The Nobel Prize in Physiology or Medicine 1990
Joseph E. Murray, E. Donnall Thomas
Nobel Lecture, December 8, 1990
"If gold medals and prizes were awarded to institutions instead of individuals, the Peter Bent Brigham Hospital of 30 years ago would have qualified. The ruling board and administrative structure of that hospital did not falter in their support of the quixotic objective of treating end-stage renal disease despite a long list of tragic failures that resulted from these early efforts - leavened only by occasional encouraging notations such as those in the identical twin case. Those who were there at the time have credited Dr. George Thorn, chairman of medicine and Dr. Francis D. Moore, chairman of surgery, with the qualities of leadership, creativity, courage, and unselfishness made the Peter Bent Brigham Hospital a unique world resource for that moment of history." (1)
Although renal transplantation had been performed sporadically during the first half of this century (2) (3), planned programs for human organ transplantation started only in the late 1940's. At that time clinicians in Paris, London, Edinburgh and Boston began renal transplantation in unmodified human recipients in spite of the warnings and pessimistic predictions of many scientists and experienced clinicians.
Many bio-scientists had difficulty understanding the determined optimism of clinicians who were willing to evaluate any type of treatment which might possibly help these terminally-ill uremic patients, most of whom were young and otherwise healthy. Tantalizing reports of functioning human renal transplants had surfaced from time to time (4) (5) (6); these hints of success were further encouragement.
In this lecture I will focus on the renal transplant program of The Peter Bent Brigham Hospital (now The Brigham & Women's Hospital) in Boston and explain how this small hospital became involved in transplantation. The medical and surgical services, along with the Department of Pathology under Dr. Gustave J. Dammin, led the way and ultimately renal transplantation involved most of the hospital in some way or other.
The full story of successful organ transplantation in man weaves together three separate pathways: the study of renal disease, skin grafting in twins, and surgical determination. A leitmotif permeates each of these pathways, i.e. a single event or report was critical for medical progress.
The first two Physicians-in-Chief, the Hersey Professor at Harvard in their day, Dr. Henry Christian and Dr. Soma Weiss, had a major interest in renal disease. When Dr. Thorn succeeded Dr. Weiss in 1943 he and his associate Dr. James O'Hare continued this interest, especially the relationship of renal disease to hypertension. After World War II Dr. Thorn invited Dr. Willelm Kolff from The Netherlands to Boston to demonstrate a dialysis machine which he had developed during his forced confinement by the Germans. Dr. Carl W. Walter helped to improve the design and thus the Kolff-Brigham "artificial kidney" was devised. It was first used in patients in 1948 and set the stage for extensive new innovative approaches to both acute reversible renal disease and end-stage failure.
Because renal dialysis provided only temporary improvement for the patient, it was logical to seek a more permanent therapy.*
Skin Grafting in Twins
This thread in the story involves the biological phenomena of monozygotic and dizygotic twinning. The monozygotic (MZ), "identical", twin experience starts with the treatment of bums, the dizygotic (DZ), "non-identical", twin story begins with freemartin cattle.**
In 1932, Dr. E. Padgett of Kansas City reported the use of skin allografts from family and unrelated donors to cover severely burned patients who had insufficient unburned donor sites for the harvesting of autografts. Although none of these skin allografts survived permanently, many would remain long enough to control infection and fluid loss and thus gain time for the donor sites to re-epithelialize. It was difficult to determine accurately the duration of survival of any one allograft; some seemed to melt away slowly and be replaced by adjacent skin, others seemed to be rejected rapidly (7).
Skin grafts from family members seemed to survive longer than those from unrelated donors. But even after observing hundreds of skin allografts, one could not be certain about their survival time. One certainty was established when Dr. J.B. Brown of St. Louis in 1937 achieved permanent survival of skin grafts exchanged between MZ twins (8).
This single observation, although restricted in application, was the only ray of light in the problem of tissue and organ replacement until Gibson and Medawar demonstrated that a second allograft from the same donor was rejected more rapidly than the first (9). This clear description of the "second set" phenomenon established that the rejection process was not immutable; instead it implied an allergic or immunological process which potentially might be manipulated.
The dizygotic twin story starts with John Hunter's description of freemartin cattle in 1779 (10). Freemartins are twin cattle in which the male is normal and the female sterile. Hunter cites Roman descriptions of the phenomenon and then described the physical characteristics of several pairs he had collected in England.
The trail does not appear again until 1917 when Lillie, not content with mere descriptions, dissected the placentae of several pairs of freemartin cattle and noted the placental intermingling of blood between these differently sexed twins (11). Thirty years elapsed before Owen published on the tolerogenic consequences of this placental intermingling of circulation (12). Following this Anderson in 1949 reported successful skin allografts between the freemartin and the normal male (13).
