Cold Spring Harbor Laboratory

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Cold Spring Harbor Laboratory
CSH Logo.png
Established 1890
President Bruce Stillman
Staff 1,200
Budget $150,000,000
Location 1 Bungtown Road, Cold Spring Harbor, NY
Website http://www.cshl.edu/
Cold Spring Harbor Laboratory Historic District
Cold Spring Harbor Laboratory is located in New York
Cold Spring Harbor Laboratory
Location Jct. of NY 25A and Bungtown Rd., Laurel Hollow, New York
Coordinates 40°51′43″N 73°28′2″W / 40.86194°N 73.46722°W / 40.86194; -73.46722Coordinates: 40°51′43″N 73°28′2″W / 40.86194°N 73.46722°W / 40.86194; -73.46722
Area 100 acres (40 ha)
Architect Multiple
Architectural style Multiple
Governing body Private
NRHP Reference # 94000198[1]
Added to NRHP March 30, 1994

Cold Spring Harbor Laboratory (CSHL) is a private, non-profit institution with research programs focusing on cancer, neuroscience, plant genetics, genomics and quantitative biology.[2]

It is one of 68 institutions supported by the Cancer Centers Program of the U.S. National Cancer Institute (NCI) and has been an NCI-designated Cancer Center since 1987.[3] The Laboratory is one of a handful of institutions that played a central role in the development of molecular genetics and molecular biology.[4]

It has been home to eight scientists who have been awarded the Nobel Prize in Physiology or Medicine. CSHL is ranked among the leading basic research institutions in the world in molecular biology and genetics.[5] The Laboratory is led by Bruce Stillman, a biochemist and cancer researcher.

Since its inception in 1890, the institution’s campus on the north shore of Long Island has also been a center of biology education. Current CSHL educational programs serve professional scientists, doctoral students in biology, teachers of biology in the K-12 system, and students from the elementary grades through high school. The CSHL Meetings & Courses program annually draws over 8,500 scientists and students to the main campus.[6] For this reason, many scientists consider CSHL a “crossroads of biological science.”[7] CSH Asia [28], in Suzhou, China, annually draws some 3,000 scientists to its meetings and courses.

Research programs[edit]

Research staff in CSHL’s 52 laboratories numbers over 600, including postdoctoral researchers; an additional 125 graduate students and 500 administrative and support personnel bring the total number of employees to over 1,200.[8]

Cell biology and genomics
RNA interference (RNAi) and small-RNA biology; DNA replication; RNA splicing; signal transduction; genome structure; non-coding RNAs; deep sequencing; single-cell sequencing and analytics; chromatin dynamics; structural biology; advanced proteomics; mass spectrometry; advanced microscopy.

Cancer research
principal cancer types under study: breast, prostate, blood (leukemia, lymphoma); melanoma; liver; ovarian and cervical; lung; brain; pancreas. Research foci: drug resistance; cancer genomics; tumor microenvironment; growth control in mammalian cells; transcriptional and post-transcriptional gene regulation.

Neuroscience
Stanley Institute for Cognitive Genomics employs deep sequencing and other tools to study genetics underlying schizophrenia, bipolar disorder, and major depression. Swartz Center for the Neural Mechanisms of Cognition studies cognition in the normal brain as a baseline for understanding dysfunction in psychiatric and neurodegenerative disorders. Other research foci: autism genetics; mapping of the mammalian brain; neural correlates of decision making.

Plant genetics
plant genome sequencing; epigenetics and stem cell fate; stem cell signaling; using genetic insights to increase yield of staple crops, e.g., maize, rice, wheat; increase fruit yield in flowering plants, e.g., tomato. Other initiatives: genetics of aquatic plants for biofuel development; lead role in building National Science Foundation’s iPlant[9] cyberinfrastructure.

Simons Center for Quantitative Biology
genome assembly and validation; mathematical modeling and algorithm development; population genetics; applied statistical and machine learning; biomedical text-mining; computational genomics; cloud computing and Big Data.

Educational programs[edit]

In addition to its research mission, CSHL has a broad educational mission. The Watson School of Biological Sciences (WSBS), established in 1998, awards the Ph.D. degree and fully funds the research program of every student. Students are challenged to obtain their doctoral degree in 4–5 years. The Undergraduate Research Program (URP) for gifted college students (established in 1959), and the Partners for the Future Program for advanced high school students (established in 1990) are now hosted at the WSBS.

