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Faculty
Bruce Beutler
Chairman
Department of Genetics
TSRI - 2000
Education
B.A., The University of California at San Diego, 1976
M.D., The University of Chicago, 1981
Awards & Activities
2009 Albany Medical Center Prize
2007 Frederik B. Bang Award (International Endotoxin and Innate Immunity Society)
2007 Doctor of Medicine honoris causa from the Technical University of Munich
2007 Balzan Prize (International Balzan Foundation, Italy and Switzerland)
2006 Gran Prix Charles-Leopold-Mayer (Académie des Sciences, France)
2006 William B. Coley Award (Cancer Research Institute, USA)
2004 Robert Koch Prize (Robert Koch Stiftung, Germany)
1994 Outstanding Investigator Award (American Federation for Clinical Research, USA)
Member The National Academy of Sciences, USA
The Institute of Medicine, USA
Association of American Physicians
American Society for Clinical Investigation
Research Focus
While many biologists begin with hypotheses about how a particular biological phenomenon operates, geneticists begin instead with a phenotype: an altered form of the phenomenon in question. Our principal interest is mammalian immune function. If we wish to understand why the mouse immune system responds to a particular molecule, we find an exceptional mouse in which it doesn’t; if we wish to understand why most mice don’t have inflammatory disease, we find an exceptional mouse that does. When a phenotype is caused by a single gene mutation, it is generally possible to find the mutation. Then we have gained fundamental insight into the phenomenon itself.
Using a genetic approach, we established some years ago that the Toll-like receptors (TLRs) serve as the key sensors used by the mammals to perceive infection. This conclusion rested upon the positional cloning of a mutation (Lpsd) that prevented mice from sensing bacterial lipopolysaccharide [Poltorak et al., Science 282:2085-2088 (1998)]. Since that time, we have established many of the essential proteins active in TLR signal transduction, but many others remain to be found.
We use random chemical mutagenesis with N-ethyl-N-nitrosourea (ENU) to produce many thousands of mice with germline mutations that affect every aspect of normal biological function. We then screen the mice to detect phenotypic change in the innate immune response. For example, the ability of macrophages to sense molecules of microbial origin (for example, lipopolysaccharide, bacterial lipopeptides, double-stranded RNA, and unmethylated DNA) is measured in vitro. The ability to cope with specific pathogens (especially mouse cytomegalovirus) is measured in vivo. Mice with inflammatory colitis, or strong resistance to specific microbes, or an abnormal complement of immune cells are identified as well. When strong deviation from normal function is detected, transmissibility of the phenotype is examined. If the phenotype is transmissible (i.e., if a bona fide mutation exists), meiotic mapping is performed to confine the mutation to a particular genomic interval. The mutation is then sought among candidate genes within the interval. To date, 274 phenotypes of all kinds have been detected in our laboratory by screening random germline mutant mice, and 140 of these mutations have immunologic effects. 170 mutations have been mapped to chromosomes, and in 145 cases, the molecular identity of the defect has been established. We now know that hundreds of genes serve the innate immune responses to microbial infections, making a life-or-death difference to animals infected with a single defined pathogen. And we have made inroads into the principal pathways of innate immune response.
Along the way, we have found many mutations that have shed light on other biological phenomena: hearing, sight, iron absorption, and development. All of these are regarded with interest, and some have started entirely new lines of biological inquiry.
Additional information about our mutagenesis work can be found at Mutagenetix.
Selected References
Du, X., Schwander, M., Moresco, E. M. Y., Viviani, P., Haller, C., Hildebrand, M. S., Pak, K., Tarantino, L., Roberts, A., Richardson, H., Koob, G., Najmabadi, H., Ryan, A. F., Smith, R. J. H., Muller, U., and Beutler, B. (2008) A catechol-O-methyltransferase that is essential for auditory function in mice and humans, Proc. Natl. Acad. Sci., USA 105, 14609-14614.
Du, X., She, E., Gelbart, T., Truksa, J., Lee, P., Xia, Y., Khovananth, K., Mudd, S., Mann, N., Moresco, E. M., Beutler, E., and Beutler, B. (2008) The serine protease TMPRSS6 is required to sense iron deficiency, Science 320, 1088-1092.
Tabeta, K., Hoebe, K., Janssen, E. M., Du, X., Georgel, P., Crozat, K., Mudd, S., Mann, N., Sovath, S., Goode, J., Shamel, L., Herskovits, A. A., Portnoy, D. A., Cooke, M., Tarantino, L. M., Wiltshire, T., Steinberg, B. E., Grinstein, S., and Beutler, B. (2006) The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9, Nat. Immunol. 7, 156-164.
Beutler, B., Jiang, Z., Georgel, P., Crozat, K., Croker, B., Rutschmann, S., Du, X., and Hoebe, K. (2006) Genetic analysis of host resistance: Toll-Like receptor signaling and immunity at large, Annu. Rev. Immunol. 24, 353-389.
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