The freemartin story culminates in the report of Billingham, Brent and Medawar describing an acquired immunological tolerance produced by neonatal injection of donor cells into a future allograft recipient (14). They indicate that it was the experimental counterpart to Owen's naturally occurring model. Although not applicable to the clinical situation, their experimental breeching of the immunological barrier was another impetus for optimism in the problem so many considered hopeless.
Sir Michael Woodruff, the pioneer transplant surgeon in Edinburgh, confirmed the freemartin concept in man when he found a pair of twins, one male the other female, who shared elements of different red cell types. Postulating a shared placental circulation between the two, he cross skin grafted them successfully (15).
In 1912, Dr. A. Carrel received a Nobel Prize "in recognition of his work on vascular suture and the transplantation of blood-vessels and organs". He clearly recognized the difference in the survival times between autografts and allografts in experimental animals, but he did not conceptualize rejection as distinct from other graft-destroying processes.
Quinby in 1916 used the canine renal autograft model to study the effect of denervation on renal function (16). Mann and Williamson a decade later noted the different survival times between canine renal autografts and allografts (17) (18), but like Carrel, they did not pursue the long-term fate of the autografts. After World War II, Dempster (19) and Simonsen (20) published extensively on canine renal transplantation concentrating on the biology and biochemistry of allograft rejection. They demonstrated that skin and kidney allografts possess a common antigen which could sensitize a recipient to a subsequent allograft of either tissue from the same donor. In these reports, there was the tacit assumption that renal autograft function would deteriorate ultimately, possibly because of lack of nerve supply and/or lymphatics.
From a physiological view, if human renal transplantation were to be successful, we needed to establish that renal transplants in the absence of an immunological barrier could function permanently. In the course of many laboratory experiments on canine renal transplantation, I had developed a reproducible operation using intra-abdominal vascular anastomoses and a uretero-cystostomy for urinary drainage, placing the kidney in the lower abdomen. This has become the universal renal transplant procedure since that time. Complete functional studies of some of these autografted kidneys two years after transplantation proved them to be completely normal (21).
The Three Trails Merge
These three trails merged at the Peter Bent Brigham in the late 1940's. All the elements for a sound renal transplant program were in order: experienced knowledge in renal disease, availability of dialysis, and skilled imaginative surgeons. To minimize morbidity, the first allografts in these unmodified human recipients were added as a third kidney in the thigh under local anesthesia. Dr. David Hume was the surgeon for these patients and he anastomosed the renal vessels of the graft to the femoral vessels of the recipient. Urine was collected in a bag from a skin ureterostomy (22).
Several of these unmodified human allografts functioned better than experimental canine allografts would have predicted. Possible explanations were an immunosuppressive effect of uremia or a beneficial effect of acute tubular necrosis (ATN) which occurred regularly in these inadequately preserved donor kidneys. One thigh transplant functioned for almost six months with return of the patient's biochemical profile and blood pressure to normal, demonstrating that transplants could rectify the pathophysiologic disorder of renal insufficiency.
The very first renal transplant in 1945 at the Brigham deserves special comment. The patient was a young woman in renal failure following obstetrical complications. The purpose of the transplant was to provide temporary renal function until her own kidneys recovered from acute tubular necrosis. Dr. Thorn recalls his inability to obtain permission to have the patient transferred to a regular operating room (this was prior to Dr. Moore's tenure) so the operation was performed on the old E-Second Ward by Dr. Charles Hufnagel, then a Research Fellow working on vascular grafts, Dr. Ernest Landsteiner, then Chief Resident in Urology, and Dr. David Hume, then Assistant Resident in Surgery. The donor kidney was anastomosed in the antecubital space under local anesthesia using a cutaneous ureterostomy.
According to Dr. Robert J. Glaser, who was assistant resident on the medical service at that time, "secretion of urine was minimal, and certainly did not, 'rescue the woman from her crisis'. The kidney functioned poorly and only transiently, and the patient continued to have a stormy course, although fortunately, despite our lack of understanding at the time of how best to treat renal shutdown, she ultimately did respond and she left the hospital with normal renal function and in good health."
Dr. Glaser further reports that her happy state was short-lived because she died a few months later of fulminating hepatitis secondary to pooled plasma infusions which she had received in the course of her treatment. Interestingly, Dr. Glaser still recalls taking care of the patient whose kidney was ultimately used as the donor transplant. "The patient had disseminated lupus erythematosis and had been in the Brigham many times. Although in patients with advanced lupus the kidney is usually badly damaged, in this particular case renal manifestations were relatively limited, and when her kidney became available it was therefore used" (23).
