A conversation with Marc Feldmann, Jacques Miller, and Max Cooper

Marc Feldmann, Ushma S. Neill

J Clin Invest. 2020;130(1):1-3. https://doi.org/10.1172/JCI134899.

Conversations with Giants in Medicine

This month, we shift our format to listen in on the conversation of three legends of immunology. Sir Marc Feldmann, Lasker awardee in 2003 for his role in discovering anti-TNF therapy, acts as interviewer, speaking with the two winners of the 2019 Albert Lasker Basic Medical Research Award: Max D. Cooper from Emory University and Jacques Miller from the Walter and Eliza Hall Institute of Medical Research (WEHI). Drs. Miller and Cooper (Figure 1) identified and defined the function of T and B cells, uncovering the organizing principle of the adaptive immune system. The full interview can be seen on the JCI website at https://www.jci.org/videos/cgms Feldmann: Thank you for this opportunity to take part in this conversation with two of my friends and heroes. We’re now three of the elder statesmen in immunology and it’s a privilege to be back together. I first met Jacques the week I started my PhD at the WEHI 50 years ago, and Max a few years later, during my first postdoc in London, as he came for a sabbatical. Can we start at the beginning — perhaps tell us where you grew up? Miller: I grew up partly in China, partly in Switzerland, and back to China, and then to Australia. My sister had contracted tuberculosis, and Switzerland was the place where people said […]

Find the latest version: https://jci.me/134899/pdf CONVERSATIONS WITH GIANTS IN MEDICINE

A conversation with Marc Feldmann, Jacques Miller, and Max Cooper

This month, we shift our format intendent’s son. I had my full quota to listen in on the conversation of of mischievousness along with get- three legends of immunology. Sir ting instilled with a set of principles Marc Feldmann, Lasker awardee and a love for learning and reading in 2003 for his role in discovering that have made an immense differ- anti-TNF therapy, acts as inter- ence in my life. One of my teachers viewer, speaking with the two win- in high school once told me, “Max, ners of the 2019 Albert Lasker Basic if you hadn’t had the parents you Medical Research Award: Max D. have, I think you would have ended Cooper from Emory University up in jail.” and Jacques Miller from the Walter Feldmann: You both did your and Eliza Hall Institute of Medi- pioneering work in basic science, in cal Research (WEHI). Drs. Miller immunology. But you both started and Cooper (Figure 1) identified in medicine. Why did you decide to and defined the function of T and study medicine rather than go into B cells, uncovering the organizing science? principle of the adaptive immune Miller: I was heavily influenced system. The full interview can be by my sister’s tuberculosis, and the seen on the JCI website at https:// fact that my other sister and I used www.jci.org/videos/cgms. to play with her and we never got it. Feldmann: Thank you for this I overheard my mother talking to opportunity to take part in this con- the doctor, who told her, “We don’t versation with two of my friends know anything about tuberculosis. and heroes. We’re now three of Hard stuff.” That spurred my curi- the elder statesmen in immu- osity. I wanted to go to medicine nology and it’s a privilege to be partly for that, and partly for the Figure 1. Jacques Miller and Max Cooper receiving the 2019 back together. I first met Jacques Albert Lasker Basic Medical Research Award in New York City on fact that I was brought up during the week I started my PhD at the September 20, 2019. World War II and people were kill- WEHI 50 years ago, and Max a few ing each other and I didn’t want to years later, during my first postdoc kill anybody. I thought I’d better in London, as he came for a sabbatical. My parents had no knowledge of study medicine, so I could patch them up Can we start at the beginning — perhaps medicine. My father was a manager of the rather than kill them. tell us where you grew up? Franco-Chinese Bank and he was a very Once I studied medicine, I became Miller: I grew up partly in China, learned person. He spoke Japanese, three even more curious because I saw diseases partly in Switzerland, and back to Chi- Chinese dialects, German, English, and like leukemia and systemic lupus erythem- na, and then to Australia. My sister had French. He was very pleased when I decid- atous and wanted to know why people got contracted tuberculosis, and Switzer- ed to go into medicine. I grew up in a very disease. That spurred my curiosity toward land was the place where people said nice, familial atmosphere. medical research. you could manage tuberculosis before Cooper: I grew up in rural Mississip- Cooper: The general practitioner in my streptomycin. We had to leave Switzer- pi. I lived on a school campus as my father small rural town in Mississippi was one of land because of the German invasion was the superintendent of a 12-grade the most treasured people in the communi- of France and we thought that the Ger- school. My mother was a teacher as well. ty. My father came from a large farm fam- mans would go through Switzerland. So My father was a mathematician who ily, had the ambitions to be a doctor, but we went back to China and stayed for loved learning. He made sure that there didn’t have the finances. They both encour- two years before the Japanese war start- were lots and lots of books in the school aged my early interest. As I learned about ed, then we left China again, this time and in our home. It was a little bit like sports and girls and how long and hard I for Australia. being the preacher’s son, to be the super- would have to study to become a doctor, my ambition waned a bit. Unfortunately, my older brother, who was in the Marines,

