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ALBERT HEWETT COONS June 28, 1912-September 30, 1978 BY HUGH O. MCDEVITT A BERT COONS, professor in the Department of Bacteriol- ogy en c! Immunology at Harvarc! Meclical School en c! a member of the National Academy of Sciences since 1962, cliec! September 30, 197S, at the age of sixty-six. He was born in GIoversville, New York, on June 2S, 1912, the son of Albert S. en c! Marion (Hewett) Coons. He was eclucatec! in GIoversville public schools, gracluatec! from Williams Col- lege in 1933, en c! receiver! the M.D. degree from Harvarc! Meclical School in 1937. He initiates! a major revolution in immunology en c! cell biology that continues to this clay by cleveloping the immu- nofluorescent technique for labeling specific antibodies with fluorescent dyes, thus permitting the detection of antibod- ies, antigens, and virtually any antigenic protein in cells en c! tissues. Fluorescent en c! immunohistochemical local- ization of foreign en c! self-proteins through the use of la- beled antibodies is now an indispensable research too! in almost every fielc! of biomeclical research en c! continues to contribute to major new discoveries in all of these fielcis. The clevelopment of the fluorescent antibody technique in the early 1940s was a technical tour cle force that requires! Dr. Coons to use the techniques of protein chemistry en c! organic chemistry. However, the impetus for the develop 27

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28 B I O G RA P H I C A L EMOIRS ment of this technique came from his meclical training en c! his interest in the pathogenesis of rheumatic fever. Following his graduation from Harvarc! Meclical School, Dr. Coons was a house officer on the Meclical Service at the Massachusetts General Hospital from ~ 937 to ~ 939. In ~ 939 he joiner! the Thornclike Memorial Laboratory at Boston City Hospital as an assistant resident in medicine. Having completer! his clinical training, Dr. Coons began a research fellowship in the Department of Bacteriology en c! Immu- nology at Harvarc! Meclical School, where he remainec! from 1940 to 1942. His research studies were interrupter! by ser- vice as a captain, en c! later as a major, in the Army Meclical Corps, where he server! as a pathologist en c! director of laboratory services with the 105th General Hospital in the southwest Pacific. He returnee! to the Department of Bacteriology en c! Im- munology as a research fellow in 1946, became an instruc- tor in 1947, en c! finally a visiting professor of bacteriology and immunology and a career investigator of the American Heart Association in 1953. He was appointee! a professor of bacteriology en c! immunology in 1970 en c! became a pro- fessor in the Department of Pathology in ~ 971. As is true of many biomeclical researchers, Dr. Coons's interest in research and immunology was originally stimu- latec! by exposure to a bright, dynamic, en c! articulate teacher en c! researcher in this case, Hans Zinsser, who was profes- sor of bacteriology en c! immunology at Harvarc! Meclical School from ~ 925 to ~ 940. Dr. Coons took Dr. Zinsser's course in immunology, which stimulates! him to work clur- ing the summer of 1935 with John Enclers, who was then an assistant professor in the department. His research project was to attempt to determine the blood levels of passively administered antibody before and after the induction of anaphylactic shock in the guinea pig. The precipitin reac

