Bruce Beutler at the Nobel Prize press conference at Karolinska, Solna
December 29, 1957 |
|Institutions||University of Texas Southwestern Medical Center|
|Alma mater||University of Chicago, University of California, San Diego|
|Notable awards||2011 Nobel Prize in Physiology or Medicine|
|Spouse||Barbara Lanzl (c. 1979-1988; divorced; 3 children)|
Bruce Alan Beutler (born December 29, 1957) is an American immunologist and geneticist. Together with Jules A. Hoffmann, he received one-half of the 2011 Nobel Prize in Physiology or Medicine, for "their discoveries concerning the activation of innate immunity" (the other half went to Ralph M. Steinman for "his discovery of the dendritic cell and its role in adaptive immunity").
Between 1959 and 1977, Beutler lived in Southern California. He received his secondary school education at Polytechnic School in Pasadena, California. He attended college at the University of California, San Diego, graduating at the age of 18 in 1976. He enrolled in medical school at the University of Chicago in 1977 and received his M.D. degree in 1981 at the age of 23.
During his childhood and early adolescent years, Beutler developed a lasting interest in biological science. Some of his formative experiences in biology included studies in the laboratory of his father, and later, in the City of Hope laboratory of Susumu Ohno, a mammalian geneticist known for his work on evolution, genome structure, and sex differentiation. In addition, he worked in the laboratories of Abraham Braude, an expert in the biology of lipopolysaccharide (LPS), also known as endotoxin, and Patricia Spear, an authority on Herpes simplex virus. Later, Beutler was to perform extensive research on both LPS and herpesviruses, aimed principally at understanding inborn host resistance to infectious diseases, often referred to as innate immunity.
Beutler majored in biology as an undergraduate at the University of California, San Diego, where he graduated in 1976 at the age of 18. He attended medical school at the University of Chicago. From 1981 to 1983 Beutler continued his medical training at the University of Texas Southwestern Medical Center in Dallas, Texas, as an intern in the Department of Internal Medicine, and as a resident in the Department of Neurology. Between 1983 and 1985 he was a postdoctoral fellow at Rockefeller University in the laboratory of Anthony Cerami. He became an Assistant Professor at Rockefeller University in 1985. He was also an Associate Physician at the Rockefeller University Hospital between 1984 and 1986.
Beutler returned to Dallas in 1986 as an assistant professor in the Department of Internal Medicine of the University of Texas Southwestern Medical Center at Dallas, and an Assistant Investigator at the Howard Hughes Medical Institute, where he retained a position for the next 14 years. He became an associate professor and an associate investigator with HHMI in 1990, and a professor in 1996.
In 2000, Beutler moved to The Scripps Research Institute in La Jolla, California, as a professor in the Department of Immunology. In 2007, he became chairman of the newly created Department of Genetics at Scripps Research. In 2011, Beutler returned to UT Southwestern Medical Center to become director of the Center for the Genetics of Host Defense.
On October 4, 2011, Beutler was named regental professor of the University of Texas System. He also sits on the Selection Committee for Life Science and Medicine which chooses winners of the Shaw Prize.
Beutler is best known for his pioneering molecular and genetic studies of inflammation and innate immunity. He was the first to isolate mouse tumor necrosis factor-alpha (TNF), and to demonstrate the inflammatory potential of this cytokine, proving its important role in endotoxin-induced shock. Subsequently, he invented recombinant molecules expressly designed to neutralize TNF, fusing the binding portion of TNF receptor proteins to the heavy chain of an immunoglobulin molecule to force receptor dimerization. These molecules were later used extensively as the drug Etanercept in the treatment of rheumatoid arthritis, Crohn's disease, psoriasis, and other forms of inflammation.
Interested in the mechanism by which LPS activates mammalian immune cells, Beutler used TNF production as a phenotypic endpoint to identify the LPS receptor. Identification of the receptor hinged on the positional cloning of the mammalian Lps locus, which had been known since the 1960s as a key genetic determinant of all biological responses to LPS. Beutler thus discovered the key sensors of microbial infection in mammals, demonstrating that one of the mammalian Toll-like receptors, TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex. The TLRs (of which ten are now known to exist in humans) are now widely known to function in the perception of microbes, each detecting signature molecules that herald infection. These receptors also mediate severe illness, including shock and systemic inflammation as it occurs in the course of an infection. They are central to the pathogenesis of sterile inflammatory and autoimmune diseases such as systemic lupus erythematosus. The research on TLRs won him the Nobel Prize in 2011.
