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Herman N. Eisen: Mentor to Many RETROSPECTIVE Herman N. Eisen: Mentor to many David M. Kranza,1 and Yuri Sykulevb sitivity to small inorganic molecules was aDepartment of Biochemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801; mediated by T cells. The myeloma tumors and bDepartment of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas that he had studied in the 1960s also served Jefferson University, Philadelphia, PA 19107 a purpose in his first foray into T cells in the 1970s. In this work, Herman’s laboratory examined the ability of cytotoxic T lympho- Herman Eisen passed away on November 2, Department of Microbiology. In 1973, Herman cytes (CTLs) to recognize and eliminate 2014, at the age of 96. During his long and was recruited to MIT by Salvador Luria, as a myeloma cells (8), for which the myeloma distinguished career, Herman was a mentor founding member of the Center for Cancer protein could serve as an antigen. to those who trained in his laboratory Research. In his autobiography, Luria stated In the early 1980s, Herman decided to (ourselves included), to those who collabo- “Cancer research is incomplete without im- devote more effort toward understanding rated with him over the years, and to many munology....For this job we captured Her- antigen recognition by T cells. His group faculty and colleagues at Massachusetts In- manEisen,aneminentimmunologist” (4). at the time (Fig. 1) was about equally di- stitute of Technology (MIT) and elsewhere. Herman remained active in research at MIT vided between antibody and T-cell proj- He will be missed by all. for the rest of his life. ects. Most individuals who were entering Herman’s long-standing and classic work Herman was a legend in the field of im- the laboratory tried their hand at cloning with antibodies was remarkable, having munology, and his work spanned a wide mouse CTL lines to investigate various yielded many honors, including election to range of topics, all tied together by the theme aspects of the specificity mediated by the the American Academy of Arts and Sci- of antigen recognition and specificity. He then undefined antigen receptor (or recep- ences, the National Academy of Sciences, began a long line of impressive discoveries by tors). One of us (D.M.K.) was charged and the Institute of Medicine, along with the establishing definitively, in a seminal 1949 with trying to identify the T-cell receptor Behring–Heidelberger and Lifetime Achieve- paper with his friend Fred Karush, that an- by producing monoclonal antibodies to ment Awards, both from the American As- tibodies were bivalent (5). Later, Herman was cell surface molecules. Soon this led to a sociation of Immunologists (AAI). He served the first to show that antibodies increase in productive collaborative effort with Susumu as President of the AAI from 1968 to 1969. affinity over time (6) (called affinity matura- Tonegawa, and the genes encoding the In high school, Herman was intrigued by tion), a process that is now used in the de- gamma and alpha chains of T-cell receptors chemistry, but his father persuaded him to velopment of virtually every antibody-based were identified, albeit in a rather circuitous pursue medicine; after clinical training in drug. In a series of studies done before mono- New York in the 1940s, Herman worked at clonal antibodies were available (i.e., from fashion (1). Perhapslessrecognizedisthefactthat,in Columbia University, Sloan Kettering Insti- hybridomas), he showed that myeloma pro- the mid-1980s, Herman’s laboratory was tute, and New York University (1, 2). During teins could be used to understand antigen bind- working on bispecific antibodies (he called this period he was particularly fascinated by ing in a homogeneous, tractable system (7). immune reactions and their specificity, an However, his interest in antibodies was them heteroantibody duplexes) (9), long be- interest that was fueled by Karl Landsteiner’s only the start. After four decades of work in forethemorerecentflurryofactivity.Hewas book, The Specificity of Serological Reactions theantibodyfield,hestartedasecondcareer also among the first to describe some of the (3). To focus more on scientific research, in in the field of T cells. His move into this area components of the CTL killing machinery: 1955, Herman moved from New York Uni- may have been spurred by his earlier experi- theserineesterases.Alookathispapers versity to Washington University in St. Louis, ments, some of which he performed on through those years illustrates how Herman where he ultimately became the Chair of the himself (1, 2), showing that skin hypersen- was involved in many of the early discoveries that have now become textbook material in the recognition and function of T cells. The parallel with his “first career” in the antibody field is striking. In fact, one of us (D.M.K.) once remarked that he seemed like a real-life case of Benjamin Button. After his initial decade of T-cell work, Herman returned to his roots with regard to the understanding of antigen recognition. Coming full circle, in the 1990s, Herman’s laboratory (Fig. 1) identified naturally occur- ring antigens (peptides) recognized by T cells (10, 11), and they measured the affinity and Fig. 1. Herman Eisen’s laboratory at the Center for Cancer Research (MIT) in 1983 (Left) and 1991 (Right). Eisen is on Author contributions: D.M.K. and Y.S. wrote the paper. the far right in both photos. David M. Kranz is to the left of Eisen in the 1983 photo, and Yuri Sykulev is to the left of 1To whom correspondence should be addressed. Email: d-kranz@ Eisen in the 1991 photo. Images courtesy of the authors. illinois.edu. 1650–1651 | PNAS | February 10, 2015 | vol. 112 | no. 6 www.pnas.org/cgi/doi/10.1073/pnas.1500050112 kinetics of the T-cell antigen receptor for its ample use of qualifiers to aspects that were A scholar until the end, Herman spent RETROSPECTIVE ligands (12). His deep understanding of the not definitive. He was to our minds the the morning that he passed away working chemical basis of recognition continued to perfect scientist. on a manuscript. Apropos of where it all shape his thinking about the specificity of In the last decade or so, Herman was able to started, the paper considers why antibody these two types of lymphocyte receptors: maintain his science “fix” by working with col- affinities remain quite heterogeneous rather antibodies and T-cell receptors. leagues on their projects. These included a fruit- than evolving toward only high-affinity We, like others in the laboratory, enjoyed ful series of studies with Jianzhu Chen (MIT), species. This is how we will remember immensely the environment that Herman many intellectually satisfying interactions with him, always enjoying the intellectual stim- fostered in his relatively modest-sized labo- Arup Chakraborty (MIT), and the occasional ulation that comes with unanswered ques- ratory. Group meetings were Thursday morn- projects he worked on with both of us. tions in science. ings, and Herman invariably brought coffee cake or cookies from a local bakery. We also had an annual cookout at his place in Woods 1 Eisen HN (2001) Specificity and degeneracy in antigen recognition: populations. Myeloma proteins with antihapten antibody activity. Hole, MA, where Herman loved to spend time Yin and yang in the immune system. Annu Rev Immunol 19:1–21. Fed Proc 29(1):78–84. relaxing with his wife Natalie and tending to 2 Herman N. Eisen, interview by Brien Williams, May 4, 2012, 8 Russell JH, Hale AH, Ginns LC, Eisen HN (1978) Periodic loss of his garden. transcript, The American Association of Immunologists Oral History reactivity of a myeloma tumor with cytotoxic thymus-derived Project, Boston, MA. Available at https://www.aai.org/About/History/ lymphocytes. Proc Natl Acad Sci USA 75(1):441–445. Herman published papers every year since Notable_Members/pdfs/OHP/Transcripts/Trans-Inv_003-Eisen_ 9 Liu MA, et al. (1985) Heteroantibody duplexes target cells for lysis by 1946, spanning eight decades. Writing a paper Herman_N-2012_Final.pdf. Accessed January 8, 2015. cytotoxic T lymphocytes. Proc Natl Acad Sci USA 82(24):8648–8652. with Herman was itself a valuable lesson (if 3 Landsteiner K (1936) The Specificity of Serological Reactions 10 Udaka K, Tsomides TJ, Eisen HN (1992) A naturally occurring (C.C. Thomas, Springfield, IL). peptide recognized by alloreactive CD8+ cytotoxic T not at times frustrating for his postdocs, as 4 Luria SE (1984) A Slot Machine, A Broken Test Tube (Harper and lymphocytes in association with a class I MHC protein. Cell 69(6): a paper could take a year to complete). Early Row, New York). 989–998. 5 Eisen HN, Karush F (1949) The interaction of purified antibody 11 Tsomides TJ, et al. (1994) Naturally processed viral peptides drafts rarely resembled final manuscripts, with homologous hapten; antibody valence and binding constant. recognized by cytotoxic T lymphocytes on cells chronically infected and he carefully studied every word and J Am Chem Soc 71(1):363. by human immunodeficiency virus type 1. JExpMed180(4): phrase. He could frame a problem in terms 6 Eisen HN, Siskind GW (1964) Variations in affinities of antibodies 1283–1293. during the immune response. Biochemistry 3:996–1008. 12 Sykulev Y, et al. (1994) Kinetics and affinity of reactions between that were clear, concise, and important. There 7 Eisen HN, Michaelides MC, Underdown BJ, Schulenburg EP, an antigen-specific T cell receptor and peptide-MHC complexes. was little hype, lots of quantitation, and Simms ES (1970) Experimental approaches to homogenous antibody Immunity 1(1):15–22. Kranz and Sykulev PNAS | February 10, 2015 | vol. 112 | no. 6 | 1651.
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