Bruce Beutler: Difference between revisions

Bruce Beutler
Bruce Beutler
	University of Texas Southwestern Medical Center, 2021; Photograph by Brian Coats
Born	December 29, 1957 (age 66); Chicago, Illinois
Nationality	American
Alma mater	University of Chicago, University of California, San Diego
Spouse(s)	Barbara Lanzl (c. 1980-1988; divorced; 3 children)
Awards	2011 Nobel Prize in Physiology or Medicine
	Scientific career
Fields	Immunology
Institutions	University of Texas Southwestern Medical Center

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Bruce Alan Beutler (/ˈbɔɪtlər/ BOYT-lər; 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 "discoveries concerning the activation of innate immunity."^[1] Beutler discovered the long-elusive receptor for lipopolysaccharide (LPS; also known as endotoxin). He did so by identifying spontaneous mutations in the gene coding for mouse Toll-like receptor 4 (Tlr4) in two unrelated strains of LPS-refractory mice and proving they were responsible for that phenotype.^[2] Subsequently, and chiefly through the work of Shizuo Akira, other TLRs were shown to detect signature molecules of most infectious microbes, in each case triggering an innate immune response.^[3]^[4]^[5]^[6]^[7]

The other half of the Nobel Prize went to Ralph M. Steinman for "his discovery of the dendritic cell and its role in adaptive immunity."^[1]

Beutler is currently a Regental Professor and Director of the Center for the Genetics of Host Defense at the University of Texas Southwestern Medical Center in Dallas, Texas.^[8]^[9]

Early life and education

Born in Chicago, Illinois, Beutler lived in Southern California between the ages of 2 and 18 (1959 to 1977). For most of this time, he lived in city of Arcadia, a northeastern suburb of Los Angeles in the San Gabriel Valley. During these years, he spent much time hiking in the San Gabriel Mountains, and in regional national parks (Sequoia, Yosemite, Joshua Tree, and Grand Canyon), and was particularly fascinated by living things.^[10] These experiences impelled an intense interest in biological science. His introduction to experimental biology, acquired between the ages of 14 and 18, included work in the laboratory of his father, Ernest Beutler, then at the City of Hope Medical Center in Duarte, CA. There he learned to assay enzymes of red blood cells and became familiar with methods for protein isolation. He published his studies of an electrophoretic variant of glutathione peroxidase,^[11] as well as the inherent catalytic activity of inorganic selenite,^[12] at the age of 17.

Beutler also worked in the City of Hope laboratory of Susumu Ohno, a geneticist known for his studies of evolution, genome structure, and sex differentiation in mammals. Ohno hypothesized that the major histocompatibility complex proteins served as anchorage sites for organogenesis-directing proteins.^[13] He further suggested that H-Y antigen, a minor histocompatibility protein encoded by a gene on the Y chromosome and absent in female mammals, was responsible for directing organogenesis of the indifferent gonad to form a testis. In studying H-Y antigen,^[14] Beutler became conversant with immunology and mouse genetics during the 1970s. While a college student at the University of California at San Diego, Beutler worked in the laboratory of Dan Lindsley, a Drosophila geneticist interested in spermatogenesis and spermiogenesis in the fruit fly. There, he learned to map phenotypes to chromosomal regions using visible phenotypic markers.^[10] He also worked in the laboratory of Abraham Braude, an expert in the biology of LPS.

Beutler received his secondary school education at Polytechnic School in Pasadena, California. A precocious student, he graduated from high school at the age of 16, enrolled in college at the University of California, San Diego, and graduated with a BA degree at the age of 18 in 1976. He then enrolled in medical school at the University of Chicago in 1977 and received his M.D. degree in 1981 at the age of 23.^[15] 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. However, he found clinical medicine less interesting than laboratory science, and decided to return to the laboratory.

Scientific contributions

Isolation of tumor necrosis factor and discovery of its inflammation-promoting effect

Beutler’s focus on innate immunity began when he was a postdoctoral associate and later an assistant professor in the lab of Anthony Cerami at Rockefeller University (1983-1986). Drawing upon skills he had acquired earlier, he isolated mouse “cachectin” from the conditioned medium of LPS-activated mouse macrophages. Cachectin was hypothesized by Cerami to be a mediator of wasting in chronic disease. Its biological activity, the suppression of lipoprotein lipase synthesis in adipocytes, was thought to contribute to wasting, since lipoprotein lipase cleaves fatty acids from circulating triglycerides, allowing their uptake and re-esterification within fat cells.^[16] By sequential fractionation of LPS-activated macrophage medium, measuring cachectin activity at each step, Beutler purified cachectin to homogeneity.^[17] Determining its N-terminal sequence, he recognized it as mouse tumor necrosis factor (TNF), and showed that it had strong TNF activity; moreover that human TNF, isolated by a very different assay, had strong cachectin activity.^[16]

Human TNF, isolated contemporaneously by other workers,^[18] had to that time been defined only by its ability to kill cancer cells. The discovery of a separate role for TNF as a catabolic switch was of considerable interest. Of still greater importance, Beutler demonstrated that TNF acted as a key mediator of endotoxin-induced shock.^[19] This he accomplished by raising an antibody against mouse TNF, which he used to neutralize TNF in living mice challenged with lipopolysaccharide (LPS).^[19] The often-lethal systemic inflammatory response to LPS was significantly mitigated by passive immunization against TNF. The discovery that TNF caused an acute systemic inflammatory disease (LPS-induced shock) presaged its causative role in numerous chronic inflammatory diseases. With J.-M. Dayer, Beutler demonstrated that purified TNF could cause inflammation-associated responses in cultured human synoviocytes: secretion of collagenase and prostaglandin E2.^[20] This was an early hint that TNF might be causally important in rheumatoid arthritis (as later shown by Feldmann, Brennan, and Maini^[21]). Beutler also demonstrated the existence of TNF receptors on most cell types,^[17] and correctly inferred the presence of two types of TNF receptor distinguished by their affinities, later cloned and designated p55 and p75 TNF receptors to denote their approximate molecular weights.^[22]^[23]^[24]^[25]^[26] Before a sensitive immunoassay for TNF was feasible, Beutler used these receptors in a binding competition assay using radio-iodinated TNF as a tracer, which allowed him to precisely measure TNF in biological fluids.^[27]

Invention of TNF inhibitors

Beutler was recruited to a faculty position at UT Southwestern Medical Center and the Howard Hughes Medical Institute in 1986. Aware that TNF blockade might have clinical applications, he (along with a graduate student, David Crawford, and a postdoctoral associate, Karsten Peppel) invented and patented recombinant molecules expressly designed to neutralize TNF in vivo (Patent No. US5447851B1).^[28] Fusing the binding portion of TNF receptor proteins to the heavy chain of an immunoglobulin molecule to force receptor dimerization,^[28] they produced chimeric reagents with surprisingly high affinity and specificity for both TNF and a closely related cytokine called lymphotoxin, low antigenicity, and excellent stability in vivo. The human p75 receptor chimeric protein was later used extensively as the drug Etanercept in the treatment of rheumatoid arthritis, Crohn's disease, psoriasis, and other forms of inflammation. Marketed by Amgen, Etanercept achieved more than $74B in sales.^[29]

Discovery of the LPS receptor, and the role of TLRs in innate immune sensing

From the mid-1980s onward Beutler was interested in the mechanism by which LPS activates mammalian immune cells (chiefly macrophages,^[16]^[19] but dendritic cells and B cells as well), sometimes leading to uncontrollable Gram negative septic shock,^[30]^[31]^[32] but also promoting the well-known adjuvant effect of LPS,^[33] and B cell mitogenesis^[34]^[35] and antibody production. A single, highly specific LPS receptor was presumed to exist as early as the 1960s, based on the fact that allelic mutations in two separate strains of mice, affecting a discrete genetic locus on chromosome 4 termed Lps, abolished LPS sensing.^[34]^[36] Although this receptor had been widely pursued, it remained elusive. Beutler reasoned that in finding the LPS receptor, insight might be gained into the first molecular events that transpire upon an encounter between the host and microbial invaders.^[37]

Utilizing positional cloning in an effort that began in 1993 and lasted five years, Beutler, together with several postdoctoral associates including Alexander Poltorak, measured TNF production as a qualitative phenotypic endpoint of the LPS response. Analyzing more than 2,000 meioses, they confined the LPS receptor-encoding gene to a region of the genome encompassing approximately 5.8 million base pairs of DNA.^[2] Sequencing most of the interval, they identified a gene within which each of two LPS-refractory strains of mice (C3H/HeJ and C57BL/10ScCr) had deleterious mutations. The gene, Tlr4, encoded a cell surface protein with cytoplasmic domain homology to the interleukin-1 receptor, and several other homologous genes that were scattered across the mouse genome. Beutler and his team thus proved that one of the mammalian Toll-like receptors, TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex.^[2]^[38]^[39] They also showed that while mouse TLR4 is activated by a tetra-acylated LPS-like molecule (lipid IVa), human TLR4 is not, recapitulating the species specificity for LPS partial structures.^[39] It was deduced that direct contact between TLR4 and LPS is a prerequisite for cell activation.^[39] Later, an extracellular component of the LPS receptor complex, MD-2 (also known as lymphocyte antigen 96), was identified by R. Shimazu and colleagues.^[40] The structure of the complex, with and without LPS bound, was solved by Jie-Oh Lee and colleagues in 2009.^[41]

Jules Hoffmann and colleagues had earlier shown that the Drosophila Toll protein, originally known for its role in embryogenesis, was essential for the antimicrobial peptide response to fungal infection.^[42] However, no molecule derived from fungi actually became bound to Toll; rather, a proteolytic cascade led to the activation of an endogenous ligand, the protein Spätzle. This activated NF-kB within cells of the fat body, leading to antimicrobial peptide secretion.

Aware of this work, Charles Janeway and Ruslan Medzhitov overexpressed a modified version of human TLR4 (which they called ‘h-Toll’) and found it capable of activating the transcription factor NF-κB in mammalian cells.^[43] They speculated that TLR4 was a “pattern recognition receptor.” However, they provided no evidence that TLR4 recognized any molecule of microbial origin. If a ligand did exist, it might have been endogenous (as in the fruit fly, where Toll recognizes the endogenous protein Spätzle, or as in the case of the IL-1 receptor, which recognizes the endogenous cytokine IL-1). Indeed, numerous cell surface receptors, including the TGFβ receptor, B cell receptor, and T cell receptor activate NF-κB. In short, it was not clear what TLR4 recognized, nor what it did. Separate publications, also based on transfection/overexpression studies, held that TLR2 rather than TLR4 was the LPS receptor.^[44]^[45]

The genetic evidence of Beutler and coworkers correctly identified TLR4 as the specific and non-redundant cell surface receptor for LPS, fully required for virtually all LPS activities. This suggested that other TLRs (of which ten are now known to exist in humans) might also act as sensors of infection in mammals,^[46] each detecting other signature molecules made by microbes whether or not they were pathogens in the classical sense of the term. The other TLRs, like TLR4, do indeed initiate innate immune responses. By promoting inflammatory signaling, TLRs can also mediate pathologic effects including fever, systemic inflammation, and shock. Sterile inflammatory and autoimmune diseases such as systemic lupus erythematosus also elicit TLR signaling, and disruption of signaling from the nucleic acid sensing TLRs can favorably modify the disease phenotype.^[47]^[48]^[49]^[50]^[51]^[52]^[53]^[54]

Random Germline Mutagenesis/Forward Genetics in the mouse

After completing the positional cloning of the Lps locus in 1998, Beutler 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 in mice through a random process using the alkylating agent ENU, detected by their phenotypic effects, and then isolated by positional cloning.^[55] This work disclosed numerous essential signaling molecules required for the innate immune response,^[56]^[57]^[58]^[59]^[60]^[61]^[62] and helped to delineate the biochemistry of innate immunity. Among the genes detected was Ticam1, implicated by an ENU-induced phenotype called Lps2.^[56] The encoded protein TICAM1, also known as TRIF, was a new adaptor molecule, binding to the cytoplasmic domains of both TLR3 and TLR4, and needed for signaling by each.

