Peter Garland Lecture - ‘Discovering TNF, TLRs, and other proteins with key importance in immunity’
Friday 24 March 2023
Peter Garland Lecture 2023 - Dr Bruce Beutler, Regental Professor and Director Center for the Genetics of Host Defence, UT Southwestern Medical Center
University of Dundee
Dundee DD1 5HL
Host: Professor Julian Blow
Location: Large Lecture Theatre, MSI, SLS
Bruce Beutler received his undergraduate degree from the University of California at San Diego in 1976 and his MD degree from the University of Chicago in 1981. After two years of residency at the University of Texas Southwestern Medical Center in Dallas, he became a postdoctoral fellow and an Assistant Professor at Rockefeller University (1983-1986).
While at Rockefeller, Beutler isolated mouse tumour necrosis factor (TNF) by following its catabolic activity on adipocytes. He was the first to understand, and to demonstrate, that TNF acts as a key executor of the host response to bacterial lipopolysaccharide (LPS) and, more generally, mediates inflammation. Returning to Dallas in 1986 as an HHMI investigator, he designed recombinant inhibitors of TNF that are still widely used in treating rheumatoid arthritis and other inflammatory diseases. But his principal interest settled on the question of what activated TNF production in the first instance. What receptors told the host when an infection was present, activating the innate immune system? To that point, none had been identified, and the question of how the host “sees” infection remained open.
Beginning in the early 1990s, Beutler used positional cloning—taking TNF production by LPS-activated mouse macrophages as a biological endpoint—to identify the LPS receptor. Spontaneous mutations in two strains of mice had long been known to prevent all responses to LPS, leaving the animals selectively vulnerable to Gram-negative bacterial infections. Beutler concluded that Toll-like receptor 4 (TLR4) acted as the signalling core of the LPS receptor and proposed that other TLRs might also recognize conserved molecular signatures of infection. For this work, which triggered a substantial realignment of thought in immunology, Beutler shared the 2011 Nobel Prize in Physiology or Medicine with Jules Hoffmann and Ralph Steinman.
Since then, Beutler has used forward genetics to decipher the signalling pathways activated by TLRs, requirements for adaptive immune function, and problems in many other areas of biology as well. He developed a platform for extremely rapid identification of causative mutations, to the point that forward genetics in the mouse is now limited only by the rate at which phenotypes can be produced and detected in screens. This platform, known as automated meiotic mapping or AMM, has most recently been turned to discovering discrete nucleotide changes that strongly suppress the growth of otherwise lethal tumours in mice.
Beutler is currently a Regental Professor and Director of the Center for Genetics of Host Defense at the University of Texas Southwestern Medical Center at Dallas. He also holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research in honour of Laverne and Raymond Willie, Sr. Before he received the Nobel Prize, his work was recognized by the Shaw Prize (2011), the Albany Medical Center Prize in Medicine and Biomedical Research (2009), election to the National Academy of Sciences and Institute of Medicine (2008), the Balzan Prize (2007), the Gran Prix Charles-Leopold-Mayer (2006), the William B. Coley Award (2005), the Robert-Koch-Prize (2004), and many other honours.
About the lecture series:
The Peter Garland Lecture was set up in 1985 to mark the achievement of Dundee’s first Professor of Biochemistry in building the Department into one of the strongest in the UK from 1970 to 1984. Fifteen Peter Garland lecturers have had or subsequently went on to win a Nobel Prize.
The talk will be followed by refreshments from 1 pm, to which everyone is invited to CTIR Street.