The Journal of Immunology, 2003, 171: 4953-4956.
Copyright © 2003 by The American Association of Immunologists
The Importance of Environment in the Production of Lymphocytes and Immunologists1
Paul W. Kincade2
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104
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Introduction
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Paul W. Kincade
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The founders of The American Association of Immunologists would likely be impressed with the many discoveries that have been made in the last 90 years. In addition, they would be astounded by the questions those findings raised and the pace of current exploration. It surprises me, however, that, despite so much progress, my area of research remains fresh and full of opportunities. We are still discovering specialized blood cell types that participate in immune responses and are far from a complete understanding of how they arise. Tomorrow’s scientists will integrate what they learn about lymphocyte formation with exciting advances soon to come in stem cell behavior and differentiation, as well as the widespread implications for tissue and organ regeneration.
Immunology has thrived in part because each generation of scientists has been willing to encourage and share with the next and I can see parallels between the production of lymphocytes and the training of new scientists. Both represent complex, multistep processes that result in highly selected individuals that then compete and cooperate in remarkable ways. In each case, aspects of production are in carefully regulated steady state equilibrium, little affected by changes in numbers of the mature product. It is easier to dissect and quantify steps in these assembly lines than to understand how progression through them is controlled by the environment. However, interesting facts are emerging that will form the basis for this discussion.
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Starting populations
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Lymphocytes, like all blood cells, derive from hematopoietic stem cells that were identified and indirectly studied long ago. However, determining how small numbers of stem cells maintain their enormous potential for self-renewal, as well as differentiation to any of the blood cell types, represents one of the major challenges of biology. The immediate precursors of B lymphocytes (pre-B cells) have also been known for some time and we have been able to purify them from human and mouse bone marrow since 1981. Pre-B cells are extremely abundant when compared with stem cells that exist among their rapidly expanding progeny. Therefore, direct assault on events concerning such extremely rare cells required the relatively recent development of magnetic bead separation and high-speed cell sorting procedures. In addition, protocols for efficiently monitoring their fate following transplantation and culture have only now become available. Even so, early progenitors of lymphocytes were long thought to diverge at an early stage from those corresponding to myeloid and erythroid lineages. Whereas recent observations suggest that is the case in adult marrow, there have fortunately been many surprises, and uncertainties about the process remain.
Activation of the RAG-1 locus is a very early event in lymphopoiesis and RAG-1/GFP knockin mice recently made it possible to isolate very primitive lymphoid progenitors in bone marrow. The EBF and E47 transcription factors known to be essential for lymphocyte formation are also present at this time, but the IL-7 cytokine receptor and Pax-5 transcription factor needed to sustain B lymphopoiesis are not yet activated. The option for myeloid and erythroid differentiation is largely down regulated when RAG-1 is first expressed, and it is now possible to track the progression of early progenitors through B, T, and NK lineages. Although the transition through various stages may be more gradual and subject to change than once thought, the long held models are generally correct for adult marrow. A series of observations suggests that pathways utilized for differentiation of fetal cells may differ significantly from the adult situation. Furthermore, stem cells and lymphoid progenitors undergo substantial developmental age-related changes early in life. Although we have learned a great deal, many important questions remain about the initial construction and subsequent replenishment of the immune system.
It is also important to understand the nature and supply of tomorrow’s immunologists. Firm commitment to a career in science might take place in high school or much later, and it would be helpful to have a sense of how it happens. There is considerable concern that some scientific fields are no longer attractive to undergraduate students. However, the popularity of biology is at an all-time high and our trainees score well on the GRE exam. Furthermore, we have good gender balance with respect to our students. In fact, the only notable shortcoming is with our recruitment of underrepresented minorities.
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Among other discoveries, Dr. Bruce Glick demonstrated the importance of the bursa of Fabricius to
development of humoral immunity in birds (1). Now retired, he was a master teacher who
effectively communicated the rewards of working in biomedical research.
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I am convinced that high school and undergraduate teachers hold the key to maintaining our current level of success and diversifying our future workforce. Dr. Bruce Glick provided my introduction to science and immunology. He was a master teacher, a gifted scientist, and one who effectively shared the excitement of investigation. He was also the first of my teachers to have made an important discovery, finding that the humoral immune system of birds is dependent on the bursa of Fabricius (1). Glick believed that research makes one a better teacher and vice versa. If we continue to be blessed with such talent scouts, the future of immunology is assured.
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Supportive/selective environments
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Lymphoid progenitors live within a wonderfully complex community of cells and molecules. Although much remains to be learned, progress has been steady in defining the nature of the environment that regulates their survival, proliferation, differentiation, and migration. We know some of the critical cell adhesion molecules and ligands that mediate interactions with stromal cells, many cytokines that are essential for lymphopoiesis, and several hormones that normally function as negative regulators. However, large families of cell interaction molecules such as Wnt and Notch likely play important roles that are only now being thoroughly investigated. Once we have identified all of the environmental components, the challenge will be to see how individual signals are coordinated to ensure that appropriate numbers of cells progress in each of the blood cell lineages.
