Billingham

Burnet

Calne

Carrel

Daston

Dausset

Dempster

Dubost

Gibson

Groth

Hamburger

Holman

Holton

Jaboulay

Küss

küss

Kœstler

Lawrence

Mathé

Medawar

Merrill

Michon

Mitchison

Morgan

Murray

Servelle

Starzl

T.E. Starzl

Unger

Voronoy Yu

English

PubMed

Crossref

Surgery: art or science? Birth of organ transplantation

Starzl, TE

D-Scholarship@Pitt

Chirurgie 1998; 123 : 225-8 © Elsevier, Paris Editorial Surgery: art or science? Birth of organ transplantation TE Starzl The revolution in organ transplantation that occurred between 1950 and 1963 can be used to illustrate the way that surgery has influenced science, all the while preserving a niche as an art form. This modern era of transplantation immunology had begun several years earlier when Peter Brian Medawar, a 24-year-old zoo-logist fresh from graduate studies at Oxford Univer-sity, was assigned to the service of the British plastic surgeon Dr Thomas Gibson to determine if skin allo-grafts could be used to treat casualties from the Battle of Britain. First in human studies [1] and then with simple and logical rabbit experiments [2], it was shown that re-jection of the skin was an immunologic phenomenon analogous to the cell mediated delayed hypersensiti-vity that confers immunity to diseases such as tuber-culosis [3-5]. The principal evidence was that repeti-tive grafts from the same donor were rejected more rapidly with each successive attempt [1,2]. The donor specific sensitisation caused by repetitive grafting confirmed previous clinical observations by the sur-geon Emil Holman of Stanford University in skin grafted burn victims [6]. THE FRENCH "TRANSPLANTATION CLUB" The potential value oftransplantation procedures had attracted the early attention of French surgeons and, eventually, many of the grand figures of French sur-gery, medicine, and science contributed to the new field. Clinical transplantation activity began in France within the first few years of the 20th century, when Jaboulay in Lyon [7] and others in France and Germany performed animal to human kidney trans-plantation [8-10]. Although the Russian Yu Yu Voronoy of Kiev reported the first known attempt at human to human renal transplantation in 1936 [11], the clinical field was quiescent until 1951 when Rene Kiiss [12] and Charles Dubost [13] of Paris and Mar-ceau Servelle of Strasbourg [14] carried out a series of cadaveric renal transplantations. A short time later, the urologist Louis Michon at the Necker Hospital (Paris) and a team of vascular surgeons reported the now commonplace transplantation of a kidney from a live volunteer donor [15]. Visitors flocked to France in the early 1950s to learn first hand from this experience, including John Mer-rill from the Peter Bent Brigham Hospital, Boston, who, with the young French physician, Jean Hambur-ger, founded the medical discipline of nephrology. As important as the early and subsequent contributions of Kiiss [16] and Hamburger [17] were to transplan-tation, the scientific basis for this specialty in France went far deeper. The roots of histocompatibility re-search were nourished in Paris by Jean Dausset (No-bel Laureate, 1980) [18]. In addition, Georges Mathe, the father of bone marrow transplantation [19], was part of the French "transplantation club" of the 1950s and early 1960s. THE SURGEONS ROLE At a technical level The kidneys in the early French cases were removed from convict donors after their execution by guillo-tine. The pelvic kidney transplant procedure original-ly used by Kiiss and refined subsequently by the French surgeons has been used hundreds of thousands of times, including for the celebrated identical 226 TE Starzl (monozygotic) twin transplantations performed by Murray (N obellaureate, 1990) and his associates [20] in Boston. The skills necessary to transplant the kid-ney (the only candidate organ until the 1960s) were applications of what became increasingly sophistica-ted conventional operative procedures during and af-ter World War II. The vascular surgical technology originated early in the century in the experimental laboratory of the Frenchman Alexis Carrel [21] (Nobel Laureate, 1912) and had a pervasive effect on essentially all surgical specialties. Although Carrel suspected that transplanted organs were not pennanently accepted because of an immunologic barrier, the biologic spe-cificity of the field of transplantation awaited the de-finitive studies of Medawar and Gibson. Such experimental work in the laboratory has