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2019 Lasker Basic Research Award Celebrates Immunologists Jacques Miller and Max Cooper

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2019 Lasker Basic Research Award Celebrates Immunologists Jacques Miller and Max Cooper NEWS The Journal of Clinical Investigation 2019 Lasker Basic Research Award celebrates immunologists Jacques Miller and Max Cooper The Lasker Foundation recognizes Jacques Miller (The Walter and Eliza Hall Institute of Medical Research) and Max D. Cooper (Emory University School of Medicine) with 2019’s Albert Lasker Basic Medical Research Award for demonstrating that B and T cells represent distinct compartments of the adaptive immune system (Figure 1). Their discoveries laid the foundations for modern immunology and groundbreaking medical advances, including monoclonal antibody therapeutics and immunotherapy. In 1960, much of immunology was embroiled in controversy, but researchers of adaptive immunity united over some key principles: Plasma cells were the source of antibodies, proteins with important roles in controlling infection. Lymphocytes could be identified in lymphoid tissues such as the spleen, lymph nodes, and the thymus. However, though immunologists had clearly demonstrated the spleen’s and Figure 1. 2019 Lasker Basic Medical Research Award recipients Jacques Miller (left) and Max D. Cooper (right). The pair have been recognized for their discovery that T and B lymphocytes represent lymph nodes’ contributions to immune distinct compartments of adaptive immunity. Dr. Miller’s photo appears courtesy of The Walter and function, the thymus was considered a Eliza Hall Institute of Medical Research. Dr. Cooper’s photo appears courtesy of Georgia Research vestigial lymphatic organ: thymectomy, at Alliance/Billy Howard. least in adult animals, had no discernible effect on immune processes. born mice, injecting virus, and regrafting displayed impaired antibody responses to Vestigial no more the thymus later in life. Unexpectedly, some injected antigens. These findings As a PhD student at the University of Lon- however, he discovered that thymecto- indicated that the thymus plays a key role don, Jacques Miller became intrigued by a my in the neonatal period resulted in the in early immune development that affects form of virus-induced murine lymphocytic adult mice having extremely poor health, lifelong immunity (1, 2). leukemia originating in the thymus. New even if not previously injected with the Miller’s conclusions challenged the reports had revealed that the disease could leukemic virus. era’s dogma that the thymus had no be transferred to a leukemia-resistant “I did a postmortem and saw lesions apparent function. They were not imme- strain of mice by injecting healthy animals in the liver, which suggested that the mice diately accepted by the scientific commu- with extracts from a sick animal’s leuke- had been infected by hepatitis virus,” Mill- nity. Although the outcomes of neonatal mic tissues. But there was a twist, as Miller er recalls. “I saw that the lymphoid system thymectomy were clear, critics argued explains: “The filtrate had to be injected was atrophic. There were not many lym- that contamination of the University of into newborn mice. If it was injected into phocytes in the circulation. There were London’s animal facilities, which were adult mice, they would not get leukemia. not many lymphocytes in the lymphoid located in a converted horse stable, pro- That interested me.” tissues. That made me wonder, ‘What’s duced lifelong immune impairment in Miller hypothesized that the leuke- happening?’” the mice. On an Eleanor Roosevelt fel- mia-causing virus could only multiply in Miller tested immune responses in lowship, Miller traveled to the US and the newborn thymus, which undergoes the neonatally thymectomized mice and repeated the experiments using the NIH’s involution with age, decreasing in size found that beyond being infection prone, germ-free mice. In sterile conditions, the and cell number. He tested this hypoth- these mice could not reject skin grafts from thymectomized mice were spared the esis by removing the thymus from new- other mouse strains or even rats. They also infectious consequences of immunode- ficiency but remained unable to reject skin grafts from rats, confirming Miller’s Copyright: © 2019, American Society for Clinical Investigation. interpretation that the thymus has a crit- Reference information: J Clin Invest. 2019;129(10):3966–3968. https://doi.org/10.1172/JCI132854. ical role in immune function. 