Michael Howard Wigler
September 3, 1947
|Alma mater||Princeton University|
Columbia University (Ph.D.)
|Children||Benjamin and Joshua|
Cold Spring Harbor Laboratory
Michael Howard Wigler (born September 3, 1947 in New York) is an American molecular biologist who has directed a laboratory at Cold Spring Harbor Laboratory since 1978 and is a member of the National Academy of Sciences. He is best known for developing methods to genetically engineer animal cells and his contributions to cancer, genomics and autism genetics.
Wigler graduated from Princeton University in 1970, majoring in mathematics, and in 1978 received his PhD from Columbia University in microbiology, and has spent the remainder of his career at Cold Spring Harbor Laboratory (CSHL).
Beginning in the late 1970s, at Columbia University, Wigler, Richard Axel and Saul Silverstein developed methods for engineering animal cells. These methods are the basis for many discoveries in mammalian genetics, and the means for producing protein therapeutics such as those used to treat heart disease, cancer and strokes.
After moving to CSHL, Wigler continued his studies of gene transfer into mammalian cells, exploring the integration of foreign DNA and its stability of expression in host cells, demonstrating the inheritance of DNA methylation patterns, and isolating the first vertebrate genes, and first human oncogenes, using DNA transfer and genetic selection. His laboratory was among the group that first showed the involvement of members of the RAS gene family in human cancer, and that point mutations can activate the oncogenic potential of cellular genes.
Wigler’s laboratory was the first to demonstrate that some regulatory pathways have been so conserved in evolution that yeast can be used as a host to study the function of mammalian genes and in particular genes involved in signal transduction pathways and cancer. This led to deep insights into RAS function, eventually solving the RAS biochemical pathway in yeasts and humans, and demonstrating the multifunctional nature of this important oncogene. From this work in fungi new cellular mechanisms were recognized for "insulating" signal transduction pathways with protein scaffolds that reduce cross-talkand for processing and localization of proteins.
During this period Wigler's lab published the first use of epitope tagging for protein purification. Following the success with epitope tagging, Wigler and collaborator Joe Sorge patented methods for the creating libraries of genes encoding diverse families of antibody molecules. The concept of antibody libraries is most often combined with the method of phage display used in development of antibody-based therapeutics.
In the early 90’s, Wigler and collaborator W. Clark Still at Columbia University developed the first method for encoding combinatorial chemical synthesis, a method for using gas chromatography tags to record reaction "history" while building vast libraries of chemical compounds. This approach is still used today for drug discovery.
In this same period, Wigler and Nikolai Lisitsyn developed the concept and applications of representational difference analysis, which led to their identification of new cancer genes, including the tumor suppressor PTEN, and by others the cancer virus-causing Kaposi's sarcoma, KSHV. In the late '90s, Drs. Wigler and Robert Lucito combined genome representations with array hybridization leading to a technique called ROMA used to show common structural variation in genomes.
In the decade since 2004, Wigler and Jim Hicks at CSHL, together with Anders Zetterberg of the Karolinska Institute, applied methods of copy number analysis for prognostication of breast cancer. The need for accurate measurement of nucleic acid molecules led to the development of varietal tags., more commonly known as unique molecular indentifiers. This work led to the first successful sequence-based analysis of the genomes of single cancer cells from tumors by Wigler's then-graduate student Nick Navin, and subsequently, tumor cells in circulation by Wigler's collaborator Jim Hicks.
In the early 2000s, Wigler, Jonathan Sebat and Lakshmi Muthuswamy began copy number analysis of healthy individuals, leading to the discovery of a new source of genetic variability, copy number variations or CNVs. The abundance of CNVs in the human genome is a major source of individual variation. The team at CSHL then continued this line of work to demonstrate that spontaneous germ-line mutation is likely to be a major cause for autism. Their observations and theories about autism provide a now widely accepted approach for understanding other human mental and physical abnormalities.
Awards And Nominations
For his contributions to biomedical research, Wigler is a recipient of numerous awards and honors and is a member of the National Academy of Science (since 1989), the American Academy of Arts and Sciences (since 1998), and is American Cancer Society Lifetime Research Professorship (since 1986).
