Anthony Cerami Award in Translational Medicine A Journey in Science: The Birth of Organ Transplantation with Particular Reference to Alloengraftment Mechanisms Thomas E Starzl University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America Online address: http://www.molmed.org doi: 10.2119/molmed.2014.00254 I was born and raised in LeMars, Iowa dition with repetitive low-voltage ven- debate for nearly 80 years, largely be- (population 5,000). After graduating tricular stimulation (7). After this demon- cause of the confusing literature gener- from high school and serving in the stration of its efficacy, cardiac pacemak- ated by experimental and clinical studies Navy (1944–1945), I earned a BA degree ing was promptly applied clinically. of portacaval shunt. In 1955, the question from Westminster College (Missouri) and These early research experiences, first resurfaced in the context of the canine MD and PhD degrees from Northwest- in neuroscience and then in cardiac auxiliary liver transplant model de- ern University (1947–1952). My PhD the- physiology, epitomized the two ends of scribed by C Stuart Welch at Albany sis in neurophysiology under the precep- the spectrum within which I labored all Medical College (8). torship of Horace W Magoun consisted the rest of my professional life: a search With Welch’s operation, the double of four interrelated articles (1–4) that col- at one extreme for fundamental biologic blood supply of the native liver was left lectively continue to gather 5–10 citations mechanisms and at the other for practi- intact, whereas an extra liver (an allo- per year after nearly 65 years (Web of cal remedies with which to treat human graft) was rearterialized and provided Science, Thomson Reuters, Philadelphia, diseases. After I returned to surgical res- with a high volume of portal venous in- PA, USA). ident duties (1954–1959), a stage large flow from an alternative source. The After completing a 1-year surgical in- enough to accommodate both kinds of “substitute” portal blood consisted of in- ternship at Johns Hopkins Hospital in activity emerged from my new interest ferior vena caval venous return from the June 1953, I suspended clinical training in the liver, its double blood supply dog’s lower body and hind legs (Figure 1, for 18 months to do an experimental and ultimately its transplantation left). When the transplanted hepatic allo- study of complete heart block, a compli- (www.starzl.pitt.edu). grafts shrank to almost half the size cation encountered with some of the first The specific issue at first was whether within a few days, the acute atrophy was human open heart operations. After per- portal venous blood had qualities that attributed to rejection. fecting a model of heart block in dogs were important for optimal liver function Based on off-duty studies of portacaval and elucidating its pathophysiology (5,6), and overall metabolic homeostasis. This shunt in dogs, my alternative interpreta- I invented a safe method to treat the con- question had been a subject of periodic tion was that Welch’s auxiliary allografts had been deprived of liver-supporting (hepatotrophic) factors in the portal blood, to which the native liver had pri- Address correspondence to Thomas E Starzl, University of Pittsburgh School of Medicine, mary access and high avidity. To test the 200 Lothrop St., Pittsburgh, PA 15213-2582. Phone: 412-383-1346; Fax: 412-624-2010; E-mail: hypothesis, I developed two more proce- [email protected]. dures during 1958–1959: simple liver re- Submitted December 16, 2014; Accepted for publication December 16, 2014; Published placement (Figure 1, middle) (9,10) and Online (www.molmed.org) June 25, 2015. replacement of the liver plus all of the other intraabdominal organs (Figure 1, right) (11). The three models in combina- tion fueled two avenues of research. MOL MED 21:227-232, 2015 | STARZL | 227 THE BIRTH OF ORGAN TRANSPLANTATION deficiencies. In a second model that pre- saged clinical bone marrow transplanta- tion for many other indications, Main and Prehn (17) obtained similar tolerance in adult mice by enfeebling their immune re- activity with irradiation before transplant- ing them with donor bone marrow cells. Such experiments were feasible only when there was a close match of mouse donor and recipient tissue (histocompati- bility) antigens. Without such a match, the immune competent donor cells were either rejected or caused graft versus host disease. Another 15 years would pass before enough human leukocyte antigens were identified to permit the prerequisite matching. Consequently, clinical bone marrow transplantation was not accomplished Figure 1. Three kinds of liver transplantation developed between 1955 and 1958 in dogs. until 1968. In contrast, kidney allografts Left: Welch’s auxiliary liver transplantation. Middle: Complete liver replacement. Right: were transplanted with 1 year or longer Multivisceral transplantation. The allograft organs are colored blue. Illustration by Jon Coulter, M.A., C.M.I. survival without tissue matching, leuko- cyte infusion or evidence of chimerism in eight