May 24, 2005 - Professor of Immunology at the Univer- sity of Cambridge ... his work on immunological memory and how the .... evolutionary timeline. Intrigued ...
BIOGRAPHY
W
hen immunologist Douglas T. Fearon was a young physician in Boston in the early 1970s, he began treating a patient with rheumatoid arthritis. For 15 years, he tried to stop the progress of the crippling disease, but the patient’s immune system continued to degrade his cartilage and destroy his joints until the disease finally killed him. Fearon learned that treating patients did not always mean saving them. In the end, real help could come only from a better knowledge of basic science. ‘‘Contrary to what I thought when I went to medical school, we weren’t really curing a whole lot of people,’’ he says. ‘‘This patient’s death told me I had to either put up or shut up. If I was committed to being a physician-scientist and making discoveries, and if not being able to cure patients truly bothered me, I had to do research 100 percent of the time.’’ To Fearon, the logic was clear. The path to making his patients well again began first with understanding what made them sick. Yet clinical duties stole time away from Fearon’s research, and his concern for his patients ironically meant he needed to stop seeing them altogether. Indeed, by the time he was elected to the National Academy of Sciences in 2001, his pursuit of basic science had led to a rewarding career as a researcher but also took him away from much that he valued: his patients, his career as an academic physician, and eventually his home country. Currently the Sheila Joan Smith Professor of Immunology at the University of Cambridge School of Clinical Medicine (Cambridge, U.K.), Fearon’s research has helped describe how the body’s two immune defense systems work together to recognize and fight pathogenic invaders. In his Inaugural Article (1) published in this issue of PNAS, Fearon presents for the first time his work on immunological memory and how the immune system remembers its prior encounters with foreign agents, through either vaccination or infection, and maintains the stem cell-like ability to produce defensive responses over a lifetime. Unacceptable Compromises Football and fiction, not cell biology, dominated Fearon’s undergraduate years. He majored in English literature and quarterbacked the football team at Williams College in Williamstown, MA, but had little star quality for either one, he says. Upon graduation, Fearon, www.pnas.org兾cgi兾doi兾10.1073兾pnas.0502415102
Douglas T. Fearon
whose father founded the first cardiac clinic at Methodist Hospital in Brooklyn, NY, decided to study medicine. ‘‘As a physician, you can do good for people, so that seemed reasonable,’’ he says. ‘‘And being a physician meant that you had to understand people. It’s also one of the reasons you might go into literature—to understand people.’’ Fearon graduated with his medical doctorate from The Johns Hopkins University School of Medicine (Baltimore, MD) in 1968. He stayed at Johns Hopkins Hospital for two years of internship and residency in medicine, where he began to see the incongruity of modern medical care. ‘‘During my residency, it was terribly exciting, because you’re saving people,’’ he recalls. ‘‘But you suddenly realize they still had the same disease at the end of the process. Patients would return to us within months, so what we’d learned in medical school seemed to be wasted effort, almost.’’ For the next two years, Fearon served as an Army Major in the United States Army Medical Corps. He spent a year in Vietnam and received a Bronze Star Medal, awarded by the Army for meritorious service. In 1972, Fearon accepted a research fellowship at Harvard Medical School and Robert B. Brigham Hospital (now Brigham and Women’s Hospital) in Boston, where he also had clinical duties. It was there that Fearon began treating the rheumatoid arthritis patient he would eventually follow for 15 years. At Harvard, Fearon learned to be a scientist in addition to being a physician.
He joined the rheumatology and immunology research laboratory of Frank Austen, who invited Fearon to join his group despite a lack of scientific background. ‘‘He always encouraged me to follow my ideas,’’ Fearon says of Austen. ‘‘He took a chance on me.’’ In fact, Austen oversaw a laboratory full of physicians like Fearon and trained them in fundamental research. ‘‘He gave us the self-assurance that we could approach clinical problems through basic science,’’ Fearon says. ‘‘This let us understand the mechanisms of diseases and move beyond the sorts of correlative observations you find in a lot of clinical research.’’ As years passed, Fearon continued to balance his work in the laboratory and the clinic. With Austen, he studied innate immunity, focusing his attention on the complement system, which supports the activity of antibodies by directly attacking microorganisms or enhancing their susceptibility to phagocytosis (2– 6). In 1984, Fearon became a full professor of medicine at Harvard Medical School and deputy chairperson of the Department of Rheumatology and Immunology at Brigham and Women’s Hospital. A defining moment in Fearon’s career came when, despite best efforts, his rheumatoid arthritis patient died. ‘‘I remember it distinctly,’’ Fearon says. ‘‘He had always been so grateful. He had an unwavering trust. But I didn’t halt the progression of the disease, so I wasn’t deserving of this trust, I felt.’’ Fearon saw that scientific limitations could sometimes trap physicians into extending care rather than cures. In 1987, Fearon returned to The Johns Hopkins University School of Medicine to head the Division of Molecular and Clinical Immunology. The chairman of the Department of Medicine, Jack Stobo, offered Fearon the resources to recruit three young scholars with dual M.D.兾Ph.D. degrees. That trio, Bob Siliciano, Drew Pardoll, and Mark Schissel, allowed Fearon to develop the new immunology graduate program at the medical school. From these and the other members of the graduate program, Fearon began to learn about adaptive immunity, which remembers past infections and is the basis of vaccines. Innate immunity, This is a Biography of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article on page 7418. © 2005 by The National Academy of Sciences of the USA