- 2007: CSHL Double Helix Medal Honoree
- Wigler, M.H., Silverstein, S., Lee, L.S., Pellicer, A., Cheng, Y. and Axel, R. (1977) "Transfer of purified herpes virus thymidine kinase gene to cultured mouse cells." Cell 11: 223-232. PMID 194704; Wigler, M., Pellicer, A., Silverstein, S., Axel, R., Urlaub, G. and Chasin, L. (1979) "DNA mediated transfer of the APRT locus into mammalian cells." Proc. Natl. Acad. Sci. USA 76: 1373-1376. PMID 286319; Wigler, M., Perucho, M., Kurtz, D., Dana, S., Pellicer, A., Axel, R. and Silverstein, S. (1980) "Transformation of mammalian cells with an amplificable dominant acting gene." Proc. Natl. Acad. Sci. U.S., 77: 3567. PMID 6251468
- Commercial application of these discoveries follows from Axel-Wigler-Silverstein patent application (U.S. 4,399,216) filed February 20, 1980, entitled, “Process for Inserting DNA into Eucaryotic Cells and for Producing Proteinaceous Materials.” http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4,399,216.PN.&OS=PN/4,399,216&RS=PN/4,399,216
- Perucho, M., Hanahan, D. and Wigler, M. (1980) "Genetic and physical linkage of exogenous sequences in transformed cells." Cell 22: 309-317. PMID 6253083
- Hanahan, D., Lane, D., Lipsich, L., Wigler, M. and Botchan, M. (1980) "Characteristics of an SV40-plasmid recombinant and its movement into and out of the genome of a murine cell." Cell 21: 127-139. PMID 6250708
- Wigler, M., Levy, D. and Perucho, M. (1981) "The somatic replication of DNA methylation. Cell 24: 33-40. PMID 6263490
- Perucho, M., Hanahan, D., Lipsich, L. and Wigler, M. (1980) "Isolation of the chicken thymidine kinase gene by plasmid rescue." Nature 285: 207. PMID 6246445
- Perucho, M., Goldfarb, M., Shimizu, K., Lama, C., Fogh, J. and Wigler, M. (1981) "Human-tumor-derived cell lines contain common and different transforming genes." Cell 27: 467-476. PMID 6101201; Goldfarb, M., Shimizu, K., Perucho, M. and Wigler, M. (1982) "Isolation and preliminary characterization of a human transforming gene from T24 bladder carcinoma cells." Nature 296: 404-409. PMID 7063039
- Shimizu, K., Goldfarb, M., Perucho, M. Wigler, M., (1983) "Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line." Proc. Natl. Acad. Sci., USA, 80: 383-387. PMID 6300838
- Taparowsky, E., Suard, Y., Fasano, O., Shimizu, K., Goldfarb, M., Wigler, M. (1982) "Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature, 300: 762-765. PMID 7177195
- Powers, S., Kataoka, T., Fasano, O., Goldfarb, M., Strathern, J., Broach, J., and Wigler, M. (1984) "Genes in Saccharomyces cerevisiae encoding proteins with domains homologous to the mammalian ras proteins." Cell, 36: 607-612. PMID 6365329; Kataoka, T., Powers, S., Cameron, S., Fasano, O., Goldfarb, M., Broach, J., and Wigler, M. (1985) "Functional homology of mammalian and yeast RAS genes." Cell, 40: 19-26. PMID 2981628
- Van Aelst, L., Barr, M., Marcus, S., Polverino, A. and Wigler, M. (1993) "Complex formation between RAS and RAF and other protein kinases." Proc. Natl. Acad. Sci. USA, 90 : 6213-6217. PMID 8327501; White, M., Nicolette, C., Minden, A., Polverino, A., Van Aelst, L., Karin, M. and Wigler, M. (1995) "Multiple RAS functions can contribute to mammalian cell transformation." Cell, 80: 533-541. PMID 7867061
- S Marcus, A Polverino, M Barr, and M Wigler (1994) "Complexes between STE5 and components of the pheromone-responsive mitogen-activated protein kinase module." PNAS PNAS August 2, 1994. 91 (16) 7762-7766. PMID 8052657
- Powers S, Michaelis S, Broek D, Santa Anna S, Field J, Herskowitz I, Wigler M (1986) "RAM, a gene of yeast required for a functional modification of RAS proteins and for production of mating pheromone a-factor." Cell, 1986 Nov 7;47(3):413-22. PMID 3533274
- Field, J., Nikawa, J., Broek, D., MacDonald, B., Rodgers, L., Wilson, I.A., Lerner, R.A. and Wigler, M. (1988) "Purification of a RAS -responsive adenylyl cyclase complex from Saccharomyces cerevisiae by use of an epitope addition method." Molecular and Cellular Biology, 8: 2159-2165. PMID 2455217
