Portal de Periódicos da CAPES

Joseph Edward Murray, M.D., 1919–2012

2013; Wolters Kluwer; Volume: 95; Issue: 7 Linguagem: Inglês

10.1097/tp.0b013e3182895cf2

1534-6080

Anthony P. Monaco,

Organ and Tissue Transplantation Research

Joseph Murray died on November 26, 2012, at the age of 93 years, of a hemorrhagic stroke he suffered 3 days earlier on Thanksgiving evening. He was active, still publishing, engaged in academia, in good spirits, and healthy right up until the end. He had enjoyed a wonderful Thanksgiving Day and dinner with four generations of his family and watched the New England Patriots football game. Considered the father of modern organ transplantation, he helped create a new field of biomedical science and clinical therapy that has permitted literally hundreds of thousands of patients throughout the world to receive curative, life-saving transplants of kidney, liver, pancreas, heart, lung, and other organs and tissues. He shared the Nobel Prize in Medicine or Physiology for his work in kidney transplantation with E. Donnell Thomas who was co-recipient for his work in bone marrow transplantation (1). That this sensitive, kind, caring man lived to see the fruition of his extraordinary legacy affirms the adage that “good things happen to good people”. Murray was born on April 1, 1919 in Milford, MA, a typical New England town. He was the son of William Murray, a lawyer and local judge, and Mary (DePasquale) Murray, a schoolteacher and liberal political activist. He enjoyed a happy, secure childhood and attended public schools. He was an excellent all-around athlete, an avid enthusiastic reader, and graduated salutatorian of his high school class. Apparently, he always wanted to be a doctor. He attended Holy Cross College in Worcester, MA, where he graduated with honors in 1940. When asked during his Harvard Medical School interview why he had gone to Holy Cross having been accepted to Dartmouth and Harvard College, he explained that he had desired a college education with a strong liberal arts component combined with strong science—hence Holy Cross. This candid answer apparently impressed the interviewer and he was accepted a week later. Indeed, the importance and interrelationship of culture, religion, individuality, and science would be evident throughout Murray’s career. At Harvard Medical School, he found surgery “thrilling and challenging” and was surprised that he was fascinated by research. Also, he encountered Drs. Francis D. Moore and George W. Thorn, two great, young teachers who would prophetically have enormous influence in his career. Following graduation from Harvard Medical School and an abbreviated surgical internship at the Peter Bent Brigham Hospital (now the Brigham & Women’s Hospital) and The Children’s Hospital of Boston, he began in 1944 active service in the U.S. Army Medical Corp. With World War II raging, he expected an immediate overseas posting, but in what was a fortuitous, random assignment he was stationed at the Valley Forge General Hospital near Philadelphia where numerous war casualties with severe burns and disfiguring wounds were treated. He became the youngest member of the plastic and reconstructive service working with the renowned plastic surgeons Drs. James Barrett Brown and Bradford Cannon (the Massachusetts General Hospital plastic surgeon who treated many burn victims of the infamous Coconut Grove fire in Boston in 1942). At Valley Forge, Murray performed numerous skin grafts on badly burned patients frequently using skin from unrelated cadaver donors because the recipient had no remaining usable self-donor sites. Such “homografts” (now allografts) invariably rejected. He noted that some burn victims, who were extremely ill and septic with compromised immune systems, accepted cadaver skin for surprisingly long periods of time. He wondered if a person’s immune system could be manipulated or modulated so that long-term transplant survival could be achieved. Murray remained at Valley Forge through 1947 and his experience there would form the foundation for his later careers in organ transplantation and plastic and reconstructive surgery (Fig. 1). Valley Forge affected Murray in another important way: he was deeply impressed with the courage, faith, resilient human spirit, and will to live shown by so many patients there in the face of repeated physical and emotional pain in the course of their treatments. This theme is repeated many times in his autobiography, “Surgery of the Soul” (2), completed in his 80th year, in which he describes a number of patients that affected his career. Many of the patients became lifelong friends. One patient was Charles Woods, a young Army flyer who sustained massive body burns in a plane crash that essentially destroyed his entire face. He endured multiple operations to rebuild his face and hands, frequently with little or no anesthesia. Murray was impressed with his