The CSHL Meetings & Courses Program brings over 8,500 scientists from around the world to Cold Spring Harbor annually to share research results – mostly unpublished—in 60 meetings, most held biannually; and to learn new technologies in 30 to 35 professional courses, most offered annually.[8] The Cold Spring Harbor Symposium series, held every year since 1933 with the exception of three years during the Second World War, has been a forum for researchers in genetics, genomics, neuroscience and plant biology. At the Banbury Center, about 25-30 discussion-style meetings are held yearly for a limited number of invited participants.

The DNA Learning Center (DNALC), founded in 1988, was among the early pioneers[10] in developing hands-on genetics lab experiences for middle and high school students. In 2013, 31,000 students on Long Island and New York City were taught genetics labs at the DNALC and satellite facilities in New York. Over 9,000 high school biology teachers have participated in DNALC teacher-training programs.[11]

The Cold Spring Harbor Laboratory Press has established a program consisting of seven journals, 190 books, laboratory manuals and protocols, and online services for research preprints.[6]

Funding[edit]

In 2012, CSHL had an operating budget of $150 million, over $100 million of which was spent on research.[12] Half of the research budget was devoted to cancer; 25% to neuroscience; 15% to genomics and quantitative biology; and 10% to plant genetics. The sources of research funding in 2012 were: 40% Federal (primarily National Institutes of Health and National Science Foundation); 32% private philanthropy; 23% endowment; 5% corporate.[8]

Founding and eugenics[edit]

Cold Spring Harbor Laboratory

The institution took root as The Biological Laboratory in 1890, a summer program for the education of college and high school teachers studying zoology, botany, comparative anatomy and nature. The program began as an initiative of Franklin Hooper, director of the the Brooklyn Institute of Arts and Sciences, the founding institution of The Brooklyn Museum.[13] In 1904, the Carnegie Institution of Washington established the Station for Experimental Evolution at Cold Spring Harbor on an adjacent parcel. In 1921, the station was reorganized as the Carnegie Institution Department of Genetics.

Between 1910 and 1939, the laboratory was the base of the Eugenics Record Office of biologist Charles B. Davenport and his assistant Harry H. Laughlin, two prominent American eugenicists of the period. Davenport was director of the Carnegie Station from its inception until his retirement in 1934. In 1935 the Carnegie Institution sent a team to review the ERO's work, and as a result the ERO was ordered to stop all work. In 1939 the Institution withdrew funding for the ERO entirely, leading to its closure. The ERO's reports, articles, charts, and pedigrees were considered scientific facts in their day, but have since been discredited. However, its closure came 15 years after its findings were incorporated into the National Origins Act (Immigration Act of 1924), which severely reduced the number of immigrants to America from southern and eastern Europe who, Harry Laughlin testified, were racially inferior to the Nordic immigrants from England and Germany. Charles Davenport was also the founder and the first director of the International Federation of Eugenics Organizations in 1925. Today, Cold Spring Harbor Laboratory maintains the full historical records, communications and artifacts of the ERO for historical,[14] teaching and research purposes. The documents are housed in a campus archive and can be accessed online[15] and in a series of multimedia websites.[16]

Carnegie Institution scientists at Cold Spring Harbor made many contributions to genetics and medicine. In 1908 George H. Shull discovered hybrid corn and the genetic principle behind it called heterosis, or “hybrid vigor.”[17] This would become the foundation of modern agricultural genetics. Clarence C. Little[18] in 1916 was among the first scientists to demonstrate a genetic component of cancer. E. Carleton MacDowell in 1928 discovered a strain of mouse called C58 that developed spontaneous leukemia – an early mouse model of cancer.[19] In 1933, Oscar Riddle isolated prolactin, the milk secretion hormone[20] and Wilbur Swingle participated in the discovery of adrenocortical hormone, used to treat Addison’s disease.

CSHL since 1940[edit]

Milislav Demerec was named director of the Laboratory in 1941. Demerec shifted the Laboratory’s research focus to the genetics of microbes, thus setting investigators on a course to study the biochemical function of the gene. During World War Two, Demerec directed efforts at Cold Spring Harbor that resulted in major increases in penicillin production.[21]

Beginning in 1941, and annually from 1945, three of the seminal figures of molecular genetics convened summer meetings at Cold Spring Harbor of what they called the Phage Group. Salvador Luria, of Indiana University; Max Delbrück, then of Vanderbilt University; and Alfred Hershey, then of Washington University, St. Louis, sought to discover the nature of genes through study of viruses called bacteriophages that infect bacteria.

