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INTERNATIONAL BENCHMARKING OF US IMMUNOLOGY RESEARCH 1 INTRODUCTION 1.1 How Important Is It For The United States To Lead In Immunology Research? Immunology encompasses fundamental scientific discovery at all levels of biological organization. It is also a practical field that provides, for example, highly specific molecular entities (antibodies) that are the basic tools for identifications (as in diagnosis) and separations in biology, medicine, and industry. Disorders of the immune system are frequent causes of human disease, ranging from congenital and acquired immunodeficiencies, such as AIDS, to autoimmune and inflammatory conditions, such as insulin-dependent diabetes and rheumatoid arthritis. The normal functions of the immune system reject transplanted cells, tissues, and organs. Pharmaceutical and biotechnological interventions to dampen immune responses in autoimmunity, inflammation, and transplantation are important segments of the pharmaceutical industry and clinical medicine, as are attempts to amplify or augment components of the immune system to help eliminate infections, cancers, and parasites that have evaded immunosurveillance. Institutions that have robust programs of research, training, teaching, and application in immunology have had (and probably will continue to have) opportunities to take advantage of immunology as a science that enriches other biomedical endeavors, to enhance the role of immunology in medicine, and to use immunology in entrepreneurial and industrial efforts. It is therefore a vital US interest to be in a position of leadership in immunology, so that the intellectual, medical, and financial benefits of immunology will be available. 1.2 What Is Immunology? Immunology has been described as the branch of life sciences that is involved in distinguishing self from nonself. All multicellular (metazoan) organisms are prey to infection or invasion. With the specialization of cells within organisms into organs and tissues that serve distinct functions, subsets of cells that survey other cells or elements for self or nonself markers have evolved to serve immune functions. In humans, as in other vertebrates, the cells that make up the immune system include some that are similar to the innate immune systems of prevertebrates and others—called lymphocytes—that appear to constitute a vertebrate invention, and are responsible for most of the adaptive immune functions of vertebrates. There are two major classes of lymphocytes: T cells, which develop in the thymus; and B cells, which develop in the bone marrow. Those two classes have different immune functions. For example, in an immune response to a viral infection, B lymphocytes are triggered by the virus to differentiate into mature effector cells that produce and secrete molecules called antibodies. Antibodies can bind to and inactivate or eliminate specific viruses before they enter cells of the body. Viruses can penetrate cells and cause them to use the viral
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INTERNATIONAL BENCHMARKING OF US IMMUNOLOGY RESEARCH genetic material as templates and instructions to produce more viruses. Once viruses enter the cells, they are largely hidden from circulating antibodies. To protect the organism against the intracellular phases of viral infection, several populations of lymphocytes, including a subpopulation of inflammatory and killer T cells, collectively isolate and eliminate virus-infected cells. T cells recognize virus-infected cells by means of cell-surface receptors (called T-cell receptors or TCRs) that adhere by molecular complementarity to "flags" on the surface of infected cells. The flags are a class of molecules that make up what is called a major list of compatibility complex (MHC), which picks up degraded fragments (about nine amino acids long) of viral proteins within the cells and bring them to the surface to be detected by TCRs on inflammatory and killer T cells. Both the magnitude and the quality of the immune responses by these types of T and B cells are regulated by helper T cells. During the course of an infection T and B cells with virus-specific receptors undergo many rounds of cell division; some cell progeny are destined to be immediate effectors of the response, and others are retained as "memory" cells. Long after an infection (or vaccination), the expanded number of memory cells guarantees that a second exposure to the same virus will be met by an expanded response which develops more rapidly, providing effective immunity before serious consequences of the infection develop. During development of the T and B lymphocytes from their precursors, members of the population that have receptors to self are usually eliminated, inactivated, or not expanded. Thus, the adaptive immune system usually ignores self and responds to nonself by providing early and effective immunity and lifelong immune memory. Much is known about this complex system, but much is yet to be learned, so immunology is still an attractive subject for training and research. For example, many immune diseases are known to be the result of mutations or alterations in particular components of the system, whereas others have an unknown etiology. Immunology attracts diverse life scientists. Perhaps because the cells of the immune system are easily obtained, the system has often been used as a leading-edge subject for studies in other disciplines. Study of homogeneous lymphocyte populations, for example, leads to research in many aspects of signal transduction, wherein cell-surface receptor engagement signals cells to divide, differentiate, or die. It can be argued that we know more about vertebrate developmental immunology than about any other developmental system, including the first isolated stem cell in any system. Much of what is known about cell-surface adhesion and recognition receptors, the genes that encode them, and the evolution of these genes comes from studies of cells of the immune system. That cells can communicate by secreted protein messages called cytokines was elucidated largely through study of cells and cytokines of the immune system. 