The scientific foundation of modern xenotransplantation rests on genetic engineering. Pigs are the preferred organ source because their organ size and physiology roughly match those of humans, but their tissues carry sugar antigens that trigger immediate and catastrophic rejection in the human immune system. The pivotal breakthrough came with the creation of pigs in which the gene for α1,3-galactosyltransferase, the enzyme responsible for producing the galactose-alpha-1,3-galactose antigen, was knocked out. These GTKO pigs removed the single most important barrier to pig-to-human transplantation. The editorial highlights that Europeans, particularly researchers associated with Erasmus University in the Netherlands, contributed to the assessment of the first GTKO pigs, while figures such as the late David White of the United Kingdom, Eckhard Wolf of Germany, and Cesare Galli of Italy advanced the genetic engineering of organ-source pigs through successive generations of edits that now include multiple human complement-regulating and anticoagulant transgenes.

Genetic modification alone, however, cannot prevent rejection. Even with increasingly compatible donor pigs, recipients require powerful immunosuppressive regimens that must control the immune response to xenogeneic tissue without leaving patients dangerously vulnerable to infection. One of the most consequential European contributions in this area came from Leo Buhler of Switzerland, whose work demonstrated the efficacy of CD40/CD154 co-stimulation blockade in xenotransplantation models. This pathway-targeting approach, which interrupts the interaction between CD40 on antigen-presenting cells and CD154 on activated T cells, proved far more effective than earlier regimens and became a cornerstone of preclinical success. The editorial notes that novel immunosuppressants have contributed to major advances in preclinical studies in which life-supporting pig organs have sustained the lives of nonhuman primates for more than a year, and in one case for as long as five years, results that were unthinkable a decade ago.

The pig-to-nonhuman primate model deserves particular attention, because it is the testing ground on which nearly every advance of the past forty years was validated. The editorial emphasizes the importance of this model, especially when compared with studies in human decedents, which, while valuable for observing early-phase organ function, cannot capture the long-term immunological and infectious dynamics that determine whether a xenograft survives. The Munich group founded and led by Bruno Reichart played a leading role in establishing successful orthotopic pig heart transplantation in nonhuman primates, a milestone that had remained elusive until then. Achieving life-supporting function in the correct anatomical position, rather than as a heterotopic auxiliary graft, required solving problems of graft perfusion, immune attack, and thrombotic complications that only prolonged survival could reveal.

Beyond solid organs, Europeans have driven progress in cellular and islet xenotransplantation, a field with direct relevance to the millions of people living with type 1 diabetes. Islet xenotransplantation in the United States has benefited from the sustained efforts of Bernhard Hering of Germany and Rita Bottino of Italy, whose work established that pig islets can achieve long-term insulin independence in nonhuman primates under appropriate immunosuppression. More recently, Pierre Gianello and his colleague Nizar Mourad in Belgium, working with Cesare Galli in Italy, introduced a novel genetic modification by which pig pancreatic islets produce substantially more insulin than those from wild-type pigs. Because pigs need and produce less insulin than humans, these specific gene edits may allow normoglycemia to be achieved in a diabetic recipient by transplanting fewer islets, easing the burden on limited donor animals and improving the feasibility of clinical application.

Pig liver xenotransplantation represents another frontier where European researchers have left a clear mark. Burcin Ekser, with roots in Turkey and Italy, has contributed to the development of liver xenograft models, a domain that poses unique challenges because the liver performs thousands of metabolic and synthetic functions and is exposed to massive portal blood flow, making it particularly vulnerable to immune-mediated injury and coagulation dysregulation. Progress in pig kidney and lung xenotransplantation has likewise advanced through the work of Europeans in the United States and in Europe, with contributions documented across the special issue from research groups spanning multiple countries. Each organ presents its own immunological and physiological profile, and the editorial makes clear that the accumulated knowledge from these organ-specific programs has been essential to preparing for human trials.

Infectious risk remains one of the most serious concerns surrounding xenotransplantation, and here Europeans have become acknowledged leaders. Joachim Denner of Germany, Linda Scobie of the United Kingdom, and Nicolas Mueller of Switzerland have shaped the field’s understanding of porcine endogenous retroviruses, pig cytomegalovirus, and other pathogens that could potentially cross the species barrier or reactivate under immunosuppression. Their work has informed screening protocols for donor herds, the design of specific pathogen-free breeding facilities, and the monitoring strategies now being applied to the first human recipients. In basic science, Joerg Seebach and Robert Rieben of Switzerland have contributed significantly over many years, elucidating the fundamental mechanisms of innate immunity, complement activation, and coagulation dysregulation that underlie xenograft rejection.

The first clinical xenotransplantation procedures in human patients have produced results that the editorial characterizes as perhaps mixed but providing considerable encouragement. Early recipients of pig hearts and kidneys have survived for varying periods, with some grafts functioning for months and others failing sooner, and each case has drawn attention to aspects that require further investigation. The road remains an uphill climb, the editors write, yet they are encouraged that further progress will likely be made in the near future. Indeed, as never before, xenotransplantation is now perceived as a probable solution to the worldwide shortage of human organs, a shortage that claims lives daily as patients wait on transplant lists for organs that never arrive.

What makes the European story distinctive is not only the science but the movement of people. Much of the research into xenotransplantation has been carried out at centers in the United States, but in many cases the work involved Europeans who had relocated permanently or temporarily across the Atlantic. Many were young surgeons or physicians gaining research experience before returning to their home countries, where several are now leaders in the field of transplantation. This transatlantic circulation of expertise created a network of knowledge that neither continent could have built alone, and the special issue documents these contributions in dedicated reviews covering pig organ xenotransplantation and pig islet and cell xenotransplantation.

The special issue also looks forward to the practical and regulatory conditions under which xenotransplantation will reach patients in Europe. A paper on the regulation of xenotransplantation in Europe addresses the legal and ethical frameworks that will govern clinical trials on the continent, while commentaries from leaders in organ allotransplantation, including experts from the Netherlands, Austria, and Italy, offer clinical perspectives on how xenotransplantation is likely to be introduced into practice. The guest editors express the hope that readers will find the collected papers informative regarding the important, and often overlooked, role that Europeans have played in the research that has enabled clinical trials of xenotransplantation to be initiated. As the first generation of pig-organ recipients writes the opening chapters of a new therapeutic era, the editorial stands as a reminder that this achievement rests on decades of patient, often unheralded, international collaboration with Europe at its core.

Subject of Research: European contributions to pig organ and islet xenotransplantation research and clinical translation

Article Title: Editorial: Europeans and xenotransplantation

Article References: Cozzi, E., & Cooper, D. K. C. (2026). Editorial: Europeans and xenotransplantation. Transplant International, 39, Article 17780. https://doi.org/10.3389/ti.2026.17780

Image Credits: AI Generated

DOI: 10.3389/ti.2026.17780

Keywords: xenotransplantation, pig organs, genetic engineering, GTKO pigs, islet transplantation, immunosuppression, CD40/CD154 blockade, organ shortage, nonhuman primates, infectious risk, Transplant International, Europe