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ALBERT HEWETT COONS 29 lion was user! to measure the levels of passively aciminis- terec! rabbit en c! horse antibodies in guinea pig bloocI. The aim of the experiment was to fins! out why horse antibocI- ies, in contrast to rabbit antibodies, were incapable of sen- sitizing guinea pigs for anaphylactic shock. The problem was never finished, en c! no clear results emerges! from these studies. Nonetheless, Dr. Coons hac! become intimately ac- quaintec! with the use of antibodies to detect foreign pro- teins in host tissue fluicis. As he sail! much later, "Somehow, though, it bent the twig." This knowlecige of the use of antibodies to detect foreign proteins in host fluicis en c! tis- sues lay dormant through the next two years of meclical school en c! through two years as a house officer at the Mas- sachusetts General Hospital. The next, en c! crucial, stage in the clevelopment of the concept that lee! to the clevelopment of the fluorescent an- tibocly technique is best clescribec! in Dr. Coons's own words, since they offer fascinating insights into how important con- cepts clevelop in the mine! of an investigator: At the end of my internship I had a six months' gap before my next ap- pointment as an Assistant Resident and I was lucky enough to spend them in Berlin. This was the summer of 1939, a period of great international excitement, just before the outbreak of the war. I did not go there as a student but as a tourist. However, I had an entree into the pathological institute at the Charite Krankenhaus where a friend, Kurt Apitz, was the Oberartz. I spent my mornings watching autopsies, and my afternoons wan- dering around talking to people in cafes and trying to improve my halting German. I also had many talks with Apitz, who was an exceptional young pathologist interested in leukemia and the Schwartzman reaction. In strange cities, visitors have many hours alone. I found myself walk- ing in the streets or sitting in my room reading or brooding. One after- noon I was thinking about rheumatic fever and about the Aschoff nodule, the microscopic lesion characteristic of it. It was at that time and I think probably in many circles still is, thought to be the result of a local hyper- sensitivity reaction involving components of the group A hemolytic strepto

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30 B I O G RA P H I C A L EMOIRS coccus and circulating antibodies or hypersensitive cells. It struck me that this theory had never been tested and indeed could not be tested without the demonstration of antibody or antigen, preferably both, in the local lesions. I considered that it might be easier to find the antigen than the antibody, for a start anyway, and that what was required was a visible microprecipitate. The notion of labelling an antibody molecule with a vis- ible label was perfectly obvious in such a context. However when I tried this notion on my friend, Apitz, he was not enthusiastic. I think he thought it was not feasible and indeed, in the terms in which I initially thought of it, as a colored molecule, it wasn't. Dr. Coons's remark that the iclea of putting a visible label on an antibody molecule was perfectly obvious was perhaps too moclest. Given the primitive knowlecige of the struc- ture, nature, isolation, en c! manipulation of antibodies in 1939, the concept of putting a visible label on an antibody molecule seems both boIc! en c! original, even if technically naive. The technical problems, which might have stymies! many young researchers, were to occupy the next several years. At this critical stage in his career Dr. Coons receiver! both support and encouragement from Dr. George Minot, direc- tor of the Thorndike Memorial Laboratory, and from John Enclers of the Department of Bacteriology en c! Immunol- ogy at Harvard. Both urger! him to pursue the problem en c! to apply for a research fellowship insteac! of continuing with clinical studies, en c! argues! that even if labeler! anti- boclies clic! not solve the problems of rheumatic fever, they wouIc! provicle a general procedure for locating proteins in tissues and cells that would obviously have wide application to countless problems. Having receiver! this initial support en c! encouragement, Dr. Coons was fortunate to receive further encouragement ant! expert assistance from a number of researchers at Harvard University. Louis Fieser, professor of organic chem- istry at Harvard, introclucec! Dr. Coons to Hugh Creech

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ALBERT HEWETT COONS 31 en c! Norman Jones, who were working in his department on the conjugation of isocyanates of various carcinogens to protein molecules. Since Dr. Coons hac! aIreacly cleterminec! that coupling of dyes to antibody molecules resultec! in im- munoprecipitates that were only faintly pink even in solu- tion, he urger! Creech to help him couple a fluorescent dye, anthracene isocyanate, to some antipneumococcal an- tiserum. This antibody solution agglutinates! specific pneu- mococci, en c! the agglutinates! bacteria were brilliantly fluo- rescent in ultraviolet light. At this point, primarily because many tissues shower! blue or rec! autofluorescence, Dr. Coons asker! Dr. Fieser if he could obtain or synthesize fluorescein isocyanate. Fluorescein was chosen because it fluoresces with a brilliant apple green color not seen in any normal tissues. Dr. Fieser assignee! a graduate student, Ernst Berliner, to this synthetic organic problem, en c! Berliner en c! Coons became fast friends. During this perioc! Coons learner! how to synthesize fluorescein isocyanate, knowlecige that was in- valuable in later years. The next step was to visualize antigen in tissue sections. To do this, a fluorescent microscope was needed. Once again, by another stroke of luck, a colleague, Dr. Allan Grafflin, assistant professor of anatomy, was engages! in the assembly of an apparatus for fluorescence microscopy. Using his single fluorescent antipneumococcal antibody conjugate, Coons was able to fins! bacterial polysaccaricle in the phagocytic cells of mice injectec! intravenously with large numbers of pneumococci en c! to carry out inhibition reactions for the establishment of specificity en c! to show that these reac- tions were reversible. Thus, by the beginning of 1942, Coons hac! succeeclec! in demonstrating the feasibility of putting fluorescent tags on antibodies en c! using them to localize foreign antigens in host tissues. His initial results were cle- scribec! in two brief papers (1941,1942) en c! the research