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IMMUNOLOGY
Biography of Douglas T. Fearon
which Fearon had studied up to that point, dates back to invertebrate ancestors and was at the time thought to be completely separate from adaptive immunity, a much younger process on the evolutionary timeline. Intrigued, Fearon began to explore the connections between innate and adaptive immunity. By the early 1990s, Fearon’s research group had found a molecular link between the two systems (7–10). To follow up on this discovery, however, he needed to learn more about adaptive immunity, which would demand more of his time. Fearon reflected again on his traditional academic medical career— juggling patients, teaching, research, and administration—and saw its potential to snuff his creative spark. ‘‘To be a good researcher, you need to have the opportunity to be intellectually inefficient,’’ he says. ‘‘You need to pursue things in a tangential way. You can’t be too focused, or else you’ll exclude potential solutions.’’ His career was primed for a more radical change. A few years later, Sir Keith Peters, the Regius Professor of Physic at the University of Cambridge, invited Fearon to join the university and start a new phase in his career. The Wellcome Trust, the largest private biomedical research foundation in the United Kingdom, would offer generous funding for Fearon’s proposed research, in addition to state-of-the-art university facilities in the Laboratory of Molecular Biology of the Medical Research Council in Cambridge, U.K. Fearon would be able to work at a research institution dedicated to fundamental problems in biology, where autonomy was valued and small interactive research groups were the norm—and where he could finally give himself wholly to his research. In 1993, Fearon moved his laboratory to Cambridge. Freedom to Start Anew During much of Fearon’s early investigations, adaptive immunity had been the hot topic in immunological research, not innate immunity. Fearon’s work helped to change that. By the mid-1990s, research in his laboratory at Johns Hopkins and the University of Cambridge and in Charles Janeway’s laboratory at Yale University (New Haven, CT) showed that innate immune systems could actually instruct the adaptive immune system. Immunologists grew excited about innate immunity and began to tie the field to their study of the immune system in general. In 1996, Fearon formally linked the innate immune system of complement to the adaptive immune system. He found that the complement
protein C3 could prime an antigen so that the adaptive immune system would be 10,000 times more likely to recognize and respond to it (11). The questions that had been driving Fearon since his postdoctoral years were finally being answered. Innate immunity had always been the hallmark of Fearon’s research, but as researchers embraced the innate immune system into their work, he turned elsewhere. Adaptive immunity became more attractive to him on its own research merits. He had always been interested in B and T cell biology and had already studied B cells in relation to innate immunity. But now Fearon saw an opportunity to study a problem unique to lymphocytes: immunological memory, or the way that lymphocytes remember past infections.
‘‘You need to pursue things in a tangential way. You can’t be too focused, or else you’ll exclude potential solutions.’’ Joining the University of Cambridge had provided an unprecedented level of freedom for Fearon, allowing him now to take a step back, free from clinical and administrative responsibilities, and devise a new line of research. Immunological memory suited his desires perfectly, providing a fundamental research question unrelated to his past work. Fearon’s new focus on immunological memory began to take shape when the journal Science invited him to write a review in 2001 (12). ‘‘I think the editor expected me to do it on innate immunity, but I was kind of tired of that and didn’t have anything new to contribute,’’ he says. Fearon had some new ideas he wanted to explore in the area of memory lymphocytes, which he thought in some ways resembled stem cells. Both stem cells and memory lymphocytes must last throughout a lifetime while producing many other cells. When memory B and T cells encounter the same antigen, even years later, they immediately produce large numbers of effector cells to specifically combat the foreign agent. Two properties allow the parallel ability in stem cells: self-renewal, in which one daughter cell replaces the parental cell while the other goes on to
7416 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0502415102