The Identical Twin Patient
In the fall of 1954, Dr. Donald Miller of the U.S. Public Health Service telephoned Dr. Merrill in order to refer a patient with severe renal disease. Moreover, Dr. Miller suggested there might be the opportunity for transplantation of a kidney because the patient had a healthy twin brother. Needless to say, the transplant team was interested in the possibility of transplanting a genetically compatible kidney. Cross skin grafting established genetic identity, renal disease was brought under control with medications and dialysis, and we were ready to apply our laboratory-tested surgical technique to man.
The only remaining problem was the ethical decision concerning the removal of a healthy organ from a normal person for the benefit of someone else. For the first time in medical history a normal healthy person was to be subjected to a major surgical operation not for his own benefit. After many consultations with experienced physicians within and outside the Brigham and with clergy of all denominations, we felt it reasonable to offer the operations to the recipient, the donor and their family. We discussed in detail the preparations, anesthesia, operations, possible complications and anticipated result.
At the conclusion of our last pre-operative discussion, the donor asked whether the hospital would be responsible for his health care for the rest of his life if he decided to donate his kidney. Dr. Harrison***, the surgeon for the donor, said, "Of course not." But he immediately followed with the question, "Ronald, do you think anyone in this room would ever refuse to take care of you if you needed help?" Ronald paused, and then understood that his future depended upon our sense of professional responsibility rather than on legal assurances.
Once the patients and the team decided to proceed with the transplant, an extra professional burden falls on the surgeon performing the donor nephrectomy because his patient is expected to survive normally. In contrast, the surgeon performing the transplant is operating on a patient otherwise doomed to die, and the nephrologist caring for these critically ill patients cannot be faulted for failure to cure.
Post-operatively the transplanted kidney functioned immediately with a dramatic improvement in the patient's renal and cardiopulmonary status. This spectacular success was a clear demonstration that organ transplantation could be life saving. In a way, it was spying into the future because we had achieved our long-term goal by bypassing, but not solving, the issue of biological incompatibility (24) (25).
Subsequent Laboratory and Clinical
The impact was worldwide and stimulated widespread laboratory attempts to breech the immunological barrier. Experimental protocols included total body X-ray treatment followed by marrow infusion, immunoparalysis by consecutive graftings, immunological enhancement or adaptation by prior exposure of the host or graft to antigen, matching of donor and recipient by red or white cell typing, and the use of drugs such as toluene and nitrogen mustard.
We continued with both clinical and laboratory studies. In a series of volunteer uremic patients, we noted a prolonged but not permanent survival of skin allografts, suggesting the uremic state itself was immunosuppressive (26). In several series of dogs we tried without success to establish a state of renal insuffiency by partial removal of renal mass, infusion of toxins directly into the renal artery, temporary ischemia, and/or thermal insult. Attempts to prolong graft survival by treating the host with steroids and/or anticoagulants also failed (27).
To study the "X-ray marrow" protocol, which seemed to have the best potential for human application, we used mice and rabbits. Using sublethal or lethal doses of total body X-ray, followed by marrow infusions from single or multiple donors, we were able to obtain a limited number of long surviving skin allografts (28).
Simultaneously during the 1950's we transplanted several more sets of identical twins. One twin transplanted in 1956 completed a pregnancy two years later (29). She is now a grandmother and the longest living renal transplant recipient. Her donor, also a grandmother, likewise is in perfect health. Initially regarded as a unique occurrence, the identical twin situation has continued to reappear worldwide. It is estimated that at least fifty patients have now received transplants from their identical twins.
Several patients were referred during these years suffering from accidental loss of a solitary kidney. Because we had obtained limited encouraging laboratory results, it seemed reasonable to treat some of these patients with an "X-ray-marrow" protocol, i.e. total body X-ray followed by marrow infusion and a renal allograft. In most of the patients, the transplanted kidneys functioned immediately and continued to do so for several weeks, but in only one of twelve patients did function persist beyond three months.
The one success was our third patient, a dizygotic twin who received a sublethal, non-marrow requiring, dose of total body X-ray, given by Dr. James B. Dealy, followed by a kidney graft from his twin brother in 1959. He recovered after a difficult complicated post-operative course; he subsequently led a full active normal life until he died of cardiac problems 25 years later. He was the world's first successful renal allograft and was the enticement and stimulus for us to continue this method of procedure until ugs became available (30) (31) (32). The Hamburger group in Paris subsequently ad a similar success with a dizygotic twin recipient following sublethal X-ray treatment.