Copyright: © 2020, American Society for Clinical Investigation. was killed in a car accident when he was Reference information: J Clin Invest. 2020;130(1):1–3. https://doi.org/10.1172/JCI134899. home on leave before going to Korea. We

jci.org Volume 130 Number 1 January 2020 1 CONVERSATIONS WITH GIANTS IN MEDICINE The Journal of Clinical Investigation were very close and he had named me as important because I was going to use a lot There was something wrong with their the beneficiary of his insurance policy. of mice. After having read what people did immune system, and I tested by grafting That took away my excuse of the financial with mouse leukemia, I thought I could do these mice before they were sick with for- aspects of becoming a physician. similar work in virus-induced leukemia. eign grafts from different strains of mice It was such a lucky break for me to go I did not realize that this path would take and even from rats, and to my amazement, into medicine. It got more interesting as I me to immunology. It seemed to work very they did not reject the grafts. learned more about physiology and diseas- well for me that I didn’t have a supervisor. Feldmann: These were very striking es. My particular interest in immunology Feldmann: Jacques, I remember that findings that underpin much of modern came when I had decided on an academic in my first year as a student I visited you immunology. Max, you’re credited with career through the encouragement of my in the animal room, I saw you do a neona- discovering the function of the bursa. Can pediatrics chief at Tulane. By that time, I tal thymectomy with your technician, and you take us through how these discoveries was very interested in immune deficiency I was hardly able to see the operation on were made? diseases and allergy. the tiny mice. Most people would not have Cooper: I started out with an interest Before beginning my immunology and thought, when they realize that a neonatal in infections of patients, and in particular, allergy fellowship, I was asked to learn an mouse is smaller than a fingernail, that this children who were congenitally unable immunofluorescence technique to study operation would have been possible. to handle infections, those either having delayed-type hypersensitivity. An immu- Miller: In the work on leukemia, I had multiple bacterial infections, pneumonia, nologist in England took me into his lab to to thymectomize adult mice. I developed ear infections, or viral infections which teach me the technique and he was baffled a technique that might have been unique were often fatal. I joined Bob Good’s group, by my answer when he asked what I was because I used to take out part of the ster- who had an interest in immunodeficien- going to do with the technique, saying, “As num knowing that the mouse would repair cy diseases and how the immune system far as I know, this immunofluorescence that — they repair very easily. I decided developed and what could go wrong. There technique is only useful for studying anti- to adopt this technique in neonatal mice. had been published a fortuitous discovery body production, not cellular immunity.” With my eyes at the time I could see what by an Ohio State poultry scientist, who I was so embarrassed that I decided I was I was doing and a slight suction — very found impaired development of antibody going to learn, if nothing else, the differ- slight — in the newborn mouse would do responses on removing the bursa of Fabri- ence between cellular and humoral immu- the job to remove the thymus completely. cius, a lymphoid organ at the end of the gut