been critical to each major step in the evolution of organ transplantation. Progress in animal models has been transferred to the clinics, and conversely, problems encountered in the patients have been brought back to the laboratory for clarification, thus a flux has been continuous since the time of Carrel. It resulted in the development of operative techniques, the improve-ment of immunosuppression, and clarification of pre-viously enigmatic physiologic principles. The objec-tive was to avoid human experimentation, rather than depend on it, when the time came to apply these po-tentially life-saving procedures in the clinic. At a leadership level A co-product of these efforts was the concept of team construction in the laboratory. The more experience gained in the laboratory, the better the team will per-fonn in the human operating room. The actual opera-tions require separate donor and recipient teams, the activities of which must be closely knit. During the transplant operation, co-operation among surgeons, anaesthesiologists, nurses, and technicians is essen-tial. From the very beginning, one of the objectives of laboratory work was to create harmony within the team, and amongst the physician specialists with whom the team would react. The core roles of the surgeons and the steps invol-ved in transplant operations are identical to those of conventional clinical practice. Someone, most com-monly but not necessarily a surgeon, inevitably will emerge from this experience as the team leader. Rigidity, impatience, selfishness, dishonesty, inhu-manity, ignorance, and poor organizational skills are disqualifying characteristics. In addition to posses-sing these graces, as well as professional competence, the leader must have those scientific instincts which allow advances. PROGRESS AND CULTURE The Journal of the American Academy of Arts and Sciences (called "Daedalus") is a quarterly publica-tion in which topics of social importance and interest are examined in depth. The winter 1998 issue entitled "Science and Culture" contained two articles that ex-plored the interface between science and art. One was written by Gerald Holton (Mallinckrodt Professor of Physics Emeritus at Harvard) [22], and the other by Lorraine Daston (Director, Max Planck Institute for the History of Science, Berlin) [23]. Both described how the influence of the imagina-tion had long awakened fear among the rank and file of scientists and physicians. Why? Because it could make up a world of its own that was livelier, lovelier, or more logical that the real world; this power, which feeds art, could be an invitation to fraud. In a 1961 issue of the New England Journal of Medicine, the "real world" of transplantation was described by F McFarland Burnet (Nobel Laureate, 1960) in sombre tenns " ... much thought has been given to ways by which tissues or organs not genetically and antigen i-cally identical with the patient might be made to sur-vive and function in the alien environment. On the whole the present outlook is highly unfavourable to success... [24]". Yet, there already was a place for legitimate dreams. Once it was established that rejection was an immune reaction, strategies had begun to evolve to weaken the recipient immune system. By 1950-51, total body irradiation [25] and adrenal cortical ste-roids [26, 27] had been shown in the experimental laboratory to delay skin rejection. The immunosup-pressive effect was either minor ifthe animals survi-ved, or lethal to the recipient if the grafts were spared. Although there appeared to be no margin of safety, the surgeon Joseph Murray demonstrated for the first time at the Peter Bent Brigham Hospital in January 1959 that human renal transplantation was feasible, following sublethal total body irradiation (TBI) of a fratemal twin recipient [28]. The success with TEl Surgery: art or science? 