Pathogenic microorganisms (bacteria, virus, fungi, and parasites) pose a constant threat to humans and animals. To combat these our bodies have developed a sophisticated immune system that builds swollen barriers and creates armies of antibodies to tackle the invaders and kill off any infected cells.
But how does our defence system work? The winners of the 2011 Nobel Prize for Physiology or Medicine were lauded by the awards committee for having ‘revolutionised our understanding of the immune system by discovering key principles for its activation’.
The sentries of our front line ‘innate’ immune system are the ‘receptor’ proteins. Finding them, what triggers them, and how they activate the immune system opens a wealth of opportunities in healthcare and medicine, and was the subject of Jules Hoffmann and (independently) Bruce Beutler’s research. They shared half the prize, the remaining half going to Ralph Steinman for his discovery of dendritic cells, which activate and regulate the reinforcements of ‘adaptive immunity’, creating anti-bodies tailor-made to tackle and remove specific microorganisms. Uniquely, Steinman’s award was made posthumously, after he died three days before the announcement.
In his Nobel Lecture, Hoffmann insisted on the crucial contributions of his many co-workers over the years when this research was being done, and namely on those of Jean-Marc Reichhart, Charles Hetru and Bruno Lemaitre.
While Beutler and associates performed their research using mice, the Hoffmann group experimented on Drosophila fruit flies, many of which bore genetic mutations. Among these were some with mutated Toll – a gene previously known to be important in embryonic development. When the Hoffmann group infected fruit flies with bacteria or fungi, they discovered that Toll mutants died because they could not mount an effective defense. They concluded that the Toll gene was involved in sensing pathogenic microorganisms and triggering the immune system.
Jules Alphonse Hoffmann was born in 1941 in Echternach, Luxembourg, where he received his early education before moving to France to study biology and chemistry, gaining his PhD under Pierre Joly at the University of Strasbourg in 1969. While there, he worked as a research assistant for the National Centre for Scientific Research (CNRS), with which he remained associated throughout his career, eventually establishing an Immune Response and Development in Insects unit in 1978 and serving as director for the CNRS Institute of Molecular and Cellular Biology from 1993. He retired from CNRS in 2006 but retained a professorship at the University of Strasbourg.
He inherited from his father a keen interest in insects and specialised in this field. From early success in the 1970s and ‘80s building on Joly’s work with locusts, Hoffmann began to focus on the insect immune system and had rapid results, finding two protein peptides in blowflies which targeted bacteria. Previously, similar peptides were only known in mammals.
In 1996, while studying immune responses in fruit flies, Hoffmann and his team found that mutations in the Toll signaling pathway left the flies more susceptible to fungal infection. This meant the Toll pathway, named from the German for ‘amazing’ and previously known mainly for its contribution to embryonic development, also serves as a sensor, detecting infectious microorganisms and alerting the immune system to produce antimicrobial peptides. Hoffmann's work prompted others to search for Toll-like receptors in mammals, leading to better understanding of the immune system and advances in treatment of anything from microbial infection to inflammatory diseases such as Crohn’s and cancer.
Hoffmann is a former President of the French National Academy of Sciences and a member of other academies including Germany, Russia and America. Among other awards he shared the 2007 Balzan Prize with Bruce Beutler, the 2004 Robert Koch Prize with Beutler and Shizuo Akira, the 2010 Keio and the 2011 Gairdner Prizes with Shizuo Akira and the 2011 Shaw Prize with Beutler and Ruslan Medzhitov. He is married to his long-time co-worker, Daniele. They have two children, both in academic careers, and four grand-children.