implacable will to live and his enormous physical and emotional courage. He recalled that although “we reconstructed his face and hands to function normally, he looked like no one you have ever seen”. When we were through, “Charles looked in the mirror, walked out into the world, and built a life full of accomplishment and happiness” (he married, had a family, became a successful businessman, even returned to flying!). Forty years later, at Murray’s invitation, he addressed the Harvard Medical School students on his experience as a patient.FIGURE 1: Portrait of Joseph E. Murray by Herbert Abrams showing Murray with emblems of his dual surgical careers: a skull representing craniofacial surgery and a photograph of the Herrick twins representing organ transplantation (courtesy of the Brigham & Women’s Hospital, Boston, MA).In 1947, Murray was discharged from the Army and returned to Boston to complete his general surgical and plastic surgical training at Brigham Hospital and The Children’s Hospital with additional plastic and reconstructive surgery training in New York with Dr. Hayes Martin and with Dr. Herb Conway. In 1951, he initiated a private practice in general and plastic surgery at Brigham Hospital (a turf battle over plastic surgery privileges temporarily limited his appointment at The Children’s Hospital to the dental service). He developed a well-deserved reputation as an expert in surgical management of aggressive head and neck tumors, and his practice grew rapidly. At that time, Brigham Hospital had a fledgling experimental renal transplant program under the direction of Dr. David Hume, an early transplant pioneer, which had been initiated by Dr. Thorn, the young Chief of Medicine, and later championed by Dr. Moore, the young Chief of Surgery. Murray was offered the opportunity to work in the renal transplant program in the Harvard Surgical Research Laboratory. The decision to join this research was not straightforward; it was considered a fool-hearty fringe project by some, not likely to work, and being associated with it might ruin his career. However, Murray’s motivation to study transplantation biology was reinforced by his admiration and respect for Thorn and Moore and he took the position. When Dr. Hume was called to serve in the Korean War, Murray eventually assumed leadership of the transplant program and laboratory. Murray and his team showed that kidneys could be removed and reimplanted in the same animal (as isografts) and could function normally for long periods (no rejection). They perfected the standard transplant operation in dogs (used in man today), which they believed would work in humans—but without means to control immune rejection were reluctant to try it. Dr. Brown (Murray’s Chief at Valley Forge) had shown that an individual would accept a skin graft from their identical twin with no sign of rejection. Murray and his team assumed that this protection would apply to any transplanted organ. They did not have to wait long to test their hypothesis. Richard Herrick, a 23-year-old male with renal failure secondary to chronic nephritis, was admitted to Brigham Hospital in October 26, 1954, with his identical twin brother for possible kidney transplant. The opportunity to perform a human kidney transplant in which immune rejection most likely would not occur was extraordinary but presented numerous medical, ethical, and legal problems. Proof of genetic identity was critical. Multiple tests were performed that supported but did not prove identity. Eventually, prolonged survival without rejection of skin grafts exchanged between the pair confirmed genetic identity. The twins were even fingerprinted as a possible measure of identity at a local police station; the encounter was picked up by the local media and promulgated to the public. The media began requesting daily progress bulletins that increased pressure on the transplant team. At one point, the sick twin requested that his potential donor brother withdraw as a donor candidate, but the latter refused. Opinion as to whether physicians had the right to put the healthy twin through a potentially hazardous donor nephrectomy in the face of uncertainty as to ultimate outcome of the transplant was divided among the extended transplant team. Eventually, Herrick had the onset of congestive heart failure, making his ultimate outcome more certain in the absence of a successful kidney transplant, and the decision was made to go ahead. Drs. Murray and Moore performed a “test run” of the operation on a cadaver to confirm that the new kidney would fit appropriately in the recipient iliac fossa. The operation was performed on December 23, 1954 and went off without incident; the kidney functioned immediately with copious urine flow. The postoperative course was surprisingly uneventful. Herrick eventually married his recovery room nurse and they had two children. He died in 1962, eight years after