  • In 1945, Delbrück’s famous Phage Course was taught for the first time, inspiring, among others, a young James D. Watson; it was repeated for many years after. CSH Symposia important in the cross-fertilization of ideas among molecular biology’s pioneers were held in 1951, 1953, 1956, 1961, 1963, and 1966.[22]
  • At the CSH Symposium in summer 1953, Watson made the first public presentation of DNA’s double-helix structure.

Nobel Prize winners who have worked at Cold Spring Harbor

  • In 1944 Barbara McClintock discovered transposons ("jumping genes"), for which she received a Nobel Prize in 1983.[23]
  • In 1952 the “Waring blender experiments” of Alfred Hershey and Martha Chase confirmed DNA as the genetic material.[24] Hershey shared a Nobel Prize with Salvador Luria and Max Delbrück in 1969, “for their discoveries concerning the replication mechanism and the genetic structure of viruses.”[25]
  • James D. Watson, CSHL Director from 1968 – 93, shared a Nobel Prize with Francis Crick and Maurice Wilkins in 1962 for their discovery of the double helix structure of DNA.[26]
  • Richard J. Roberts and Phillip A. Sharp shared a Nobel in 1993 for the discovery of discontinuous, or “split” genes, which revealed the RNA splicing mechanism.[27]
  • Carol Greider, who in 1992 discovered a relationship between cellular aging and damage to the ends of chromosomes, called telomeres, shared a Nobel Prize in 2009 with Elizabeth Blackburn and Jack W. Szostak for their work on telomere biology.[28]

Contemporary research at CSHL[edit]

  • in 1973, Richard J. Roberts begins development and dissemination of a large library of restriction enzymes, basic tools for molecular biology;[29]
  • in 1981 Michael Wigler co-discovers H-RAS, the first human cancer-causing gene, or oncogene;
  • in 1988 Edward Harlow demonstrates that cancer-causing and cancer-preventing genes (oncogenes and tumor-suppressor genes) interact;[30]
  • in 1994, Bruce Stillman reconstitutes DNA replication in a test tube;[31]
  • in 2002, Gregory Hannon’s team develops technology to generate libraries of short-hairpin RNAs (shRNAs), giving researchers the ability to switch genes on and off in living cells;[32]
  • in 2004, Wigler and Jonathan Sebat discover that enhancements and deletions of genetic material called copy number variations are common across the human population;[33]
  • in 2007, Wigler and Sebat discover that spontaneous or de novo mutations are found in people with autism;[34]
  • in 2007, Hannon, Emily Hodges, Z. Xuan and W. Richard McCombie develop technology to sequence the exome, the small subset of protein-coding genes within the much larger genome—now a mainstay of identifying genetic mutations in disease;[35]
  • in 2011, Wigler, James Hicks and Nick Navin perform the first genomic profile of single cancer cells from a patient’s tumor;[36]
  • in 2011, Christopher Vakoc discovers an important new drug target, BRD4, for a lethal form of Acute Myelogenous Leukemia (AML);[37]
  • in 2012, clinical trials begin for a drug to treat the fatal childhood disease Spinal Muscular Atrophy (SMA), based on Adrian Krainer’s insights about alternative splicing.[38]

CSHL leadership[edit]

In 1962, the Department of Genetics, no longer supported by the Carnegie Institution of Washington, formally merged with the Biological Laboratory to form the Cold Spring Harbor Laboratory of Quantitative Biology. In 1970, the name was simplified to Cold Spring Harbor Laboratory.

James D. Watson served as the Laboratory's director and president for 35 years. Upon taking charge in 1968, he focused the Laboratory on cancer research, creating a tumor virus group and successfully obtaining federal funds for an expansion of cancer research capabilities. Watson placed CSHL on a firm financial footing. Inspired by his Nobel collaborator, Francis Crick, Watson initiated a major push to scale-up CSHL research on the brain and psychiatric disorders, beginning in the late 1980s. In 1990, work was completed on the Arnold and Mabel Beckman Laboratory, and the Marks Neuroscience Building was opened in 1999. In 1994, Watson ceased being director of the Laboratory and assumed the title of president. In 2004 he was named chancellor, a position he held until October 2007,[39] when he retired at the age of 79 after views attributed to him on race and intelligence appeared in the British press.[40][41] He is now chancellor emeritus.