227 could not be duplicated at the Boston centre, but five more examples of long survival (two with unrelated kidney donors) were reported from Paris during the next 3 years on the services of Rene Kiiss [29] and Jean Hamburger [30]. Three years later (April, 1962), it was shown that the same result could be accomplished pharmacolo-gically, using chronic therapy with azathioprine [31]. This advance was preceded by extensive studies in dogs by the Englishman Sir Roy CaIne [32]. Although the clinical results with azathioprine alone were no better than with total body irradiation, the fog of pes-simism surrounding clinical organ transplantation lif-ted dramatically in 1962 when azathioprine was sys-tematically combined with dose-manoeuvrable prednisone at the University of Colorado [33]. Rejec-tion that developed despite azathioprine treatment could be reversed surprisingly easily with high doses of the prednisone. More importantly, the subsequent need for maintenance immunosuppression with both drugs frequently declined. The same characteristic cycle of immunologic con-frontation and resolution was soon observed with the liver [34], ultimately with all other transplanted who-le organs, and over the next 3 decades with each of the increasingly potent new baseline drugs substitu-ted for azathioprine. Recognition, reversal, and the progressively easier control of rejection was the base upon which the new and increasingly practical mul-tidisciplinary specialty of transplantation was cons-tructed. Thirty years and a revolution in immunology elapsed before the meaning of the mysterious change in host/graft relationship that began in the first few weeks after transplantation was resolved. This was made possible by a study of the still-sur-viving early Colorado kidney and liver recipients who by then were as long as 30 years post-transplantation [35, 36]. Donor leukocytes of bone marrow origin (including pluripotent stem cells), which are part of the structure of all organ grafts (the so-called "pas-senger leukocytes"), had migrated from the trans-planted organs and could still be found in small num-bers in the recipient skin, heart, lymph nodes, blood, and elsewhere. It is only now becoming clear how changes in the organ and the host caused by the mi-gration and persistence of these donor cells allow "al-lograft acceptance" [37]. How could the activities so long ago of the persons named here from France, England and the United States have had such an impact on medicine and science, particularly in a modem era in which indivi-duals are increasingly viewed as mere cogs in a mul-tidisciplinary machine? By obliterating the artificial distinction between art and science perhaps they were able to exercise the imagination and creativity of the artist. Their expressions of individuality allowed them to see and create things far beyond the reach of the comfortable Philistines who criticized their ef-forts at the time. In his book, "The Sleepwalkers", Arthur Krestler wrote: "". 'Progress' can by definition never go wrong; [Darwinian] evolution constantly does; and so does the evolution of ideas, including those of 'exact science'. New ideas are thrown up spontaneously like mutations; the vast majority of them are useless crank theories, the equivalent of biological freaks without survival-value" [38]. Viewed from the vantage point of 1998, the ideas of the French surgeons of a half century ago, and Carrel long before then, were any-thing but freaks. They were part of the primordium for the birth of organ transplantation. REFERENCES 1 Gibson T, Medawar PB. The fate of skin homografts in man. J Anat 1963; 77 : 299-310 2 Medawar PB. The behavior and fate of skin autografts and skin homografts in rabbits. J Anal 1944 ; 78 : 176-99 3 Mitchison NA. Passive transfer of transplantation immunity. Pmc R Soc Land (Biol) 1954; 141 : 72-87 4 Billingham R, BrentL, Medawar P. Quantitative studies on tissue transplantation immunity. II. The origin, strength and duration of actively and adoptively acquired immunity. Pmc R Soc Land (Bioi) 1954; 143 : 58-80 5 Lawrence HS. Homograft sensitivity. An expression of the im-munologic origins and consequences of individuality. Physiol Rev 1959; 39: 811-59 6 Holman E. Protein sensitization in isoskin grafting; is the latter of practical value? Surg Gynecol Obstet 1924 ; 38 : 100-6 7 Jaboulay M. Greffe du rein au pli du coude par sutures arterielles et veineuses. (Kidney grafts in the antecubital fossa by arterial and venous anastomosis). Lyon Med 1906 ; 107 : 575 8 Unger E. Nierentransplantation. (Kidney transplantation). Wie-ner klinische Wochenschrift 1910 ; 47: 573 9 Groth CG. Landmarks in clinical renal transplantation. Surg GVllecolObstet 1972 ; 134 : 323-8 10 e~u T. In: Landes RE, ed. Clio Chirurgica: Renal Transplallla-lion. Austin, Texas: Silvergirl, Inc; 1991 II Voronoy Yu Yu. Sobre el bloqueo del aparato reticuloendotelial del hombre en algunas formas de intoxicacion pm cl sublimado y sohre la transplantacion del rinon cadaverico como metodo de tratllniento de la anuria consecutiva a aquella intoxicacion. (Blocking the reticuloendothelial system inman in some forms of