Another phenotype, called 3d to connote a “triple defect” in TLR signaling, affected a gene of unknown function called Unc93b1.^[58] TLRs 3, 7, and 9 (nucleic acid sensing TLRs) failed to signal in homozygotes for the mutation. These TLRs were found to be endosomal, and physically interact with the UNC93B1 protein which transports them to the endosomal compartment.^[63] Humans with mutations in UNC93B1, the human ortholog of the same gene, were subsequently found to be susceptible to recurrent Herpes simplex virus (HSV) encephalitis, in which reactivation of latent virus occurs repeatedly in the trigeminal ganglion at the base of the midbrain, leading to cortical neuron death.^[64]

Yet another protein needed to make the endosomal environment suitable for TLR signaling was SLC15A4, identified based on the phenotype feeble.^[65] feeble was identified in a screen in which immunostimulatory DNA was administered to mice intravenously with measurement of the systemic type I interferon response. Failure of this response, which is dependent on TLR9 signaling from plasmacytoid dendritic cells (pDC) was observed in homozygous mutants, and subsequently, failure of TLR7 (but not TLR3) signaling was observed as well. Because the feeble mutation suppressed SLE in mice,^[50] the SLC15A4 protein has become a target of interest for drug development.^[66]

In all, Beutler and colleagues detected 77 mutations in 36 genes in which ENU-induced mutations created defects of TLR signaling, detected due to faulty TNF and/or interferon responses. These genes encoded all TLRs kept under surveillance in screening, all of the four adapter proteins that signal from TLRs, kinases and other signaling proteins downstream, chaperones needed to escort TLRs to their destinations, proteins that promote the availability of TLR ligands, proteins involved in vesicle transport, and proteins involved in transcriptional responses to TLR signaling, or the post-translational processing of TNF and/or type I interferons (the proteins assayed in screening).

Beutler and colleagues also used ENU mutagenesis to study the global response to a defined infectious agent. They measured susceptibility to mouse cytomegalovirus (MCMV) and identified numerous genes that make a life-or-death difference during infection, terming this set of genes the MCMV "resistome".^[67]^[68] These genes were grouped into "sensing," "signaling," "effector," "homeostatic," and "developmental" categories, some of which were wholly unexpected. In the homeostatic category, for example, K_ir6.1 ATP-sensitive potassium channels in the smooth muscle of the coronary arteries serve an essential role in the maintenance of blood flow during MCMV infection, and mutations that damage these channels cause sudden death during infection.^[69]

Other genetic screens in the Beutler laboratory were used to identify genes that mediate homeostatic adaptations of the intestinal epithelium following a cytotoxic insult;^[70]^[71]^[72]^[73]^[74]^[75]^[76] prevent allergic responses,^[77] diabetes,^[78]^[79] or obesity;^[80]^[81]^[82] support normal hematopoiesis;^[83]^[84]^[85]^[86]^[87]^[88]^[89]^[90]^[91]^[92] and enable humoral and cellular immunity.^[93]^[94]^[95]^[96] Some of these (beginning ~2015) were identified by a new process called automated meiotic mapping, which enabled greatly accelerated mutation identification compared to traditional genetic mapping (see below). In the course of their work, Beutler and his colleagues also discovered genes required for biological processes such as normal iron absorption,^[97] hearing,^[98] pigmentation,^[99]^[100] metabolism,^[80]^[82]^[101]^[102]^[103] and embryonic development.^[104] Many human diseases were ultimately linked to variants in the corresponding human genes after initial identification in the mouse by the Beutler laboratory,^[64]^[105]^[106]^[107] or by the laboratories of collaborating investigators.^[108]^[109]^[110]

Invention of Automated Meiotic Mapping

Prior to 2013, despite the development of methods for massively parallel sequencing and their application in finding induced germline mutations,^[111]^[112]^[113] positional cloning remained a slow process, limited by the need to genetically map mutations to chromosomal intervals to ascertain which induced mutation (among the average of approximately 60 changes in coding and splicing function induced per pedigree) was responsible for an observed phenotype. This required expansion of a mutant stock, outcrossing to a mapping strain, backcrossing, and genotypic and phenotypic analysis of F2 offspring. Moreover, when phenotypic screening was performed prior to positional cloning, only large effect size mutations (producing essentially qualitative phenotypes) were recoverable.

Beutler invented a means of instantly identifying ENU-induced mutations that cause phenotypes.^[114] The process, called automated meiotic mapping (AMM), eliminates the need to breed mutant mice to a mapping strain as required in classical genetic mapping and flags causative mutations as soon as phenotypic assay data are collected. In a laboratory setting, it accelerates positional cloning approximately 200-fold, and permits ongoing measurement of genome saturation as mutagenesis progresses.^[115] Not only qualitative phenotypes, but subtle quantitative phenotypes, are detectable and mapped to individual mutations; hence the sensitivity of forward genetics is dramatically increased. AMM depends on statistical computation to detect associations between mutations in either the homozygous or heterozygous state and deviant phenotypes.^[114] In addition, machine learning software, trained on the outcome of many thousands of experiments in which putative causative mutations were re-created and re-assayed for phenotype, is used to assess data quality.^[116] As of 2022, more than 260,000 ENU-induced non-synonymous coding or splice site mutations had been assayed for phenotypic effects, and more than 5,800 mutations in approximately 2,500 genes had been declared causative of phenotype(s). For certain screens, such as flow cytometry performed on the blood of germline mutant mice, more than 55% saturation of the genome has been achieved (i.e., more than 55% of all genes in which mutations will create flow cytometric aberrations in the peripheral blood have been detected, most of them based on assessment of multiple alleles, as of July 2021).^[116]

AMM led to the discovery of many new immunodeficiency disorders,^[86]^[87]^[88]^[89]^[90]^[91]^[92]^[83]^[96] and disorders of bone morphology or mineral density,^[109]^[110] vision,^[117] and metabolism.^[80]^[82]^[102]^[103] Of note, AMM was used in the identification of a chemosensor that mediates innate fear behavior in mice and an autism gene found first in mice and then shown to cause autism in humans.^[108]^[118] AMM has also permitted high speed searches for mutations that suppress or augment disease phenotypes; for example, the development of autoimmune (Type 1) diabetes in mice of the NOD strain.^[78]^[79] It offers a rational way to investigate the pathogenesis of complex disease phenotypes in general, in which many loci invariably contribute to susceptibility or resistance to disease, and disease occurs in those individuals with an unfavorable imbalance between these opposing influences.

Developing drugs that activate TLRs

Beutler has collaborated with Dale L. Boger and his research group to identify synthetic small molecule agonists of mammalian TLRs, which may be used in combination with defined molecular antigens to precisely target and coordinate innate and adaptive immune responses.^[119]^[120]^[121]^[122]^[123]^[124]^[125]

Awards and recognition

Awards

1993 - Alexander von Humboldt Fellow; Germany
1994 - Young Investigator Award (American Federation for Clinical Research); United States
2001 - “Highly Cited” Researcher, Institute for Scientific Information; United States
2004 - Robert Koch Prize (Robert Koch Stiftung); Germany (shared with Jules A. Hoffmann and Shizuo Akira)
2006 - William B. Coley Award (Cancer Research Institute); United States (shared with Shizuo Akira)
2006 - Gran Prix Charles-Léopold Mayer (Académie des Sciences); France
2007 - Recipient of NIH/NIGMS MERIT Award; United States
2007 - Balzan Prize (International Balzan Foundation); Italy and Switzerland (shared with Jules A. Hoffmann)
2008 - Frederik B. Bang Award (The Stanley Watson Foundation); United States
2008 - “Citation Laureate,” Thomson Reuters
2009 - Will Rogers Institute Annual Prize for Scientific Research; United States
2009 - Albany Medical Center Prize in Medicine and Biomedical Research; United States (shared with Charles A. Dinarello and Ralph M. Steinman)^[126]
2010 - University of Chicago, Professional Achievement Citation; United States
2011 - Shaw Prize; China (shared with Jules A. Hoffmann and Ruslan M. Medzhitov)
2011 - Nobel Prize in Physiology or Medicine; Sweden (shared with Jules A. Hoffmann and Ralph M. Steinman)^[1]
2012 - Drexel Medicine Prize in Immunology; United States
2013 - Rabbi Shai Shacknai Memorial Prize in Immunology and Cancer Research, The Hebrew University of Jerusalem; Israel
2013 - Distinguished Service Award, University of Chicago; United States
2013 - Korsmeyer Award; United States
2016 - UCSD Distinguished Alumnus Award; United States

Honorary Doctoral Degrees

2007 - Doctor Med. Honoris Causa, Technical University of Munich; Germany
2009 - Honorary Doctoral Degree, Xiamen University; China
2012 - Honorary Professor, Trinity College; Ireland
2013 - Honorary Professor, Peking University; China
2014 - Honorary Professor, Shanghai Jiao Tong University; China
2014 - Chair of the Beutler Institute Council, Xiamen University; China
2014 - Honorary Professor, Xiamen University; China
2015 - Doctor Honoris Causa, University of Chile; Chile
2015 - Doctor Honoris Causa, University of Marseille; France
2015 - Doctor Honoris Causa, University of Brasilia; Brazil
2015 - Doctor Honoris Causa,^[127] Norwegian University of Science and Technology (NTNU); Norway
2015 - Honorary Professor at Naresuan University; Thailand
2016 - Honorary Doctorate, University of Athens; Greece
2017 - Doctor Med. Honoris Causa, University of Ottawa; Canada
2017 - Honorary Professor, Tianjin University; China
2019 - Honorary Degree, Jewish Theological Seminary; United States
2019 - Laurea Magistrale honoris causa in Medicina e Chirurgia (LM41),^[128] Universita Magna Grecia of Catanzaro; Italy

Honorary and Learned Societies

1990 - Elected Member, American Society for Clinical Investigation; United States
2001 - Elected Member, Association of American Physicians; United States
2008 - Elected Member, National Academy of Medicine (formerly the Institute of Medicine); United States
2008 - Elected Member, National Academy of Sciences; United States
2009 - Elected Associate (Foreign) Member, European Molecular Biology Organization (EMBO)
2012 - Officier de la Legion D’Honneur; France
2012 - Elected Member,^[129] German National Academy of Sciences (Leopoldina); Germany
2013 - Elected Member, American Academy of Arts & Sciences; United States
2015 - Elected Member, Royal Academy of Medicine; Belgium
2015 - Elected Foreign Member, Academy of Athens; Greece
2016 - Corresponding Member, Class of Physical Sciences, Accademia delle Scienze; Italy
2018 - Elected Fellow of the AACR Academy; United States

Family

Bruce Beutler was the third son of Ernest Beutler (1928-2008) and Brondelle May Beutler (née Fleisher; 1928-2019). His siblings included two older brothers (Steven [b. 1951] and Earl [b. 1954]), and a younger sister, Deborah [b. 1962]). Ernest, Bruce, Steven and Deborah were all physicians while Earl, a software engineer and entrepreneur, worked together with Ernest to create bibliographic retrieval software for publishing scientists (see Reference Manager) as well as other software products.

