Anthony Monaco

Medawar Prize Laureate (1998)

In View: People in Transplantation
Anthony Monaco, MD Harvard transplantation surgeon and retiring editor of Transplantation, 1971–2014

Transplantation: What event or person led you into the field of transplantation?

AM: I wanted to be a journalist (a foreign correspondent, no less), but my father discouraged me from this ambition. He knew several very successful, established journalists in Philadelphia but felt that their life style was unstable and not suitable for his youngest son. Being a medical doctor was my second choice: local doctors were revered figures in our close knit South Philadelphia neighborhood. My interest in medical research started by age 12 after reading the novel ‘Arrowsmith’ by Sinclair Lewis, the story of a young physician whose idealism is tested by the complex and competitive culture of contemporary medical research. I enrolled in Harvard Medical School in 1952, and in 1954 Dr. Joseph Murray and his team performed the first successful kidney transplant. This was an electrifying clinical milestone that stimulated—but did not solidify—my interest in transplantation and immunology. During my surgical residency at the Massachusetts General Hospital (1956–1963), my interests had been thoracic surgery, surgical oncology, and the nascent field of cancer immunology. In 1960, during a year of basic science research at Harvard Medical School with the immunologist Dr. Albert Coons, I had my first meeting with Peter Medawar during his celebrated Dunham Lectures on “Allograft Immunity and Immunological Tolerance.” I remember his polished, captivating, erudite presentation as the seminal event that initiated my interest in transplantation. In 1963, at the completion of my surgical residency, I joined Paul Russell at the MGH who just started a clinical transplant program and a research laboratory to begin what has been a happy and fulfilling career.

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Transplantation: When did you publish your first paper and what was the paper you were most proud of writing?

AM: I published my first paper in 1957 as a second year surgical resident, a case report and literature review of a rare form of female cancer. I am most proud of 2 series of papers resulting from my early laboratory work in transplantation biology. The first was the demonstration of the extraordinary immunosuppressive effects of rabbit anti-mouse antilymphocyte serum (ALS, ALG) with my MGH colleagues in the mid-1960s.1-3 These papers were published after MFA Woodruff’s report of the modest immunosuppressive effect of ALS on rat skin allograft survival4 that did not get the recognition and attention it deserved. A striking aspect of our antimouse ALS was its extraordinary potency. Mouse skin allografts transplanted across strong histocompatibility barriers onto ALS treated recipients enjoyed extended, rejection-free survival and exhibited excellent health and vitality with luxuriant hair growth—a rare and unusual result until this time using other immunosuppressive strategies. The other remarkable finding was the ability of rabbit anti-canine lymphocyte ALS to prolong the survival of whole organ renal allografts in bilaterally nephrectomized recipients.4 This study essentially demonstrated the potential usefulness of adjunctive induction therapy for solid organ transplantation—the major indication for ALS in clinical transplantation. These studies sparked the interest in ALS research of investigators throughout the world whose work collectively established ALS as the first line biological reagent to suppress experimental alloimmunity and eventually resulted in the clinical ALS preparations widely employed today. I am amazed and obviously gratified that after over fifty years since the publication of these studies, ALS remains the most widely used biological immunosuppressive agent for induction in clinical organ transplantation—currently it retains 50% of the market share.

The other studies performed in my laboratory of the Harvard Medical School Surgical Service of the Boston City Hospital which I started in 1967 I am most proud of involved the demonstration of the unique tolerogenicity of donor bone marrow cells (BM) to facilitate alloimmune hyporesponsiveness and tolerance. We had previously shown that the profound peripheral and tissue lymphopenia and associated immune suppression induced by ALS was intensified and prolonged by prior adult thymectomy.5 We had also hypothesized that this lymphocyte depletion was analogous to the transient immunological immaturity associated with the neonatal state, and thus might possibly facilitate tolerance. Indeed, adult thymectomized, ALS-treated mice that had received large doses of F1 hybrid lymphoid cells (to avoid GVHD) were easily rendered tolerant to H-2 incompatible skin grafts.6 In an effort to define a clinically applicable tolerance strategy, my late colleague Mary Wood and I compared the ability of low doses of various types of homozygous allogeneic lymphoid cells to induce hyporesponsiveness/tolerance in ALS-treated recipients. BM cells were found to be superior to other types of lymphoid cells for tolerance induction after ALS treatment.7 Donor BM infusions also augmented renal allograft survival in ALS-treated dogs. Subsequent mechanistic studies demonstrated that ALS administration alone induced formation of non-specific T-suppressor cells: skin grafting induced donor alloantigen suppressor cell specificity and bone marrow infusion produced donor-derived suppressor cells. Moreover, the modest degrees of tolerance achieved by ALS-BM treatment in incompatible HLA allografts were converted to robust, indefinite tolerant states by finite courses of cyclosporine or rapamycin.8,9 These studies are now highly relevant in the four currently successful clinical renal tolerance protocols that employ donor BM infusion combined with biological lymphocyte depletion and finite periods of standard immunosuppression.10 I believe that donor BM has unique tolerogenic properties and donor BM infusions will be common to most all successful clinical tolerance strategies.