Since 1994 biochemist and cancer biologist Bruce Stillman has led the Laboratory as director, and since 2003 as president. Stillman, a member of the National Academy of Sciences and a Fellow of the Royal Society, also continues to run a basic research lab, devoted to the study of DNA replication and chromosome maintenance. Stillman is credited with the 1991 discovery and elucidation of the mechanism of the Origin Recognition Complex (ORC), a highly conserved protein complex that recognizes and binds to specific DNA sequences, marking starting points for replication of the entire genome.[42]

Stillman has presided over a major expansion of the Laboratory, its size growing threefold since he became director. With construction completed on six linked laboratory buildings on the Hillside Campus in 2009, CSHL added much-needed new laboratory space for cancer and neuroscience research, as well as space for a new program on quantitative biology to bring experts in mathematics, computer science, statistics, and physics to problems in biology.

Notes and references[edit]

  1. ^ "National Register Information System". National Register of Historic Places. National Park Service. 2009-03-13. 
  2. ^ As described here: [1] and here: [2]
  3. ^ [3]
  4. ^ Horace Freedland Judson, The Eighth Day of Creation: The Makers of the Revolution in Biology (Simon & Schuster, 1979), esp. pp. 65-69; also: 44-46; 53; 57-58; 62; 70; 82; 185; 232; 239; 247; 273; 321; 368; 392; 454; 458-59; 572-73.
  5. ^ See Thompson Reuters Essential Science Indicators, [4]. The ranking is based on average citation frequency of faculty research papers published between January 2002 and December 2012. (96.94 citations of each CSHL paper, average.)
  6. ^ a b [5]
  7. ^ Examples include: Francis Collins, M.D., Ph.D., current director of the U.S. National Institutes of Health: [6]; Nobel laureate Sydney Brenner: [7]; Nobel laureate Eric Kandel, M.D., referring to the institutional setting of CSHL's graduate school: [8]; See also: R. Sanders Williams, “Sputnik, Slime Molds, and Botticelli in the Making of a Physician-Scientist,” in David A. Schwartz, ed., Medicine, Science and Dreams: The Making of Physician-Scientists (Springer, 2010, p. 103.)
  8. ^ a b c [9]
  9. ^ IPlant Collaborative and [10]
  10. ^ See early DNALC annual reports: 1985: [11]; and 1988: [12]. For the educational milieu at the time hands-on learning caught on nationally, see: Kyle, Jr. W.C., Bonnstetter, R.J., McClosky, J. & Fults, B.A. (1985). "What Research Says: Science through discovery: Students love it," Science and Children, 23 (2), 39-41; Lumpe, A.T. & Oliver, J.S. (1991) “Dimensions of Hands-on Science,” The American Biology Teacher, 53 (6), 345-348; Rutherford, F. J. & Ahlgren, A. (1990), Science for All Americans (New York: Oxford University Press), p. 186ff.; Schmieder, A.A. & Michael-Dyer, G. (1991)., ”State of the scene of science education in the nation,” Paper presented at the Public Health Service National Conference, Washington, D.C.
  11. ^ DNA Learning Center, 2013 Annual Report, in press.
  12. ^ http://www.cshl.edu/images/stories/about_us/pdfs/2013-CSHL-factsheet.pdf
  13. ^ Watson, Edith L. (1991). Houses for Science: a Pictorial History of the Cold Spring Harbor Laboratory. CSHL Press, 1991. pp. 20–23. ISBN 9780879694036. 
  14. ^ See Daniel J. Kevles, In the Name of Eugenics: Genetics and the Uses of Human Heredity (Alfred A. Knopf, 1985); Elof A. Carlson: The Unfit: The History of a Bad Idea (Cold Spring Harbor Laboratory Press, 2001); Jan A. Witkowski and John R. Inglis, eds., Davenport’s Dream: 21st Century Reflections on Heredity and Eugenics (Cold Spring Harbor Laboratory Press, 2008)
