Stuart Schreiber

Stuart L. Schreiber
Born (1956-02-06) February 6, 1956
Fields Chemical Biology
Institutions Harvard University, Broad Institute
Alma mater University of Virginia, Harvard University
Doctoral advisor Yoshito Kishi
Known for Organic Synthesis
Notable awards ACS Award in Pure Chemistry (1989)
Ciba-Geigy Drew Award for Biomedical Research (1992)
Wolf Prize (2016)

Stuart L. Schreiber (born 6 February 1956) is a scientist at Harvard University and the Broad Institute. He has been a pioneer in chemical biology for over 20 years. His name is closely associated with the increasingly common 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. During the 1980s and '90s, he provided dramatic advances in biology using this approach, and, in the past ten years, his systematization efforts have made this one of the fastest growing areas of life-science research.

Education and Training

Schreiber obtained a Bachelor of Science degree in Chemistry from the University of Virginia, 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.

Key discoveries, 1980s and 1990s

Schreiber started his research work in Organic Synthesis, pioneering concepts such as the use of photocycloaddition 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 and the immunosuppressant FK-506.

Following his co-discovery of 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.[1] 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.[2] This landmark discovery, an early example of defining an entire cellular signaling pathway from the cell surface to the nucleus, can be appreciated when it is considered that 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[3][4]) through proximity effects. Schreiber and Crabtree demonstrated that small molecules could activate a signaling pathway in an animal with temporal and spatial control.[5] Dimerizer kits have been distributed freely to (as of February, 2005) 898 laboratories at 395 different institutions worldwide, resulting thus far in over 250 peer-reviewed publications from the scientific community. Its promise in gene therapy has been highlighted by the ability of a small molecule to induce production of Erythropoietin (EPO) in primates without diminution over, thus far, a six-year period, and more recently in phase II human clinical trials for treatment of graft-vs-host disease (ARIAD Pharmaceuticals, Inc.).

In 1994, Schreiber and co-workers discovered that the small molecule rapamycin simultaneously binds FKBP12 and mTOR (originally named FKBP12-rapamycin binding protein, FRAP).[6] Using diversity-oriented synthesis and small-molecule screening, Schreiber helped illuminate the nutrient-response signaling network involving TOR proteins in yeast and mTOR in mammalian cells. Small molecules such as uretupamine[7] 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.[8]

In 1995, Schreiber and co-workers discovered that the small molecule lactacystin binds and inhibits specific catalytic subunits of the proteasome,[9] a protein complex responsible for the bulk of proteolysis in the cell, as well as proteolytic activation of certain protein substrates. Lactacysin was the first non-peptidic proteasome inhibitor discovered and has become a major tool for the study of proteasome function in biochemistry and cell biology. Lactacystin modifies the amino-terminal threonine of specific proteasome subunits. This discovery helped to establish the proteasome as a mechanistically novel class of protease: an amino-terminal threonine protease.

In 1996, Schreiber and co-workers used the small molecules trapoxin and depudecin to characterize molecularly the histone deacetylases (HDACs).[10] Prior to Schreiber’s work in this area, the HDAC proteins had not been isolated – despite many attempts by others in the field who had been inspired by Allfrey's detection of the enzymatic activity in cell extracts over 30 years earlier. Coincident with the HDAC discovery, David Allis and colleagues reported their discovery of 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.[11] The work by chromatin researchers has shined a bright light on chromatin as a key regulatory element rather than simply a structural element.

Advancing chemical biology through the 1990s and 2000s

During the past 10 years, Schreiber has attempted to systematize the application of small molecules to biology through the development of diversity-oriented synthesis (DOS),[12] chemical genetics,[13] and ChemBank.[14] 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 [15][16][17] provided many new, potentially disruptive insights into biology. For example, Schreiber and collaborator Tim Mitchison used cytoblot screening to discover monastrol – the first small-molecule inhibitor of mitosis that does not target tubulin. Monastrol was shown to inhibit kinesin-5, a motor protein[18] 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. 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 discovered 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.[19] More than 100 laboratories from over 30 institutions have performed small-molecule screens at the screening center he developed (Broad Chemical Biology (BCB), formerly the Harvard ICCB), leading to many small-molecule probes (81 probes were reported in the 2004 literature alone) and insights into biology. To facilitate the open sharing of small-molecule-based insights, Schreiber pioneered the development of the assay-data repository and analysis environment named ChemBank, which was launched on the Internet in 2003. A complete rework of ChemBank (v2.0), which makes accessible to the public results and analyses from 1,209 small-molecule screens that have yielded 87 million measurements, was re-launched in March 2006.

Schreiber’s laboratory has served as a focal point for the field of chemical biology, first by the ad hoc use of small molecules to study three specific areas of biology, and then through the more general application of small molecules in biomedical research. As a principal architect of chemical biology, he has influenced the public and private research communities. Academic screening centers have been created that emulate the Broad Institute Chemical Biology Program; 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 (Chemistry & Biology, ChemBioChem, Nature Chemical Biology, ACS Chemical Biology) to cover the field. Schreiber has been involved in the founding of three biopharmaceutical companies based on chemical biology principles: Vertex Pharmaceuticals, Inc. (VRTX), Ariad Pharmaceuticals, Inc. (ARIA), and Infinity Pharmaceuticals, Inc (INFI). These companies have produced new medicines in several areas of disease, including AIDS and cancer.

Selected Awards

Notes and references

  1. 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.
  2. Schreiber SL, Crabtree GR (1995). "Immunophilins, ligands, and the control of signal transduction". Harvey Lectures. 91: 99–114. PMID 9127988.
  3. 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.
  4. 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.
  5. "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.
  6. 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. doi:10.1038/369756a0. PMID 8008069.
  7. "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.
  8. 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.
  9. 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: 726–31. doi:10.1126/science.7732382. PMID 7732382.
  10. Taunton J, Hassig CA, Schreiber SL (April 1996). "A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p". Science. 272 (5260): 408–11. doi:10.1126/science.272.5260.408. PMID 8602529.
  11. 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.
  12. (a) Schreiber SL (March 2000). "Target-oriented and diversity-oriented organic synthesis in drug discovery". Science. 287 (5460): 1964–9. 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. 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.
  13. "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.
  14. 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. doi:10.1126/science.1083395. PMID 12690189.
  15. 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.
  16. "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.
  17. MacBeath G, Schreiber SL (September 2000). "Printing proteins as microarrays for high-throughput function determination". Science. 289 (5485): 1760–3. doi:10.1126/science.289.5485.1760. PMID 10976071.
  18. 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.
  19. 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.
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