A Tribute to Thomas E. Starzl, MD, PHD (2002)

It has been said that what one should gauge of the importance of an individual's work by the legacy that they leave in their students, by measuring the change in a discipline, and by the impact of their work on the beneficiaries. By all accounts, Dr Thomas Starzl has done as much for the field of organ transplantation as any other individual. Dr Thomas Starzl's pioneering efforts in organ transplantation for four decades have resulted in clinically proven treatments for patients with end-staged organ failure, who were previously doomed to death. His contributions to immunosuppression, organ procurement, organ preservation, tissue matching, surgical transplant technology, and the team approach to organ transplantation paved the way for the acceptance of heart, lung, pancreas, intestinal, liver, and kidney transplantation. Other studies, ranging from the understanding of immune regulation to the genetic causes of organ failure, have added to the knowledge of nontransplant medical and scientific fields. The body of Dr Starzl's works serves as the foundation and inspiration for many of the most exciting and promising scientific investigations being conducted today. The feasibility of clinical organ transplantation using an unrelated donor could not be established until the advent of nonspecific immunosuppression. The outlook for transplantation was grim because of the inability to control rejection. Dr Starzl combined the marginally effective drugs, azathioprine (AZA) and prednisone, in a strategy (1962–63) that made kidney transplantation a viable option for treatment of end-stage renal disease. The joint manipulation of these drugs allowed: 1reversal of rejection (not previously thought to be possible) (1Starzl TE Marchioro TL Waddell WR The reversal of rejection in human renal homografts with subsequent development of homograft tolerance.Surg Gynecol Obstet. 1963; 117: 385-395PubMed Google Scholar);2long-term kidney acceptance without immunologic invalidism (2Starzl TE Porter KA Andres G et al.Long-term survival after renal transplantation in humans.Ann Surg. 1970; 172: 437-472Crossref PubMed Scopus (124) Google Scholar);3survival of the majority of recipients, from which, the world's longest surviving cohort of allograft recipients are currently constituted. He was the first to recognize that host-graft adaptation that occurs in the months following transplantation and is the basis for transplantation success because it permits lower doses of immunosuppressive drugs. The practical application of clinical transplantation could not proceed without effective organ preservation. Dr Starzl introduced the first major innovation in hypothermia, when canine liver allografts were cooled by infusion of chilled fluids into the vascular bed of hepatic allografts via the portal vein (3Starzl TE Experience in Hepatic Transplantation. W.B. Saunders Company, Philadelphia1969Google Scholar). In a logical extension, the technique was applied to clinical kidney transplantation in 1962–63 (4Starzl TE Experience in Renal Transplantation. W.B. Saunders Company, Philadelphia1964Google Scholar). Today, intravascular cooling is the first step in the preservation of all whole organ grafts. For cadaver donors, this is most often done in situ with the flexible method of multiple organ procurement, which allows the kidneys, liver, pancreas, small intestine, heart, and lungs to be removed from cadaver donors without jeopardizing any of the individual organs (5Starzl TE Hakala TR Shaw BW et al.A flexible procedure for multiple cadaveric organ procurement..Surg Gynecol Obstet. 1984; 158: 223-230PubMed Google Scholar). This technique, described by Dr Starzl in 1982, was quickly adopted as a worldwide standard. The sharing of organs from a common donor by recipient teams from widely separated centers became routine by the mid-1980s. Using AZA-prednisone plus anti-lymphocyte globulin (ALG) (6Starzl TE Marchioro TL Porter KA Iwasaki Y Cerilli GJ The use of heterologous antilymphoid agents in canine renal and liver homotransplantations and in human renal homo-transplantations.Surg Gynecol Obstet. 1967; 124: 301-318PubMed Google Scholar), the first liver transplantation was carried out in 1963 (7Starzl TE Marchioro TL von Kaulla KN Hermann G Brittain RS Waddell WR Homotransplantation of the liver in humans.Surg Gynecol Obstet. 