Nobel Laureate Lecture Series: Bruce Beutler
July 19 @ 17:00 - 19:00
Germline mutagenesis to identify essential components of the mammalian immune system
Formerly a slow and arduous process, forward genetics in mammals has recently become much faster. It is now limited only by the rate at which mutations can be screened for their phenotypic effects. When a phenotype is detected, its mutational cause is usually identified immediately, whether it is well known or novel. Not only the causative mutation, but all non-causative mutations as well, are detected and recorded in the process. In this way, many genes are exonerated as others are implicated in the biological phenomena under study. Even relatively weak phenotypic effects can be detected and ascribed to causative mutations with confidence in quantitative screens. During the past few years, more than 1,000 phenotypes have been ascribed to causative mutations using the new high-throughput approach. At present writing, we have damaged or destroyed about 36% of all genes and examined the mutant alleles twice or more in the homozygous state using an average of 88 assays per mouse. Many new immunodeficiencies have been identified, and a general impression of the cause of more common disease phenotypes, such as allergy, has emerged from our work.
Dr. Bruce Beutler studied medicine at the University of Chicago. Early in his career he isolated mouse TNF, and discovered its inflammatory properties. Later he developed TNF inhibitor proteins that found widespread use in clinical medicine. Using genetics, and taking the TNF response as a biological endpoint, he then identified Toll-like receptor 4 as the mammalian sensor of bacterial lipopolysaccharides. These groundbreaking studies of innate immune sensing and response earned Beutler the 2011 Nobel Prize in Physiology or Medicine (shared with J. Hoffmann and R. Steinman). Beutler directs the Center for the Genetics of Host Defense, UT Southwestern Medical Center, Dallas, TX.
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