mercuric chloride intoxication and the transplantation of the cadaver kidney as a method of treatment for the anuria resulting from this intoxication). El Siglo Medico 1937 ; 97: 296 228 TE Starzl 12 KUss R, Teinturier J, Milliez P. Quelques essais de greffe de rein chez l'hornrne. Mem A cad Chir 1951 : 77 : 755-64 13 Dubost C, Oeconomos N, Nenna A, Milliez P. Resultats d'une tentative de greffe renale. Bull Soc Med Hop Paris 1951 ; 67 : 1372-82 14 Servelle M, Soulie P, Rougeullc 1. Greffe d'un rein de supplicie it une malade avec rein unique congenital, atteinte de nephrite chronique hypertensive azotemique. Bull Soc Med Hop Paris 1951; 67: 99-104 15 Michon L, Hamburger J, Oeconomos N. Delinotte P, Richet G, Vaysse J et al. U ne tentative de transplantation renale chez l'homme. Aspects medicaux et biologiques. Press Med 1953 : 61 : 1419-23 16 KUss R. Legrain M, Mathe G, Nedey R, Camey M. Homologous human kidney transplantation. Experience with six patients. Post-grad Med J 1962; 38 : 528-31 17 Hamburger J, VaysscJ, Crosnier J, Auvert J. Lalanne CL, Hopper J Jr. Renal homotransplantation in man after radiation of the re-cipient. Am J M ed 1962 ; 32 : 854-71 18 Dausset J. The HLA Adventure. In: PI Terasaki, ed. History of HLA: Ten Recollections. Los Angeles, CA: UCLA Tissue Typing Laboratory; 1990. p 1-19 19 Mathe G, Amiel JL, Schwarzenberg L, Cattan A, Schneider M. Haematopoietic chimera in man after allogenic (homologous) bone marrow transplantation. Br Med J 1963 ; 2 : 1633-5 20 Merrill JP, Murray JE, Harrison JH, Guild WR. Successful ho-motransplantation of the human kidney between identical twins. JAMA 1956; 160: 277-82 21 Carrel A. The operative technique for vascular anastomoses and transplantation of viscera. Lyon Med 1902 ; 98: 85 22 Holton G. Einstein and the cultural roots of modern science. Dae-dalus JAm A cad Arts & Sci Wimer 1998. p 1-44 23 Daston L. Fear and loathing of the imagination in science. Dae-dalus JAm Acad Arts & Sci Wimer 1998. p 73-95 24 Burnet FM. The new approach to immunology. N Engl J Med 1961; 264: 24-34 25 Dempster WJ, Lennox B, Boag JW. Prolongation of survival of skin homotransplants in the rabbit by irradiation of the host. Br J Exp Pathol 1950; 31 : 670-9 26 Billingham RE, Krohn PL, Medawar PB. Effect of cortisone on survival of skin homografts in rabbits. BrMedJ1951 ; 1: 1157-63 27 Morgan JA. The influence of cortisone on the survival of homo-grafts of skin in the rabbit. Surgery 1951 ; 30 : 506-15 28 Merrill JP, Murray JE, Harrison JH, Friedman EA, Dealy 18 Jr, Dammin GJ. Successful homotransplantation of the kidney be-tween non-identical twins. N Engl J Med 1960; 262: 1251-60 29 KUss R, Legrain M, Mathe G, Nedey R, Carney M. Homologous human kidney transplantation. Experience with six patients. Post-grad Med J 1962 ; 38 : 528-31 30 Hamburger J, Vaysse J, Crosnier J, Auvert J, Lalanne CL, Hopper J J r. Renal homotransplantation in man after radiation of the re-cipient. Am J Med 1962 ; 32 : 854-87 31 Murray JE, Merrill JP, Harrison JH, Wilson RE, Dammin GJ. Prolonged survival of human-kidney homografts by immunosup-pressive drug therapy. N Engl J Med 1963 ; 268: 1315-23 32 Caine RY.lnhibition of the rejection ofrenal homografts in dogs with purine analogues. Transplant Bull 1961 ; 28 : 445 33 Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homo grafts with subsequent development of ho-mograft tolerance. Surg Gynecol Obstet 1963 ; 117 : 385-95 34 Starzl TE, Marchioro TL, Rifkind D, Holmes JH, Rowlands DT Jr, Waddell WR. Factors in successful renal transplantation. Sur-gery 1964; 56: 296-318 35 Starzl TE. Demetris AJ, Murase N. Ildstad S, Ricordi C. Trucco M. Cell migration, chimerism, and graft acceptance. Lancet 1992; 339 : 1579-82 36 Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, lldstad S et al. Cell migration and chimerism after whole-organ trans-plantation: The basis of graft acceptance. Hepatology 1993 ; 17 : 1127-52 37 Starzl TE, Zinkernagel R. The regulation of immune reactivity by antigen migration and localization: a comparison of "tole-rance" to infectious agents and allografts. N Engl J Med [in press] 38 Kcestler A. The Sleepwalkers. London: Hutchinson & Co; 1959 

Surgery: Art or science? Birth of organ transplantation

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Surgery: Art or Science? Birth of organ transplantation

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Surgery: Art or science? Birth of organ transplantation

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