Over the past two decades, Dr. Bruce Beutler has been a central
figure in the innate immunity "renaissance." He will deliver the
Jan. 18 R.E. Dyer Lecture, "Sensing Infection: Toll-Like Receptors
and the Genetic Analysis of Mammalian Innate Immunity." It will
be held at 3 p.m. in Masur Auditorium, Bldg. 10. Beutler is professor
in the department of immunology at Scripps Research Institute,
where he and his colleagues have established one of the most ambitious
and successful mutagenesis efforts undertaken in mice, using the
germline mutagen ENU to identify key components of the TLR signaling
pathways, as well as genes required for resistance to viral pathogens.
Beutler was the first to isolate mouse tumor necrosis factor (TNF)
and the first to recognize the role of TNF as a mediator of inflammation.
Using TNF, he went on to identify the principal receptors through
which animals sense microbial infections. This is widely regarded
as one of the most fundamental advances in immunology and has opened
a vibrant new field.
His work in innate immunity began in the 1980s when he isolated
cachectin from lipopolysaccharide (LPS)-activated murine macrophages.
By protein sequencing and cDNA cloning, he proved its identity
to be TNF, the human ortholog of which was cloned contemporaneously
by other investigators. Thus, Beutler was the first to realize
that TNF could mediate diverse effects of LPS-induced shock. He
proved this by passively immunizing mice against TNF and challenging
them with LPS; that demonstrated them to be LPS-resistant. This
established a causal link between TNF and inflammation and ignited
widespread interest in the blockade of TNF for treatment of inflammation.
From 1986 to 1999 at UT Southwestern Medical Center and Howard
Hughes Medical Institute in Dallas, Beutler studied the regulation
of TNF biosynthesis. He initiated a classical genetic study in
1993 aimed at the positional cloning of two allelic mutations that
rendered C3H/HeJ and C57BL/10ScCr mice entirely refractory to LPS.
Utilizing TNF production as the signaling endpoint in genetic mapping,
Beutler proved that the culpable mutations affected the gene encoding
Toll-like receptor 4 (TLR4). The proof that TLR4 was an essential
component of the mammalian LPS receptor led to the demonstration
that other TLRs sense other conserved molecules of microbial origin
and to our present understanding of how the host recognizes most
Beutler is a strong advocate of the "phenotype first" approach
that has brought biology some of its most spectacular gains. He
has received many honors for his work, including the 2004 Robert
Koch Prize, which he shared with Jules Hoffman and Shizuo Akira.
The R.E. Dyer lecture is part of the NIH Director's Wednesday
Afternoon Lecture Series. No registration is required. For more
information or reasonable accommodation call (301) 594-5595.