The First Successful Cadaveric
Transplant in Man
Although we began our first experiments in rabbits using ThioTEPA as a substitute for total body X-ray treatment in 1958 (33), the real breakthrough came with the introduction of immunosuppressive drugs by Schwartz and Dameshek in 1959 (34). They prevented rabbits from producing antibody against human serum albumin by treating them for two weeks with the antimetabolite, 6-Mercaptopurine. This "drug-induced tolerance" remained after drug treatment was stopped, even though the animals could react normally against another protein antigen, bovine gamma globulin. Thus, the tolerance seemed to be specific for an antigen introduced at the time of drug administration. Roy Calne in London (35) and Charles Zukoski in Virginia (36) tested this drug in the canine renal transplant model and had encouraging results.
On the advice of Sir Peter Medawar, in 1960 Calne came to Boston to' work with me in Dr. Francis D. Moore's Department at the Harvard Medical School and the Peter Bent Brigham Hospital. Calne introduced us to Dr. Hitchings and Dr. Elion of the Burroughs-Wellcome Laboratories who became enthusiastic collaborators. Following Calme's arrival and with the use of drugs supplied by Dr. Hitchings the improvement in allograft survival was rapid and dramatic. Soon we had many bilaterally nephrectomized dogs in our laboratory living on solitary renal allografts. Some survived for months, eventually for years. One produced a normal litter sired by a drug treated allografted male. One dog recovered from a severe osteomyelitis of the mandible, indicating he was not an immunological cripple, a state we feared might result from prolonged use of the drugs (37). During this time we were testing other drugs from Hitchings and Elion, who were frequent visitors and knew most of our dogs by name. The experimental drug, BW- 322, the imidazole derivative of 6-MP, seemed to have the best therapeutic index. This drug is now known as azathioprine, or Imuran, and was used throughout the world to support organ transplantation for 20 years. Now newer drugs are available and under study to extend their usefulness and diminish toxicity.
Reassured by these results, we decided to use these drugs in humans for immunosuppression. The first renal transplant recipient to receive azathioprine was an adult transplanted with an unrelated kidney in March 1961. The transplant functioned well for over one month, but the patient died of drug toxicity because the dosage required in dogs was toxic for man.
Our second patient also died of drug toxicity even though we halved the dose used for our first patient. For the first time in our experience we were able to reverse the rejection process. When we discontinued the drug because of leucopenia, rejection started to occur. As his leucopenia improved, we re-started the drug which reversed the rejection process and his renal function improved. Nevertheless he did succumb to sepsis after a month (38).
Our third patient, transplanted in April 1962, was treated with azathioprine following a cadaveric renal allograft. He survived over one year and was the world's first successful unrelated renal allograft. We reported these results in the New England Journal of Medicine (39) and a case report in the Journal of the American Medical Association followed (40). Dr. Willard Goodwin, at the University of California in Los Angeles, almost immediately introduced the use of corticosteroids as a further adjunct to the treatment (41). Subsequently, several transplantation groups worldwide began their own productive transplantation programs.
By 1965, one year survival rates of allografted kidneys from living related donors were approaching 80% and from cadavers 65%. Regional and national donor procurement programs were established along with an International Renal Transplant Registry (42). Optimism and enthusiasm were high as new drugs and other methods of immune suppression were tested along with refinements in tissue typing and improved organ preservation. Anti-lymphocyte serum and globulin prepared in horse, sheep and rabbit along with thoracic duct drainage of lymphocytes were among the more promising regimens tested. Currently it is estimated that more than 200,000 human renal transplants have been performed worldwide.
The success with renal allografts naturally led to attempts to transplant other organs. Moore developed the surgical technique for orthotopic canine liver transplantation (43), the model procedure used by Starzl for first successful human liver allografts (44). Calne, returning to Cambridge, England, also developed an extensive human liver transplantation experience. For almost 15 years Starzl and Calne performed the vast majority of the world's human liver transplants (45). Today, the operation is second only to kidney in frequency and is performed universally.
The next organ to be transplanted was the heart. Lower and Shumway had developed the surgical technique in dogs in 1961 and were planning a careful program for cardiac transplantation in humans. After Barnard's first human cardiac transplant in 1967, many other cardiac surgeons with little or no immunological background rapidly accumulated large numbers of heart-transplanted patients, only to witness them all die of rejection within a few months. This period between 1968-1970 was undoubtedly transplantation's darkest hour. The sole redeeming feature in heart transplantation was the continuation of Shumway's program in Stanford which achieved permanent success in 1970 (46). Today, with the development of newer drugs, cardiac transplantation is a recognized and accepted form of treatment.
