Volume 116, Issue 5 , Pages 1170-1171, November 2005
Jacques Miller on the thymus
Article Outline
I doubt if there is another person living who has made a greater contribution to immunology.
—Sir Gustav Nossala
Jacques F. A. P. Miller (1931–)
Jacques F(rancis) A(lbert) P(ierre) Miller (Fig 1), born of French parentage in Nice, was educated in Australia at St Aloysius College and the University of Sidney (BS Med, 1953; MB, 1953). After completion of medical studies and a hospital internship, he left for England, having been awarded a fellowship at the Chester Beaty Institute of Cancer Research in London. Aiming for an ultimate career in experimental pathology, he then began to undertake original work on the thymus, for which he received doctoral degrees from the University of London, a PhD in 1960 and a DSc in 1965. During the intervening years, he was in the United States as a fellow of the Eleanor Roosevelt International Union Against Cancer at the National Cancer Institute of the National Institutes of Health and then again in London as reader in experimental pathology at the Chester Beaty Institute. In 1966, Gustav Nossalb recruited him back to Australia as the head of the Department of Experimental Pathology—subsequently renamed the Thymus Biology Unit—at the Walter and Eliza Hall Institute of Medical Research in Melbourne. Remaining there for the duration of an outstanding and internationally recognized career, he currently continues to conduct a productive, rigorous research program in immunologic science as emeritus professor of experimental pathology.
Fig 1.
Jacques F. A. P. Miller, BS Med, PhD, DSc (1931–).
Miller's seminal investigations on the thymus and lymphocytes opened up a new area of biomedical science: the field of T-cell biology. In 1961, he was the first to show that the thymus was essential for the normal development of the immune system.1 In the absence of a thymus, mice were highly susceptible to intercurrent infections, deficient in lymphocytes, unable to reject foreign skin grafts, and prone to the development of certain types of tumors. Four years later, in 1965, studies by Claman and his associates suggested a cooperative process involving thymus and bone marrow cellular elements in immune-mediated hemolytic activity. However, in the absence of distinguishing cell markers, their data could not implicate which cell suspension contained either effector or auxiliary cells or the manner in which these cells interacted.2 It remained for Miller, later in 1965, to first demonstrate functional identification of the 2 major classes of lymphocytes, showing that thymus-derived cells were not antibody-forming cell precursors but rather helped bone marrow–derived cells produce antibody.3 These findings changed the course of immunology and have been directly responsible for the explosive growth of studies on lymphocyte heterogeneity and function, T-cell response to virus-infected cells, tolerance, autoimmunity, immunodeficiency, AIDS, and other diseases of immune aberration.
Miller's fundamental research studies, meritorious contributions to medical science, and credits for more than 400 scientific publications are reflected in the numerous honors, recognitions, and awards he has received from national and international academic and professional organizations and foundations. Among others are the Langer-Teplitz Cancer Research Award (United States); the Gairdner Foundation International Award (Canada); the Encyclopaedia Britannica Award; the Scientific Medal of the Zoological Society of London; the Burnet Medal of the Australian Academy of Sciences; the Paul Ehrlich Ludwig Darmstaeder Award (Germany); the Shacknai Memorial Prize of Hadassah Medical School (Israel); the St Vincent Prize for Medical Research (Italy); the first Sandoz Immunology Prize; the first Medawar Prize of the Transplantation Society; the Croonian Prize Lecturer of the Royal Society; the J. Allyn Taylor International Prize for Medicine, John Robarts Institute; and a University of Sydney honorary MD degree. Particularly noteworthy among the accompanying citations were those of the Faulding-Florey Medal for major discovery in biomedical science of benefit to human health and the Copley Prize of the Royal Society, noting the Society's highest award for any branch of science. Among society special distinctions were elections to the position of Fellow of the Royal Society, Foreign Associate of the US National Academy of Sciences, Honorary Member of the American Association of Immunologists, and Foreign Member of the Belgian Royal Academy of Medicine.
Miller's seminal discoveries not only had a major effect on bringing about reassessments and changes in the direction of immunologic research, they also offered new insight for medical practice to incorporate in its informational base. Previously, clinicians were limited to hypothetical concepts in making nonevidence-based evaluations and judgments of thymus enlargements reflected by radiographic images. Considerations covered a broad range of opinions that varied from vestigial preinvolution tissue with little, if any, function to pathologic involvements requiring intervention. The finding of thymus hyperplasia with allergic disorders in infants offered a circumstantial association for believing in a causal relationship, even in the conceptual existence of a “thymocolymphatic” state responsible for the hypersensitivity manifestations.4 At the other extreme of belief was the putative diagnosis of a disorder termed “thymic asthma.” Roentgenographic visualization of an enlarged thymic shadow overlying the mediastinum, demonstrable shortly after birth, was not unusual. Accompanying detection of any abnormal breath sound, not even necessarily of asthmatic character, had its proponents for inducing immediate destructive reduction in size of the thymus by means of x-ray therapy, with its intended aim to relieve arbitrarily presumed pressure on bronchial airways and nerves.
The occasional demonstration of an enlarged thymus and asthma of purely allergic cause, as only a coincidental infantile occurrence, both emphasized that care needed to be taken in how to regard such an association and raised questions about the need for intervention. That this fact did not dissuade proponents of causal association, unfortunately, was exemplified by a pioneer at the forefront of developing a leading clinic for pediatric allergy and asthma. His expressed belief was that “a good rule is never to start skin tests on any child with this type of shadow until the thymus has been reduced in size with adequate roentgen ray therapy. The reason is that a constitutional reaction in any infant with an enlarged thymus carries added dangers resulting from status lymphaticus.”5
As a consequence of Miller's discoveries, along with its implications, textbooks of pediatrics and medicine were soon spelling out revised, valid, data-based information and guidance for preserving the thymus and its role in the generation of immunity.
In the stepwise unfolding and uncovering of knowledge on the immune function of the thymus, Miller's own words provide an especially insightful and intriguing account. We are delighted and privileged to have and to present his response to our invitation to prepare a summary of this historically relevant development and experience in the pages that immediately follow.c
References
- . Immunological function of the thymus. Lancet. 1961;2:748–749
- . Thymus-marrow cell combinations—synergism in antibody production. Proc Soc Exp Biol Med. 1966;122:1167–1171
- . Cell to cell interactions in the immune response. II. The source of hemolysin-forming cells in irradiated mice given bone marrow and thymus or thoracic duct lymphocytes. J Exp Med. 1968;128:821–837
- . Allergy in practice. Chicago: Year Book; 1944;p. 78
- . Allergy in infancy and childhood. In: Cooke RA editors. Allergy in theory and practice. Philadelphia: Saunders; 1947;p. p. 436
- a Statement by Gustav Nossal, former director and current patron and governor of the Walter and Eliza Hall Institute of Medical Research, on the occasion of the award of the Faulding-Florey Medal to Jacques Miller in 2000.
- b Gustav J(oseph) V(ictor) Nossal (MB, PhD) (1931-) succeeded Sir Frank MacFarlane Burnett in 1966 as Director of the Walter and Eliza Hall Institute.
- c A more detailed account can be found in Miller JFAP. Events that led to the discovery of T cell development and function—a previous recollection. Tissue Antigens 2004;62:509-17.
PII: S0091-6749(05)00610-X
doi:10.1016/j.jaci.2005.03.033
Volume 116, Issue 5 , Pages 1170-1171, November 2005