Ernest Beutler was a hematologist and medical geneticist famed for his studies of G-6-PD deficiency,^[130] other hemolytic anemias,^[131]^[132] iron metabolism,^[133] glycolipid storage diseases,^[134] and leukemias,^[135]^[136] as well as his discovery of X chromosome inactivation.^[137] He was a Professor and department chairman at The Scripps Research Institute contemporaneously with Bruce. The two collaborated productively on several topics prior to Ernest Beutler’s death in 2008.^[11]^[12]^[138]^[139]^[140]^[141]

Both of Ernest Beutler’s parents were physicians.^[142] Bruce Beutler’s paternal grandmother, Kathe Beutler (née Italiener, daughter of Anna Rothstein, 1896-1999),^[143] was a pediatrician, trained at the Charité hospital in Berlin, earning her medical diploma in 1923. Käthe Italiener married Alfred Beutler in 1925. Also a physician, Alfred Beutler was a cousin to the spectral physicist, Hans G. Beutler (1896-1942), who worked at the Kaiser Wilhelm Institute and the University of Berlin before emigrating to the USA in 1936. He continued his work at the University of Chicago until his death.^[144]

One of Käthe’s Beutler’s first cousins was Kurt Rosenthal (aka Curtis Ronald), a banker and grandfather of Pamela Ronald,^[145] who discovered the first plant sensor of a molecule derived from a microbial pathogen. Known as XA21, this protein exhibits structural homology to TLR4 (shown by Beutler to be the LPS receptor). Notably, while both Beutler and Ronald were pioneers in the genetics of innate immunity, neither was aware of the other’s work and its possible relevance to their own prior to making their respective discoveries of mammalian and plant sensors of infection. Käthe Beutler, however, was aware that each was a scientist and a member of her extended family. She had informed each of the other’s existence, though she lacked detailed knowledge of their work.^[145]

Bruce Beutler married Barbara Beutler (née Lanzl) in 1980 and divorced in 1988. Three sons were born to the couple: Daniel Beutler (born 1983), Elliot Beutler (born 1984), and Jonathan Beutler (born 1987). Elliot Beutler, a physicist, is currently a postdoctoral associate at University of Washington, Seattle. Coincidentally, his work is topically related to that of Hans G. Beutler, his first cousin, thrice removed. Jonathan Beutler, a plant biologist, is a Ph.D. candidate at the University of British Columbia, Vancouver.

References

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^ ^a ^b ^c Poltorak, A.; He, X.; Smirnova, I.; Liu, M. Y.; Van Huffel, C.; Du, X.; Birdwell, D.; Alejos, E.; Silva, M.; Galanos, C.; Freudenberg, M.; Ricciardi-Castagnoli, P.; Layton, B.; Beutler, B. (December 11, 1998). "Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene". Science. 282 (5396): 2085–2088. doi:10.1126/science.282.5396.2085. ISSN 0036-8075. PMID 9851930.
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^ Hemmi, H.; Takeuchi, O.; Kawai, T.; Kaisho, T.; Sato, S.; Sanjo, H.; Matsumoto, M.; Hoshino, K.; Wagner, H.; Takeda, K.; Akira, S. (December 7, 2000). "A Toll-like receptor recognizes bacterial DNA". Nature. 408 (6813): 740–745. doi:10.1038/35047123. ISSN 0028-0836. PMID 11130078.
^ Takeuchi, O.; Hoshino, K.; Kawai, T.; Sanjo, H.; Takada, H.; Ogawa, T.; Takeda, K.; Akira, S. (October 1, 1999). "Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components". Immunity. 11 (4): 443–451. doi:10.1016/s1074-7613(00)80119-3. ISSN 1074-7613. PMID 10549626.
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^ Takeuchi, Osamu; Sato, Shintaro; Horiuchi, Takao; Hoshino, Katsuaki; Takeda, Kiyoshi; Dong, Zhongyun; Modlin, Robert L.; Akira, Shizuo (July 1, 2002). "Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins". Journal of Immunology (Baltimore, Md.: 1950). 169 (1): 10–14. doi:10.4049/jimmunol.169.1.10. ISSN 0022-1767. PMID 12077222.
^ Ravindran, S. (2013). "Profile of Bruce A. Beutler". Proceedings of the National Academy of Sciences. 110 (32): 12857–8. Bibcode:2013PNAS..11012857R. doi:10.1073/pnas.1311624110. PMC 3740904. PMID 23858464.
^ "Center for the Genetics of Host Defense - UT Southwestern, Dallas, TX". Retrieved March 9, 2023.{{cite web}}: CS1 maint: url-status (link)
^ ^a ^b "Bruce A. Beutler - Biographical - NobelPrize.org". Retrieved March 9, 2023.{{cite web}}: CS1 maint: url-status (link)
^ ^a ^b Beutler, E.; West, C.; Beutler, B. (October 1974). "Electrophoretic polymorphism of glutathione peroxidase". Annals of Human Genetics. 38 (2): 163–169. doi:10.1111/j.1469-1809.1974.tb01947.x. ISSN 0003-4800. PMID 4467780.
^ ^a ^b Beutler, E.; Beutler, B.; Matsumoto, J. (July 15, 1975). "Glutathione peroxidase activity of inorganic selenium and seleno-DL-cysteine". Experientia. 31 (7): 769–770. doi:10.1007/BF01938453. ISSN 0014-4754. PMID 1140308.
^ Ohno, S. (January 1977). "The original function of MHC antigens as the general plasma membrane anchorage site of organogenesis-directing proteins". Immunological Reviews. 33: 59–69. ISSN 0105-2896. PMID 66186.
^ Beutler, B.; Nagai, Y.; Ohno, S.; Klein, G.; Shapiro, I. M. (March 1978). "The HLA-dependent expression of testis- organizing H-Y antigen by human male cells". Cell. 13 (3): 509–513. doi:10.1016/0092-8674(78)90324-0. ISSN 0092-8674. PMID 77737.
^ Easton, John (October 10, 2011). "Alumnus Bruce Beutler, MD'81, to receive 2011 Nobel Prize in Medicine". uchicago news. Retrieved March 9, 2023.
^ ^a ^b ^c Beutler, B.; Greenwald, D.; Hulmes, J. D.; Chang, M.; Pan, Y. C.; Mathison, J.; Ulevitch, R.; Cerami, A. (August 1, 1985). "Identity of tumour necrosis factor and the macrophage-secreted factor cachectin". Nature. 316 (6028): 552–554. doi:10.1038/316552a0. ISSN 0028-0836. PMID 2993897.
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^ Beutler, E.; Yeh, M.; Fairbanks, V. F. (January 15, 1962). "The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker". Proceedings of the National Academy of Sciences of the United States of America. 48 (1): 9–16. doi:10.1073/pnas.48.1.9. ISSN 0027-8424. PMC 285481. PMID 13868717.
^ Beutler, Bruce; Beutler, Ernest (December 12, 2002). "Toll-like receptor 4 polymorphisms and atherogenesis". The New England Journal of Medicine. 347 (24): 1978–1980, author reply 1978–1980. ISSN 1533-4406. PMID 12479194.
^ Beutler, E.; Gelbart, T.; Han, J. H.; Koziol, J. A.; Beutler, B. (January 1989). "Evolution of the genome and the genetic code: selection at the dinucleotide level by methylation and polyribonucleotide cleavage". Proceedings of the National Academy of Sciences of the United States of America. 86 (1): 192–196. doi:10.1073/pnas.86.1.192. ISSN 0027-8424. PMC 286430. PMID 2463621.
^ Truksa, Jaroslav; Gelbart, Terri; Peng, Hongfan; Beutler, Ernest; Beutler, Bruce; Lee, Pauline (November 2009). "Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6". British Journal of Haematology. 147 (4): 571–581. doi:10.1111/j.1365-2141.2009.07873.x. ISSN 1365-2141. PMID 19751239.
^ Du, Xin; She, Ellen; Gelbart, Terri; Truksa, Jaroslav; Lee, Pauline; Xia, Yu; Khovananth, Kevin; Mudd, Suzanne; Mann, Navjiwan; Moresco, Eva Marie Y.; Beutler, Ernest; Beutler, Bruce (May 23, 2008). "The serine protease TMPRSS6 is required to sense iron deficiency". Science. 320 (5879): 1088–1092. doi:10.1126/science.1157121. ISSN 1095-9203. PMC 2430097. PMID 18451267.
^ Wailoo, Keith. "Ernest Beutler QA - Hematology.org". Retrieved March 9, 2023.{{cite web}}: CS1 maint: url-status (link)
^ Hildebrandt, Sabine; Kammertöns, Thomas; Lechner, Christian; Schmitt, Philipp; Schumann, Ralf R. (2019). "Dr. Käthe Beutler, 1896–1999". Medizinhistorisches Journal. 54 (4): 294–346. doi:10.25162/mhj-2019-0009. ISSN 0025-8431.
^ "HANS G. BEUTLER, 46, PHYSICIST, IS DEAD; Research Aide on the Chicago U. Faculty Was Spectroscopist". The New York Times. December 19, 1942. Retrieved March 9, 2023.
^ ^a ^b Scudellari, Megan (April 1, 2011). "Family Affair". The Scientist. Archived from the original on May 5, 2012. Retrieved March 9, 2023.

External links

Official website
Works on the topic Bruce Beutler at Wikisource

External links

Bruce A. Beutler on Nobelprize.org including the Nobel lecture How Mammals Sense Infection: From Endotoxin to the Toll-like Receptors
Nobel Prize Inspiration Initiative
Scientific Publications – All publications of articles by Bruce A. Beutler listed in PubMed.
How we sense microbes: Genetic dissection of innate immunity in insects and mammals – Brief review of recent work, written with Jules A. Hoffmann.
Persistent Prospector - MD. Bruce Beutler by Ruth Williams
2011 Video presentation by Dr. Bruce Beutler at University of Texas
Discovery of TLR4 and his Nobel Prize Award displayed at Perot Museum of Nature and Science in Dallas, TX.

[Nobel-1] "Nobel Prize in Physiology or Medicine 2011" (Press release). Nobel Foundation. October 3, 2011.