1.3 Immunology As An Academic Discipline Immunologists are at work in virtually every life science department or division. But there are very few departments of immunology in academe. The multidisciplinary nature of immunology research is probably a major reason that immunology is so well connected with the more traditional subjects (such as biochemistry, genetics, and microbiology), whose approaches define their disciplines. It also explains the ready translation of discoveries in immunology to such clinical subjects as rheumatology, surgery (in transplantation), endocrinology (in diabetes), neurology (in multiple sclerosis), and allergy. Although those connections have served immunology and the other subjects well and have probably protected immunologists from the isolation that their jargon could lead them into, immunology might be less of a force in academic politics and less of a presence in the
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INTERNATIONAL BENCHMARKING OF US IMMUNOLOGY RESEARCH undergraduate and graduate curricula of many universities than it would otherwise be because it does not have departmental status at most institutions. Not being or being in a discipline with departmental status, immunology and immunologists are unevenly distributed in the totality of US academic institutions. Entrepreneurial and clinical efforts in immunology largely have the same uneven distribution. 1.4 What Is The International Nature Of Immunology? Excellent research in immunology is conducted throughout the world. Researchers are part of a tightly knit and highly collaborative international community and hence, immunology as a discipline has become an international effort. International collaboration in the different subfields of immunology has facilitated exchanges in information that have enabled exciting breakthroughs to be made. Factors that have contributed to international collaboration have been the training of young scientists from around the world in graduate institutions in the United States, training of young US scientists in foreign immunology centers, internationally attended scientific conferences, the increasing facility of electronic forms of communication, and the use of English as the standard tongue of communication. 1.5 What Are Some Caveats? Immunology is an essentially multidisciplinary field, and immunological research overlaps with many other disciplines, including molecular and cellular biology, genetics, and biochemistry. Immunology serves as a foundation for the design and testing of varied biologic hypotheses. Therefore, this benchmarking assessment will be valuable not only to the field of immunology, but also to other biological disciplines. Conversely, although this is a definitive strength of this report, it must be noted that it was sometimes difficult to identify and characterize specific attributes that apply solely to immunology. Additional caveats apply to the method used in this analysis. Given the lack of quantitative data that can be compared on an international basis, the panel used a number of techniques and, looked at the degree to which the results conformed to develop its conclusions. The panel was not able to assess this question in an objective way, but it used the expertise and judgment of its members and the limited information and data available to develop its conclusions. More details on the methods and the limitations of each are provided in Chapter 2. 1.6 Panel Charge And Rationale The panel was asked to conduct a comparative international assessment to answer three questions: What is the position of the US research in the field relative to the research performed in other regions or countries? What key factors influence the US performance in the field? On the basis of current trends in the United States and abroad, what will be the future relative position of the United States in the field in the near term and the longer term?
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INTERNATIONAL BENCHMARKING OF US IMMUNOLOGY RESEARCH The panel was asked only to develop findings and conclusions not recommendations. Its primary objective was to obtain a comprehensive overview of the field of immunology that included characterizing the key factors of the field, assessing the resources necessary for conducting and supporting immunologic research, and identifying trends in the types of research being done in the field. The panel strove to maintain an international perspective as it collected and analyzed the data for this report. The panel assessed the current position of the United States relative to leadership in four subfields of immunology, and the benchmarking results themselves are presented in Chapter 2 of this report. The determinants of leadership that have influenced US advancement in the field are discussed in Chapter 3. Chapter 4 assimilates past leadership determinants and current benchmarking results to predict future US leadership status in the field.
Representative terms from entire chapter: