By: Emma Robinson, Biological Sciences and English ‘2027
Animal-to-human organ transplantation, otherwise known as xenotransplantation, could revolutionize transplant medicine and save millions of lives. In the 17th and 18th centuries, blood transfusions from various organisms into humans were attempted as a method of blood replacement. In the 19th century, skin grafts, especially using frog skin, were utilized experimentally. In the 1900s, chimpanzee kidney and heart transplants were also attempted without successful outcomes [1]. Current transplant medicine focuses on transplantation of organs grown in pigs as chimpanzees have become endangered. Pig organs are a promising option as they are quite similar to those of humans and they are easy to genetically modify [2].
The experimental use of pig tissues in human medicine has been ongoing for over half a century. Pig tissue has been used to replace heart valves since the 1960s. They are often a great option for older patients who are at lower risk for the structural valve deterioration associated with long-term use. This structural valve deterioration is likely due to immune rejection of the tissue [3]. Skin grafts from pigs are also currently used on a short term basis on burn victims while they wait for the availability of other grafts, but are not long term options because of immune rejection [4].
The current focus of xenotransplantation is the transplant of whole organs. Before transplanting solid pig organs directly into humans, transplant trials were performed in non-human primates. [5]. There were several pig-derived kidney transplants into chimpanzees and baboons that proved to be successful for even up to a year. However, the differing immune systems of non-human primates mean these transplants offer limited insights into xenotransplantation success in humans[5]. In 2022, three pig-to-human kidney transplants were completed. These surgeries were performed on brain-dead patients with family consent for the benefit of medical science, not life extension, resulting in short-term experiments. Two of the experiments lasted 54 hours and the third lasted 77 hours. In all three cases, the kidneys functioned properly for the entire planned experiment time [5]. However, this was not enough time to tell how the transplants would fare long-term. Another kidney xenotransplant was performed on a brain-dead patient in 2023, lasting a total of 61 days. This team was able to better understand the immune response to the kidney and did note rejection that required increasing immunosuppression medication. This observation was completed on September 13, 2023 and the doctors continue to evaluate their findings [6].
Finally, several transplants have been completed in patients in attempts to extend life. Within the past two years, two heart transplants from pigs to humans have had limited success. The first recipient, a man named David Bennet Sr., was able to live two months with the transplanted heart. Doctors gained new insights from this transplantation despite Bennet going into cardiac failure at the end of the two months. Bennet was never a candidate for a traditional transplant because he was in end stage heart failure along with other health complications [7]. The main issue the team found in this xenotransplantation was immune rejection. This was likely worsened by Mr. Bennet's immunocompromised state before surgery which prevented the use of proper anti-rejection measures. The team found that an antibody-containing drug administered to the patient after surgery might have contributed to the aggressive immune response [7]. There is also some evidence that a virus called porcine cytomegalovirus may have laid dormant and later impacted the health of the transplanted organ [8]. However, it was an important finding that the organ was not initially rejected during the first seven weeks after the transplant [7]. The second recipient was able to live for six weeks with a xenotransplanted heart. This patient was also in end-stage heart failure at the time of transplant. The final paper has not been published on this trial, but earlier articles indicate that the donor pig had undergone 10 gene mutations to alleviate negative immune responses [9]. The most recent development in the field of xenotransplantation was a pig kidney to viable 62-year-old human recipient in renal failure on March 16, 2024. The pig underwent a record total of 69 genomic edits to decrease the risk of rejection by the patient. Current updates state the transplant has been successful thus far [10].
The moderate success of xenotransplantation opens up a new life saving treatment for patients in need of organ replacement. However, there are technological and ethical challenges that still need to be addressed. These organs must be grown in animals that are genetically modified for this purpose. This is a point of contention amongst animal rights activists as animals being used in any experiments or tests in medicine are subject to some level of harm or discomfort. The patients who are undergoing these early xenotransplantations are also either brain-dead or have no other treatment options. While family or patient approval is obtained, the question remains whether it is ethical to put humans through procedures that have minimal chance of a beneficial outcome to the patients themselves.
There are still major issues with immune rejection of these organs. Although these procedures are initially successful in the few recent xenotransplantations, they have not yet proven to be viable long-term solutions. However, if the immune barriers can be overcome, millions of lives could be saved. Instead of waiting for years on a transplant list, patients could receive life-saving xenotransplants quickly and avoid the irreversible impacts of long-term organ failure.
References
Cooper, D. (2012). A brief history of cross-species organ transplantation. Proceedings (Baylor University. Medical Center), 49-57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246856/
Groth, C. G. (2007). The potential advantages of transplanting organs from pig to man: A transplant surgeon's view. Indian Journal of Urology, 305-309. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721611/
Manji, R. A., & Manji, J. S. (2020). Studying xenograft rejection of bioprosthetic heart valves. Methods in Molecular Biology, 227-243. https://pubmed.ncbi.nlm.nih.gov/32002912/
Yamamoto, T., Iwase, H., King, T. W., Hara, H., & Cooper, D. K. C. (2018). Skin xenotransplantation: Historical review and clinical potential. Burns, 44(7), 1738-1749. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160369/
Boyle, P. (2022, February 23). How pig organs made their way into humans: The slow advance to transplant kidneys and hearts. AAMC. Retrieved February 28, 2024, from https://www.aamc.org/news/how-pig-organs-made-their-way-humans-slow-advance-transplant-kidneys-and-hearts
Two-Month study of pig kidney xenotransplantation gives new hope to the future of the organ supply. (2023, September 14). NYU Langone Health. Retrieved February 28, 2024, from https://nyulangone.org/news/two-month-study-pig-kidney-xenotransplantation-gives-new-hope-future-organ-supply
Kotz, D. (2023, June 30). Lessons learned from world's first successful transplant of genetically-modified pig heart into human patient. University of Maryland School of Medicine. Retrieved February 28, 2024, from https://www.medschool.umaryland.edu/news/2023/lessons-learned-from-worlds-first-successful-transplant-of-genetically-modified-pig-heart-into-human-patient-.html
Aschheim, K., & DeFrancesco, L. (2023). Xenotransplantation: How close are we? Nature Biotechnology, 41, 452-460. https://www.nature.com/articles/s41587-023-01730-x
Kotz, D. (2023, September 22). UM medicine faculty-scientists and clinicians perform second historic transplant of pig heart into patient with end-stage cardiovascular disease. University of Maryland School of Medicine. Retrieved February 28, 2024, from https://www.medschool.umaryland.edu/news/2023/um-medicine-faculty-scientists-and-clinicians-perform-second-historic-transplant-of-pig-heart-into-patient-with-end-stage-cardiovascular-disease.html
Mallapaty, S., & Kozlov, M. (2024, March 22). First pig kidney transplant in a person: What it means for the future. Nature. Retrieved March 31, 2024, from https://www.nature.com/articles/d41586-024-00879-y