriented organic synthesis make possible the systematic exploration of biology”, S L Schreiber, C&E News, 2003, 81, 51-61.
  16. Strausberg RL, Schreiber SL (April 2003). "From knowing to controlling: a path from genomics to drugs using small molecule probes". Science. 300 (5617): 294–5. Bibcode:2003Sci...300..294S. doi:10.1126/science.1083395. PMID 12690189.
  17. Stockwell BR, Haggarty SJ, Schreiber SL (February 1999). "High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications". Chemistry & Biology. 6 (2): 71–83. doi:10.1016/S1074-5521(99)80004-0. PMID 10021420.
  18. "Printing Small Molecules as Microarrays and Detecting Protein-Ligand Interactions en Masse" Gavin MacBeath, Angela N. Koehler, Stuart L. Schreiber J. Am. Chem. Soc. 1999, 121, 7967-7968.
  19. MacBeath G, Schreiber SL (September 2000). "Printing proteins as microarrays for high-throughput function determination". Science. 289 (5485): 1760–3. Bibcode:2000Sci...289.1760M. doi:10.1126/science.289.5485.1760 (inactive 2020-03-05). PMID 10976071.
  20. Schreiber SL (July 2005). "Small molecules: the missing link in the central dogma". Nature Chemical Biology. 1 (2): 64–6. doi:10.1038/nchembio0705-64. PMID 16407997.
  21. Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (October 1999). "Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen". Science. 286 (5441): 971–4. doi:10.1126/science.286.5441.971. PMID 10542155.
  22. Wainwright, Claire E.; Elborn, J. Stuart; Ramsey, Bonnie W.; Marigowda, Gautham; Huang, Xiaohong; Cipolli, Marco; Colombo, Carla; Davies, Jane C.; De Boeck, Kris (2015-07-16). "Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR". New England Journal of Medicine. 373 (3): 220–231. doi:10.1056/NEJMoa1409547. ISSN 0028-4793. PMC 4764353. PMID 25981758.
  23. Kato, Nobutaka; Comer, Eamon; Sakata-Kato, Tomoyo; Sharma, Arvind; Sharma, Manmohan; Maetani, Micah; Bastien, Jessica; Brancucci, Nicolas M.; Bittker, Joshua A. (2016). "Diversity-oriented synthesis yields novel multistage antimalarial inhibitors". Nature. 538 (7625): 344–349. Bibcode:2016Natur.538..344K. doi:10.1038/nature19804. PMC 5515376. PMID 27602946.
  24. Viswanathan, Vasanthi S.; Ryan, Matthew J.; Dhruv, Harshil D.; Gill, Shubhroz; Eichhoff, Ossia M.; Seashore-Ludlow, Brinton; Kaffenberger, Samuel D.; Eaton, John K.; Shimada, Kenichi (2017). "Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway". Nature. 547 (7664): 453–457. doi:10.1038/nature23007. PMC 5667900. PMID 28678785.
  25. "National Academy of Medicine Elects 85 New Members". National Academy of Medicine. 15 October 2018. Retrieved 2 May 2019.
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