Michael Wigler

Last updated
Michael Wigler
Born
Michael Howard Wigler

(1947-09-03) September 3, 1947 (age 72)
New York
NationalityAmerican
Alma mater Princeton University
Columbia University (Ph.D.)
Spouse(s)Edith
ChildrenBenjamin and Joshua
Scientific career
Institutions Columbia University
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.

Contents

Education

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).

Career

Beginning in the late 1970s, at Columbia University, Wigler, Richard Axel and Saul Silverstein developed methods for engineering animal cells. [1] 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. [2]

After moving to CSHL, Wigler continued his studies of gene transfer into mammalian cells, exploring the integration of foreign DNA [3] and its stability of expression in host cells, [4] demonstrating the inheritance of DNA methylation patterns, [5] and isolating the first vertebrate genes, [6] and first human oncogenes, [7] 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, [8] and that point mutations can activate the oncogenic potential of cellular genes. [9]

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. [10] 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. [11] From this work in fungi new cellular mechanisms were recognized for "insulating" signal transduction pathways with protein scaffolds that reduce cross-talk [12] and for processing and localization of proteins. [13]

During this period Wigler's lab published the first use of epitope tagging for protein purification. [14] 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. [15] 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 1990s, 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. [16] This approach [17] is still used today for drug discovery.

In this same period, Wigler and Nikolai Lisitsyn developed the concept and applications of representational difference analysis, [18] which led to their identification of new cancer genes, including the tumor suppressor PTEN, [19] 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 [20] used to show common structural variation in genomes. [21]

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. [22] The need for accurate measurement of nucleic acid molecules led to the development of varietal tags, [23] more commonly known as unique molecular identifiers. This work led to the first successful sequence-based analysis of the genomes of single cancer cells [24] 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. [21] 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. [25] Their observations and theories about autism provide a now widely accepted approach for understanding other human mental and physical abnormalities.

Awards

Related Research Articles

Ras GTPase GTP-binding proteins functioning on cell-cycle regulation

Ras is a family of related proteins which is expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells. Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours.

KRAS protein-coding gene in the species Homo sapiens

The KRAS gene provides instructions for making a protein called K-Ras, part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The K-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. In this way the K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus. It is called KRAS because it was first identified as an oncogene in KirstenRAt Sarcoma virus. The viral oncogene was derived from cellular genome. Thus, KRAS gene in cellular genome is called a proto-oncogene.

Neuroblastoma RAS viral oncogene homolog protein-coding gene in the species Homo sapiens

NRAS is an enzyme that in humans is encoded by the NRAS gene. It was discovered by a small team of researchers led by Robin Weiss at the Institute of Cancer Research in London. It was the third RAS gene to be discovered, and was named NRAS, for its initial identification in human neuroblastoma cells.

RAC3 mammalian protein found in Homo sapiens

Ras-related C3 botulinum toxin substrate 3 (Rac3) is a G protein that in humans is encoded by the RAC3 gene. It is an important component of intracellular signalling pathways. Rac3 is a member of the Rac subfamily of the Rho family of small G proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.

GPR68 protein-coding gene in the species Homo sapiens

Ovarian cancer G-protein coupled receptor 1 is a protein that in humans is encoded by the GPR68 gene.

G3BP1 protein-coding gene in the species Homo sapiens

Ras GTPase-activating protein-binding protein 1 is an enzyme that in humans is encoded by the G3BP1 gene.

RRAS2 protein-coding gene in the species Homo sapiens

Ras-related protein R-Ras2 is a protein that in humans is encoded by the RRAS2 gene.

RAB18 protein-coding gene in the species Homo sapiens

Ras-related protein Rab-18 is a protein that in humans is encoded by the RAB18 gene.

RAB14 protein-coding gene in the species Homo sapiens

Ras-related protein Rab-14 is a protein that in humans is encoded by the RAB14 gene.

KIAA1967 protein-coding gene in the species Homo sapiens

KIAA1967, also known as Deleted in Breast Cancer 1, is a protein which in humans is encoded by the KIAA1967 gene.

RIN1 protein-coding gene in the species Homo sapiens

Ras and Rab interactor 1 is a protein that in humans is encoded by the RIN1 gene.

RASSF2 protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 2 is a protein that in humans is encoded by the RASSF2 gene.

OR2K2 protein-coding gene in the species Homo sapiens

Olfactory receptor 2K2 is a protein that in humans is encoded by the OR2K2 gene.

EML4 protein-coding gene in the species Homo sapiens

Echinoderm microtubule-associated protein-like 4 is a protein that in humans is encoded by the EML4 gene.

RAB25 protein-coding gene in the species Homo sapiens

Ras-related protein Rab-25 is a protein that in humans is encoded by the RAB25 gene. It is thought to act as a promoter of tumor development.

CD248 protein-coding gene in the species Homo sapiens

Endosialin is a protein that in humans is encoded by the CD248 gene.

RAB6C protein-coding gene in the species Homo sapiens

Ras-related protein Rab-6C is a protein that in humans is encoded by the RAB6C gene.

TAL2 protein-coding gene in the species Homo sapiens

T-cell acute lymphocytic leukemia 2, also known as TAL2, is a protein which in humans is encoded by the TAL2 gene.

CNTROB protein-coding gene in the species Homo sapiens

Centrobin is a protein that in humans is encoded by the CNTROB gene. It is a centriole-associated protein that asymmetrically localizes to the daughter centriole, and is required for centriole duplication and cytokinesis.

Recombinant adeno-associated virus (rAAV) based genome engineering is a genome editing platform centered on the use of recombinant rAAV vectors that enables insertion, deletion or substitiution of DNA sequences into the genomes of live mammalian cells. The technique builds on Mario Capecchi and Oliver Smithies' Nobel Prize–winning discovery that homologous recombination (HR), a natural hi-fidelity DNA repair mechanism, can be harnessed to perform precise genome alterations in mice. rAAV mediated genome-editing improves the efficiency of this technique to permit genome engineering in any pre-established and differentiated human cell line, which, in contrast to mouse ES cells, have low rates of HR.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Perucho, M., Hanahan, D. and Wigler, M. (1980) "Genetic and physical linkage of exogenous sequences in transformed cells." Cell 22: 309-317. PMID   6253083
  4. ↑ 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
  5. ↑ Wigler, M., Levy, D. and Perucho, M. (1981) "The somatic replication of DNA methylation. Cell 24: 33-40. PMID   6263490
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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=6,503,759.PN.&OS=PN/6,503,759&RS=PN/6,503,759
  18. ↑ Lisitsyn, N., Lisitsyn, N. and Wigler, M. (1993) "Cloning the differences between two complex genomes." Science 259: 946-951. PMID   8438152
  19. ↑ 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
  20. ↑ 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
  21. 1 2 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
  22. ↑ 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
  23. ↑ Varietal counting of nucleic acids for obtaining genomic copy number information. https://patents.google.com/patent/US20140065609
  24. ↑ 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
  25. ↑ 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.
  26. ↑ "Michael Wigler". www.nasonline.org. Retrieved 2020-04-29.
  27. ↑ "AACR G.H.A. Clowes Memorial Award: Past Recipients". American Association for Cancer Research (AACR). Retrieved 2020-04-29.
  28. ↑ "Honors and Awards". Vagelos College of Physicians and Surgeons. 2017-07-06. Retrieved 2020-04-29.
  29. ↑ "Michael H. Wigler". American Academy of Arts & Sciences. Retrieved 2020-04-29.
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