1963; 177: 659-676Google Scholar). It was the first time that a vital extra-renal organ was engrafted in a human. Although the control of rejection was initially imperfect, when Dr Starzl introduced the strategy of cyclosporine use with corticosteroids in 1979 (8Starzl TE Klintmalm GBG Porter KA Iwatsuki S Schroter GRJ Liver transplantation with use of cyclosporin A and prednisone.New Engl J Medical. 1981; 305: 266-269Crossref PubMed Scopus (379) Google Scholar), the difficult procedure of liver transplantation became clinically practical. With the introduction of the even more potent tacrolimus in 1989 (9Starzl TE Todo S Fung J Demetris AJ Venkataramanan R Jain A FK506 for liver, kidney and pancreas transplantation.Lancet. 1989; 2: 1000-1004Abstract PubMed Scopus (815) Google Scholar), multivisceral and intestinal transplantation were successfully launched (10Starzl TE Rowe MI Todo S et al.Transplantation of multiple abdominal viscera.JAMA. 1989; 261: 1449-1457Crossref PubMed Scopus (266) Google Scholar), based on a long history of laboratory research in this area (11Starzl TE Kaupp HA Brock DR et al.Long-term survival after renal transplantation in humans.Ann Surg. 1970; 172: 437-472Crossref PubMed Google Scholar). Although each of these major steps allowed a larger proportion of patients to survive, the basic management strategy introduced in 1963 always remained the same. Why the strategy worked remained inexplicable until Dr Starzl's discoveries of chimerism in 1992 (12Starzl TE Demetris AJ Murase N Ildstad S Ricordi C Trucco M Cell migration, chimerism, and graft acceptance.Lancet. 1992; 339: 1579-1582Abstract PubMed Scopus (939) Google Scholar). In 1964, Dr Starzl described hyperacute rejection of kidneys from ABO incompatible donors. This was extended in 1965, when he and Terasaki showed that recipients possessing antigraft cytotoxic antibodies hyperacutely rejected kidneys, and introduced the universally used lymphocytotoxic crossmatch test (13Terasaki PI Marchioro TL Starzl TE et al.Sero-typing of human lymphocyte antigens. preliminary trials on long-term kidney homograft survivors. National Academy of Sciences-National Research Council. Histocompatibility Testing, Washington, DC1965: 83-96Google Scholar). Notwithstanding these early studies in histocompatibility, he sought to understand various immunologic enigmas, which he felt were incompatible with the prevailing notion that the allograft was envisioned as defenseless and vulnerable to immunologic attack in proportion to its histocompatibility disparity from that of the recipient. In 1992, he and his colleagues reported ubiquitous low level donor leukocyte chimerism in his patients who had received whole organs as long as 3 decades earlier. They confirmed in animals that the ‘passenger leukocytes’ of bone marrow origin, which are normal components of whole organs, had migrated from the grafts after transplantation and had survived in the recipient. The interaction of these cells with the recipient immunocytes, each reactive to the other, was postulated to be the fundamental explanation of organ allograft acceptance. Distinguishing himself from other modern day researchers and clinicians, Dr Starzl embodies the true ‘Renaissance’ physician-scientist, who is as adept in the laboratory as he is at the patient's bedside. He achieved vigorous investigative training during completion of his doctoral thesis, ‘Mechanisms Involved in the production of Certain Electroencephalographic patterns,’ which is still heralded as a milestone in understanding neural pathways. Combining this with keen surgical training in general and thoracic surgery, Dr Starzl became interested in liver physiology and derangements seen in liver failure. His inquisitive instinct was alerted by the observation as early as 1959 that, for optimal results, a transplanted liver required factors present in the normal portal venous blood (14Starzl TE Kaupp HA Brock DR Lazarus RE Johnson RV Reconstructive problems in canine liver homotransplantations.Surg Gynecol Obstet. 1960; 111: 733-743PubMed Google Scholar). He speculated from the outset that the organs draining into the portal vein or perhaps the liver itself produced ‘hepatotrophic’ factors that modulated the liver's size, capacity for regeneration and function (15Starzl TE Watanabe K Porter KA Putnam CW Effects of insulin, glucagons, and insulin/glucagons infusions on liver morphology and cell division after complete portocaval shunt in dogs.Lancet. 