Lasker~DeBakey Clinical Medical Research Award Essay - The Long Reach of Liver Transplantation

Aug 26, 2026

A personal essay tracing Thomas E. Starzl’s research path leading to modern liver transplantation, from early training and experimental work on cardiac conduction and pacemaking to the development of canine abdominal organ transplant models. It explains how the double blood supply of the liver prompted studies of portal factors, rejection versus hepatotrophic deprivation, and the design of liver replacement and multivisceral allograft experiments. The narrative then connects animal tolerance models, immunological matching, and azathioprine-based immunosuppression to the clinical adoption of transplantation for human liver diseases.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages4

Reading Time10 min

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The Long Reach of Liver Transplantation

Experimental foundations and transplant models

Hepatotrophic factors in portal blood

Human organ transplantation and immune tolerance

Lasker~DeBakey CLiniCaL meDiCaL researCh awarD eSSaY The long reach of liver transplantation Thomas E Starzl After graduating from high school in my hometown of Le Mars, Iowa, I had a stint in the US Navy (1944–1945), earned a BA degree from Westminster College in Missouri (1947) and completed two years of medical school at Northwestern University (1947–1949). I then dropped out to do research in neurophysiology under the inspiring tutelage of Horace W. Magoun, first at Northwestern and subsequently atthe then-new medical school of the University of California, Los Angeles. With MD and PhD degrees from Northwestern, I served a one-year internship at Johns Hopkins Hospital before doing a full-time, 18-month study of complete heart block, which was a frequent complication with the first human open-heart operations. The experiments involved creation of a canine model of heart block and treatment of its adverse consequences with repetitive low-voltage ventricular stimulation—the first epicardial pacemaking. The experimental transplant models After I returned to my duties as a surgical resident (1954–1959), discussions with surgical colleagues about the liver’s double-blood supply prompted my spare-time development of canine models of abdominal organ transplant. The question was whether hormone-and nutrientrich portal blood was important for optimal total-body metabolism and, specifically, for liver health. This subject had been unresolved for nearly 80 years because of the confusing literature on portacaval shunt (Eck’s fistula). The canine model of auxiliary liver transplantation described in 1955 by C. Stuart Welch at Albany Medical College epitomized the controversy. While leaving the blood supply of the native liver intact, Welch arterialized the extra liver (an allograft) but provided its portal inflow with systemic venous return from the lower part of Thomas E. Starzl is Director Emeritus, Thomas E. Starzl Transplantation Institute, Professor of Surgery, Distinguished Service Professor, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. [e-mail: mangantl@upmc.edu](e-mail: mangantl@upmc.edu) the body (Fig. 1a). The dramatic shrinkage of the transplanted liver was attributed to rejection. My alternative explanation was that the allograft had been deprived of liver-supporting (hepatotrophic) factors in the portal blood. In 1958–1959, I developed two procedures to test this hypothesis. One was liver replacement1 (Fig. 1b). The other was removal of the liver and all the other intra-abdominal organs and replacement of them with a multivisceral allograft2 (Fig. 1c). The three models in combination generated parallel avenues of research. The first concerned the metabolic crossregulation of the different abdominal organs and, in particular, the importance of their relative anatomic positions. By showing that endogenous insulin and other molecules in portal blood play a crucial part in the control of the liver’s size, ultrastructure, function and capacity for regeneration3, the hepatotrophic research contributed importantly to the scientific basis of liver transplantation and filled in present and future gaps throughout hepatology and regenerative medicine. Human organ transplantation Despite the intrinsic scientific interest of the transplant operations, their use as a treatment for human liver diseases was the dominant theme in my laboratory and in clinical research from 1958 onward. Unbeknownst to me, 1958 also marked the start of similar efforts by Francis D. Moore at the Peter Bent Brigham Hospital (now Brigham and Women’s Hospital) in Boston. At the time, the only evidence that rejection might be avoidable came from epochal experiments done by Rupert Billingham, Leslie Brent and Peter Medawar in 1953, in which allogeneic spleen cells were transplanted into immunologically immature mice. This model presaged bone marrow transplantation in immunodeficient humans. Ina second model, which heralded clin

FAQs

What research question drove Starzl’s liver transplant model development?

Whether hormone- and nutrient-rich portal blood is essential for optimal total-body metabolism and specifically for liver health.

How did Starzl interpret the shrinkage of transplanted liver allografts?

He proposed that the allograft may have been deprived of liver-supporting (hepatotrophic) factors in portal blood, rather than shrinkage being solely due to rejection.

What key immunological ideas influenced the move from animal models to clinical transplantation?

Donor-specific tolerance depended on histocompatibility antigen matching, and clinical bone marrow transplantation required enough human leukocyte antigens to permit matching, while pharmacological immunosuppression such as azathioprine enabled earlier graft acceptance in select cases.

Aug 26, 2026

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