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32 B I O G RA P H I C A L EMOIRS was halter! while he joiner! the army en c! spent the next four years in the South Pacific. Much work remainec! to be clone before the fluorescent antibody methoc! conic! be generally applicable to a wicle variety of biological problems. When Dr. Coons returnee! to the Department of Bacteriology en c! Immunology in 1946, he fount! that no one in Fieser's Department of Organic Chemistry was interested in synthesizing fluorescein isocy- anate. He therefore cleciclec! to synthesize his fluorescent compounds himself, a process that was slow and painful. With sufficient fluorescein isocyanate available, many of the other technical problems were tacklecI. With his colleagues Gene Connolly en c! Melvin Kaplan, Coons began studying frozen sections en c! cliscoverec! the problem of nonspecific staining of tissues by fluorescent-labelec! antibody solutions. This lee! to the use of acetone-ciriec! tissue extracts as an absorbing agent to remove nonspecific staining. With the availability of frozen sections en c! antibody solu- tions that clic! not bins! nonspecifically to tissues, the fluo- rescent antibody technique became wiclely applicable to many problems in immunology and cell biology. This led to a series of papers on the localization of a variety of antigens in animal tissues ~ ~ 950, I-4, ~ 95 ~ ~ en c! on the localization of viral antigens in infectec! tissues. These crucial papers hac! a major impact on immunology en c! relater! fielcis. The clem- onstration that virtually any protein could be localized in tissues by the fluorescent antibody methoc! lee! to its use in many laboratories around the world by immunologists, mi- crobiologists, pathologists, and cell biologists. The fluorescent antibody technique permitter! the stucly of the fate of antigens in tissues, the expression of many different cell proteins in tissues, the identification of cells producing specific antibodies, detection of immune com- plexes en c! complement in lesions of serum sickness en c! in

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ALBERT HEWETT COONS 33 giomeruTonephritis, the location of viral antigens in infectec! cells en c! of tumor antigens in malignant cells, en c! the use of the fluorescent antibody methoc! in a wicle variety of experimental settings. At the same time, Dr. Coons embarkoc! on a stucly of mechanisms of antibody production en c! clevelopec! meth- ocis for detecting specific antibody in cells producing that antibody in tissue sections of spleen ant! lymph nocles ~ ~ 955, ~ ~ . This lee! to a series of studies on antibody procluc- tion ~ ~ 955,2) en c! on specific inhibition of antibody forma- tion cluring immunological paralysis (1959~. These studies, showing sharply localizes! clusters of plasma cells all pro- clucing antibody of the same specificity, both foreshaclowoc! en c! supporter! the clonal selection theory of antibody for- mation. Dr. Coons was among the first to perceive that a cletailec! unclerstancling of the mechanisms of antibody formation would require the clevelopment of techniques for the study of in vitro antibody production. This lee! to a series of pa- pers from his laboratory on the establishment en c! analysis of in vitro secondary antibody responses. These studies were among the first to establish reproclucible secondary anti- bocly responses in vitro, to demonstrate the critical role of early cellular proliferation in the in vitro secondary response, en c! to permit analysis of the effect of a wicle variety of drugs, including chIoramphenico! and coIchicine (1963,1- 3~. As the importance of the immunofluorescent technique became apparent, Dr. Coons was wiclely honoree! by his col- leagues. He received the Lasker Award in 1959, the Paul EhrTich Awarc! in 1961, the Passano Awarc! in 1962, the Gairciner Foundation Annual Awarc! in 1963, en c! the Emil von Behringer Prize in 1966, as well as honorary Sc.D. cle- grees from Williams College, Yale University, en c! Emory

