Chercheurs

Médecine / SMITHIES, OLIVER

oliver.smithies

Position

Excellence Professor of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA.

Thèmes de recherche

His research interests include the construction of animal models of complex human genetic diseases to facilitate better studies of their genetics and the resultant pathology and to help develop new modes of treatment, including gene therapy. Major effort currently is on hypertension and on hemoglobinopathies.

Smithies co-discovered a technique to introduce DNA material in cells, replicated a natural process called homologous DNA recombination. He thought that genetic disorders could be treated by correcting mutations in bone marrow cells, or stem cells. This “gene targeting” led to the creation of transgenic mice, or “designer mice,” that replicated human disease. Smithies’ lab produced the first animal model of cystic fibrosis, a disease caused by one defective gene, and also studied high blood pressure, atherosclerosis and other diseases.

This method also enabled scientists to study specific genes by creating “knock-out mice.” By targeting and removing, or knocking out, a specific gene, researchers can find out what happens when it’s missing. Smithies has used the analogy of removing a steering wheel from a car; without it you soon find out why it has a steering wheel. Now this research method is commonplace in biomedical research and has been the basis for thousands of published papers.

Prix et récompenses

Nobel Prize in Physiology or Medicine 2007, with Sir Martin J. Evans and Mario R. Capecchi, "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells"

Albert Lasker Award for Basic Medical Research 2001, with Martin Evans and Mario R. Capecchi, "For the development of a powerful technology for manipulating the mouse genome with exquisite precision, which allows the creation of animal models of human disease".

Publications

Smithies O and Kim H-S. Targeted gene duplication and disruption for analyzing quantitative genetic traits in mice. Proc Natl Acad Sci USA 91:3612-3615, 1994.

Kim H-S, Krege JH, Kluckman KD, Hagaman JH, Hodgin JB, Best CF, Jennette JC, Coffman TM, Maeda N and Smithies O. Genetic control of blood pressure and the angiothensiogen locus. Proc Natl Acad Sci 92:2735-2739, 1995.

Tsuda H, Maynard-Currie CE, Reid LH, Yoshida T, Edamura K, Maeda N, Smithies O, Jakobovits A. Inactivation of the mouse HPRT locus by a 203-bp retroposon insertion and a 55-kb gene-targeted deletion: Establishment of new HPRT-deficient mouse embryonic stem cell lines. Genomics 1997;42:413-421.

Smithies O. A mouse view of hypertension. Hypertension 1997;30:1318-1324.

Morham SG, Langenback R, Mohler J, Smithies O. Characterization of prostaglandin H synthase 2 deficient mice and implications for mechanisms of NSAID action in eicosanoids and other bioactive lipids. In: Cancer Inflammation and Radiation Injury (3). Honn et al (eds). New York: Plenum Press 1997.

Kuziel WA, Morgan SJ, Dawson TC, Griffin S, Smithies O, Ley K, Maeda N. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci USA 1997;94:12053-12058.

Oliver PM, Fox JE, Kim R, Rockman HA, Kim H-S, Reddick RL, Pandey KN, Milgram SL, Smithies O, Maeda N. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci USA 1997;94:14730-14735.

Oliver PM, John SWM, Purdy KE, Kim R, Maeda N, Goy MF, Smithies O. Natriuretic peptide receptor 1 expression influences blood pressures of mice in a dose-dependent manner. Proc Natl Acad Sci USA 1998;95:2547-2551.

Hagaman JR, Moyer JS, Bachman ES, Sibony M, Magyar PL, Welch JE, Smithies O, Krege JH, O’Brien DA. Angiotensin-converting enzyme and male fertility. Proc Natl Acad Sci USA 1998;95:2552-2557.

Lewis J, Yang B, Kim R, Sierakowska H, Kole R, Smithies O, Maeda N. A common human ß globin splicing mutation modeled in mice. Blood 1998;91(6):2152-2156.

Whitney III JB, Leder A, Lewis J, Popp RA, Paszty C, Rubin EM, Shehee WR, Townes TM, Smithies O. Rapid genotyping of mice with hemoglobinopathies and globin transgenes. Biochem Genet 1998;36:65-77.

Tumpey TM, Cheng H, Cook DN, Smithies O, Oakes JE, Lausch RN. Absence of macrophage inflammatory protein-1? prevents the development of blinding herpes stromal keratitis. J Virol 1998;72:3705-3710.

Oliverio MI, Kim HS, Ito M, Le T, Audoly L, Best CF, Hiller S, Kluckman K, Maeda N, Smithies O, Coffman TM. Reduced growth, abnormal kidney structure, and AT2-mediated blood pressure in mice lacking both AT1A and AT1B receptors for angiotensin II. Proc Natl Acad Sci USA 1998;95:15496-15501.

Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA, Smithies O. Generation and reproductive phenotypes of mice lacking estrogen receptor-?. Proc Natl Acad Sci USA 1998;95:15677-15682.

Thomas DW, Mannon RB, Mannon PJ, Latour A, Oliver PA, Hoffman M, Smithies O, Koller BH, Coffman TM. Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2. J Clin Invest 1998;102:1994-2001.

Fern RJ, Yesko CM, Thornhill BA, Kim HS, Smithies O, Chevalier RL. Reduced angiotensinogen expression attenuates renal interstitial fibrosis in obstructive nephropathy in mice. J Clin Invest 1999;103:39-46.

Kim HS, Maeda N, Oh GT, Fernandez LG, Gomez RA, Smithies O. Homeostasis in mice with genetically decreased angiotensinogen is primarily by an increased number of renin-producing cells. J Biol Chem 1999;274 (In press).

Hatada S, Kuziel W, Smithies O, Maeda N. The influence of chromosomal location on the expression of two transgenes in mice. J Biol Chem 1999;274:948-955.

Pandey KN, Oliver PM, Maeda N, Smithies O. Regulation of serum testosterone levels by the natriuretic peptide receptor-A in gene-knockout and gene-duplicated mutant mouse models. Submitted to Endocrinology 1999.

Maeda N, Smithies O. Studying the genetics of complex but common human diseases using mice. In press.