nity. I retreated to the library. I found a book In fact, neonatal thymectomy was easier that was sometimes called “the cloacal thy- by the previous director of the WEHI, Sir than adult thymectomy because the adult mus.” He started with the idea that it was Frank MacFarlane Burnet, on clonal selec- animals got pneumothorax very easily, but affecting development and sexual matu- tion theory. It was written so well and in the newborns did not. ration. It didn’t affect either of those, but such an understandable fashion that I just Feldmann: Can you take us back even a postdoc came by, asked for some of his fell in love with immunology. further to explain how you discovered birds for an antibody demonstration and Feldmann: The love affair was recipro- that the thymus was an immunological made the discovery that there were none. cated. Another theme I’d like to discuss is organ, when everybody else thought it That work and Jacques’ findings made the role of personal insight versus the role was just a relic? us realize that it was particularly important of supervision. Were you actually super- Miller: Everyone said it was a useless to go back early to look at the thymus and vised when you were a trainee, or did you organ, a graveyard for dying lymphocytes. this second organ. We did experiments come upon your findings via your own I was working on mouse leukemia, which spurred by observations in immune-defi- innate insights? begins in the thymus and spreads. Mouse cient children where the thymus and the Cooper: When I joined Bob Good’s leukemia can be induced by virus, and at small lymphocytes hadn’t developed well, group in Minneapolis, I asked what I should that time the virus had to be given to new- but they still had plasma cells, and made do. He said, “When I went to Rockefeller, born mice. I decided to investigate whether lots of immunoglobulins and antibodies. Maclyn McCarty didn’t tell me what to do. the virus could multiply outside the thy- In order to test whether the thymus and In fact, he left for a European holiday.” I mus. I took the thymus out of newborn the bursa were complementary or doing was directed to start working on the ideas mice, then gave the virus, and then grafted different things, we realized we needed to I mentioned during my interview. I quickly the thymus back later to see whether the remove them earlier or reset the immuno- exhausted those ideas without making any virus had multiplied in the absence of thy- logical clock. We did the latter by exposing great discoveries. mic tissue. As a result of this work, I noticed newly-hatched chicks to almost lethal irra- Miller: When I first arrived in Pollards that mice thymectomized at birth were diation together with removal of the thy- Wood for scientific research in the UK, I very sick after about 3 or 4 months, but I mus or the bursa of Fabricius. was supposed to be supervised by Robert never saw sickness in adult thymectomized When they grew up and recovered Harris, but within a few weeks he left, as mice. In post-mortems I noted they lacked from the irradiation effects, we found he was given a much better job at Nation- lymphocytes and had lesions in the liver, absolutely clear-cut results that indicated al Institutes for Medical Research. I was which suggested they had been infected by that the thymus gave rise to lymphocytes left without a supervisor, but I was able to hepatitis virus, which is endemic in mouse that were responsible for graft rejection inherit his animal space, which was very colonies but usually doesn’t bother them. and other cellular immune functions. The

