|T H E N I H C A T A L Y S T||J U L Y A U G U S T 2002|
'LIFETIME' ACHIEVEMENT A WORK IN PROGRESS
In the four decades between the 1963 publication of his first paper"Relationship of gamma globulin to the fibrils of secondary human amyloid"and his seven contributions to the literature thus far in 2002 (two published, three in press, two submitted) that address the differentiation of memory T cells and the activities of interleukin-4 (IL-4), there has occurred what William Paul calls a "revolution" in the field of immunology.
He doesnt credit his own role in fomenting that revolutionbut his peers are well aware of it. This past spring, he received the American Association of Immunologists 2002 Lifetime Achievement Award. The NIH Catalyst interviewed him shortly after.
Asked to list some of the achievements especially pleasing to him, Paul cited the "wonderful colleagues" that had been his trainees and "a lot of the research that has been done here." Much of that research has involved IL-4.
Paul discovered and purified IL-4, characterized and traced the signaling mechanism of the IL-4 receptor, and elucidated the regulation of IL-4 production. He demonstrated the role of IL-4 in the production of IgE antibodies, the regulation of allergic inflammatory diseases, and the polarization of T-cell responses to the Th2 type. He elucidate how T lymphocytes recognize and respond to antigen and how B lymphocytes develop and are activated.
Paul began his research career as a clinical associate in the NCI Endocrinology Branch from 1962 to 1964. He returned to NIH in 1968 as a principal investigator in the NIAID Laboratory of Immunology and became chief of that lab in 1970, a position he holds to this day.
From 1994 to 1997, he was also director of the Office of AIDS Researchin which capacity he was instrumental in advancing the establishment of the Vaccine Research Center (VRC). He has authored more than 520 papers and edited more than 30 books.
Q: How has immunology changed in the 30-plus years that youve been chief of the Laboratory of Immunology?
PAUL: Basic immunology has lived through a complete revolution in the past 30 years. Immunology in 1970 and immunology in 2002 are completely different beasts. In 1970 we didnt have any of the cellular or molecular understanding of immunity we have nowpeople were still struggling over how many immunoglobulin genes there were. The recognition that there were T cells and B cells came only in the late 60s. The field has been transformed by improved understanding of the mechanism of immunoglobulin diversification, the whole concept of a T-cell receptor, the role of major histocompatibility complex, and the recognition of different subsets of lymphocytes.
Q: How have these findings affected public health?
PAUL: Public health changes are always much slower than scientific discoveries, but one great contribution of immunology to public health lies in vaccine biology. The old paradigm for vaccine generation was to look for the immunogen that evoked an immune response in a person who recovered from the disease. You would then try to use that information as a guide to choosing the immunogen to make your vaccine.
We now know that certain types of oligomers interact with specific receptors to turn on the immune system and that activated dendritic cells and macrophages make interleukin-12 and other co-stimulants. These types of discoveries combined with improved understanding of T- and B-cell collaboration have led to the development of better vaccines. For example, work done here at NIH [by NICHDs John Robbins and Rachel Schneerson; see "NICHD Scientists Garner 1996 Lasker Award," The NIH Catalyst, NovemberDecember 1996] demonstrated that the conjugation of the capsular polysaccharide of Haemophilus influenzae type B (Hib) to an appropriate protein could make a superior immunogen and an improved vaccine. The development of such conjugate vaccines was a great step forward in rational vaccine design; the Hib conjugate vaccine basically eliminated H. influenzae infection in infants in the United States. This was the principal cause of childhood meningitis and also an enormous cause of mental retardation.
Interventions in autoimmune disease are probably where you see the greatest impact of knowledge gained about immune responses. Therapies for autoimmune disease based on understanding of whole cytokine networks are coming forward. Introduction of treatment for rheumatoid arthritis based on blocking certain cytokines such as tumor necrosis factora is an example of the impact this new knowledge is having.
Q: What are some of the important questions immunologists need to answer in the future?
PAUL: The only way to answer that is to tell you what people are doingand one can perhaps predict what should be donebut, generally speaking, predictions are chiefly useful for entertainment afterwards.
It seems to me that we have to learn how persistent infection is able to evoke a continuously effective state of immunity and mimic that with nonliving or engineered immunogens.
I dont think we really understand prime-boost: Why does vaccination with a DNA vaccine followed by an adenovirus or a poxvirus boost work better than DNA followed by DNA? I dont think we understand that.