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Appropriately considered a founder of modern immunology, Dr. Max Cooper first defined the
developmental origins of separate classes of lymphocytes (8). His spectacular
scientific career includes contributions to many aspects of basic and clinical immunology. He is
also a gifted mentor who positively influenced many careers.
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If cells and molecules are critical for support of lymphopoiesis in bone marrow, a mentor represents the most important part of a graduate student’s environment. I was fortunate to be the first student of a young professor who was fresh from a series of landmark discoveries. Dr. Max Cooper is a gifted teacher who was easy to respect and like. Students have often heard me tell about one of our few disagreements because of the important lesson it conveys. At my first scientific meeting, I enthusiastically introduced Max to someone as "my boss." Soon after, Max was to point out that he would be glad to be my mentor, colleague and friend, but not my boss. From that moment, I understood that students should assume primary responsibility for decisions about experiments as well as career paths. At the same time, trainees must be given the freedom, support, and respect necessary to be successful masters of their destinies. While I have received valuable advice from many people over the years, not one of them has attempted to "direct" my research.
A number of committees have explored the training environment for biomedical scientists and recommended best practices (2, 3). These include greater use of individual fellowships and formal training programs, rather than research grants, as mechanisms of support. National Research Service Award fellowships from National Institutes of Health paid for my formal training, while the Arthritis Foundation supported two postdoctoral years and the launching of my career as an independent investigator. National Institutes of Health and private foundation fellowships emphasize the production of scientists rather than publications and encourage career development in a number of ways. The distinction between trainees and other valuable members of the laboratory workforce is especially important at the postdoctoral stage, and the status of recipients of individual fellowships is clear. Thus, the mechanism of support can be an important aspect of the training environment.
The Walter & Eliza Hall Institute in Melbourne, Australia is a remarkable institution where I joined eager young scientists from around the world for postdoctoral training. Everyone was assigned to a "Unit," but there was little pressure to follow any particular line of investigation. Headed by Dr. Donald Metcalf, the prestigious Cancer Research Unit successfully competed with much larger and better-funded teams elsewhere in learning about normal and malignant blood cell precursors. I remember Metcalf as one who led by example and fostered an outstanding environment for creativity. Many of these features were characteristic of the late Basel Institute for Immunology, where I frequently visited and enjoyed a sabbatical. I know unfortunately, of no other institution that allows trainees as much freedom.
There is much discussion about a trend toward "large-scale biomedical science" in the United States, and there are some indications that this applies to immunology. For example, the average number of authors per paper in The Journal of Immunology increased from 3.4 in 1982 to 6.0 in 2002. In addition, while numbers of RO1-type National Institutes of Health grants remain stable, the size of the awards has grown by 14% per year. The nature and significance of big science was recently considered in an Institute of Medicine study (4). One conclusion was that a reasonable balance has to be achieved between large, multidisciplinary programs and individual, investigator-initiated projects. Large-scale science will employ a new generation of scientists with management skills and can provide a means for broad advances in translational research. On the other hand, it is unlikely to provide typical academic research incentives such as publication credit. In addition, large programs do not necessarily offer the opportunities for innovation and career development that are essential to good training environments. If laboratories continue to grow with respect to size and connectivity, we will need to make sure these trends do not diminish the attractiveness of immunology for students. Teamwork is important in all areas of science and large teams are needed to address particularly complex, crosscutting questions. However, paradigm-challenging ideas continue to emerge from small groups going where their imaginations lead.
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Production versus need
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Although the bone marrow carefully controls the numbers of lymphocytes it produces, there is no evidence that it can sense the need for mature cells elsewhere. Rather, newly formed cells appear to emerge throughout life and then compete for access to niches such as those within follicles and marginal zones of the spleen. Attracted to and organized in those structures by chemokines, B cells respond to survival-promoting cytokines such as BAFF. Multiple mechanisms ensure that those lymphocytes display useful, but not potentially harmful, Ag receptors, because this represents an important determinant of their long-term success. Initial survival and expansion of pre-B cells in bone marrow requires display of pre-B cell receptor complexes, whereas lymphocytes that pass this qualifying exam may undergo receptor editing or replacement at the immature small B cell stage. The fate of these diploma-carrying cells in the periphery is largely governed by chance and market forces. However, participation in immune responses, somatic hypermutation of Ig genes, and selection allows B cells to become even more useful citizens. The immune system benefits from diversity as well as specialization, periodic replenishment, and experience.
Similarly, graduate training is not effectively and deliberately adjusted according to scientific manpower requirements. It is extremely difficult to forecast those needs, but some of the influential factors are known. Since 1995, the numbers of graduate students have been steady and approximately 600 Ph.D.s are awarded in Microbiology and Immunology each year. The time to degree represents another constant, and Ph.D. recipients are usually 31 years old. The numbers of U.S.-trained postdoctoral fellows have been stable since 1995, while we continue to import many scientists who already hold Ph.D.s (5). Our nation has always benefited from this infusion of new talent from strong training environments elsewhere.