The positional cloning of Lps was completed in 1998. Beutler thereafter continued to apply a forward genetic approach to the analysis of immunity in mammals. In this process, germline mutations that alter immune function are created through a random process using the alkylating agent ENU, detected by their phenotypic effects, and then isolated by positional cloning. His work disclosed numerous essential signaling molecules required for the innate immune response, and helped to delineate the biochemistry of innate immunity.
ENU mutagenesis was also used by Beutler and colleagues to study the global response to a defined infectious agent. By screening mutant mice for susceptibility to mouse cytomegalovirus (MCMV), they identified a large number of genes that make a life-or-death difference during infection, and termed this set of genes the MCMV "resistome". These genes fall into "sensing," "signaling," "effector," "homeostatic," and "developmental" categories, and some of them were wholly unexpected. For example, Kir6.1 ATP-sensitive potassium channels in the smooth muscle of the coronary arteries serve an essential homeostatic role during infection by this microbe, and mutations that affect them cause sudden death during infection.
In the course of their work, Beutler and his colleagues identified genes required for other important biological processes, including the regulation of iron absorption, hearing, and embryonic development, since their disruption by ENU created strikingly abnormal visible phenotypes.
Controversy has arisen regarding whether the Nobel Prize had been rightly given to Beutler, as Janeway and Medzhitov were actually the first to discover the link between adaptive and innate immunity, whilst Beutler simply found the receptor for LPS. Furthermore, there have been concerns regarding the conduct of Beutler in giving dueful recognition to other labs and their contributions to the field, in inflating his own contributions and in refusing to acknowledge that his work was more than likely influenced by the findings of Janeway and Medzhitov  The paper for which Beutler was awarded the Nobel Prize was published nearly simultaneously to two other papers identifying TLR4 as the LPS receptor, one by the research group of Danielle Malo accepted for publication four days before Beutler's prize winning paper was published, and a second paper by the research group of Shizuo Akira that was submitted for publication four days after Beutler's paper was published.
Awards and recognition
Beutler has been elected to numerous honorary academic societies. These include the United States National Academy of Sciences and the Institute of Medicine. Beutler is also an Associate Member (foreign associate) of the European Molecular Biology Organization (EMBO), and a member of the Association of American Physicians, and the American Society for Clinical Investigation.
Other notable honors have included:
- Nobel Prize in Physiology or Medicine (2011, shared with Jules A. Hoffmann and Ralph M. Steinman)
- Shaw Prize (2011, shared with Jules A. Hoffmann and Ruslan M. Medzhitov)
- Will Rogers Institute Annual Prize for Research (2009)
- Albany Medical Center Prize (2009, shared with Charles A. Dinarello and Ralph M. Steinman)
- Balzan Prize for Innate Immunity (2007, shared with Jules A. Hoffmann).
- Doctor of Medicine Honoris causa from the Technical University of Munich Germany, (2007).
- William B. Coley Award of the Cancer Research Institute, US (2006, shared with Shizuo Akira).
- Grand Prix Charles-Leopold Mayer of the Académie des Sciences, France (2006).
- Robert Koch Prize of the Robert Koch Foundation, Germany (2004, shared with Jules A. Hoffmann and Shizuo Akira).
- Institute for Scientific Information has listed Beutler as an ISI highly cited researcher since the year 2001, marking him as an influential figure in the field of immunology. He has also been listed by Thomson-Reuters as a Citation Laureate.
- Doctor honoris causa of the Norwegian University of Science and Technology, Norway (2015).
Beutler is Ashkenazi Jewish, the son of Ernest Beutler (geneticist) and Brondelle May Fleisher (journalist). He married Barbara Beutler (née Lanzl) in 1980 and divorced in 1988, Beutler has three children: Daniel (born 1983), Elliot (born 1984), and Jonathan (born 1987).
Bruce's grandmother, Kathe Beutler, was the first cousin of Kurt Rosenthal, grandfather of Pamela Ronald, who discovered the first plant pattern recognition receptor, XA21. The Beutler and Rosenthal families fled Berlin after Hitler came to power and reunited in California after the war.