Single and double lung transplantation have followed, as well as combined heart-lung transplants. Transplantation of the pancreas, with or without an accompanying renal graft, is commonly done. Multiple organ transplants in combination with liver and parts of the intestinal tract have also been successful. In 1989, there were 8,890 kidney, 2,160 liver, 1,673 heart, 413 pancreas, and 67 heart-lung transplants performed in the United States alone (47).
Ironically, allografts of skin, the tissue used classically in most of the early studies of transplantation, have proven to be the most difficult to transplant. Skin is the ultimate protection of the individual against the environment and therefore over the ages has evolved into our strongest barrier against foreign proteins. The earlier conventional wisdom was that the fate of skin allografts predicted the results of other transplants. Commenting on the contrasting survival rates of skin and kidney allografts in immunosuppressed dogs, Medawar proclaimed with his customary flair that the success of organ transplantation has "overthrown the doctrinal tyranny of skin grafts" (48).
Although thousands of young lives have already been saved by the use of various immunosuppressive regimens, serious complications still occur as a result of the treatment. The ultimate aim is to achieve an immunological tolerance between donor and recipient, eliminating entirely the need for drugs. There are hints both in the laboratory (49) and in man (50) that the liver itself can produce tolerogenic factors which may reduce or eliminate the need for immunosuppressive drugs. Discovering or uncovering naturally occurring immunosuppressive substances seems likely. It surely is as probable as the prospect of obtaining successful organ transplants was 45 years ago.
* (Chronic dialysis was not developed until ten years later by Schribner in Seattle). In the late 1940's during a Grand Rounds at the Brigham, I was astounded to hear Dr. Thorn say, "The best way to treat hypertension is to remove both kidneys!" The entire audience gasped. The seed for the Brigham renal transplant program had been planted.
6. Michon, L., Hamburger, J., Economos, N., Delinotte, P., Richet, G., Vaysse, J. Antoine, B.: Une Tentative de Transplantation Renale chez L'Homme: Aspects Medicolaux et Biologiques. La Presse Medicale: 61: 1419, 1953
28. Wilson, R.E., Dealy, J.B., Sadowsky, N., Corson, J.M., and Murray, J.E.: Transplantation of Homologous Bone Marrow and Skin From Common Multiple Donors Following Total Body Irradiation. Surgery. 46: 261, 1959
30. Murray, J.E., Merrill, J.P., Dammin, G.J., Dealy, J.B., Walter, C.W., Brooke, M.S. and Wilson, R.E.: Study of Transplantation Immunity After Total Body Irradiation: Clinical and Experimental Investigation. Surgery. 48: 272, 1960
31. Merrill, J.P., Murray, J.E., Harrison, J.H., Friedman, E.A., Dealy, J.B. and Dammin, G.J.: Successful Homotransplantation of the Kidney Between Nonidentical Twins. New Eng. J. Med. 262: 1251, 1960
32. Murray, J.E., Merrill, J.P., Dammin, G.J., Dealy, J.B., Alexandre, G.P.J. and Harrison, J.H.: Kidney Transplantation in Modified Recipients. Ann. Surg. 156:337, 1962 568 Physiology or Medicine 1990
41, Goodwin, W.E., Kaufman, J.J., Mims, M.M., Turner, R.D., Glassock, R., Goldman, R. and Maxwell, M.M.: Human And Renal Transplantation I. Clinical Experiences with Six cases of Renal Transplantation. J. Urol. 89: 13,1963
43. Moore, F.D., Smith, L.L., Burnap, T.K., Dallenbeck, F.D., Dammin, G.J.,Gruber, U.F., Shoemaker, W.C., Steenburg, R.W., Ball, M.R., & Belko, J.S.: One Stage Homotransplantation of the Liver following Total Hepatectomy in Dogs. Transplantation Bulletin. 6: 103, 1959
44. Starzl, T.E., Groth, C.G., Brettschneider,L., Penn,I., Fulginiti, V.A., Moon, J.B., Blanchard, H., Martin, A.J., Porter, K.A.: Orthotopic Transplantation of the Human Liver Ann. Surgery 168: 392,1968
49. Calne, R.Y., Sells, R.A., Pena, J.R., Davis, D.R., Millard, P.R., Herbertson, B.M., Binns, R.M., Davies, D.A.L.: Induction of Immunological Tolerance by Porcine Liver Grafts. Nature. 223: 472, 1969
From Nobel Lectures, Physiology or Medicine 1981-1990, Editor-in-Charge Tore Frängsmyr, Editor Jan Lindsten, World Scientific Publishing Co., Singapore, 1993
Copyright © The Nobel Foundation 1990
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