3966 jci.org Volume 129 Number 10 October 2019 The Journal of Clinical Investigation NEWS Clinical conundrums and clarity Hoping to clarify the roles of the thy- and we showed that antibody-forming cell Miller’s findings were well received in mus and bursa, Cooper performed com- precursors came from the bone marrow, Robert Good’s lab at the University of Min- binations of bursectomy and thymec- whereas cells responsible for rejection of nesota, where researchers had observed tomy in newly hatched chicks and then skin grafts or virus-infected cells came similar phenomena. Soon after Miller’s exposed them to near-lethal levels of from the thymus.” initial reports on thymic function, Max whole-body irradiation to eliminate any The findings, published in 1968 (6, Cooper joined Good’s team with the goal lymphocytes generated before hatching. 7), elucidated the emerging model of of teasing apart the biology underlying Evaluation of immunological integrity thymus- and bursa-specific functions, congenital immune deficiency diseases. weeks after recovery from irradiation delineating two distinct populations Cooper began his career as a pediatri- yielded unambiguous results: bursec- of thymus- derived and bursa- or bone cian trained in clinical allergy and immu- tomized and heavily irradiated chick- marrow–derived cells, which we know nology, but was drawn to immunology ens had normal thymus development today as T and B cells. Following Miller research in response to the challenging and intact cellular immunity, but were and Mitchell’s reports, an explosion of clinical conundrums posed by immuno- completely devoid of germinal centers, immunological discovery further clari- deficient patients: “I quickly realized that if plasma cells, and immunoglobulins. In fied functions and interactions of T and I was going to contribute anything original contrast, thymectomized and irradiat- B lymphocytes. In 1974, John Owen, Mar- to their care, I would have to start all over ed chickens were primarily deficient in tin Raff, and Cooper, working at Univer- again.” Cooper decided to pursue basic small lymphocytes and cellular immune sity College London, demonstrated that immunology research under the guidance of functions; they made germinal centers, B cells could be generated in cultures of Dr. Good, an esteemed immunologist and plasma cells, and immunoglobulins, with fetal liver and in adult bone marrow (8). clinician who would become most famous moderately impaired specific antibody for performing the first non-twin bone mar- responses (4, 5). The results clearly sup- From foundations to row transplant. “Good’s environment was ported a dual lineage model of lympho- breakthroughs a good fit for me because he was interested cyte differentiation that elucidated the Following these seminal discoveries, Miller in immune system development, immuno- pathogenesis of immunodeficiency dis- and Cooper pursued lines of investigation deficiency diseases, evolution, transplanta- eases, including agammaglobulinemia that established additional groundwork for tion, the complement system, lymphoprolif- and Wiskott-Aldrich syndrome, and clinically significant advances in immunol- erative diseases, and autoimmunity.” aligned with results Miller and others had ogy. For recent generations of scientists, “The prevailing viewpoint then was observed in mammals. it’s likely difficult to envision studying that circulating lymphocytes derived from immunology before this modern under- the thymus were converted into plasma Illuminating distinct standing of the adaptive immune system. cells following antigen stimulation” Coo- lymphocyte origins Cooper agrees: “Once you know some- per explains. However, discordant clini- Distinguishing the functions of the thy- thing it seems as if you always knew it.” cal characteristics of boys with X-linked mus and bursa kicked immunologists into Though officially retired, Jacques Mill- agammaglobulinemia and Wiskott-Aldrich high gear. Cooper recalls, “We learned er’s tenacious interest in new areas of immu- syndrome suggested that lymphopenia from the Till and McCulloch group that nology keeps him involved at the Walter and and immunodeficiency could be uncou- stem cells gave rise to all the different Eliza Hall Institute. The microbiome and pled from defective antibody production. blood cell types. Others showed that advances in immunotherapy, particularly A block in the lymphocyte to plasma cell hematopoietic stem cells gave rise to cells those involving Tregs, hold his interest as conversion could explain X-linked agam- populating the thymus, and then Moore particularly exciting areas of progress. Of maglobulinemia, but the profound lym- and Owen showed in birds that lymphoid being recognized with the Lasker Award, he phocyte deficiency and thymic atrophy in cells in the thymus and bursa came from says: “I am very, very honored and I’m hum- contrast with plasma cell and immunoglob- circulation. That information allowed bled to get it. And, of course, I’m delighted.” ulin abundance he observed in Wiskott- us to construct a working model of how Max Cooper’s work continues at Emo- Aldrich patients argued against the single hematopoietic stem cells give rise to the ry University. His exploration
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