- "Nobel Prize in Physiology or Medicine 2011" (Press release). Nobel Foundation. 3 October 2011.
- Ravindran, S. (2013). "Profile of Bruce A. Beutler". Proceedings of the National Academy of Sciences 110 (32): 12857–8. doi:10.1073/pnas.1311624110. PMC 3740904. PMID 23858464.
- Beutler, B.; Greenwald, D.; Hulmes, J. D.; Chang, M.; Pan, Y. -C. E.; Mathison, J.; Ulevitch, R.; Cerami, A. (1985). "Identity of tumour necrosis factor and the macrophage-secreted factor cachectin". Nature 316 (6028): 552–554. doi:10.1038/316552a0. PMID 2993897.
- Beutler, B., et al. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229(4716):869-71, 1985
- Peppel,K., et al. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J.Exp.Med. 174(6):1483-9, 1991
- Sultzer, B.M. Genetic control of leucocyte responses to endotoxin. Nature 219(5160):1253-4, 1968
- Poltorak, A., et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085-8, 1998
- Christensen,S.R., et al. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 25(3):417-28, 2006
- Hoebe,K., et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424(6950):743-8, 2003
- Hoebe,K., et al. CD36 is a sensor of diacylglycerides. Nature 433(7025):523-7, 2005
- Tabeta, K., et al. The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nature Immunol. 7(2):156-64, 2006
- Beutler, B.; Crozat, K.; Koziol, J. A.; Georgel, P. (2005). "Genetic dissection of innate immunity to infection: The mouse cytomegalovirus model". Current Opinion in Immunology 17 (1): 36–43. doi:10.1016/j.coi.2004.11.004. PMID 15653308.
- Croker, B.; Crozat, K.; Berger, M.; Xia, Y.; Sovath, S.; Schaffer, L.; Eleftherianos, I.; Imler, J. L.; Beutler, B. (2007). "ATP-sensitive potassium channels mediate survival during infection in mammals and insects". Nature Genetics 39 (12): 1453–1460. doi:10.1038/ng.2007.25. PMID 18026101.
- Du, X.; She, E.; Gelbart, T.; Truksa, J.; Lee, P.; Xia, Y.; Khovananth, K.; Mudd, S.; Mann, N.; Moresco, E. M. Y.; Beutler, E.; Beutler, B. (2008). "The serine protease TMPRSS6 is required to sense iron deficiency". Science 320 (5879): 1088–1092. doi:10.1126/science.1157121. PMC 2430097. PMID 18451267.
- 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.; Beutler, B. (2008). "A catechol-O-methyltransferase that is essential for auditory function in mice and humans". Proceedings of the National Academy of Sciences 105 (38): 14609–14614. doi:10.1073/pnas.0807219105. PMC 2567147. PMID 18794526.
- Smyth, I.; Du, X.; Taylor, M. S.; Justice, M. J.; Beutler, B.; Jackson, I. J. (2004). "The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis". Proceedings of the National Academy of Sciences 101 (37): 13560–13565. doi:10.1073/pnas.0402760101. PMC 518794. PMID 15345741.
- Qureshi, Salman T.; Larivière, Line; Leveque, Gary; Clermont, Sophie; Moore, Karen J.; Gros, Philippe; Malo, Danielle (1999-02-15). "Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4)". The Journal of Experimental Medicine 189 (4): 615–625. doi:10.1084/jem.189.4.615. ISSN 0022-1007. PMID 9989976.
- Hoshino, Katsuaki; Takeuchi, Osamu; Kawai, Taro; Sanjo, Hideki; Ogawa, Tomohiko; Takeda, Yoshifumi; Takeda, Kiyoshi; Akira, Shizuo (1999-04-01). "Cutting Edge: Toll-Like Receptor 4 (TLR4)-Deficient Mice Are Hyporesponsive to Lipopolysaccharide: Evidence for TLR4 as the Lps Gene Product". The Journal of Immunology 162 (7): 3749–3752. ISSN 0022-1767. PMID 10201887.
- Greg McGarry (3 October 2011). "Immune System Pioneers Share America’s Largest Prize in Medicine". press release. Albany Medical Center.
- Kristoffer Furberg (20 March 2015). "169 nye NTNU-doktorer hedret". Universitetsavisa (in Norwegian).
- Genealogy of the Beutler family
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