Herman Eisen (1918–2014)

Herman Eisen died unexpectedly on November 2 after spending the day working on a manuscript on the time evolution of the heterogeneity of antibody responses during affinity maturation. Herman, as he was known to all of us in the field, was 96, the last of the great immunochemists whose collective work established the rules governing the basis for immunological specificity. He had an extraordinary career with a continuous record of important contributions that extended for more than six decades—from the 1940s, before the structure of antibodies was known, to the present, now dominated by the puzzling and fascinating questions focused on T cell recognition of peptide-MHC complexes.View Large Image | View Hi-Res Image | Download PowerPoint SlideHerman started his career at New York University after obtaining a medical degree in 1943. He was so impressed by the classical monograph of Karl Landsteiner on The Specificity of Serological Reactions that he decided to focus his efforts on immunochemistry and study antibodies. A major interest at this time was on the development of antibody responses and the specificities of the antibody molecules that emerged. Immunochemistry was an extremely active field with a major focus on examining the nature of antibody- antigen reactions by precipitation, hemagglutination, or complement fixation, which were complex assays. When Herman entered the field in the late 1940s, nothing much was known of the structure of immunoglobulins. This was before Rodney Porter and Gerry Edelman’s classical studies that defined the two-chain structure of immunoglobulins. Herman decided to study antibody reactivity to the hapten benzene arsonate, rather than more complex protein antigens, which often confounded interpretation of the experimental findings. Using the technique of equilibrium dialysis, Herman and Fred Karush showed, for the first time, that antibody molecules had two binding sites for antigen. This was a major finding, and its publication in JACS in 1949 marked the first of Herman’s many high impact studies during a long and productive career.Herman’s work subsequently advanced to the in-depth analysis of contact sensitivity to dinitrofluorobenzene compounds. We now know that this skin reactivity is a T cell-dependent delayed hypersensitivity. These studies brought Herman to the attention of Barry Wood and Carl Moore, who were sequential heads of the Department of Medicine at Washington University in St. Louis. Both were visionary physicians, keen on establishing a strong research base in a medical department. Herman was recruited to the Dermatology Division and moved to St. Louis with his growing family in 1955. As Herman recently related to Sondra Schlesinger, who conducted extensive interviews with him, “I knew nothing about dermatology. I knew enough however to keep my mouth shut.” In fact, upon joining the Washington University faculty, he spent most of his time in his research laboratory. Eventually Herman transferred to the Department of Microbiology and Immunology where he became chair in 1961.At Washington University, he continued to examine the reactions to hapten-protein conjugates, eventually taking his studies to the cellular level. This work focused on 2-4 dinitrophenyl (DNP) conjugated to immunogenic carrier proteins. The studies led to a milestone observation—one of the seminal findings on immune responses—that the affinity of the antibody response increases over time. It is therefore worthwhile recalling these experiments. Rabbits were immunized with DNP-protein conjugates and specific antibodies were analyzed after various time intervals. Herman was able to precisely measure antibody affinity for antigen using fluorescence quenching approaches and observed that the affinity of serum antibodies to the DNP hapten increased several hundred-fold over time, a major study done with Gregory Siskind. Later when Lisa Steiner and Herman isolated lymph node cells and determined antibody affinity, they documented that the time dependent increase in antibody affinity occurred at the cellular level. In these early experiments, Herman’s laboratory also noted the heterogeneity in affinities of antibodies, and an in-depth study of this heterogeneity was the subject of his last study.These experiments were the first to demonstrate the process of affinity maturation. Affinity maturation was compatible with the clonal selection theories that were developed at about this time. At the same time, these experiments argued strongly against the alternative template theory that antibodies acquired their specificity by folding around antigen molecules. Affinity maturation was later explained at the molecular level when the genetic basis of antibody responses were uncovered, somatic mutations of the genes encoding the variable segments of the antibody molecules became known, and the germinal center