[:1-2] Poltorak, A.; He, X.; Smirnova, I.; Liu, M. Y.; Van Huffel, C.; Du, X.; Birdwell, D.; Alejos, E.; Silva, M.; Galanos, C.; Freudenberg, M.; Ricciardi-Castagnoli, P.; Layton, B.; Beutler, B. (December 11, 1998). "Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene". Science. 282 (5396): 2085–2088. doi:10.1126/science.282.5396.2085. ISSN 0036-8075. PMID 9851930.

[3] Hemmi, Hiroaki; Kaisho, Tsuneyasu; Takeuchi, Osamu; Sato, Shintaro; Sanjo, Hideki; Hoshino, Katsuaki; Horiuchi, Takao; Tomizawa, Hideyuki; Takeda, Kiyoshi; Akira, Shizuo (January 22, 2002). "Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway". Nature Immunology. 3 (2): 196–200. doi:10.1038/ni758. ISSN 1529-2908. PMID 11812998.

[4] Hemmi, H.; Takeuchi, O.; Kawai, T.; Kaisho, T.; Sato, S.; Sanjo, H.; Matsumoto, M.; Hoshino, K.; Wagner, H.; Takeda, K.; Akira, S. (December 7, 2000). "A Toll-like receptor recognizes bacterial DNA". Nature. 408 (6813): 740–745. doi:10.1038/35047123. ISSN 0028-0836. PMID 11130078.

[5] Takeuchi, O.; Hoshino, K.; Kawai, T.; Sanjo, H.; Takada, H.; Ogawa, T.; Takeda, K.; Akira, S. (October 1, 1999). "Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components". Immunity. 11 (4): 443–451. doi:10.1016/s1074-7613(00)80119-3. ISSN 1074-7613. PMID 10549626.

[6] Takeuchi, O.; Kawai, T.; Mühlradt, P. F.; Morr, M.; Radolf, J. D.; Zychlinsky, A.; Takeda, K.; Akira, S. (July 1, 2001). "Discrimination of bacterial lipoproteins by Toll-like receptor 6". International Immunology. 13 (7): 933–940. doi:10.1093/intimm/13.7.933. ISSN 0953-8178. PMID 11431423.

[7] Takeuchi, Osamu; Sato, Shintaro; Horiuchi, Takao; Hoshino, Katsuaki; Takeda, Kiyoshi; Dong, Zhongyun; Modlin, Robert L.; Akira, Shizuo (July 1, 2002). "Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins". Journal of Immunology (Baltimore, Md.: 1950). 169 (1): 10–14. doi:10.4049/jimmunol.169.1.10. ISSN 0022-1767. PMID 12077222.

[profile-8] Ravindran, S. (2013). "Profile of Bruce A. Beutler". Proceedings of the National Academy of Sciences. 110 (32): 12857–8. Bibcode:2013PNAS..11012857R. doi:10.1073/pnas.1311624110. PMC 3740904. PMID 23858464.

[9] "Center for the Genetics of Host Defense - UT Southwestern, Dallas, TX". Retrieved March 9, 2023.{{cite web}}: CS1 maint: url-status (link)

[:0-10] "Bruce A. Beutler - Biographical - NobelPrize.org". Retrieved March 9, 2023.{{cite web}}: CS1 maint: url-status (link)

[:32-11] Beutler, E.; West, C.; Beutler, B. (October 1974). "Electrophoretic polymorphism of glutathione peroxidase". Annals of Human Genetics. 38 (2): 163–169. doi:10.1111/j.1469-1809.1974.tb01947.x. ISSN 0003-4800. PMID 4467780.

[:33-12] Beutler, E.; Beutler, B.; Matsumoto, J. (July 15, 1975). "Glutathione peroxidase activity of inorganic selenium and seleno-DL-cysteine". Experientia. 31 (7): 769–770. doi:10.1007/BF01938453. ISSN 0014-4754. PMID 1140308.

[13] Ohno, S. (January 1977). "The original function of MHC antigens as the general plasma membrane anchorage site of organogenesis-directing proteins". Immunological Reviews. 33: 59–69. ISSN 0105-2896. PMID 66186.

[14] Beutler, B.; Nagai, Y.; Ohno, S.; Klein, G.; Shapiro, I. M. (March 1978). "The HLA-dependent expression of testis- organizing H-Y antigen by human male cells". Cell. 13 (3): 509–513. doi:10.1016/0092-8674(78)90324-0. ISSN 0092-8674. PMID 77737.

[15] Easton, John (October 10, 2011). "Alumnus Bruce Beutler, MD'81, to receive 2011 Nobel Prize in Medicine". uchicago news. Retrieved March 9, 2023.

[:2-16] Beutler, B.; Greenwald, D.; Hulmes, J. D.; Chang, M.; Pan, Y. C.; Mathison, J.; Ulevitch, R.; Cerami, A. (August 1, 1985). "Identity of tumour necrosis factor and the macrophage-secreted factor cachectin". Nature. 316 (6028): 552–554. doi:10.1038/316552a0. ISSN 0028-0836. PMID 2993897.

[:3-17] Beutler, B.; Mahoney, J.; Le Trang, N.; Pekala, P.; Cerami, A. (May 1, 1985). "Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells". The Journal of Experimental Medicine. 161 (5): 984–995. doi:10.1084/jem.161.5.984. ISSN 0022-1007. PMC 2187615. PMID 3872925.

[18] Aggarwal, B. B.; Kohr, W. J.; Hass, P. E.; Moffat, B.; Spencer, S. A.; Henzel, W. J.; Bringman, T. S.; Nedwin, G. E.; Goeddel, D. V.; Harkins, R. N. (February 25, 1985). "Human tumor necrosis factor. Production, purification, and characterization". The Journal of Biological Chemistry. 260 (4): 2345–2354. ISSN 0021-9258. PMID 3871770.

[:4-19] Beutler, B.; Milsark, I. W.; Cerami, A. C. (August 30, 1985). "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin". Science. 229 (4716): 869–871. doi:10.1126/science.3895437. ISSN 0036-8075. PMID 3895437.

[20] Dayer, J. M.; Beutler, B.; Cerami, A. (December 1, 1985). "Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts". The Journal of Experimental Medicine. 162 (6): 2163–2168. doi:10.1084/jem.162.6.2163. ISSN 0022-1007. PMC 2187983. PMID 2999289.

[21] Feldmann, M.; Brennan, F. M.; Maini, R. N. (1996). "Role of cytokines in rheumatoid arthritis". Annual Review of Immunology. 14: 397–440. doi:10.1146/annurev.immunol.14.1.397. ISSN 0732-0582. PMID 8717520.

[22] Engelmann, H.; Novick, D.; Wallach, D. (January 25, 1990). "Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors". The Journal of Biological Chemistry. 265 (3): 1531–1536. ISSN 0021-9258. PMID 2153136.

[23] Loetscher, H.; Pan, Y. C.; Lahm, H. W.; Gentz, R.; Brockhaus, M.; Tabuchi, H.; Lesslauer, W. (April 20, 1990). "Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor". Cell. 61 (2): 351–359. doi:10.1016/0092-8674(90)90815-v. ISSN 0092-8674. PMID 2158862.

[24] Nophar, Y.; Kemper, O.; Brakebusch, C.; Englemann, H.; Zwang, R.; Aderka, D.; Holtmann, H.; Wallach, D. (October 1, 1990). "Soluble forms of tumor necrosis factor receptors (TNF-Rs). The cDNA for the type I TNF-R, cloned using amino acid sequence data of its soluble form, encodes both the cell surface and a soluble form of the receptor". The EMBO journal. 9 (10): 3269–3278. doi:10.1002/j.1460-2075.1990.tb07526.x. ISSN 0261-4189. PMC 552060. PMID 1698610.

[25] Schall, T. J.; Lewis, M.; Koller, K. J.; Lee, A.; Rice, G. C.; Wong, G. H.; Gatanaga, T.; Granger, G. A.; Lentz, R.; Raab, H. (April 20, 1990). "Molecular cloning and expression of a receptor for human tumor necrosis factor". Cell. 61 (2): 361–370. doi:10.1016/0092-8674(90)90816-w. ISSN 0092-8674. PMID 2158863.

[26] Smith, C. A.; Davis, T.; Anderson, D.; Solam, L.; Beckmann, M. P.; Jerzy, R.; Dower, S. K.; Cosman, D.; Goodwin, R. G. (May 25, 1990). "A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins". Science. 248 (4958): 1019–1023. doi:10.1126/science.2160731. ISSN 0036-8075. PMID 2160731.

[27] Poltorak, A.; Peppel, K.; Beutler, B. (February 28, 1994). "Receptor-mediated label-transfer assay (RELAY): a novel method for the detection of plasma tumor necrosis factor at attomolar concentrations". Journal of Immunological Methods. 169 (1): 93–99. doi:10.1016/0022-1759(94)90128-7. ISSN 0022-1759. PMID 8133076.

[:5-28] Peppel, K.; Crawford, D.; Beutler, B. (December 1, 1991). "A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity". The Journal of Experimental Medicine. 174 (6): 1483–1489. doi:10.1084/jem.174.6.1483. ISSN 0022-1007. PMC 2119031. PMID 1660525.

[29] Gardner, Jonathan (November 1, 2021). "A three-decade monopoly: how Amgen built a patent thicket around its top-selling drug | BioPharma Dive". BioPharma Dive. Retrieved March 9, 2023.

[30] Beutler, B.; Poltorak, A. (July 2001). "Sepsis and evolution of the innate immune response". Critical Care Medicine. 29 (7 Suppl): S2–6, discussion S6–7. doi:10.1097/00003246-200107001-00002. ISSN 0090-3493. PMID 11445725.

[31] Beutler, Bruce (1988). "Orchestration of septic shock by cytokines: the role of cachectin (tumor necrosis factor)". In Roth, B. (ed.). Molecular and Cellular Mechanisms of Septic Shock. New York: Alan R. Liss, Inc. pp. 219–235.

[32] Beutler B (1992). "Cytokines in Shock: 1992". In Lamy M, Thijs LG (eds.). Mediators of Sepsis. Heidelberg: Springer Berlin. pp. 51–67.

[33] Johnson, A. G.; Gaines, S.; Landy, M. (February 1, 1956). "Studies on the O antigen of Salmonella typhosa. V. Enhancement of antibody response to protein antigens by the purified lipopolysaccharide". The Journal of Experimental Medicine. 103 (2): 225–246. doi:10.1084/jem.103.2.225. ISSN 0022-1007. PMC 2136584. PMID 13286429.

[:6-34] Coutinho, A.; Meo, T. (December 1978). "Genetic basis for unresponsiveness to lipopolysaccharide in C57BL/10Cr mice". Immunogenetics. 7 (1): 17–24. doi:10.1007/BF01843983. ISSN 0093-7711. PMID 21302052.

[35] Watson, J.; Riblet, R. (November 1, 1974). "Genetic control of responses to bacterial lipopolysaccharides in mice. I. Evidence for a single gene that influences mitogenic and immunogenic respones [sic] to lipopolysaccharides". The Journal of Experimental Medicine. 140 (5): 1147–1161. doi:10.1084/jem.140.5.1147. ISSN 0022-1007. PMC 2139714. PMID 4138849.

[36] Sultzer, B. M. (September 21, 1968). "Genetic control of leucocyte responses to endotoxin". Nature. 219 (5160): 1253–1254. doi:10.1038/2191253a0. ISSN 0028-0836. PMID 4877918.

[37] Beutler, Bruce (January 2002). "Toll-like receptors: how they work and what they do". Current Opinion in Hematology. 9 (1): 2–10. doi:10.1097/00062752-200201000-00002. ISSN 1065-6251. PMID 11753071.

[38] Du, X.; Poltorak, A.; Silva, M.; Beutler, B. (1999). "Analysis of Tlr4-mediated LPS signal transduction in macrophages by mutational modification of the receptor". Blood Cells, Molecules & Diseases. 25 (5–6): 328–338. doi:10.1006/bcmd.1999.0262. ISSN 1079-9796. PMID 10660480.

[:7-39] Poltorak, A.; Ricciardi-Castagnoli, P.; Citterio, S.; Beutler, B. (February 29, 2000). "Physical contact between lipopolysaccharide and toll-like receptor 4 revealed by genetic complementation". Proceedings of the National Academy of Sciences of the United States of America. 97 (5): 2163–2167. doi:10.1073/pnas.040565397. ISSN 0027-8424. PMC 15771. PMID 10681462.

[40] Shimazu, R.; Akashi, S.; Ogata, H.; Nagai, Y.; Fukudome, K.; Miyake, K.; Kimoto, M. (June 7, 1999). "MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4". The Journal of Experimental Medicine. 189 (11): 1777–1782. doi:10.1084/jem.189.11.1777. ISSN 0022-1007. PMC 2193086. PMID 10359581.

[41] Park, Beom Seok; Song, Dong Hyun; Kim, Ho Min; Choi, Byong-Seok; Lee, Hayyoung; Lee, Jie-Oh (April 30, 2009). "The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex". Nature. 458 (7242): 1191–1195. doi:10.1038/nature07830. ISSN 1476-4687. PMID 19252480.

[42] Lemaitre, B.; Nicolas, E.; Michaut, L.; Reichhart, J. M.; Hoffmann, J. A. (September 20, 1996). "The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults". Cell. 86 (6): 973–983. doi:10.1016/s0092-8674(00)80172-5. ISSN 0092-8674. PMID 8808632.

[43] Medzhitov, R.; Preston-Hurlburt, P.; Janeway, C. A. (July 24, 1997). "A human homologue of the Drosophila Toll protein signals activation of adaptive immunity". Nature. 388 (6640): 394–397. doi:10.1038/41131. ISSN 0028-0836. PMID 9237759.

[44] Kirschning, C. J.; Wesche, H.; Merrill Ayres, T.; Rothe, M. (December 7, 1998). "Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide". The Journal of Experimental Medicine. 188 (11): 2091–2097. doi:10.1084/jem.188.11.2091. ISSN 0022-1007. PMC 2212382. PMID 9841923.

[45] Yang, R. B.; Mark, M. R.; Gray, A.; Huang, A.; Xie, M. H.; Zhang, M.; Goddard, A.; Wood, W. I.; Gurney, A. L.; Godowski, P. J. (September 17, 1998). "Toll-like receptor-2 mediates lipopolysaccharide-induced cellular signalling". Nature. 395 (6699): 284–288. doi:10.1038/26239. ISSN 0028-0836. PMID 9751057.

[46] Beutler, B.; Poltorak, A. (June 2000). "Positional cloning of Lps, and the general role of toll-like receptors in the innate immune response". European Cytokine Network. 11 (2): 143–152. ISSN 1148-5493. PMID 10903793.

[47] Christensen, Sean R.; Shupe, Jonathan; Nickerson, Kevin; Kashgarian, Michael; Flavell, Richard A.; Shlomchik, Mark J. (September 2006). "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): 417–428. doi:10.1016/j.immuni.2006.07.013. ISSN 1074-7613. PMID 16973389.

[48] Brown, Grant J.; Cañete, Pablo F.; Wang, Hao; Medhavy, Arti; Bones, Josiah; Roco, Jonathan A.; He, Yuke; Qin, Yuting; Cappello, Jean; Ellyard, Julia I.; Bassett, Katharine; Shen, Qian; Burgio, Gaetan; Zhang, Yaoyuan; Turnbull, Cynthia (May 2022). "TLR7 gain-of-function genetic variation causes human lupus". Nature. 605 (7909): 349–356. doi:10.1038/s41586-022-04642-z. ISSN 1476-4687. PMC 9095492. PMID 35477763.

[49] Leibler, Claire; John, Shinu; Elsner, Rebecca A.; Thomas, Kayla B.; Smita, Shuchi; Joachim, Stephen; Levack, Russell C.; Callahan, Derrick J.; Gordon, Rachael A.; Bastacky, Sheldon; Fukui, Ryutaro; Miyake, Kensuke; Gingras, Sebastien; Nickerson, Kevin M.; Shlomchik, Mark J. (October 2022). "Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus". Nature Immunology. 23 (10): 1457–1469. doi:10.1038/s41590-022-01310-2. ISSN 1529-2916. PMC 9561083. PMID 36151396.

[:8-50] Baccala, Roberto; Gonzalez-Quintial, Rosana; Blasius, Amanda L.; Rimann, Ivo; Ozato, Keiko; Kono, Dwight H.; Beutler, Bruce; Theofilopoulos, Argyrios N. (February 19, 2013). "Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus". Proceedings of the National Academy of Sciences of the United States of America. 110 (8): 2940–2945. doi:10.1073/pnas.1222798110. ISSN 1091-6490. PMC 3581947. PMID 23382217.

[51] Kono, Dwight H.; Haraldsson, M. Katarina; Lawson, Brian R.; Pollard, K. Michael; Koh, Yi Ting; Du, Xin; Arnold, Carrie N.; Baccala, Roberto; Silverman, Gregg J.; Beutler, Bruce A.; Theofilopoulos, Argyrios N. (July 21, 2009). "Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus". Proceedings of the National Academy of Sciences of the United States of America. 106 (29): 12061–12066. doi:10.1073/pnas.0905441106. ISSN 1091-6490. PMC 2715524. PMID 19574451.

[52] Lau, Christina M.; Broughton, Courtney; Tabor, Abigail S.; Akira, Shizuo; Flavell, Richard A.; Mamula, Mark J.; Christensen, Sean R.; Shlomchik, Mark J.; Viglianti, Gregory A.; Rifkin, Ian R.; Marshak-Rothstein, Ann (November 7, 2005). "RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement". The Journal of Experimental Medicine. 202 (9): 1171–1177. doi:10.1084/jem.20050630. ISSN 0022-1007. PMC 2213226. PMID 16260486.

[53] Leadbetter, Elizabeth A.; Rifkin, Ian R.; Hohlbaum, Andreas M.; Beaudette, Britte C.; Shlomchik, Mark J.; Marshak-Rothstein, Ann (April 11, 2002). "Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors". Nature. 416 (6881): 603–607. doi:10.1038/416603a. ISSN 0028-0836. PMID 11948342.

[54] Viglianti, Gregory A.; Lau, Christina M.; Hanley, Timothy M.; Miko, Benjamin A.; Shlomchik, Mark J.; Marshak-Rothstein, Ann (December 2003). "Activation of autoreactive B cells by CpG dsDNA". Immunity. 19 (6): 837–847. doi:10.1016/s1074-7613(03)00323-6. ISSN 1074-7613. PMID 14670301.

[55] Beutler, Bruce; Du, Xin; Xia, Yu (July 2007). "Precis on forward genetics in mice". Nature Immunology. 8 (7): 659–664. doi:10.1038/ni0707-659. ISSN 1529-2908. PMID 17579639.

[:9-56] Hoebe, K.; Du, X.; Georgel, P.; Janssen, E.; Tabeta, K.; Kim, S. O.; Goode, J.; Lin, P.; Mann, N.; Mudd, S.; Crozat, K.; Sovath, S.; Han, J.; Beutler, B. (August 14, 2003). "Identification of Lps2 as a key transducer of MyD88-independent TIR signalling". Nature. 424 (6950): 743–748. doi:10.1038/nature01889. ISSN 1476-4687. PMID 12872135.

[57] Hoebe, Kasper; Georgel, Philippe; Rutschmann, Sophie; Du, Xin; Mudd, Suzanne; Crozat, Karine; Sovath, Sosathya; Shamel, Louis; Hartung, Thomas; Zähringer, Ulrich; Beutler, Bruce (February 3, 2005). "CD36 is a sensor of diacylglycerides". Nature. 433 (7025): 523–527. doi:10.1038/nature03253. ISSN 1476-4687. PMID 15690042.

[:10-58] Tabeta, Koichi; Hoebe, Kasper; Janssen, Edith M.; Du, Xin; Georgel, Philippe; Crozat, Karine; Mudd, Suzanne; Mann, Navjiwan; Sovath, Sosathya; Goode, Jason; Shamel, Louis; Herskovits, Anat A.; Portnoy, Daniel A.; Cooke, Michael; Tarantino, Lisa M. (January 15, 2006). "The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9". Nature Immunology. 7 (2): 156–164. doi:10.1038/ni1297. ISSN 1529-2908. PMID 16415873.

[59] Croker, Ben A.; Lawson, Brian R.; Rutschmann, Sophie; Berger, Michael; Eidenschenk, Celine; Blasius, Amanda L.; Moresco, Eva Marie Y.; Sovath, Sosathya; Cengia, Louise; Shultz, Leonard D.; Theofilopoulos, Argyrios N.; Pettersson, Sven; Beutler, Bruce Alan (September 30, 2008). "Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger". Proceedings of the National Academy of Sciences of the United States of America. 105 (39): 15028–15033. doi:10.1073/pnas.0806619105. ISSN 1091-6490. PMC 2567487. PMID 18806225.

[60] Shi, Hexin; Wang, Ying; Li, Xiaohong; Zhan, Xiaoming; Tang, Miao; Fina, Maggy; Su, Lijing; Pratt, David; Bu, Chun Hui; Hildebrand, Sara; Lyon, Stephen; Scott, Lindsay; Quan, Jiexia; Sun, Qihua; Russell, Jamie (December 7, 2015). "NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component". Nature Immunology. 17 (3): 250–258. doi:10.1038/ni.3333. ISSN 1529-2916. PMC 4862588. PMID 26642356.

[61] Sun, Lei; Jiang, Zhengfan; Acosta-Rodriguez, Victoria A.; Berger, Michael; Du, Xin; Choi, Jin Huk; Wang, Jianhui; Wang, Kuan-Wen; Kilaru, Gokhul K.; Mohawk, Jennifer A.; Quan, Jiexia; Scott, Lindsay; Hildebrand, Sara; Li, Xiaohong; Tang, Miao (November 6, 2017). "HCFC2 is needed for IRF1- and IRF2-dependent Tlr3 transcription and for survival during viral infections". The Journal of Experimental Medicine. 214 (11): 3263–3277. doi:10.1084/jem.20161630. ISSN 1540-9538. PMC 5679162. PMID 28970238.

