2011 Nobel Laureate in Physiology or Medicine Jules A. Hoffmann, Ph.D., provided the keynote address on innate immunity at the Genetics Society of America's Annual Drosophila Research Conference on Apr. 3, 2013
A young scientist's astute observation - that grasshoppers don't get sick - eventually led to profound insights into our own immunity. Jules Hoffmann, PhD, Professor of Integrative Biology at Strasbourg University, Institute of Advanced Science, France Emeritus, and 2011 Nobel Prize recipient in Physiology or Medicine is the scientist who made these insights. He described his scientific journey in the keynote lecture on April 3, 2013, the opening night of the Genetics Society of America's 54th Annual Drosophila Research Conference in Washington, D.C., April 3-7, 2013.
A father who was "an enthusiastic entomologist" and a high school biology teacher sparked Dr. Hoffmann's early interest in insects, in post-World War II Luxembourg. Later, Dr. Hoffmann marveled at the apparent ability of grasshoppers to evade infection, even when he transplanted organs among them as an undergraduate at the University of Strasbourg. How did this happen?
For his doctoral work at the Institute of Zoology in Strasbourg, France, he discovered a blood-producing tissue near the insect's heart that when damaged with X-rays, led to body-wide infection and failure to molt. After earning his PhD in experimental biology in 1969, Dr. Hoffmann pursued endocrinology for postdoctoral work. In 1978 he became director of the laboratory of endocrinology and immunology at the University of Strasbourg.
In 1990, Dr. Hoffmann's lab replaced the grasshopper with the fruit fly, Drosophila melanogaster, and moved on to a genetic dissection of antimicrobial defense. The group focused on innate immunity, the ancient arm of the immune defense that provides generalized protection against common pathogens.
"At that time, innate immunity was not considered as essential and hardly studied at all. Immunity was mainly seen in the context of antibodies and vaccination" - the responses of the adaptive (acquired) immune response, he said. Innate immunity is front-line and immediate; adaptive immunity has memory and specificity.
Dr. Hoffmann and his colleagues' expected the innate immune system in the fly to be completely different from that in a mammal, but they were in for a surprise. Within a few years, thanks to Dr. Hoffmann's lab and the work of several other labs in mammals, including those of Charles A. Janeway, MD, and Bruce A. Beutler, MD, they showed that flies and mammals share many of the mechanisms of innate immunity. "These range from receptors for microbial aggressors, to intracellular signaling cascades, which control the expression of immune response genes, and the genes encoding potent antimicrobial peptides," Dr. Hoffmann explained.
Genomic analysis enabled the Hoffmann group to set the date for the emergence of innate immunity. "Innate immunity appeared with multicellularity, possibly one billion years ago. The various zoological phyla have played with a toolbox of genes encoding receptors, adaptors, kinases, transactivators, and antimicrobial peptides according to their own agendas, essentially their own environments and pathogens," he said.
At the crux of the Hoffmann lab body of work is the Toll receptor, a protein that straddles the cell membranes of immune system "sentinel" cells, detecting molecular nametags of pathogens from the outside and transducing messages to the inside, activating and orchestrating defense against infection.