Transplantation: What was the most formative experience of your career?

AM: Everything I have learned, felt and derived from the many patients I have cared for. As a young academic clinician-scientist, I with many others was eager to solve the barriers to clinical transplantation. Our main motivation was to help our patients, nevertheless, ambition, desire for recognition, and interest in promotion also contributed to our enthusiasm. I came to appreciate, as I assume most transplant professionals have, the enormous contributions that our patients make to our work in spite of the onerous burdens they must endure. Although clinical organ transplantation offers patients and their families hope and opportunity for a renewed and extended life, the transplantation voyage comes with a myriad of stressful and persistent uncertainties. One could argue that such uncertainty exists in the treatment of all chronic diseases, but organ transplantation seems an especially severe example. The emotional stress of the transplant process, however, must be severe. I can only admire our patients’ grit and fortitude in the face of their persistent trials. As a long term survivor of a major illness, I am enormously thankful of my good fortune.

Transplantation: What was the best experience in your career?

AM: As with most people in academic medicine, I realized the most gratification and enjoyment from the successful treatment and outcomes achieved for my patients and from producing significant and impactful research. I have also enjoyed a parallel, stimulating and fulfilling continuum experience with from my membership during the early days of transplantation in small groups of international scientists and clinicians who were bonded in the study of transplantation biology and clinical transplantation—the group Peter Medawar referred to as the “transplant club”. I remember his joking admonition to me when I joined the club in the mid-1960s at a special meeting of antilymphocyte serum investigators at the Ciba Foundation House in London, “Tony you are in the club now and there is only one requirement for club membership—do not solve the problem of transplantation and spoil it for everyone!” This early group of transplant professionals played a major role in founding the journal Transplantation and The Transplantation Society (TTS). The journal and the society currently exert a powerful influence and leadership role on all aspects of transplantation worldwide. The transplant “club” is now the international transplant community—a worldwide brotherhood of scientists and clinicians working together to alleviate human suffering through organ and tissue transplantation. Being a part of this wonderful story has been a great joy for me and my wife. We will always cherish the wonderful relationships that we have developed with dear friends throughout the (transplant) world.

Transplantation: What was the worst experience of your career?

AM: As with other clinicians, the worst experience(s) of my career involves the unexpected loss of any patient that I have cared for. My worst experience was the loss of a dear friend and physician colleague from a cardiac arrhythmia on the day after I had performed a straightforward, uneventful kidney transplant. I think about it very often and it still makes me sad.

Transplantation: What do you most like to do when not working?

AM: My favorite individual pastime is reading—books on history, biography, politics, historical novels and the occasional mystery/thriller. I remember on my first day of medical school we were told that no matter how hard we worked in medicine we should read something non-medical every day—presumably to maintain a balanced outlook. I have followed this admonition all my life. I always have a book going. I am also a news “junkie.” I watch TV news at every opportunity and never miss the Sunday morning talk shows. Even when I am working in my study, I have the TV on (with sound off) so I do not miss some urgent or breaking news. When I was younger I enjoyed walking, tennis, ocean swimming and downhill skiing. I had to give up ocean swimming after my laryngectomy and I stopped skiing last year although I still enjoy going to my ski house in Vermont to chop wood, walk in the outdoors, look at the snow fall and, of course, read by the fire. In the spring and summer I like to work in my garden. Also, my wife and I love to travel. Membership in the international transplant community has afforded us numerous wonderful opportunities to see many parts of the world and foster friendships with our many international friends and their families. At this time in my life I think I derive the most enjoyment from time spent with my wife, children, grandchildren and close friends.

Transplantation: Where do you expect the greatest advancement in the transplantation field in the next 10 years?

