J. Hoffmann: Acceptance Speech – Bern, 23.11.2007

USA - France/Luxembourg

Bruce Beutler and Jules Hoffmann

2007 Balzan Prize for Innate Immunity

For their discovery of the genetic mechanisms responsible for innate immunity. They have worked in close cooperation to develop a new vision of the molecular defence strategy deployed by animals across a wide evolutionary spectrum against infectious agents. Their work has led to very promising medical applications.

Mr. Federal Councillor,
Members of the Balzan Foundation,
Ladies and Gentlemen,

I wish to start by expressing my deep gratitude to the International Balzan Foundation for the attribution of the 2007 Balzan Prize for Innate Immunity, together with my friend Bruce Beutler.

Conscious of the list of distinguished scholars who have been similarly recognized by the Balzan Foundation, I receive this prize with gratitude and deep humility.

My co-recipient, Bruce Beutler, and I are especially pleased that the award recognizes for the first time the field of innate immunity, thus bestowing  on it a mantle of nobility. Let me elaborate shortly on the concept of innate immunity: We humans, together with some 45,000 extant vertebrate species, fight microbial infections through two defensive arms: one is referred to as innate immunity, the other as adaptive immunity. More than 3 million invertebrate species, however, with whom we co-exist on this planet, rely solely, but very efficiently, on innate immunity to fight microbial  aggressions. Innate immune mechanisms were discovered in the late 19th century by Nobel Laureate Eliah Metchnikoff. This was several decades before the adaptive arm became recognized. However, for most of the 20^th  century, research on host defenses was centered on adaptive immunity. Scholars were attracted by the hallmark of this defense, that is, the generation of vast repertoires of antigen receptors on lymphocytes, as well as by the process of vaccination dependent on the clonal expansion of lymphocytes. In contrast, innate immunity was a neglected field of research. The neglect was such that our group had difficulties, when we submitted our first results on the genetics of the innate host defense of the fruitfly Drosophila, to convince the Editors that it was appropriate to refer to this defense as “immunity” at all.

This situation has now changed. We have gained in recent years a good understanding of the mechanisms that allow the innate immune response to play a vital role against invading microorganisms. We have discovered how this defense line recognizes pathogens and in response activates signaling pathways that eventually lead to the expression of a cohort of genes whose products cooperate to fight invading microbes. I would just like to stress here that one of the most surprising outcomes of the studies of the Beutler laboratory and my  laboratory, and those of others who got involved in the field, was the discovery of stringent similarities between the innate defense mechanisms in flies and mammals, including humans. This holds true both at the level of receptors for microbial ligands and for the signaling cascades and the transcriptional control of immune-response genes which I have just mentioned. Clearly, the players which we discovered and their functions in flies and mice, derive from an ancestral immune response which must have been in place 600 or 700 million years ago, predating the separation of the groups that would eventually lead to present-day flies and mammals. Only later in evolution, probably around 450 millions of years ago, did vertebrates add adaptive immunity to their defense armamentarium, while still relying on an efficient innate immune response in the first line.

Leaving now innate immunity, its concepts and mechanisms, to other forums than the celebration this afternoon, I would like to look back for an instant, to those persons without whose insights, teachings and support, I would not have had a chance to stand here today. My father, Jos Hoffmann, a professor of biology and a devout entomologist in Luxembourg, introduced me to the field of zoology for which he conveyed upon me his exceptional enthusiasm. Pierre Joly, at the Institute of Zoology of the University of Strasbourg  trained me in experimental biology and, together with Aimé Porte, in cellular biology. During a postdoctoral period in Marburg in Germany, Peter Karlson, one of the most distinguished German chemical physiologists, polished my understanding of biochemistry and chemical endocrinology. I owe to these giants more than their training : they all had a profound, enthusiastic although sometimes critical, vision of life sciences, which has marked my life. All four have disappeared now but survive in the scientific endeavours  that they have initiated and fostered.

I have been exceptionally fortunate to recruit early on first class co-workers in the laboratory. Actually, my first student became my wife and Daniele is with us in this audience. She accepted many sacrifices in our common scientific and family lives, for which I am deeply indebted to her. Many young scientists have joined me over the years and have made significant contributions to our discoveries which I am pleased to underline here. They have pursued their careers in Strasbourg or elsewhere. I want to mention Charles Hetru, Marie Lagueux, Jean-Marc Reichhart, Jean-Luc Dimarq, Philippe Bulet, Jean-Luc Imler, Julien Royet and Elena Levashina. I wish to make a special mention of Bruno Lemaitre, who was the first professional Drosophila geneticist to join our group and who has made an eminent contribution to the discovery of the immune function of Toll in the fruitfly. My co-workers, their own students and our post-doctoral fellows have immensely contributed to our present understanding of the basic mechanisms of antimicrobial defenses in Drosophila and have helped establishing this system as a paradigm for innate immunity in general.

The research which we performed over this long period was generously and continuously supported by the Centre National de la Recherche Scientifique, the main French research Agency. Without that support and without the positions which the agency provided to the persons working with me, either as researchers or as technical assistants, we would not have been able to be competitive in our field. I do hope that the changes which are now being implemented in the organization and the support of French Science will leave a significant role to the CNRS.

It is a particular pleasure to share this Prize with Bruce Beutler. For nearly ten years now, we have been interacting, both scientifically and through animated discussions on geopolitics, religions and music. I value Bruce as a dear friend and inspirer. I would also like to acknowledge long-standing friendly cooperations with Alan Ezekowitz from Harvard, now the Senior Executive for Research at Merck, the late Charlie Janeway from Yale University, and Fotis Kafatos who now heads the European Council for Research, a 2-billion euro endeavour by the European Union which, we all hope, will give a strong impetus to European research.

I would like to close on a very personal note. I received my very first scientific Prize here in Bern in 1979, nearly 30 years ago. It was a prize sponsored by the Wander Foundation and I had been nominated by Professor Martin Lüscher, a renowned insect physiologist at the University of Bern who tragically passed away in the same year. I keep a dear memory of Professor Lüscher  and a great respect for his scientific achievements. I am particularly pleased that Madame Noémie Lüscher could attend this ceremony, together with Professor Lanzrein, the scientific successor of Martin Lüscher at the University of Bern. Both were at my side during the 1979 reception of the Wander Prize.

I thank you for your kind attention.