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bursa of Fabricius was instead essential for tions between thymus-dependent cells won’t be able to fully understand diseases development of germinal centers, plasma and bursa-dependent cells, which were like cancer, autoimmune disease, degen- cells, and antibody production, and we quickly renamed to T and B cells? erative disease, or inflammatory diseases could put back the bursal cells that weren’t Feldmann: Soon after he retired, that destroy every organ. We’re not even irradiated and restore in bursectomized MacFarlane Burnet published in the Cold close yet, we have a long way to go. and irradiated animals the whole B lin- Spring Harbor Proceedings quite a pes- As to your other question, everything eage, or bursa-dependent lineage. simistic view of the future of immunol- has to be understood in an evolutionary Feldmann: With hindsight, it’s so clear ogy, thinking that most great discoveries sense to provide meaningful answers in that the principles that you uncovered are were already made, and future scientists biology. Our relatively recent activities true in mammals and birds have really fun- would simply argue over minutiae. Are toward understanding how our adaptive damental importance. As I recall, the work you more sanguine? Where will we be 50 immune system evolved meant going to that you did, Jacques and Max, was not ini- years from now? jawless vertebrates — lampreys and hag- tially that highly appreciated. Miller: I think immunology has a great fish — because all of the surviving jawed Miller: When you say it wasn’t appre- future. We need to produce antibodies vertebrates have T and B cells that use ciated, I think one should say the data that are long-lasting and specific in order immunoglobulin-based receptors to rec- were accepted; you could not possibly talk to improve vaccination and therefore we ognize antigens and the same basic histo- against the data when you see a mouse need to work out details about interactions compatibility system. with four different skin grafts of different between follicular T helper cell and B cells. We’ve found that the jawless verte- colors and even a rat skin graft. You can’t We need to work out all the details of the brates also have T-like and B-like cells, but argue against the data, but you can argue interaction at the molecular level, at the they use different kinds of building blocks against the interpretation. level of lymphokines, and see whether we — leucine-rich repeats or LRRs — to con- My interpretation was that the immune can improve such interactions. We need struct their diverse antigen receptors and system develops as a result of early thymus to find vaccines for malaria, for HIV, for antibodies. We think the lamprey antibod- function, and their interpretation was that influenza. We should be able to activate T ies, particularly because of their remark- my mice, having been raised in converted cells that are specific for the internal pep- able antigen specificity and evolutionary horse stables, were so prone to infections tide of the influenza virus, so that we could distance from us, will allow their use for that the additional trauma of thymecto- have a response that is specific for all influ- diagnostic purposes and perhaps even for my or irradiation and thymectomy in the enza strains. therapy of malignancies by identifying nov- adult would precipitate immunodeficien- The interaction between the microbi- el tumor antigens. We have early proof of cy. That’s what led me to go to NIH cour- ome and the immune system is also very principle data on that, but still have a long tesy of an Eleanor Roosevelt Fellowship to important in order for us to understand way to go to reach both goals. repeat the entire work in germ-free tanks. what goes on in disorders like inflamma- Feldmann: What other paths might These mice could not be infected because tory bowel disease. The innate immune you have found interesting if not for immu- they were germ-free. We put skin grafts system needs to be looked at very carefully nology and medicine? on them after thymectomizing in early because gamma delta cells are very com- Miller: I would have gone into astron- life and the skin grafts were never reject- mon in the intestine and we’re not quite omy, but at that time there were no satel- ed even if they were highly disparate at sure what they do, again for example, in lites, nothing like that. I didn’t want to end the major H2 locus. I think that convinced inflammatory bowel disease. We know up teaching physics in a school. I thought most immunologists that the thymus must that they produce inflammatory response I needed something exciting and that next have some function. but what do they actually respond to in a best thing was medicine. Cooper: Clinicians were a little more way which could cure? The interaction Cooper: I started college on a football accepting than basic immunologists between T cells and cancer cells is also scholarship as a quarterback. It turned out particularly because at that time, there important because we need to understand I was the least capable quarterback and was not a wide appreciation of an evolu- why not all cancers can be cured by target- the slowest man on the team, including tionary approach to understanding the ing T cells. So yes, there’s tons of things to the coaches. It was clear that I was never immune system. I don’t think Jacques and do in immunology. going to gain fame and fortune as an ath- I ever doubted the importance of what Feldmann: Max, I’d like to ask you the lete. I loved to sing and I loved music. My we found. It was just a question of how same question, but also can you tell us a secret ambition if I could have gone back to answer some of the questions that our little about your latest project on evolu- and recreated my life, I would have been a new view asked. If T cells, or thymus- tionary immunology, exploring immune saxophone player. dependent lymphocytes, didn’t make molecules in lampreys and hagfish which I antibodies, how did they see antigens? was stunned to read about some years ago. Marc Feldmann, Where in the world was an equivalent site Cooper: To build on Jacques’s more Kennedy Institute of Rheumatology, for generating B cells that were needed specific answer, until we know enough to make antibodies in mammals like us? about how the immune system develops University of Oxford And how did the cooperation actually and functions and about all of the cells Ushma S. Neill, occur? Or were there functional interac- that the immune system interacts with, we JCI Editor at Large

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