reactions were elucidated. In brief, the progressive increase in intrinsic affinity over time is due to repeated rounds of Darwinian selection of B cells whose receptors bind more strongly to antigen, and results in antibodies that are increasingly more potent against an invading pathogen. This theory thus linked the “fitness” of a B cell to the affinity of the antibody it produces for antigen. This concept underlies the development of vaccines that protect us against a variety of diseases. Affinity maturation is also mimicked in countless academic and industrial laboratories for the discovery of antibody-based therapies.Interested in examining the process at a single cell level, Herman went on to examine myeloma proteins thinking that perhaps he would be able to find a homogeneous antibody molecule. This eventually led him to examine the myeloma tumors developed by Michael Potter at the National Institutes of Health, where he found some, like MOPC-315, that produced antibody that bound DNP. The approach of analyzing myeloma proteins as a monoclonal source of antibodies preceded the discovery of hybridomas by Kohler and Milstein by about 10 years, and provided a raison d’etre for monoclonal antibodies that could be generated against virtually any antigen. Herman’s studies of these myeloma cells revealed the polyspecificity of some antibodies, an issue that captured his interest based on his broad knowledge of antibody specificities and affinities.Herman left St. Louis in 1973 to become a founding member of the Cancer Center at the Massachusetts Institute of Technology (MIT). Salvador Luria recruited him to anchor efforts in cancer immunology. At this time, immunology was changing dramatically. Now the field not only had antibodies and B cells to deal with but also T cells and with them a new way of antigen recognition. Unlike B cells or their antibody products, T cells did not recognize soluble antigens, but instead peptide fragments that were associated with self MHC molecules. For an immunochemist like Herman, accustomed to precise measurement of immunological reactivities of antibodies in free solution, this was a new world. However, it was one which he immediately understood and rapidly became involved in. He had to adapt to fully understand this new immune complexity—and so he did—and proceeded to make major contributions to our understanding of the T cell system. One of his most significant contributions to T cell biology came from the analysis of an isolated CD8 T cell clone, called 2C, derived in his laboratory. 2C was unique because it recognized an allogeneic class I MHC molecule, as well as a syngeneic MHC molecule. Examining 2C and its natural ligands provided Herman with insights into the plasticity of the recognition of peptide-MHC complexes. His group also reported that activated CD8+ T cells could kill a target cell bearing a single peptide-MHC complex! In toto, his findings underscored the importance of the CD8+ T cell subset to immunity to viruses, cancer, and transplantation reactions. The availability of 2C also allowed others to examine the 2C clone in other contexts, fostering precise understanding of negative and positive selection of T cells and becoming the first T cell receptor-pMHC complex to be crystallized.In 1989, Herman retired—the last generation of faculty members who had to retire at age 70—but only in the formal sense. For several years, he maintained an active laboratory that continued to make important discoveries. After closing his laboratory around 2005, he continued to work closely with several MIT colleagues on scientific problems. One of us (A.K.C.) was greatly influenced by Herman’s thinking in considering the specificity-degeneracy puzzle in T cell recognition of antigen and its implications for human immune responses.Herman guided the field in many ways, not only through his scientific findings but also through prominent reviews and editorials. His deep knowledge of the literature in immunology extending back to the 1930s was an unparalleled repository of knowledge that many younger colleagues and students benefited from until the last day of his life. He wrote the immunology chapter in Microbiology, the textbook edited by Bernard Davis that became for many years the standard teaching textbook for microbiology and immunology students.Herman was also an extraordinarily generous colleague whose integrity was respected by all. The term “gentleman-scholar” is often used loosely—in Herman’s case it was an apt description of the scientist and the man.Herman received many honors through his career; among them were his election to the National Academy of Science, the Institute of Medicine of the National Academies, and the American Academy of Arts and Science. He also received the Lifetime Achievement Award of the American Association of Immunologists in 1997 and served as the President of this body in 1968.