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[113] Xia, Yu; Won, Sungyong; Du, Xin; Lin, Pei; Ross, Charles; La Vine, Diantha; Wiltshire, Sean; Leiva, Gabriel; Vidal, Silvia M.; Whittle, Belinda; Goodnow, Christopher C.; Koziol, James; Moresco, Eva Marie Y.; Beutler, Bruce (December 2010). "Bulk segregation mapping of mutations in closely related strains of mice". Genetics. 186 (4): 1139–1146. doi:10.1534/genetics.110.121160. ISSN 1943-2631. PMC 2998299. PMID 20923982.

[:30-114] Wang, Tao; Zhan, Xiaowei; Bu, Chun-Hui; Lyon, Stephen; Pratt, David; Hildebrand, Sara; Choi, Jin Huk; Zhang, Zhao; Zeng, Ming; Wang, Kuan-wen; Turer, Emre; Chen, Zhe; Zhang, Duanwu; Yue, Tao; Wang, Ying (February 3, 2015). "Real-time resolution of point mutations that cause phenovariance in mice". Proceedings of the National Academy of Sciences of the United States of America. 112 (5): E440–449. doi:10.1073/pnas.1423216112. ISSN 1091-6490. PMC 4321302. PMID 25605905.

[115] Wang, Tao; Bu, Chun Hui; Hildebrand, Sara; Jia, Gaoxiang; Siggs, Owen M.; Lyon, Stephen; Pratt, David; Scott, Lindsay; Russell, Jamie; Ludwig, Sara; Murray, Anne R.; Moresco, Eva Marie Y.; Beutler, Bruce (January 30, 2018). "Probability of phenotypically detectable protein damage by ENU-induced mutations in the Mutagenetix database". Nature Communications. 9 (1): 441. doi:10.1038/s41467-017-02806-4. ISSN 2041-1723. PMC 5789985. PMID 29382827.

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[117] Chen, Bo; Aredo, Bogale; Ding, Yi; Zhong, Xin; Zhu, Yuanfei; Zhao, Cynthia X.; Kumar, Ashwani; Xing, Chao; Gautron, Laurent; Lyon, Stephen; Russell, Jamie; Li, Xiaohong; Tang, Miao; Anderton, Priscilla; Ludwig, Sara (June 9, 2020). "Forward genetic analysis using OCT screening identifies Sfxn3 mutations leading to progressive outer retinal degeneration in mice". Proceedings of the National Academy of Sciences of the United States of America. 117 (23): 12931–12942. doi:10.1073/pnas.1921224117. ISSN 1091-6490. PMC 7293615. PMID 32457148.

[118] Wang, Yibing; Cao, Liqin; Lee, Chia-Ying; Matsuo, Tomohiko; Wu, Kejia; Asher, Greg; Tang, Lijun; Saitoh, Tsuyoshi; Russell, Jamie; Klewe-Nebenius, Daniela; Wang, Li; Soya, Shingo; Hasegawa, Emi; Chérasse, Yoan; Zhou, Jiamin (May 23, 2018). "Large-scale forward genetics screening identifies Trpa1 as a chemosensor for predator odor-evoked innate fear behaviors". Nature Communications. 9 (1): 2041. doi:10.1038/s41467-018-04324-3. ISSN 2041-1723. PMC 5966455. PMID 29795268.

[119] Morin, Matthew D.; Wang, Ying; Jones, Brian T.; Mifune, Yuto; Su, Lijing; Shi, Hexin; Moresco, Eva Marie Y.; Zhang, Hong; Beutler, Bruce; Boger, Dale L. (October 31, 2018). "Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists". Journal of the American Chemical Society. 140 (43): 14440–14454. doi:10.1021/jacs.8b09223. ISSN 1520-5126. PMC 6209530. PMID 30272974.

[120] Morin, Matthew D.; Wang, Ying; Jones, Brian T.; Su, Lijing; Surakattula, Murali M. R. P.; Berger, Michael; Huang, Hua; Beutler, Elliot K.; Zhang, Hong; Beutler, Bruce; Boger, Dale L. (May 26, 2016). "Discovery and Structure-Activity Relationships of the Neoseptins: A New Class of Toll-like Receptor-4 (TLR4) Agonists". Journal of Medicinal Chemistry. 59 (10): 4812–4830. doi:10.1021/acs.jmedchem.6b00177. ISSN 1520-4804. PMC 4882283. PMID 27050713.

[121] Wang, Ying; Su, Lijing; Morin, Matthew D.; Jones, Brian T.; Mifune, Yuto; Shi, Hexin; Wang, Kuan-Wen; Zhan, Xiaoming; Liu, Aijie; Wang, Jianhui; Li, Xiaohong; Tang, Miao; Ludwig, Sara; Hildebrand, Sara; Zhou, Kejin (September 11, 2018). "Adjuvant effect of the novel TLR1/TLR2 agonist Diprovocim synergizes with anti-PD-L1 to eliminate melanoma in mice". Proceedings of the National Academy of Sciences of the United States of America. 115 (37): E8698–E8706. doi:10.1073/pnas.1809232115. ISSN 1091-6490. PMC 6140543. PMID 30150374.

[122] Wang, Ying; Su, Lijing; Morin, Matthew D.; Jones, Brian T.; Whitby, Landon R.; Surakattula, Murali M. R. P.; Huang, Hua; Shi, Hexin; Choi, Jin Huk; Wang, Kuan-wen; Moresco, Eva Marie Y.; Berger, Michael; Zhan, Xiaoming; Zhang, Hong; Boger, Dale L. (February 16, 2016). "TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS". Proceedings of the National Academy of Sciences of the United States of America. 113 (7): E884–893. doi:10.1073/pnas.1525639113. ISSN 1091-6490. PMC 4763747. PMID 26831104.

[123] Su, Lijing; Athamna, Muhammad; Wang, Ying; Wang, Junmei; Freudenberg, Marina; Yue, Tao; Wang, Jianhui; Moresco, Eva Marie Y.; He, Haoming; Zor, Tsaffrir; Beutler, Bruce (July 27, 2021). "Sulfatides are endogenous ligands for the TLR4-MD-2 complex". Proceedings of the National Academy of Sciences of the United States of America. 118 (30): e2105316118. doi:10.1073/pnas.2105316118. ISSN 1091-6490. PMC 8325290. PMID 34290146.

[124] Su, Lijing; Wang, Ying; Wang, Junmei; Mifune, Yuto; Morin, Matthew D.; Jones, Brian T.; Moresco, Eva Marie Y.; Boger, Dale L.; Beutler, Bruce; Zhang, Hong (March 28, 2019). "Structural Basis of TLR2/TLR1 Activation by the Synthetic Agonist Diprovocim". Journal of Medicinal Chemistry. 62 (6): 2938–2949. doi:10.1021/acs.jmedchem.8b01583. ISSN 1520-4804. PMC 6537610. PMID 30829478.

[125] Yang, Ming-Hsiu; Russell, Jamie L.; Mifune, Yuto; Wang, Ying; Shi, Hexin; Moresco, Eva Marie Y.; Siegwart, Daniel J.; Beutler, Bruce; Boger, Dale L. (July 14, 2022). "Next-Generation Diprovocims with Potent Human and Murine TLR1/TLR2 Agonist Activity That Activate the Innate and Adaptive Immune Response". Journal of Medicinal Chemistry. 65 (13): 9230–9252. doi:10.1021/acs.jmedchem.2c00419. ISSN 1520-4804. PMC 9283309. PMID 35767437.

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[132] Beutler E (2006). "Disorders of red cells resulting from enzyme abnormalitites". In Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT (eds.). Williams Hematology. New York: McGraw-Hill. pp. 603–632.

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[134] Beutler, Ernest (July 2006). "Lysosomal storage diseases: natural history and ethical and economic aspects". Molecular Genetics and Metabolism. 88 (3): 208–215. doi:10.1016/j.ymgme.2006.01.010. ISSN 1096-7192. PMID 16515872.

[135] Beutler, E.; Blume, K. G.; Bross, K. J.; Chillar, R. K.; Ellington, O. B.; Fahey, J. L.; Farbstein, M. J.; Schmidt, G. M.; Spruce, W. E.; Turner, M. A. (1979). "Bone marrow transplantation as the treatment of choice for "good risk" adult patients with acute leukemia". Transactions of the Association of American Physicians. 92: 189–195. ISSN 0066-9458. PMID 398617.

[136] Piro, L. D.; Carrera, C. J.; Carson, D. A.; Beutler, E. (April 19, 1990). "Lasting remissions in hairy-cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine". The New England Journal of Medicine. 322 (16): 1117–1121. doi:10.1056/NEJM199004193221605. ISSN 0028-4793. PMID 1969613.

[137] Beutler, E.; Yeh, M.; Fairbanks, V. F. (January 15, 1962). "The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker". Proceedings of the National Academy of Sciences of the United States of America. 48 (1): 9–16. doi:10.1073/pnas.48.1.9. ISSN 0027-8424. PMC 285481. PMID 13868717.

[138] Beutler, Bruce; Beutler, Ernest (December 12, 2002). "Toll-like receptor 4 polymorphisms and atherogenesis". The New England Journal of Medicine. 347 (24): 1978–1980, author reply 1978–1980. ISSN 1533-4406. PMID 12479194.

[139] Beutler, E.; Gelbart, T.; Han, J. H.; Koziol, J. A.; Beutler, B. (January 1989). "Evolution of the genome and the genetic code: selection at the dinucleotide level by methylation and polyribonucleotide cleavage". Proceedings of the National Academy of Sciences of the United States of America. 86 (1): 192–196. doi:10.1073/pnas.86.1.192. ISSN 0027-8424. PMC 286430. PMID 2463621.

[140] Truksa, Jaroslav; Gelbart, Terri; Peng, Hongfan; Beutler, Ernest; Beutler, Bruce; Lee, Pauline (November 2009). "Suppression of the hepcidin-encoding gene Hamp permits iron overload in mice lacking both hemojuvelin and matriptase-2/TMPRSS6". British Journal of Haematology. 147 (4): 571–581. doi:10.1111/j.1365-2141.2009.07873.x. ISSN 1365-2141. PMID 19751239.

[141] Du, Xin; She, Ellen; Gelbart, Terri; Truksa, Jaroslav; Lee, Pauline; Xia, Yu; Khovananth, Kevin; Mudd, Suzanne; Mann, Navjiwan; Moresco, Eva Marie Y.; Beutler, Ernest; Beutler, Bruce (May 23, 2008). "The serine protease TMPRSS6 is required to sense iron deficiency". Science. 320 (5879): 1088–1092. doi:10.1126/science.1157121. ISSN 1095-9203. PMC 2430097. PMID 18451267.

