Bruce A. Beutler

Bruce A. Beutler, an immunologist and geneticist, was born in Chicago, Illinois on 29 December, 1957, and is a US citizen. He is a Professor and Chairman of the Department of Genetics at The Scripps Research Institute, in La Jolla, California, USA. His father, Ernest Beutler, a hematologist and medical geneticist, was also a Professor and Department Chairman at Scripps. The third of four children, Beutler was preceded by older brothers Steven Merrill Beutler (b. 1952) and Earl Bryan Beutler (b. 1954), and followed by a younger sister, Deborah Ann Beutler (b. 1962).

Education

Between 1959 and 1977, Beutler lived in Southern California. He received his secondary school education at Polytechnic School in Pasadena, CA. 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 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.

Academic Positions

From 1981 to 1983 Beutler continued his medical training at the University of Texas Southwestern Medical Center in Dallas, TX 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, CA, as a Professor in the Department of Immunology. In 2007, he became Chairman of the newly created Department of Genetics at Scripps.

Principal Scientific Contributions

Beutler is best known for his pioneering molecular and genetic studies of inflammation and innate immunity. During his postdoctoral fellowship, he was the first to isolate mouse tumor necrosis factor-alpha (TNF) [Beutler, B., et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316(6028):552-4, 1985] , and to demonstrate the inflammatory potential of this cytokine, proving its important role in endotoxin-induced shock [Beutler, B., et al. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229(4716):869-71, 1985] . 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 [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] . 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 [Sultzer, B.M. Genetic control of leucocyte responses to endotoxin. Nature 219(5160):1253-4, 1968] . Beutler's work revealed that one of the mammalian Toll-like receptors, TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex [Poltorak, A., et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282(5396):2085-8, 1998] , and suggested that all of the TLRs (of which ten are now known to exist in humans) function in the perception of microbes, each detecting signature molecules that herald infection.

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 [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] 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" [Beutler,B., et al. Genetic dissection of innate immunity to infection: the mouse cytomegalovirus model. Curr.Opin.Immunol. 1:36-43, 2005] . These genes fall into "sensing," "signaling," "effector," "homeostatic," and "developmental" categories, and some of them were wholly unexpected. For example, ion 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 [Croker,B., et al. ATP-sensitive potassium channels mediate survival during infection in mammals and insects. Nat.Genet. 39(12):1453-60, 2007] .

In the course of their work, Beutler and his colleagues identified genes required for other important biological processes, including the regulation of iron absorption [Du,X., et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320(5879):1088-92, 2008] , hearing [Du,X., et al. A catechol-O-methyltransferase that is essential for auditory function in mice and humans. Proc.Natl.Acad.Sci., USA, "in press", 2008] , and embryonic development [Smyth, I., et al. The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis. Proc.Natl.Acad.Sci., USA 101(37):13560-5, 2004] , since their disruption by ENU created strikingly abnormal visible phenotypes.

Awards and Recognition

Beutler received the prestigious Balzan Prize in 2007 together with Jules A. Hoffmann for his studies of innate immunity.

Other notable honors have included:

The William B. Coley Award of the Cancer Research Institute, USA (2006, shared with Shizuo Akira).

The Gran Prix Charles-Leopold Mayer of the Académie des Sciences, France (2006).

The Robert Koch Prize of the Robert Koch Foundation, Germany (2004, shared with Jules A. Hoffmann and Shizuo Akira).

Beutler is a member of the United States National Academy of Sciences (2008), the Institute of Medicine (2008), the Association of American Physicians (2001), and the American Society for Clinical Investigation (1990).

The 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.

Family

Married to Barbara Beutler (née Lanzl) in 1980 and divorced in 1988, Beutler has three children: Daniel (b. 1983), Elliot (b. 1984), and Jonathan (b. 1987).

References

External links

* [http://www.balzan.com/default.aspx?lang=en The Balzan Foundation] - Official site
* [http://www.robert-koch-stiftung.de/ The Robert Koch Foundation] - Official site
* [http://www.scripps.edu/genetics/beutler/ The Bruce Beutler Laboratory] - Official site
* [http://mutagenetix.scripps.edu/ Mutagenetix] - Archive of mutations positionally cloned in the Beutler laboratory
* [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&orig_db=pubmed&term=beutler%20b%20OR%20beutler%20ba&cmd=&cmd_current= Scientific Publications] – All publications of articles by Bruce A. Beutler listed in PubMed.
* [http://idw-online.de/pages/de/news237418 How we sense microbes: Genetic dissection of innate immunity in insects and mammals] – Brief review of recent work, written with Jules A. Hoffmann.