B. Beutler: 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 am delighted to share the Balzan Prize this year, and feel that I am doing so partly on behalf of the innate immunity field as a whole. This award celebrates a resurgent science that lay dormant for several decades. While all immunologists were aware of the importance that innate immunity has in protecting us from disease, deep insights into the molecular events that occur during an innate immune response have been gained only during the past few years. The work for which Professor Hoffmann and I are being honored has opened the door to much new understanding in immunology. We have begun to see precisely how animals become aware of microbial infection and begin to combat it.
When I began my work in innate immunity more than 25 years ago, I quickly began to realize how very little was known. Although microbes had been recognized as the cause of infectious diseases for more than one hundred years, we didn’t really understand how the host could perceive them. How did the host ‘recognize’ an infection? How did the inflammatory response to infection begin? What were the key molecular interactions? Here were some of the most fundamental questions in immunology, and they begged a reductionist solution. By finding the answers, we might hope to understand not only inflammation that occurs during infection, but inflammation in general: inflammation as we see it in rheumatoid arthritis, for example, or in systemic lupus erythematosus, or in other autoimmune diseases.
Beginning in the early 1990s, my colleagues and I worked ardently to answer these questions as they applied to mammals. We worked through five lean years, during which we had no publications to show for our efforts. We were determined to find a certain ‘magic molecule’ that could tell when infection was present. We knew that this molecule must exist, but finding it was a difficult task. I do not wish to describe our studies at a technical level today, but want only to tell you a bit about the moment of discovery and how it felt, because I still remember it vividly today.
The identification of the molecule we sought was sudden and occurred on a particular evening just over nine years ago. From one minute to the next, we knew with certainty how some microbes are detected, and had a very good idea as to how most microbes are detected in mammals. For those among you who love music, you might try to think of a stirring major chord from your favorite composition, and you will have an idea of how I felt at that instant. As notes converge in a chord, several important lines of scientific inquiry converged in a single molecule, and a number of new hypotheses immediately presented themselves for testing. In addition to these feelings of consonance, and in addition to intellectual satisfaction, there was the thrill of a five-year search that was rewarded all at once with the object we had been seeking. In fact, I was shaking with excitement and somewhat breathless, to the point that I had difficulty telling my colleagues what I had just seen.
From that evening forward, it seemed that a tremendously complex phenomenon – inflammation, with all of the thousands of molecular and cellular events that it incorporates – could be traced to a handful of molecular sensors that initiate the process, and in some instances, to a single molecule. It now is quite clear that a very small number of proteins are the ultimate gatekeepers of the most powerful inflammatory reactions we know.
It is a great pleasure to share the Balzan Prize with Professor Jules Hoffmann. The beautiful work that he and his colleagues did in advance of our own was a brilliant and resonant ‘note’ in the ‘chord’ that I spoke of earlier. When it became clear that we were pursuing an evolutionarily conserved apparatus for immune defense, we immediately began to work together, and we have shared many new scientific insights as well as a true friendship ever since.
I want to mention a number of people who supported me in my work. Drs. Alexander Poltorak, Irina Smirnova, Kasper Hoebe, Xin Du, and several other trainees who have worked with me over the years deserve much credit. My colleague Betsy Layton, who has been with me for 21 years, has taken upon herself all of the administrative details of my work so that I have been free to think about scientific problems and how best to solve them. Chris Galanos, Marina Freudenberg, Robert Munford, and other scientists in the innate immunity field shaped my views of how microbial perception occurs. And I was greatly inspired by the diverse accomplishments of Rudi Balling, Jean-Louis Guenet, and other members of the mouse genetics community. They gave me confidence that we would succeed.
To both of my parents, I owe the optimism and persistence necessary for all serious scientific pursuits. They set me on my present course. My father, Professor Ernest Beutler, who is ill and could not be here today, is an extraordinary scientist, and was my earliest teacher. In fact, I still collaborate with him to this day. I was also lucky to be taught at a young age by Professor Susumu Ohno, who founded some of the principles of molecular evolution that are now second nature to us, and by Professor Daniel Lindsley, who showed me in very practical terms what genetics can do.
Nadia Krochin, whom I have known for 23 years, gave me encouragement when I most needed it. And my three sons, Danny, Elliot and Jonathan, deserve my gratitude as well. On occasion, I have worked hard to set an example for them and they, too, pushed me to succeed, though perhaps without realizing it.
Again, my deepest thanks for this great honor.