Portrait of an optimist

I come from a family of lawyers. When I was growing up, the only scientist in the family was my uncle, who was a physicist. But I was interested in science, and as a boy collected rocks and kept my “chemistry cabinet” in a spare room at my father’s law firm in Rome where I smelled up the place from time to time with failed experiments. When I finished high school at the Liceo Classico Torquato Tasso in Rome, I was, however, at a crossroads, trying to decide whether to pursue a career in science or medicine, both of which provided a way to positively influence the world. It seemed to me that Medicine tackled problems “one patient at a time,” while science promised to be able to get to the root of a problem to solve it once and for all. I did my studies at the University of Rome where, mentored by Professors Gino Doria and Luciano Adorini, I got my Doctor of Biological Sciences degree in 1984. Gino and Luciano had a strong influence on my choice of a career in immunology, and immunology seemed the perfect solution to that earlier dilemma of science versus medicine, as it was emerging as a discipline based on solid scientific rigor but at the same time had direct medical application. Plus, little did I realize at the time how relevant immunology would be to another emerging interest of mine, computers. In fact, one of my early papers, published in 1986 with Gino and Luciano, described computer code specifically designed for immunological applications. By then, encouraged by my academic mentors, I knew that to gain exposure to the highest impact science I would have to do a post-doc in the US. I was thoroughly committed to immunology, so I was delighted when Gino and Luciano arranged for me to meet John Kappler and Pippa Marrack at National Jewish Hospital in Denver who, along with Howard Grey, led a top-notch immunology group, pushing forward the frontiers of T cell immunobiology. All 3 were already giants in the field of basic immunology, and all would later become members of the National Academy of Sciences. Howard interviewed me during my visit with John and Pippa and offered me a job on the spot. I was not sure why: although I was very determined and enthusiastic, the only thing I was “famous” for at the time was driving my Autobianchi like a maniac in Rome traffic. Later I realized he thought that my immunological background and the fact I could write rudimentary computer programs might be an asset in addressing his hypotheses related to MHC function. In the mid-80s, those hypotheses were controversial. Grey and other scientists like Emile Unanue and Paul Allen at Washington University in St. Louis were providing the first experimental proof that the function of MHC proteins displayed on immune cells was to bind peptides and “present them” to the T cell receptor (TCR) as a way of activating a T cell response. Many in the field remained unconvinced and believed that MHC and antigens must be recognized by 2 different receptors on the T cell surface. Eager to be in the center of things, I realized that if this novel “antigen-presentation” idea was right, it would have a revolutionary impact and profoundly change the field. Grey also struck me as a rigorous, old-fashioned scientist, or as one of my mentors said, if he said something, you could hang your hat on it. So I accepted the job and went to Denver to begin postdoctoral studies in 1986. Moving from Rome to Denver was a shock, but not an unpleasant one. There was just so much snow, and, speaking of hats, I’d never seen people wearing cowboy hats in the street until then. But I had no regrets: my first years working with fellow postdocs like Soren Buus were extremely productive and led to a series of papers providing direct evidence that the function of MHC Class II molecules is in fact to bind short antigenic peptides and present them to T cells. What was not clear was how a single MHC molecule could recognize so many different peptide antigens (epitopes) and still retain specificity. We were able, with the aid of an Apple IIe computer housed in a corner of my bedroom, to detect that different MHCs indeed recognized very loosely defined “sequence motifs." We were excited because, we knew that being able to make these predictions could have significant clinical impact in studying immune responses at an unprecedented level of precision. These discoveries also validated my choice of science as a career, as they suggested ways to create peptides to inhibit MHC-associated autoimmune disease or accelerate development of immunotherapeutic vaccines. In 1988, San Diego biotech pioneer Ted Green convinced Howard to leave Denver to head Cytel, a new biotech company in La Jolla whose mission was to develop immunomodulator drugs, based on blocking the MHC peptide binding site. In Denver, I was still hard at work characterizing peptide binding to MHC, and the idea of relocating to a place as beautiful as La