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 === Discovery of the LPS receptor, and the role of TLRs in innate immune sensing ===
-From the mid-1980s onward Beutler was interested in the mechanism by which LPS activates mammalian immune cells (chiefly [[macrophage]]s,<ref name=":2" /><ref name=":4" /> but [[dendritic cell]]s and [[B cell]]s as well), sometimes leading to uncontrollable Gram negative septic shock,<ref>{{Cite journal |last=Beutler |first=B. |last2=Poltorak |first2=A. |date=July 2001 |title=Sepsis and evolution of the innate immune response |url=https://pubmed.ncbi.nlm.nih.gov/11445725 |journal=Critical Care Medicine |volume=29 |issue=7 Suppl |pages=S2–6; discussion S6–7 |doi=10.1097/00003246-200107001-00002 |issn=0090-3493 |pmid=11445725}}</ref><ref>{{Cite book |last=Beutler |first=Bruce |title=Molecular and Cellular Mechanisms of Septic Shock |publisher=Alan R. Liss, Inc. |year=1988 |editor-last=Roth |editor-first=B. |location=New York |pages=219–235 |chapter=Orchestration of septic shock by cytokines: the role of cachectin (tumor necrosis factor)}}</ref><ref>{{Cite book |last=Beutler |first=Bruce |title=Mediators of Sepsis |publisher=Springer Berlin |year=1992 |veditors=Lamy M, Thijs LG |location=Heidelberg |pages=51–67 |chapter=Cytokines in Shock: 1992}}</ref> but also promoting the well-known adjuvant effect of LPS,<ref>{{Cite journal |last=Johnson |first=A. G. |last2=Gaines |first2=S. |last3=Landy |first3=M. |date=1956-02-01 |title=Studies on the O antigen of Salmonella typhosa. V. Enhancement of antibody response to protein antigens by the purified lipopolysaccharide |url=https://pubmed.ncbi.nlm.nih.gov/13286429 |journal=The Journal of Experimental Medicine |volume=103 |issue=2 |pages=225–246 |doi=10.1084/jem.103.2.225 |issn=0022-1007 |pmc=2136584 |pmid=13286429}}</ref> and B cell mitogenesis<ref name=":6">{{Cite journal |last=Coutinho |first=A. |last2=Meo |first2=T. |date=December 1978 |title=Genetic basis for unresponsiveness to lipopolysaccharide in C57BL/10Cr mice |url=https://pubmed.ncbi.nlm.nih.gov/21302052 |journal=Immunogenetics |volume=7 |issue=1 |pages=17–24 |doi=10.1007/BF01843983 |issn=0093-7711 |pmid=21302052}}</ref><ref>{{Cite journal |last=Watson |first=J. |last2=Riblet |first2=R. |date=1974-11-01 |title=Genetic control of responses to bacterial lipopolysaccharides in mice. I. Evidence for a single gene that influences mitogenic and immunogenic respones to lipopolysaccharides |url=https://pubmed.ncbi.nlm.nih.gov/4138849 |journal=The Journal of Experimental Medicine |volume=140 |issue=5 |pages=1147–1161 |doi=10.1084/jem.140.5.1147 |issn=0022-1007 |pmc=2139714 |pmid=4138849}}</ref> and antibody production. A single, highly specific LPS receptor was presumed to exist as early as the 1960s, based on the fact that allelic mutations in two separate strains of mice, affecting a discrete genetic locus on chromosome 4 termed ''Lps'', abolished LPS sensing.<ref name=":6" /><ref>{{Cite journal |last=Sultzer |first=B. M. |date=1968-09-21 |title=Genetic control of leucocyte responses to endotoxin |url=https://pubmed.ncbi.nlm.nih.gov/4877918 |journal=Nature |volume=219 |issue=5160 |pages=1253–1254 |doi=10.1038/2191253a0 |issn=0028-0836 |pmid=4877918}}</ref> Although this receptor had been widely pursued, it remained elusive. Beutler reasoned that in finding the LPS receptor, insight might be gained into the first molecular events that transpire upon an encounter between the host and microbial invaders.<ref>{{Cite journal |last=Beutler |first=Bruce |date=January 2002 |title=Toll-like receptors: how they work and what they do |url=https://pubmed.ncbi.nlm.nih.gov/11753071 |journal=Current Opinion in Hematology |volume=9 |issue=1 |pages=2–10 |doi=10.1097/00062752-200201000-00002 |issn=1065-6251 |pmid=11753071}}</ref>
+From the mid-1980s onward Beutler was interested in the mechanism by which LPS activates mammalian immune cells (chiefly [[macrophage]]s,<ref name=":2" /><ref name=":4" /> but [[dendritic cell]]s and [[B cell]]s as well), sometimes leading to uncontrollable Gram negative septic shock,<ref>{{Cite journal |last=Beutler |first=B. |last2=Poltorak |first2=A. |date=July 2001 |title=Sepsis and evolution of the innate immune response |url=https://pubmed.ncbi.nlm.nih.gov/11445725 |journal=Critical Care Medicine |volume=29 |issue=7 Suppl |pages=S2–6; discussion S6–7 |doi=10.1097/00003246-200107001-00002 |issn=0090-3493 |pmid=11445725}}</ref><ref>{{Cite book |last=Beutler |first=Bruce |title=Molecular and Cellular Mechanisms of Septic Shock |publisher=Alan R. Liss, Inc. |year=1988 |editor-last=Roth |editor-first=B. |location=New York |pages=219–235 |chapter=Orchestration of septic shock by cytokines: the role of cachectin (tumor necrosis factor)}}</ref><ref>{{Cite book |last=Beutler |first=Bruce |title=Mediators of Sepsis |publisher=Springer Berlin |year=1992 |veditors=Lamy M, Thijs LG |location=Heidelberg |pages=51–67 |chapter=Cytokines in Shock: 1992}}</ref> but also promoting the well-known adjuvant effect of LPS,<ref>{{Cite journal |last=Johnson |first=A. G. |last2=Gaines |first2=S. |last3=Landy |first3=M. |date=1956-02-01 |title=Studies on the O antigen of Salmonella typhosa. V. Enhancement of antibody response to protein antigens by the purified lipopolysaccharide |url=https://pubmed.ncbi.nlm.nih.gov/13286429 |journal=The Journal of Experimental Medicine |volume=103 |issue=2 |pages=225–246 |doi=10.1084/jem.103.2.225 |issn=0022-1007 |pmc=2136584 |pmid=13286429}}</ref> and B cell mitogenesis<ref name=":6">{{Cite journal |last=Coutinho |first=A. |last2=Meo |first2=T. |date=December 1978 |title=Genetic basis for unresponsiveness to lipopolysaccharide in C57BL/10Cr mice |url=https://pubmed.ncbi.nlm.nih.gov/21302052 |journal=Immunogenetics |volume=7 |issue=1 |pages=17–24 |doi=10.1007/BF01843983 |issn=0093-7711 |pmid=21302052}}</ref><ref>{{Cite journal |last=Watson |first=J. |last2=Riblet |first2=R. |date=1974-11-01 |title=Genetic control of responses to bacterial lipopolysaccharides in mice. I. Evidence for a single gene that influences mitogenic and immunogenic {{sic|nolink=y|reason=error in source|respones}} to lipopolysaccharides |url=https://pubmed.ncbi.nlm.nih.gov/4138849 |journal=The Journal of Experimental Medicine |volume=140 |issue=5 |pages=1147–1161 |doi=10.1084/jem.140.5.1147 |issn=0022-1007 |pmc=2139714 |pmid=4138849}}</ref> and antibody production. A single, highly specific LPS receptor was presumed to exist as early as the 1960s, based on the fact that allelic mutations in two separate strains of mice, affecting a discrete genetic locus on chromosome 4 termed ''Lps'', abolished LPS sensing.<ref name=":6" /><ref>{{Cite journal |last=Sultzer |first=B. M. |date=1968-09-21 |title=Genetic control of leucocyte responses to endotoxin |url=https://pubmed.ncbi.nlm.nih.gov/4877918 |journal=Nature |volume=219 |issue=5160 |pages=1253–1254 |doi=10.1038/2191253a0 |issn=0028-0836 |pmid=4877918}}</ref> Although this receptor had been widely pursued, it remained elusive. Beutler reasoned that in finding the LPS receptor, insight might be gained into the first molecular events that transpire upon an encounter between the host and microbial invaders.<ref>{{Cite journal |last=Beutler |first=Bruce |date=January 2002 |title=Toll-like receptors: how they work and what they do |url=https://pubmed.ncbi.nlm.nih.gov/11753071 |journal=Current Opinion in Hematology |volume=9 |issue=1 |pages=2–10 |doi=10.1097/00062752-200201000-00002 |issn=1065-6251 |pmid=11753071}}</ref>
 Utilizing [[positional cloning]] in an effort that began in 1993 and lasted five years, Beutler, together with several postdoctoral associates including Alexander Poltorak, measured TNF production as a qualitative phenotypic endpoint of the LPS response. Analyzing more than 2,000 [[Meiosis|meioses]], they confined the LPS receptor-encoding gene to a region of the genome encompassing approximately 5.8 million base pairs of [[DNA]].<ref name=":1" /> Sequencing most of the interval, they identified a gene within which each of two LPS-refractory strains of mice (C3H/HeJ and C57BL/10ScCr) had deleterious mutations. The gene, ''Tlr4'', encoded a cell surface protein with cytoplasmic domain homology to the [[interleukin-1 receptor]], and several other homologous genes that were scattered across the mouse genome. Beutler and his team thus proved that one of the mammalian Toll-like receptors, TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex.<ref name=":1" /><ref>{{Cite journal |last=Du |first=X. |last2=Poltorak |first2=A. |last3=Silva |first3=M. |last4=Beutler |first4=B. |date=1999 |title=Analysis of Tlr4-mediated LPS signal transduction in macrophages by mutational modification of the receptor |url=https://pubmed.ncbi.nlm.nih.gov/10660480 |journal=Blood Cells, Molecules & Diseases |volume=25 |issue=5-6 |pages=328–338 |doi=10.1006/bcmd.1999.0262 |issn=1079-9796 |pmid=10660480}}</ref><ref name=":7">{{Cite journal |last=Poltorak |first=A. |last2=Ricciardi-Castagnoli |first2=P. |last3=Citterio |first3=S. |last4=Beutler |first4=B. |date=2000-02-29 |title=Physical contact between lipopolysaccharide and toll-like receptor 4 revealed by genetic complementation |url=https://pubmed.ncbi.nlm.nih.gov/10681462 |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=97 |issue=5 |pages=2163–2167 |doi=10.1073/pnas.040565397 |issn=0027-8424 |pmc=15771 |pmid=10681462}}</ref> They also showed that while mouse TLR4 is activated by a tetra-acylated LPS-like molecule (lipid IVa), human TLR4 is not, recapitulating the species specificity for LPS partial structures.<ref name=":7" /> It was deduced that direct contact between TLR4 and LPS is a prerequisite for cell activation.<ref name=":7" />  Later, an extracellular component of the LPS receptor complex, MD-2 (also known as lymphocyte antigen 96), was identified by R. Shimazu and colleagues.<ref>{{Cite journal |last=Shimazu |first=R. |last2=Akashi |first2=S. |last3=Ogata |first3=H. |last4=Nagai |first4=Y. |last5=Fukudome |first5=K. |last6=Miyake |first6=K. |last7=Kimoto |first7=M. |date=1999-06-07 |title=MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4 |url=https://pubmed.ncbi.nlm.nih.gov/10359581 |journal=The Journal of Experimental Medicine |volume=189 |issue=11 |pages=1777–1782 |doi=10.1084/jem.189.11.1777 |issn=0022-1007 |pmc=2193086 |pmid=10359581}}</ref> The structure of the complex, with and without LPS bound, was solved by Jie-Oh Lee and colleagues in 2009.<ref>{{Cite journal |last=Park |first=Beom Seok |last2=Song |first2=Dong Hyun |last3=Kim |first3=Ho Min |last4=Choi |first4=Byong-Seok |last5=Lee |first5=Hayyoung |last6=Lee |first6=Jie-Oh |date=2009-04-30 |title=The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex |url=https://pubmed.ncbi.nlm.nih.gov/19252480 |journal=Nature |volume=458 |issue=7242 |pages=1191–1195 |doi=10.1038/nature07830 |issn=1476-4687 |pmid=19252480}}</ref>

