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.
The Toll receptor had been discovered in 1985 as a regulator of embryo polarity, but Dr. Hoffmann's group linked it to fungal infection in flies in 1996 and then to Gram-positive bacterial infections. During this time Dr. Hoffmann became director of the CNRS Institute of Cellular and Molecular Biology. A year later, Dr. Janeway and his lab at Yale discovered Toll-like receptors that activate and amplify the specific, adaptive immune response in humans.
Dr. Hoffmann acknowledged many scientists and labs who helped him in the discovery that Toll was the sensor of innate immunity in the fly. In 2011 he received the Nobel Prize in Physiology or Medicine shared with Dr. Beutler, who had shown that Toll-like receptors performed a similar role in mammals, and Ralph M. Steinman, MD, for his discovery of the dendritic cell and its roll in adaptive immunity.
As if a foreshadowing of the year to come, in 2010, Dr. Hoffmann received the Keio Medical Science Prize with Shizuo Akira, MD, PhD. But 2011, turned out to be the year of celebration for Dr. Hoffmann. Not only did he receive the Nobel Prize with Drs. Beutler and Steinman, but he also received the CNRS Gold Medal, the Shaw Prize in Life Science and Medicine with Drs. Beutler and Ruslan M. Medzhitov, and the Canada Gairdner Award for Medical Research with Dr. Akira.
But the broader lesson from Dr. Hoffmann's work may be its celebration of basic research. "Our work on antimicrobial defenses in insects started out of curiosity. We realized that insects in our breeding colonies of grasshoppers were very resistant to infections, and we didn't understand the mechanisms of this resistance," he said. At that time institutional funding didn't depend on relevance or potential applications. "Scientific curiosity was accepted as a reason to undertake our research. This was exactly 50 years ago; I am afraid that things would be much more difficult today," he added.