transplantation from recurrence of the original kidney disease. His brother, Ronald, lived a normal life and succumbed to heart disease at age 79. A friend of Murray aware of his strong religious convictions asked him years later whether he prayed before the historic Herrick operation. Murray replied that he did not alter his daily prayer pattern in any way; he noted that he considered every day to be a call to prayer and that he followed the popular theologian Thomas Merton that one’s work should be a wordless prayer. The operations’ complete success was a tremendous boost to transplantation scientists and clinicians alike (3). There was worldwide enthusiasm and hope that research would permit life-saving organ transplantation not only in those whose immune systems were identical but also in people whose immune response to the transplant was modulated or suppressed. Murray and his team accomplished their second landmark transplant when they successfully transplanted a kidney to John Riteris in January 14, 1959 from his nonidentical twin brother, Andrew, using a protocol of immune suppression involving sublethal total body irradiation and rescue with stored recipient autologous bone marrow. The kidney functioned immediately, but leucopenia and massive life-threatening perirenal infection developed later necessitating life-saving bilateral nephrectomies. The recipient eventually made a complete recovery enjoying normal renal function for nearly another 30 years until he died of congestive heart failure. No less an expert than Thomas Starzl felt that this was the most important case, psychologically and otherwise, in the history of clinical organ transplantation (2) because Riteris was the first human being in whom the immune barrier was overcome to allow a successful organ transplantation (4). Murray and colleagues eventually gave up using the total body irradiation/autologous bone marrow protocol because of inconsistent results, high rates of infection, and excessive mortality. Murray’s third monumental achievement was the introduction of safe chemical immune suppression. Dr. Robert Schwartz and William Dameshek (hematologists at Tufts University Medical School in Boston, MA) reported that the anticancer drug 6-mercaptopurine (6-MP), previously synthesized by Drs. George Hitchings and Gertrude Elion of the Burroughs-Welcome Co., had immunosuppressive properties (5). Rabbits given 6-MP plus an antigen to which they would usually make antibodies failed to make an antibody response to the antigen while their ability to make antibodies to other antigens was preserved—this was essentially drug-induced immunologic tolerance. In addition, Roy Calne in Cambridge and later Charles Zukoski in Virginia had begun using the drug with some encouraging results in canine renal allografts. At the suggestion of Peter Medawar, Calne came to work with Murray on this project. Their early results with 6-MP in prolonging canine renal allograft survival were very encouraging and served to foster a fruitful collaboration with Hitchings and Elion. They tested more than twenty 6-MP derivative drugs, finally concluding that azathioprine (Imuran) was the most effective. Not only did the dogs enjoy long-term normal functioning kidneys, but also they were very healthy, lively, and even able to procreate and deliver normal offspring. During 1961, Murray and his group performed kidney transplants in three different patients using allogeneic kidneys obtained from neonates (unrelated kidneys removed as part of neurosurgical shunting procedures for hydrocephalus in two patients and another from one deceased [cadaver] donor). All three patients died from infection and/or nonfunction probably related to Imuran overdose. The fourth patient (Mel Doucette) was undergoing dialysis at Brigham Hospital on April 5, 1962, when a 30-year-old man undergoing open-heart surgery died on the operating table and became available as a cadaver donor. The emergency transplant and the operation went smoothly, with the kidney functioning on the fifth postoperative day. At Murray’s insistence to avoid drug toxicity, the immunosuppressive therapy was low-dose Imuran 2 to 4 mg/kg as opposed to 10 to 12 mg/kg used in the initial patients without supplemental total body irradiation. The patient did extremely well and after 1 year was reported in the New England Journal of Medicine (6), a report that became a major impetus to worldwide transplantation. The mid and late sixties saw a proliferation of renal transplant programs throughout the United States and Europe. Unbridled enthusiasm for this new medical miracle fostered eagerness to move forward at any cost. Murray advocated for slow, steady progress and emphasized the importance to achieve excellent long-term results. He chaired the First International Conference on Human Kidney Transplantation organized by the National Academy of Science/National Research Council in 