The unemployment rate for biomedical scientists continues to be extremely low (1.1%), while inflation adjusted growth of the National Institutes of Health budget during the last 10 years has averaged 7% and steadily increasing amounts have been spent for industrial R&D in the life sciences. Numbers of investigators with at least one National Institutes of Health grant have not increased dramatically and the age distribution of scientists suggests retirement rates will eventually increase (5). Information of this kind suggests that we are not over-training, but do not allow accurate prediction of future workforce needs. Although we can be confident of continued demand, the job descriptions for tomorrow’s immunologists may be somewhat different from the present.
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Career paths and job prospects
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Many diagrams attempt to depict a sequence through which genes are expressed as stem cells give rise to early lymphocytes. However, it is likely that there are cell-to-cell differences. For example, we obtained evidence that some, but not all NK precursors have a recent history of RAG-1 expression, and one-half of them appear to proceed through a CD45R+ stage. Similarly, at least five distinct types of cells in bone marrow have the potential to turn into T lymphocytes under experimental circumstances, but which of these normally colonizes the thymus remains unclear. In addition to implying that all cells follow an identical path to their destinations, the existing diagrams are misleading in other ways. The differentiation of hematopoietic stem cells to newly formed lymphocytes represents a narrowing of options that is both gradual and progressively less reversible.
Views are changing about the training for biomedical research as well as the nature and diversity of jobs that can be expected in the future. Approximately 1,700 students are currently enrolled in Master’s programs in biology, now being reinvented as Professional Science Master’s degrees. This is an interesting development because it could encourage larger and more diverse populations of students to undergo advanced training. That would, in turn, provide a larger base from which to recruit technicians and Ph.D. students. As in my case, obtaining a Master’s degree need not add to the total training time for students that go on to complete a Ph.D.
Clinical departments in medical schools report an expansion of employment of Ph.D.s (4.7% per year). However, Ph.D. faculty in basic science departments have increased more slowly (1.9% per year) and actually declined in Microbiology and Immunology (6). Furthermore, the retirement/attrition rate for those scientists has declined to 
6.5% per year. Much of the hiring in academia has involved non-tenure faculty. Only 14% of trainees in the biomedical sciences have a tenure-track appointment 5–6 years after obtaining the Ph.D. degree. While much attention has been focused on this tightening job market, we must remember that 36% of our scientists are employed in industry and an additional 14% work in the government (7). Those positions offer many unique rewards that may not be sufficiently stressed to immunology students.
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Concluding thoughts
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AAI members have probably always shared the excitement of immunology research with potential scientists. That is certainly the case today, and I know of no organization that does a better job of identifying talent worldwide and encouraging the development of young investigators. Many leading immunologists recall having given their first presentation, led their first session, or presented their first plenary lecture at an AAI meeting. Our organization also monitors stipends, benefits, new investigator funding, and other issues important to trainees. Moreover, AAI sustains the careers of established scientists through activities conducted by 12 outstanding committees. The dedicated volunteers who serve on those committees create an environment that we all enjoy. In a time of great scientific opportunity, AAI must continue to ensure that there are great opportunities for scientists.
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Footnotes
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1 Presidential Address presented at the Annual Meeting of The American Association of Immunologists, May 6, 2003, Denver, Colorado. 
2 Address correspondence and reprint requests to Dr. Paul W. Kincade, Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, 825 North East 13th Street, Oklahoma City, OK 73104. E-mail address: Paul-Kincade{at}omrf.ouhsc.edu
Received for publication September 25, 2003.
Accepted for publication September 26, 2003.
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References
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- Glick, B., T. S. Chang, R. G. Jaap. 1956. The bursa of Fabricius and antibody production. Poult. Sci. 35:224.
- Committee on Science Engineering Public Policy (U.S.). 2000. Enhancing the Postdoctoral Experience for Scientists and Engineers: A Guide for Postdoctoral Scholars, Advisers, Institutions, Funding Organizations, and Disciplinary Societies The National Academies Press, Washington, DC.
- National Research Council (U.S.). Committee on Dimensions Causes. 1998. Implications of Recent Trends in the Careers of Life Scientists. Trends in the Early Careers of Life Scientists The National Academies Press, Washington, DC.
- S. J. Nass, and B. W. Stillman, eds. Committee on Large-Scale Science and Cancer Research, National Cancer Policy Board, Institute of Medicine and Division on Earth and Life Studies, National Research Council (U.S.). Large-Scale Biomedical Science: Exploring Strategies for Future Research 2003 The National Academies Press, Washington, DC.
- Garrison, H. H., S. A. Gerbi, and P. W. Kincade. 2003. In an era of scientific opportunity, are there opportunities for biomedical scientists? FASEB J. In press.
- 2003. Number of Full-Time Faculty in Medical Schools by Department. AAMC Medical School Profile System.
- 1999. Employed U.S. Scientists and Engineers, by Highest Degree Attained, Occupation, and Employment Sector. SESTAT. National Science Foundation.
- Cooper, M. D., R. D. A. Peterson, M. A. South, R. A. Good. 1966. The functions of the thymus system and the bursa system in the chicken. J. Exp. Med. 123:75.[Abstract]
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Introduction
Starting populations