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34 B I O G RA P H I C A L EMOIRS University. He is survived by his wife, Phyllis (Watts), his son, Albert H., {r., en c! four daughters, Elizabeth, Susan, Hilary, and Wendy. A shy, bright, articulate, en c! gentle man with a woncler- ful, if private, sense of humor, Dr. Coons began his career with the iclea of becoming a clinician en c! perhaps a teacher in a meclical school. Stimulatec! by Zinsser en c! Enclers to stucly immunology, en c! pondering the problems of rheu- matic fever in a small hotel room in Berlin, he clevelopec! the boic! en c! elegant iclea of putting a sensitive visible label on antibody molecules. Given encouragement by mentors en c! help from colleagues, he carrier! through all of the technically clifficult steps requires! to take an elegant but impractical iclea into the realm of everyday application. Al- though acutely aware of the encIless possibilities openec! up by his technique, he nonetheless remainec! a little amazes! en c! perhaps a bit embarrassed at how wiclely successful his methoc! became. He left a legacy that will only grow with the passing years, as well as acivice to his colleagues that is also a description of his own research methocis: ,~ Imaginative approaches and the fruitful association of apparently unre- lated phenomena are the result of indirection, brooding, indolence. In the beginning a store of facts and methods in the end the free hand. (1961)

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ALBERT HEWETT COONS SELECTED BIBLIOGRAPHY 1941 35 With H. J. Creech and R. Jones. Immunological properties of an antibody containing a fluorescent group. Proc. Soc. Exp. Biol. Med. 47:200. 1942 With H. J. Creech, R. N. Jones, and E. Berliner. The demonstration of pneumococcal antigen in tissues by the use of fluorescent antibody. 7. Immunol. 45:159. 1950 With M. H. Kaplan. Localization of antigen in tissue cells. II. Im- provements in a method for the detection of antigen by means of fluorescent antibody. 7. Exp. Med. 91:1 . With M. H. Kaplan and H. W. Deane. Localization of antigen in tissue cells. III. Cellular distribution of pneumococcal polysac- charides types II and III in the mouse. 7. Exp. Med. 91:15. With J. C. Snyder, F. S. Cheever, and E. S. Murray. Localization of antigen in tissue cells. IV. Antigens of rickettsiae and mumps virus. 7. Exp. Med. 91:31. With A. G. S. Hill and H. W. Deane. Localization of antigen in tissue cells. V. Capsular polysaccharide of Friedlander bacillus, type B in the mouse. J. Exp. Med. 92:35. 1951 With E. H. Leduc and M. H. Kaplan. Localization of antigen in tissue cells. VI. The fate of injected foreign proteins in the mouse. J. Exp. Med. 93:173. 1955 With E. H. Leduc and J. M. Connolly. Studies on antibody produc- tion. I. A method for the histochemical demonstration of specific antibody and its application to a study of the hyperimmune rab- bit. J. Exp. Med. 102:49. With E. H. Leduc and J. M. Connolly. Studies on antibody produc- tion. II. The primary and secondary responses in the popliteal lymph node of the rabbit. 7. Exp. Med. 102:61.

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36 BIOGRAPHICAL MEMOIRS 1959 With E. Sercarz. Specific inhibition of antibody formation during immunologic paralysis and unresponsiveness. Nature 184:1080. 1961 The beginnings of immunofluorescence. 7. Immunol. 87:499. 1963 With M. C. Michaelides. Studies on antibody production. V. The secondary response in vitro. f. Exp. Med. 119:1035. With T. F. O'Brien. Studies on antibody production. VII. The effect of 5-bromodeoxyuridine on the in vitro anamnestic antibody re- sponse. 7. Exp. Med. 1 19: 1063. With C. T. Ambrose. Studies on antibody production. VIII. The inhibitory effect of chloramphenicol on the synthesis in antibody in tissue culture. 7. Exp. Med. 1 19:1075.

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