v t e Laureates of the Nobel Prize in Physiology or Medicine
1901–1925	1901: Emil Behring 1902: Ronald Ross 1903: Niels Finsen 1904: Ivan Pavlov 1905: Robert Koch 1906: Camillo Golgi / Santiago Ramón y Cajal 1907: Alphonse Laveran 1908: Élie Metchnikoff / Paul Ehrlich 1909: Emil Kocher 1910: Albrecht Kossel 1911: Allvar Gullstrand 1912: Alexis Carrel 1913: Charles Richet 1914: Róbert Bárány 1915 1916 1917 1918 1919: Jules Bordet 1920: August Krogh 1921 1922: Archibald Hill / Otto Meyerhof 1923: Frederick Banting / John Macleod 1924: Willem Einthoven 1925
1926–1950	1926: Johannes Fibiger 1927: Julius Wagner-Jauregg 1928: Charles Nicolle 1929: Christiaan Eijkman / Frederick Gowland Hopkins 1930: Karl Landsteiner 1931: Otto Warburg 1932: Charles Scott Sherrington / Edgar Adrian 1933: Thomas Morgan 1934: George Whipple / George Minot / William Murphy 1935: Hans Spemann 1936: Henry Dale / Otto Loewi 1937: Albert Szent-Györgyi 1938: Corneille Heymans 1939: Gerhard Domagk 1940 1941 1942 1943: Henrik Dam / Edward Doisy 1944: Joseph Erlanger / Herbert Gasser 1945: Alexander Fleming / Ernst Chain / Howard Florey 1946: Hermann Muller 1947: Carl Cori / Gerty Cori / Bernardo Houssay 1948: Paul Müller 1949: Walter Hess / António Egas Moniz 1950: Edward Kendall / Tadeusz Reichstein / Philip Hench
1951–1975	1951: Max Theiler 1952: Selman Waksman 1953: Hans Krebs / Fritz Lipmann 1954: John Enders / Thomas Weller / Frederick Robbins 1955: Hugo Theorell 1956: André Cournand / Werner Forssmann / Dickinson W. Richards 1957: Daniel Bovet 1958: George Beadle / Edward Tatum / Joshua Lederberg 1959: Severo Ochoa / Arthur Kornberg 1960: Frank Burnet / Peter Medawar 1961: Georg von Békésy 1962: Francis Crick / James Watson / Maurice Wilkins 1963: John Eccles / Alan Hodgkin / Andrew Huxley 1964: Konrad Bloch / Feodor Lynen 1965: François Jacob / André Lwoff / Jacques Monod 1966: Francis Rous / Charles B. Huggins 1967: Ragnar Granit / Haldan Hartline / George Wald 1968: Robert W. Holley / Har Khorana / Marshall Nirenberg 1969: Max Delbrück / Alfred Hershey / Salvador Luria 1970: Bernard Katz / Ulf von Euler / Julius Axelrod 1971: Earl Sutherland Jr. 1972: Gerald Edelman / Rodney Porter 1973: Karl von Frisch / Konrad Lorenz / Nikolaas Tinbergen 1974: Albert Claude / Christian de Duve / George Palade 1975: David Baltimore / Renato Dulbecco / Howard Temin
1976–2000	1976: Baruch Blumberg / Daniel Gajdusek 1977: Roger Guillemin / Andrew Schally / Rosalyn Yalow 1978: Werner Arber / Daniel Nathans / Hamilton O. Smith 1979: Allan Cormack / Godfrey Hounsfield 1980: Baruj Benacerraf / Jean Dausset / George Snell 1981: Roger Sperry / David H. Hubel / Torsten Wiesel 1982: Sune Bergström / Bengt I. Samuelsson / John Vane 1983: Barbara McClintock 1984: Niels Jerne / Georges Köhler / César Milstein 1985: Michael Brown / Joseph L. Goldstein 1986: Stanley Cohen / Rita Levi-Montalcini 1987: Susumu Tonegawa 1988: James W. Black / Gertrude B. Elion / George H. Hitchings 1989: J. Michael Bishop / Harold E. Varmus 1990: Joseph Murray / E. Donnall Thomas 1991: Erwin Neher / Bert Sakmann 1992: Edmond Fischer / Edwin G. Krebs 1993: Richard J. Roberts / Phillip Sharp 1994: Alfred G. Gilman / Martin Rodbell 1995: Edward B. Lewis / Christiane Nüsslein-Volhard / Eric F. Wieschaus 1996: Peter C. Doherty / Rolf M. Zinkernagel 1997: Stanley B. Prusiner 1998: Robert F. Furchgott / Louis Ignarro / Ferid Murad 1999: Günter Blobel 2000: Arvid Carlsson / Paul Greengard / Eric Kandel
2001–present	2001: Leland H. Hartwell / Tim Hunt / Paul Nurse 2002: Sydney Brenner / H. Robert Horvitz / John E. Sulston 2003: Paul Lauterbur / Peter Mansfield 2004: Richard Axel / Linda B. Buck 2005: Barry Marshall / Robin Warren 2006: Andrew Fire / Craig Mello 2007: Mario Capecchi / Martin Evans / Oliver Smithies 2008: Harald zur Hausen / Luc Montagnier / Françoise Barré-Sinoussi 2009: Elizabeth Blackburn / Carol W. Greider / Jack W. Szostak 2010: Robert G. Edwards 2011: Bruce Beutler / Jules A. Hoffmann / Ralph M. Steinman (posthumously) 2012: John Gurdon / Shinya Yamanaka 2013: James Rothman / Randy Schekman / Thomas C. Südhof 2014: John O'Keefe / May-Britt Moser / Edvard Moser 2015: William C. Campbell / Satoshi Ōmura / Tu Youyou 2016: Yoshinori Ohsumi 2017: Jeffrey C. Hall / Michael Rosbash / Michael W. Young 2018: James P. Allison / Tasuku Honjo 2019: Gregg L. Semenza / Peter J. Ratcliffe / William Kaelin Jr. 2020: Harvey J. Alter / Michael Houghton / Charles M. Rice 2021: David Julius / Ardem Patapoutian 2022: Svante Pääbo 2023: Katalin Karikó / Drew Weissman 2024: Victor Ambros / Gary Ruvkun

v t e 2011 Nobel Prize laureates
Chemistry	Dan Shechtman (Israel)
Literature (2011)	Tomas Tranströmer (Sweden)
Peace (2011)	Ellen Johnson Sirleaf (Liberia) Leymah Gbowee (Liberia) Tawakkul Karman (Yemen)
Physics	Saul Perlmutter (United States) Adam Riess (United States) Brian P. Schmidt (Australia/United States)
Physiology or Medicine	Bruce A. Beutler (United States) Jules A. Hoffmann (France) Ralph M. Steinman (Canada/United States)
Economic Sciences	Christopher A. Sims (United States) Thomas J. Sargent (United States)
Nobel Prize recipients 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

v t e Shaw Prize laureates
Astronomy	Jim Peebles (2004) Geoffrey Marcy and Michel Mayor (2005) Saul Perlmutter, Adam Riess and Brian Schmidt (2006) Peter Goldreich (2007) Reinhard Genzel (2008) Frank Shu (2009) Charles Bennett, Lyman Page and David Spergel (2010) Enrico Costa and Gerald Fishman (2011) David C. Jewitt and Jane Luu (2012) Steven Balbus and John F. Hawley (2013) Daniel Eisenstein, Shaun Cole and John A. Peacock (2014) William J. Borucki (2015) Ronald Drever, Kip Thorne and Rainer Weiss (2016) Simon White (2017) Jean-Loup Puget (2018) Edward C. Stone (2019) Roger Blandford (2020) Victoria Kaspi and Chryssa Kouveliotou (2021) Lennart Lindegren and Michael Perryman (2022) Matthew Bailes, Duncan Lorimer and Maura McLaughlin (2023) Shrinivas R. Kulkarni (2024)
Life science and medicine	Stanley Norman Cohen, Herbert Boyer, Yuet-Wai Kan and Richard Doll (2004) Michael Berridge (2005) Xiaodong Wang (2006) Robert Lefkowitz (2007) Ian Wilmut, Keith H. S. Campbell and Shinya Yamanaka (2008) Douglas Coleman and Jeffrey Friedman (2009) David Julius (2010) Jules Hoffmann, Ruslan Medzhitov and Bruce Beutler (2011) Franz-Ulrich Hartl and Arthur L. Horwich (2012) Jeffrey C. Hall, Michael Rosbash and Michael W. Young (2013) Kazutoshi Mori and Peter Walter (2014) Bonnie Bassler and Everett Peter Greenberg (2015) Adrian Bird and Huda Zoghbi (2016) Ian R. Gibbons and Ronald Vale (2017) Mary-Claire King (2018) Maria Jasin (2019) Gero Miesenböck, Peter Hegemann and Georg Nagel (2020) Scott D. Emr (2021) Paul A. Negulescu and Michael J. Welsh (2022) Patrick Cramer and Eva Nogales (2023) Stuart H. Orkin and Swee Lay Thein (2024)
Mathematical science	Shiing-Shen Chern (2004) Andrew Wiles (2005) David Mumford and Wentsun Wu (2006) Robert Langlands and Richard Taylor (2007) Vladimir Arnold and Ludwig Faddeev (2008) Simon Donaldson and Clifford Taubes (2009) Jean Bourgain (2010) Demetrios Christodoulou and Richard S. Hamilton (2011) Maxim Kontsevich (2012) David Donoho (2013) George Lusztig (2014) Gerd Faltings and Henryk Iwaniec (2015) Nigel Hitchin (2016) János Kollár and Claire Voisin (2017) Luis Caffarelli (2018) Michel Talagrand (2019) Alexander Beilinson and David Kazhdan (2020) Jean-Michel Bismut and Jeff Cheeger (2021) Noga Alon and Ehud Hrushovski (2022) Vladimir Drinfeld and Shing-Tung Yau (2023) Peter Sarnak (2024)

Authority control databases
International	ISNI VIAF WorldCat
National	Germany United States France BnF data Netherlands Israel Belgium
Academics	ORCID Leopoldina
People	DDB
Other	IdRef

Revision as of 02:32, 14 March 2023

Early life and education

Scientific contributions

Isolation of tumor necrosis factor and discovery of its inflammation-promoting effect

Invention of TNF inhibitors

Discovery of the LPS receptor, and the role of TLRs in innate immune sensing

Random Germline Mutagenesis/Forward Genetics in the mouse

Invention of Automated Meiotic Mapping

Developing drugs that activate TLRs

Awards and recognition

Awards

Honorary Doctoral Degrees

Honorary and Learned Societies

Family

See also

References

External links

External links