AM: I believe that the major advances in transplantation in the next ten years will be in the areas of stem cell technologies, improvement in quality and quantity of organs suitable for transplantation and increased application of tolerance protocols. The transplant community should prepare to assume a major role in this endeavor by becoming experts in stem cell research and technology. The next 10 years should also see increased applications of successful tolerance protocols—a stated goal of the TTS. Tolerance has already been achieved with protocols that essentially utilize drugs and immunosuppressive strategies used in transplantation for years but now applied in different combinations and sequences in association with tolerogenic bone marrow infusions.10 These protocols have been surprisingly effective with very acceptable risk/benefit ratios. It is also likely that we may be able to induce tolerance without—at least initially—understanding the exact mechanism through which it is achieved. I believe that more academic transplant programs should undertake tolerance protocols.

Transplantation: What would your advice be to the young medical student seeking your opinion on getting into this field?

AM: I would encourage any academically inclined medical student to pursue this field. Few medical specialties other than transplantation offer such opportunity to impact patients’ lives in such a positive way and to pursue bench to bedside research. I would emphasize that a strong grounding in basic science is more important than ever, irrespective of what area of clinical activity or research emphasis the individual focuses on. Much needs to be done and the opportunities are limitless. The advent of stem cell therapy should only brighten and broaden the horizons.

Transplantation: What is your advice to the young clinician/scientist in transplantation?

AM: I would preface my advice by saying how much I admire them. Modern organ transplantation is one of the most demanding medical specialties. Clinician/scientists in transplantation combine an extraordinary knowledge of basis science with consummate clinical skills to care for an increasingly complex group of patients in the face of frustrating circumstances beyond their control: reduced hospital staff and financial support, demanding night call and emergency schedules, excessive and time consuming government regulations, requirements to meet pathway milestones, publically published patient and graft survival rates, to name a few, and looming through all this - the self-imposed and externally reinforced pressure to obtain grants and generate high quality research. This situation can be a perfect storm to for disillusion and burn out. I caution our department chairs and directors as well as the young transplant clinician/scientists to be cognizant of this danger and to take steps to ameliorate it. I say to our young clinician/scientists that your career in transplantation should be an enjoyable, rewarding, albeit a demanding journey. Be proud of your clinical and research accomplishments. Learn from, but do not be limited or paralyzed by your mistakes. Do not be consumed by the demands of or your devotion to transplantation to the detriment of your family, friends and loved ones. Keep your family and loved ones close to you and let them share in the joy of your successes and the disappointment of your failures.

Transplantation: January 2015 - Volume 99 - Issue 1 - p 10-12 doi: 10.1097/TP.0000000000000589

The Medawar Prize - 1998

Antilymphocyte Serum, Donor Bone Marrow and Tolerance to Allografts: The Journey is the Reward

It is an enormous honor and privilege to receive the Medawar Prize. I express my sincere gratitude to themembers of the prize committee and to all members of the society. It is especially happy for me that I share this prize with two individuals — Fritz Bach and Felix Rapaport — who are not only gifted transplantation scientists but also respected colleagues and cherished friends. I congratulate them both.

Highlighted Articles

An epigenetic, transgenerational model of increased mental health disorders in children, adolescents and young adults

Anthony P Monaco
Eur J Hum Genet. 2021 Mar;29(3):387-395. doi: 10.1038/s41431-020-00726-4. Epub 2020 Sep 18.

Prevalence rates of mental health disorders in children and adolescents have increased two to threefold from the 1990s to 2016. Some increase in prevalence may stem from changing environmental conditions in the current generation which interact with genes and inherited genetic variants. Current measured genetic variant effects do not explain fully the familial clustering and high heritability estimates in the population.

The beginning of clinical tolerance in solid organ allografts

Anthony P Monaco
Exp Clin Transplant. 2004 Jun;2(1):153-61.

Development of effective multidrug immunosuppressive regimens and improvements in the management of chronically immunosuppressed patients have produced extraordinary patient and allograft survival in clinical organ transplantation. Unfortunately, significant problems of morbidity and mortality related to chronic immunosuppression remain. Thus, there is an enormous motivation and interest in inducing specific unresponsiveness (tolerance) to clinical solid organ allografts.

Chimerism in organ transplantation: conflicting experiments and clinical observations

Anthony P Monaco
Transplantation 2003 May 15;75(9 Suppl):13S-16S. doi: 10.1097/01.TP.0000067945.90241.F4.

The concepts of chimerism has influenced our thinking about tolerance and rejection of organs and tissues since the beginning of modern transplantation. In macrochimerism, persisting donor-specific cells are easily detectable by flow cytometry at levels of several to 100%, usually after transient lymphoablation and bone marrow (or other cell) transplantation.

Highlighted Videos

Dr. Monaco: In their own words:

ASTS interview

Interview with Anthony Monaco on the occasion of the 50th anniversary of The Transplantation Society

The Transplanation Society, 2016



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