1962, which was attended by leading members of the transplant community, including Medawar in his role as founder of modern transplantation biology. At Medawar’s suggestion, a National Kidney Transplant Registry (the forerunner of the current UNOS Registry) was established at Brigham Hospital with Murray as director. Murray also served on the Harvard University Committee on the Definition of Death chaired by Dr. Henry K. Beecher, which advocated for the determination of death based on permanent loss of brain function rather than cessation of breathing and heartbeat, which remains the standard today (7). In addition, Dr. Murray served on the NIH Surgical Studies section (1962–1966) and the Immunobiology Study Section (1967–1971) and as Chairman of the American Board of Plastic Surgery (1969–1970). Throughout this period of intense national and international responsibilities, he remained a very hands-on Chief of Renal Transplant Program at Brigham Hospital and Director of the Surgical Research Laboratory at Harvard, where he mentored a galaxy of fellows that included such future transplant luminaries as (Sir) Roy Calne, Guy Alexandre, K.A. Porter, A.G.R. Sheil, J.M. Dubernard, S. Strober, A.G. Diethelm, Alan Birtch, Richard Wilson, Nicholas Tilney, and Charles B. Carpenter, to name a few. Murray’s monumental contributions to organ transplantation overshadowed the fact that, from the very beginning of his career, he was also an active, practicing academic plastic surgeon who dealt with the most challenging and difficult cases, many of which demanded complex daring, innovative solutions not previously attempted. His experience with successful treatment of childhood head, neck, and face tumors, particularly orbital rhabdomyosarcomas, was extraordinary. The legendary Dr. Sidney Farber, father of modern pediatric oncology, was awed by his successful results and became a mentor and booster. Murray performed (with Dr. Leonard Swanson) the first total one-stage correction of the facial deformities associated with Crouzon syndrome (craniosynostosis) in the United States on August 18, 1966 (8), only to learn that Dr. Paul Tessier had accomplished a similar feat months earlier in France (2). Tessier’s more elegant technique for correcting craniofacial deformities became adopted throughout the world. Murray and Tessier became fast friends and Tessier became an active consultant member of Brigham Hospital/The Children’s Hospital Plastic Surgery Service and its Craniofacial Deformity Service. Under Murray’s enlightened leadership, this latter program functioned as a multidisciplined organization that grew to one of the few craniofacial centers in the United States that attracted patients from all over the world. As with many of his patients, Murray’s first patient with Crouzon syndrome (Walter Murphy) became a lifelong friend; he went to Holy Cross (Murray’s alma mater), married, had three children, and became a successful market analyst; coincidentally, his wife was a kidney transplant recipient. In 1971, Murray resigned as Chief of Transplant Surgery at Brigham Hospital to devote more time to his career as Chief of Plastic Surgery at Brigham Hospital and The Children’s Hospital and to nurture and expand the developing specialty of craniofacial surgery. He and his team extended their surgical treatments to patients with variant forms of craniosynostoses, hemifacial microsomia, and other deformities. One of these patients was Raymond Francis McMillan, a boy born with Moebius syndrome, a condition involving heart defects and multiple facial deformities so severe he was relegated to a mental institution. He was released at age 21 and referred to Dr. Murray and his team. In a series of operations, they eventually repaired his jaw, palate, and nose so he could swallow his saliva and smile and his heart defect was corrected. Eventually, the patient took his place in the world, lived on his own, obtained a high school equivalency degree, and eventually (through Murray’s intercession) worked in one of the hospital laboratories. Murray later said the surgery permitted his inner self to grow and glow. The title of Murray’s autobiography “Surgery of the Soul” was the term he used to describe this phenomenon (2). Murray also traveled extensively as visiting professor to multiple countries including India, Iran, and others to teach young plastic surgeons his surgical techniques and philosophy. His unique experiences in these societies affirmed his convictions that even simple plastic surgical procedures to correct benign deformities of appearance could have an enormous impact beyond cosmetic changes in improving the individual’s social acceptability and life quality. At age 66, three months before his scheduled retirement as Chief of Plastic and Reconstructive Surgery at Brigham Hospital and The Children’s Hospital, Dr. Murray suffered a substantial stroke from which he fortunately made a