human recipients during the The first investigative pathway con- Animals permanently endowed with 1959–1962 period (Table 1) in which I cerned the metabolic cross-regulation of donor cells (donor leukocyte chimerism) was developing the canine liver trans- the different abdominal organs. By dem- could accept other tissues from the same plant models. onstrating that primary hepatic access to donor but from no other donor (donor- Patients 1–7 had been sublethally irra- endogenous insulin and other molecules specific tolerance). This “neonatal toler- diated in advance of transplantation with in portal blood played a crucial role in ance” model was the experimental virtually no immunosuppression after- the control of liver size, ultrastructure, surrogate of human bone marrow trans- ward. The nonirradiated eighth recipient function and the capacity for regenera- plantation for the treatment of immune was treated daily after transplantation tion (12,13), the “hepatotrophic” research contributed importantly to the scientific base of liver transplantation while foster- Table 1. Characteristics of the first successful transplantations of kidney allografts with ≥ ing fundamental nontransplant research 6 months’ survival. that continues to the present day in re- Donor generative medicine (14) and intermedi- Physician Site Date relationship Survival ary metabolism (15). Joseph E Murray Boston, MA 24 January 1959 Fraternal twin 20 years The second developmental pathway Jean Hamburgera Paris, France 22 June 1960 Fraternal twin 26 years involved the potential use of liver, kid- Rene Küssa Paris, France 22 June1960 Unrelated 18 monthsb ney and other kinds of organ transplan- Jean Hamburgera Paris, France 19 December 1960 Mother 22 monthsb tation for the treatment of human dis- Rene Küssa Paris, France 12 March 1961 Unrelated 18 monthsb eases. Although the initial prospects Ralph Shackman London, England 16 March 1961 Brother 3 years seemed bleak, this became the dominant Jean Hamburgera Paris, France 12 February 1962 Cousin 15 yearsc d objective by the end of 1958. The only ev- Joseph E Murray Boston, MA April 1962 Unrelated 17 months idence that tissue or organ rejection Thomas E Starzl Denver, CO 1961–1963 Mixed series >50 years might be avoidable had come from ex- For annotations, see Starzl and Fung (44). periments reported 5 years earlier by aKuss and Hamburger described periodic administration of adrenal cortical steroids with Billingham, Brent and Medawar showing these patients. that allogeneic spleen cells could be bPatient death occurred at listed time. transplanted into immunologically im- cPatient underwent successful retransplantation in the 1970s. mature mice (16). dFirst success with drugs-only immunosuppression (no radiation). 228 | STARZL | MOL MED 21:227-232, 2015 ANTHONY CERAMI AWARD IN TRANSLATIONAL MEDICINE with azathioprine, a drug for which pre- versal of rejection in human renal homo- ponent of the canine liver operation. clinical testing was done in dogs by Roy grafts with subsequent development of After single failed attempts in Boston (at Calne (with Joseph Murray in Boston, homograft tolerance” (18). “the Brigham”) and in Paris, all human MA) and Charles Zukoski (with David Although none of the kidney recipi- liver transplant activity ceased world- Hume in Richmond, VA). Although the ents were off immunosuppression at the wide until the summer of 1967. possibility of pharmacologic immuno- time of the reports, tolerance was in- During the nearly 4-year moratorium, suppression had been greeted with opti- ferred from a declining need for treat- problems that contributed to the 1963 mism, this collapsed when, in a clinical ment after rejections were reversed. In failures were systematically addressed: renal transplant trial of azathioprine at some cases, the need eventually de- blood coagulation, organ preservation, the Peter Bent Brigham Hospital (Bos- clined to zero, exemplified by five pa- infection, complications of veno-venous ton), the only survival exceeding 6 tients in the original Colorado series bypasses and immunosuppression. In months in more than a dozen cases was who currently bear the world’s longest addition, organ graft availability was that of the eighth patient in Table 1. surviving kidney allografts after 50–52 revolutionized by acceptance of brain By this time, I had moved to the Uni- posttransplant years. All have been off death. After reopening the hepatic trans- versity of Colorado (Denver) and ob- immunosuppression for 14–50 years plant program in July 1967, multiple ex- tained a supply of azathioprine for its (19). amples of liver recipient survival for evaluation in our canine kidney and liver At the time the iconic Denver clinical more than 1 year were produced (23). In transplant models. In conformity with series was inaugurated in 1962, the only the autumn of 1969, I published a second studies done elsewhere, only 5–10% of other kidney transplant program in book, this one entitled Experience in He- the dogs survived for 100 d. When daily America with clinical activity was at the patic Transplantation (24).