- US Patent for Method for generating libraries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules Patent (Patent # 6,303,313) https://patents.justia.com/patent/6303313
- Ohlmeyer, M.H.J., Swanson, M.N., Dillard, L.W., Reader, J.C., Asouline, G., Kobayashi, R., Wigler, M., Still, W.C. (1993) "Complex synthetic chemical libraries indexed with molecular tags." Proc. Natl. Acad. Sci. USA, 90: 10922-10926. PMID 7504286
- Lisitsyn, N., Lisitsyn, N. and Wigler, M. (1993) "Cloning the differences between two complex genomes." Science 259: 946-951. PMID 8438152
- Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S., Puc, J., Miliarcsis, C., Rodgers, L., McCombie, R., Bigner, S.H., Giovanella, C., Ittman, M., Tycko, B., Hibshoosh, H., Wigler, M.H. and Parsons, R. (1997) "PTEN a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer." Science, 275: 1943-1947. PMID 9072974
- Lucito, R., Nakamura, M., West, J.A., Han, Y., Chin, K., Jensen, K., McCombie, R., Gray, J.W., and Wigler, M. (1998) "Genetic analysis using genomic representations." Proc.Natl.Acad.Sci.USA 95: 4487-4492. PMC 22516; Lucito, R., Healy, J., Alexander, J., Reiner, A., Esposito, D., Chi, M., Rodgers, L., Brady, A., Sebat, J., Troge, J., West, J., Rostan, S., Nguyen, K.C.Q., Powers, S., Ye, K.Q., Olshen, A., Venkatraman, E., Norton, L. and Wigler, M. (2003) "Representational oligonucleotide microarray analysis: a high –resolution method to detect genome copy number variation." Genome Research 13: 2291-2305. PMC 403708
- Sebat, J., Muthuswamy, L., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M., Navin, N., Lucito, R., Healy, J., Hicks, J., Ye, K., Reiner, A., Gilliam, T.C., Trask, B., Patterson, N., Zetterberg, A., Wigler, M. (2004) "Large-Scale Copy Number Polymorphism in the Human Genome." Science, 305: 525-528. PMID 15273396
- Hicks, J., Krasnitz, A., Lakshmi, B., Navin, N., Riggs, M., Leibu, E., Esposito, D., Alexander, J., Troge, J., Grubor, V., Yoon, S., Wigler, M., Ye, K., Børresen-Dale, A-L., Naume, B., Schlicting, E., Norton, L., Hagerstrom, T., Skoog, L., Auer G., Maner, S., Lundin, P., and Zetterberg, A., (2005) "Novel Patterns of genomic rearrangement and their association with survival in breast cancer." Genome Research 16:1465–1479. PMC 1665631
- Varietal counting of nucleic acids for obtaining genomic copy number information. https://patents.google.com/patent/US20140065609
- 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, R., Hicks, J., Wigler, M. (2011) "Tumor evolution inferred by single cell sequencing." Nature, 472: 90-94. PMID 21399628
- Sebat, J., Lakshmi, B., Malhotra, D., Lese-Martin, C., Troge, J., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., Leotta, A., Pai, D., Zhang, R., Lee, Y-H., Hicks, J., Spence, S.J., Lee, A.T., Puura, K., Lehtimäki, T., Ledbetter, D., Gregersen, P.K., Bregman, J., Sutcliffe, J.S., Jobanputra, V., Chung, W., Warburton, D., King, M-C., Skuse, D., Geschwind, D.H., Gilliam, T.C., Ye, K., Wigler, M. (2007) "Strong association of de novo copy number mutations with autism." Science 316: 445-449. PMID 17363630; Zhao, X., Leotta, A., Qiu, S., Kustanovich, V., Lajonchere, C., Geschwin, D.H., Lord, C., Sebat, J., Ye., K. and Wigler, M. (2007) "A unified genetic theory for sporadic and inherited autism. Proc. Natl. Acad. Sci., USA 104: 12831-12836. PMC 1933261; Levy, D., Ronemus, M., Yamrom, B., Lee, Y-H., Leotta, A., Kendall, J., Marks, S., Lakshmi, B., Pai, D., Ye, K., Buja, A., Krieger, A., Yoon, S., Troge, J., Rodgers, L., Iossifov, I., Wigler, M. (2011) "Rare de novo and transmitted copy-number variation in autistic spectrum disorders." Neuron, 70: 886-897. PMID 21658582; Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y-H., Narzisi, G., Leotta, A., Kendall, J., Grabowska, E., Ma, B., Marks, S., Rodgers, L., Stepansky, A., Troge, J., Andrews, Bekritsky, M., Pradhan, K., Ghiban, E., Kramer, M., Parla, J., Demeter, R., Fulton, L., Fulton, R.S., Magrini, V.J., Ye, K., Darnell, J.C., Darnell, R.B., Mardis, E.R., Wilson, R.K., Schatz, M.C., McCombie, W.R., Wigler, M. (2012) "De novo gene disruptions in children on the autistic spectrum." Neuron, 74: 285-299.