complete recovery. Although he was cleared to return to surgery, he elected to retire completely from patient care, lecturing, and administrative responsibilities. He enjoyed a relatively brief 4-year retirement. This all changed when he was awarded the Nobel Prize in December 1990. He knew that he had been nominated several times previously so he had assumed that the Nobel committee had considered his research too oriented to patient care. After receiving the award, he felt an increased responsibility and respect to the many other surgeons who had made excellent scientific advances while at the same time taking care of their patients and whom he deemed equally deserving of the prize. This was very evident in the respect in public and private that he expressed for his fellow transplant pioneers. He donated the prize money to Harvard Medical School, Brigham Hospital, and The Children’s Hospital. After the Nobel Prize, he enjoyed renewed demand as a speaker, regularly attended meetings, lectures, and seminars, kept up with the scientific progress in transplantation, supported all aspects of the transplant movement, and relished speaking to medical students whom he regularly extolled that this was the best time ever to be a doctor because “you can heal and treat conditions that were untreatable a few years earlier”. It was clear that he relished that his two careers of organ transplantation and reconstructive plastic surgery had come full circle. One of this author’s fondest memories was attending an early morning lecture given by Joe Murray a few years ago on special cases in reconstructive plastic surgery in his career (several have been referred to in this article). The last case he described (with great awe and pleasure) was not one of his own cases but rather the first successful face transplant—the ultimate reconstructive allotransplant! In addition to the Nobel Prize, he received numerous other awards including the Francis Amory Prize (American Academy of Arts and Sciences), the Gold Medal of the International Society of Surgeons, the Ferdinand C. Valentine Medal and Award (New York Academy of Medicine), the National Kidney Foundation Award, the Olof Af Acrel Medal (Swedish Surgical Society), the Nathan Smith Award (New England Surgical Society), the Bigelow Medal (Boston Surgical Society), the Medallion for Scientific Achievement (American Surgical Association), the Sabin Award of Americans for Medical Progress, and the Lifetime Achievement Award (Massachusetts Medical Society). He was elected a member of the National Academy of Sciences and of the Institute of Medicine and was a member of the Pontifical Academy of Science (Rome, Italy). He received honorary fellowships in the Royal Colleges of Surgeons of London, Edinburgh, Canada, and Ireland and the Royal Society of Medicine. Dr. Murray is survived by his devoted wife of more than 67 years, Virginia (Link) Murray—“Bobby”, an aspiring singer whom he met at a concert while in Medical School; his six children—his sons Richard, J. Link, and Thomas and his daughters Virginia Murray, Margaret Murray Dupont, and Dr. Katherine Murray Leisure; and his 18 grandchildren and 9 great grandchildren. He was a lifelong resident of Wellesley, MA, and a perennial summer resident of Chappaquiddick Island (off Martha’s Vineyard Island) where he and his family pitched tents on an undeveloped piece of land for several summers while they personally built their own simple vacation home on the island paradise. Murray was an avid tennis player, swimmer, sailor, hiker, camper, and mountain climber—an absolute all-around nature lover (he was proud of his local reputation as a “nature freak”). A photograph in his autobiography shows him 20 feet from the summit of the Matterhorn, with his guide about to make the final ascent on September 21, 1971. The funeral mass held at St. Paul’s Church in Wellesley, MA, on December 1, 2012 was a true celebration of his life. The sadness of his passing was muted by his children and grandchildren who eulogized that he showed love, generosity, empathy, and sensitivity not only to his patients and family but also to all people he met in his long life. Murray requested that a two minute interval of silence be held during his funeral in respect and gratitude for the Quaker influence in his life, starting from his Valley Forge Hospital days when the Quakers cared for many English children sent there for safety during World War II. Then there were the many references to his eternal optimism—he saw the good in everything, his glass was always half-full, he saw difficulties as opportunities, and even his stroke was a “creative illness” (9). Indeed, he gifted the congregation with a last example of his optimism: his request that a musician friend lead his casket out of the church playing a recessional trumpet solo of Louie Armstrong’s “It’s a Wonderful World”. For Joe Murray, it really was a wonderful world.