  15. ^ CSHL Archives general search: “eugenics” [13] Carnegie Institution of Washington Eugenics Record Office Collection: [14] Charles B. Davenport Collection: [15] The study of human heredity; Methods of collecting, charting, and analyzing data: [16] The Eugenics Record Office at the end of twenty-seven months work: [17]
  16. ^ DNALC web pages on Eugenics: [18]; DNALC Image Archives on the Eugenics Movement: [19]; [20]; DNALC Chronicle of eugenics: [21];
  17. ^ See Shull, GH (1907). "THE SIGNIFICANCE OF LATENT CHARACTERS". Science 25 (646) (May 17, 1907). pp. 792–794. [doi:10.1126/science.25.646.792. PMID 17810906]; Shull, GH (1907). "SOME LATENT CHARACTERS OF A WHITE BEAN". Science 25 (647) (May 24, 1907). pp. 828–832. [doi:10.1126/science.25.647.828-b. PMID 17828973].
  18. ^ See Little CC 1920, “The Heredity of Susceptibility to a Transplantable Sarcoma (J.W.B.) of the Japanese Waltzing Mouse,” Science 51: 467-68.
  19. ^ See Richter MN and MacDowell EC 1930, “Studies on Leukemia in Mice: I: The Experimental Transmission of Leukemia,” J. Exp. Med. 51: 659-73.
  20. ^ See Oscar Riddle, Robert W. Bates and Simon W. Dykshorn, “A New Hormone of the Anterior Pituitary,” Proc. Soc. Exp. Biol. Med. 1932 xxix: 1211-1212.
  21. ^ See U.S. Patent 2,445,748 (July 27, 1948). Demerec used x-ray mutagenesis to produce a high-yielding strain of Penicillium mold. This facilitated a fivefold increase in penicillin production.
  22. ^ “Coming of Phage: Celebrating the Fiftieth Anniversary of the First Phage Course,” Pamphlet, 14 pp., 1995. Cold Spring Harbor Laboratory.
  23. ^ [22] See the classic paper McClintock B 1951 “Chromosome Organization and Genic Expression” (Cold Spring Harbor Symp. Quant. Biol 16: 13-47).
  24. ^ A.D. Hershey and Martha Chase, “Independent Functions of Viral Protein and Nucleic Acid in Growth of Bacteriophage,” J. General Physiology (Sept. 20, 1952) 36:1, 39-56.
  25. ^ [23]
  26. ^ [24]
  27. ^ [25]
  28. ^ [26]
  29. ^ Restriction enzyme; ^ Roberts RJ (November 1976). "Restriction endonucleases". CRC Crit. Rev. Biochem. 4 (2): 123–64. doi:10.3109/10409237609105456. PMID 795607.
  30. ^ Nature. 1988 Jul 14;334(6178):124-9. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Whyte P, Buchkovich KJ, Horowitz JM, Friend SH, Raybuck M, Weinberg RA, Harlow E.
  31. ^ J Biol Chem. 1994 Apr 8;269(14):10923-34. Reconstitution of complete SV40 DNA replication with purified replication factors. Waga S, Bauer G, Stillman B.
  32. ^ Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS. Genes Dev. 2002 Apr 15;16(8):948-58.
  33. ^ Large-scale copy number polymorphism in the human genome. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Månér S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M. Science. 2004 Jul 23;305(5683):525-
  34. ^ Strong association of de novo copy number mutations with autism. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M. Science. 2007 Apr 20;316(5823):445-9. Epub 2007 Mar 15.
  35. ^ Genome-wide in situ exon capture for selective resequencing. Hodges E, Xuan Z, Balija V, Kramer M, Molla MN, Smith SW, Middle CM, Rodesch MJ, Albert TJ, Hannon GJ, McCombie WR. Nat Genet. 2007 Dec;39(12):1522-7. Epub 2007 Nov 4.
  36. ^ Tumor evolution inferred by single-cell sequencing. Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M. Nature. 2011 Apr 7;472(7341):90-4. doi: 10.1038/nature09807. Epub 2011 Mar 13.
  37. ^ RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR. Nature. 2011 Aug 3;478(7370):524-8. doi: 10.1038/nature10334.
  38. ^ http://www.utsandiego.com/news/2014/Feb/22/isis-spinal-muscular-atrophy-trial/
  39. ^ [27]
  40. ^ James watson#cite note-Africans-45
  41. ^ James watson#cite note-Suspension-46
  42. ^ Cell cycle control of DNA replication. Stillman B. Science. 1996 Dec 6;274(5293):1659-64. Review.

External links[edit]