differentiate; and prevention of senescence, in which cells escape the natural aging process. If memory lymphocytes shared the abilities of stem cells to selfrenew and evade senescence, it might be the key to understanding immunological memory (12). Tracking Killer T Cells with BCL6b Fearon spent the next few years following up on these ideas, exploring memory T cells and one particular transcription factor, BCL6b. In his Inaugural Article (1), he and his colleagues found that BCL6b was important in the magnitude of response of memory CD8⫹ T cells, or killer T cells, to a second encounter with antigen. In mice deficient in BCL6b, this secondary immune response is reduced by 3- to 4-fold. Fearon and his team found that this decrease occurs because BCL6b acts as a transcriptional repressor to the cytokine signaling that drives CD8⫹ T cell differentiation, and this repression in effect allows the responding memory CD8⫹ T cells to self-renew. Yet BCL6b is not the only key to immunological memory, Fearon says, because the BCL6b knockout mice still showed a secondary response, albeit reduced. ‘‘I think I oversold myself on BCL6b being the only way that memory occurs in CD8⫹ T cells,’’ he says. ‘‘It is part of it, but it’s an add-on to something more fundamental that is required for development of memory lymphocytes in the first place.’’ His laboratory thus continues to look for other factors necessary for self-renewal in CD8⫹ T cells. Fearon also wonders how these cells block senescence and keep their ability to replicate. ‘‘Every time you have an infection, you make millions of new effector CD8⫹ T cells,’’ he says. ‘‘And if you have HIV, you’re doing that almost on a daily basis. The stress for replication of CD8⫹ T cells is enormous.’’ Interesting answers should come in a few years, he says. Looking for Common Ground With experience in both camps, Fearon clearly sees how the intersection of science and medicine can be a puzzling place. He finds that, while basic scientists embrace the possibility of their research helping to cure disease, clinicians may not always equally value pure science. ‘‘I find that being a scientist can hurt my ability to communicate with clinicians, because I’m not seeing patients—basically, because I’m not one of them. Yet medicine is the reason that I do research.’’ Fearon worries about this apparent cultural divide between basic research and clinical medicine. ‘‘From a policy Nuzzo
Maini of Imperial College London relied on basic research done previously by Lloyd Old of the Sloan–Kettering Cancer Institute (New York) and Anthony Cerami, formerly of The Rockefeller University (New York). ‘‘This should remind us that, in the best of circumstances, basic and clinical research are synergistic,’’ says Fearon. ‘‘The over-promotion of either will adversely affect the other. There must be a constant attempt to achieve balance.’’ Physicians and scientists can draw inspiration from a common desire to help their fellow human beings, Fearon says, and they need not necessarily be brilliant, either. Motivation may be enough to propel them onward.
‘‘There’s an unfortunate tendency to think that people who have made scientific contributions are different than others, or inherently more intelligent,’’ Fearon says. ‘‘In my case, that is not true at all.’’ Looking back over his career, Fearon sees the force of his motivations still driving him ahead. ‘‘I don’t know what other people feel like when they’re elected to the Academy. It’s a marvelous recognition, a mark of approval by the leaders in your field,’’ he says. ‘‘But I presume that people consider it just as a step along the way, and not a way of saying you’ve arrived. Since I haven’t yet arrived at any kind of disease cure, it’s still a very unfinished process for me.’’
1. Manders, P. M., Hunter, P. J., Telaranta, A. I., Carr, J. M., Marshall, J. L., Carrasco, M., Murakami, Y., Palmowski, M. J., Cerundolo, V., Kaech, S. M., et al. (2005) Proc. Natl. Acad. Sci. USA 102, 7418–7425. 2. Fearon, D. T. & Austen, K. F. (1977) Proc. Natl. Acad. Sci. USA 74, 1683–1687. 3. Fearon, D. T. (1979) Proc. Natl. Acad. Sci. USA 76, 5867–5871. 4. Weis, J. J., Tedder, T. F. & Fearon, D. T. (1984) Proc. Natl. Acad. Sci. USA 81, 881–885.
5. Klickstein, L. B., Wong, W. W., Smith, J. A., Weis, J. H., Wilson, J. G. & Fearon, D. T. (1987) J. Exp. Med. 165, 1095–1112. 6. Weis, J. J., Toothaker, L. E., Smith, J. A., Weis, J. H. & Fearon, D. T. (1988) J. Exp. Med. 167, 1047–1066. 7. Carter, R. H., Spycher, M. O., Ng, Y. C., Hoffman, R. & Fearon, D. T. (1988) J. Immunol. 141, 457–463. 8. Weisman, H. F., Bartow, T., Leppo, M. K., Marsh, H. C., Boyle, M. P., Carson, G. R., Concino, M. F., Roux, K. H., Weisfeldt, M. L. &
Fearon, D. T. (1990) Science 249, 146 –151. 9. Matsumoto, A. K., Kopicky-Burd, J., Carter, R. H., Tuveson, D. A., Tedder, T. F. & Fearon, D. T. (1991) J. Exp. Med. 173, 55–64. 10. Carter, R. H. & Fearon, D. T. (1992) Science 256, 105–107. 11. Dempsey, P. W., Allison, M. E. D., Akkaraju S., Goodnow, C. C. & Fearon, D. T. (1996) Science 271, 348–350. 12. Fearon, D. T., Manders, P. & Wagner, S. D. (2001) Science 293, 248–250.
BIOGRAPHY
point of view, it could lead to a competitive relationship that distorts the overall goals of biomedical research,’’ he says. He admits that scientists’ desire to understand fundamental principles of biology seems to clash with academic clinicians’ commitment to overcome a specific disease. But focusing too narrowly on particular clinical problems may not be the best strategy for physicians. In fact, some specific disease treatments stem from unrelated basic work elsewhere, he points out, as was the case with the first truly effective treatment for rheumatoid arthritis. The development of the antibody to tumor necrosis factor for this purpose by academic clinicians Marc Feldmann and Ravinder
IMMUNOLOGY
Regina Nuzzo, Science Writer
Nuzzo
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