Right now we understand many of the individual pathways and mechanisms of the immune system in some detail, but our understanding of how they are integrated into a fully functioning immune system is quite poor. Ideally, we would like to predict the outcome of any perturbation to the system, but we need to develop tools to understand on a quantitative basis the working dynamics and interactions of the individual components. We also need to advance ways to handle the immense amount of information we have. I think theres going to be a big emphasis on biomathematics.
Q: How can the Human Genome Project be used to advance immunology?
PAUL: There is enormous information to be extracted about the structure of genes that in principal may tell you something about the behavior of systems. What we want is to learn how all the components of the system work together. What do individual cells do, what determines their behavior, and how do the cells integrate various signals? That will be the basis for rational target selection in developing drugs to treat complex diseases.
Q: How has NIH changed since you first started here?
PAUL: Its a much more complex institution today, but some of the key elements have remained. Attitudes toward research have not changed. NIH is fundamentally a data-driven institution with a very high standard of scientific inquiry. The intramural research program has a real devotion to understanding and to [solving] problems of importance to human biology.
There is a real sense of community and of discovery amongst people here. There is a much greater feeling, I think, of collegiality and cooperation than at other places where there is a lot of competition for funding.
The Immunology Interest Group (IIG), for example, is an outgrowth of the previously informal NIH immunology community. It has been very collegial since the first day I came here. Theres been lots of collaboration. Even when people arent collaborating, the interactions have been just terrific. The administration has been very sensitive to the need to provide scientists the freedom to pursue important research.
NIH has always had a substantial presence of non-U.S. scientists, but now the mix and the places people come from are much wider. There are all sorts of enormously intelligent people that come from all sorts of backgrounds, and this is a great advantage. At one time, the physicians draft was a tool to get terrific people. We are all happy there is no draft anymore, and now we draw on all sorts of mechanisms to get our superb scientists.
Q: How has the increase in government funding to NIH affected intramural research?
PAUL: During the doubling of the NIH budget, the intramural budgets have not gone up so much; theyve been relatively modest compared to the overall growth in NIH funding, most of which has been extramural.
Nevertheless, weve had the good fortune to see a lot of new construction on campus that makes up a long-standing deficit of growth in terms of physical plant. Its been very much needed and is very important to the future of NIH.
But one great thing about this institution is that the limiting step is not the battle to obtain resources to undertake an experiment; its ones ability to come up with creative ideas to carry it out. This freedom really gives the scientist the opportunity to put an idea to the test. Were very fortunate that we dont spend the vast majority of our time trying to raise money. Its a great advantageand a great responsibility.
Q: You had a lot of influence in getting the Vaccine Research Center started. Do you think that devoting substantial resources to a single goal in one center is a strong research model?
PAUL: I think its a good model.
There is no question that the classical model of individual laboratories with specific research goals that develop as opportunities are pursued is a critical model of inquiry that must persist. But with the growth of technology, new opportunities also arise that can best be capitalized on with the development of single- or limited-purpose entitiescenters, if you likein which technologies can be marshaled in a way that no single laboratory can manage. The VRC is such an example.
I think that NIH as a whole could benefit from having a number of these limited-purpose, highly technological centersand I think we will see more as a result of the bioterrorism initiatives. I dont think NIH as a whole should be simply made up of these centers, and we must still have a substantial number of programs that retain the free-inquiry model. One other point about this research model is that the centers dont necessarily have to be immortal. They need to exist for as long as their purpose is still valid.
Q: What role do you think the NIH should play in responding to bioterrorism?
PAUL: I think the need to respond to terrorism is rather like the need to respond to HIV. A national emergency arises and a national resource like the NIH has the means and responsibility to respond to itthat is one of the reasons it exists. Within an institution as large and diverse as ours, taking a reasonable chunk and letting it respond to a national emergency is absolutely essential, and we are very well prepared to do it. The resources devoted to the bioterrorism initiative, like the AIDS initiative, have to be proportional to the problem. We have to retain the ability to develop new knowledge that can be the basis of these kinds of focused efforts.
Q: Which of your lifetime achievements are you particularly proud of?
PAUL: Im proud of a lot of the research that has been done here, and Im extremely proud of the wonderful colleagues Ive had as trainees. Three of my former postdocs are now members of the National Academy of Sciences.
As [do] all scientists who have had long careers, I think about the opportunities missed. The key is to not miss as many in the future. . . .
Lifetime achievement awards imply that youve accomplished all that you are going toI still feel that there is much more left to do.
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