1976; 1: 821-825Abstract PubMed Scopus (184) Google Scholar). This concept led to the pioneering use of portacaval shunting for treatment of hereditary hypercholesterolemia and the identification of the key role of the liver in cholesterol metabolism, verified decades later by the use of liver transplantation for correction of homozygous familial hypercholesterolemia. In addition, this work had profound implications in the development of liver transplantation, paving the way for the technical achievements for the success of this procedure, such as the development of veno-venous bypass for mesenteric decompression during liver transplantation in 1984. In 1994, at the end of a trail that stretched back 30 years, a unique growth regulatory gene called ‘augmenter of liver regeneration’ was found in the mouse, rat, and human liver (16Francavilla A Hagiya M Porter KA Polimeno L Ihara I Starzl TE Augmenter of liver regeneration: its place in the universe of growth factors.Hepatology. 1994; 20: 747-757Crossref PubMed Scopus (122) Google Scholar). Dr Starzl's contributions to the scientific literature include more than 2000 scientific articles. In a study released in May 1999, by the Philadelphia-based Institute for Scientific Information, he was the physician/scientist in the world most cited in any field of medicine during the period from 1981 to June 1998. Many of these reports elucidated principles, essentially all were applicable to the transplantation of the full spectrum of tissues and organs, and thus have implications far beyond the specialty of transplantation. Dr Starzl's impact in healthcare extends outside of the operating room and wards. With the proof that organ transplantation was feasible, Dr Starzl helped to formulate guidelines for this new field at landmark ethics conferences in London (1965) and San Francisco (1967). These were the first efforts to address the problems and abuses that might occur at the fragile margin between experimentation and treatment; the inevitable shortage of organs if the field advanced; the question of brain death; equitable allocation of organs; and how to pay the costs of the developing technology. His role in public policy development is highlighted by his pivotal role in the 1983 NIH consensus conference which approved liver transplantation as a therapeutic modality. In addition, his input helped to establish a system for organ procurement and equitable organ allocation that was adopted by the United Network for Organ Sharing (UNOS), and ultimately as a worldwide standard (17Starzl TE Hakala T Tzakis A et al.A multifactorial system for equitable selection of cadaveric kidney recipients.JAMA. 1987; 257: 3073-3075Crossref PubMed Scopus (67) Google Scholar). Because many of the steps he took during the development of the field were considered revolutionary at the time, Dr Starzl frequently faced opposition and criticism. Instead of abandoning his efforts, he called upon an inner strength to promote social and medical acceptance of transplantation through his tireless efforts to educate scientists, other professionals, and the public (18Starzl TE The Puzzle People. University of Pittsburgh Press, Pennsylvania1992Crossref Google Scholar). The literally hundreds of surgeons and physicians from around the world, who studied in Chicago, Denver and Pittsburgh, all contributed to the team lead by Dr Starzl. As noted by Dr Ben Eiseman, a colleague of Dr Starzl while he was at the University of Colorado (19Eiseman B The Puzzle People: Memoirs of a Transplant Surgeon.Arch Surg. 1992; 127: 1009-1112Crossref PubMed Scopus (3) Google Scholar): ‘He had the ability to attract a diverse group from many walks of life to his surgical team. Even more important, he stimulated his team to superhuman effort by the sheer excitement and sense of importance of the grand experience of which each member was a part. Seldom has any surgeon been able to multiply the effectiveness of his own hands so completely by involving others in his experiments in the laboratory or on the wards as did Starzl. He was always out in front and never asked of anyone else more than he asked of himself.’ It is with this in mind, that his students, colleagues and friends assemble to pay tribute to Dr Starzl with a Festschrift in his honor.