The History of Transplants and How Xenotransplantation can be Used to Save Human Lives
A kidney transplant was the first human organ transplant to be successfully performed in 1954.(1) Many of the previous attempts all ended in rejection and even as technological advances continued over the next 15 years, the overall survival rate still remained relatively low.(2) The early successful kidney organ transplants were performed in identical and dizygotic twins originally, but through immunosuppression by total body irradiation and other chemical suppressants, successful transplants in non-twin recipients became possible. The addition of chemical immunosuppressants, such as prednisone and azathioprine, drastically improved 1-year graft survival rates, and opened the door to the formation of many new transplant centres across the United States. Liver, heart and pancreas transplants followed in the late 1960s, while lung and intestinal organ transplants were not successfully performed until the 1980s. Organ preservation techniques further expanded the potential of organ sharing across transplant centres, allowing for the expansion of the field.(3) These early successes were possible as medical advancements in preventing and treating organ rejection were made.
Today, organ transplant recipients must commit to a cocktail of immunosuppressants, usually for the rest of their lives, to be able to accept an organ from donors. In 2021, over 40, 000 Americans received a transplanted organ – the largest number of transplants ever to be performed in a single year.(4) Even with this impressive feat, about a dozen people waiting for transplants die each day due to the shortage of organs.
We are now on the cusp of a new revolution in transplant technology – xenotransplantation, which allows us to utilize animal cells, tissues or organs for in human recipients. A strong medical unmet need exists for tissue and organ transplants, as the demand for organ transplants far exceeds the available supply. Xenotransplantation is a promising alternative to bridge this gap in the supply and demand of organs, tissues and cells.(5) Currently, animal valves are used in clinical practice, but these grafts are largely structural tissues that don’t rely on any animal cells and the tissues are repopulated with human recipient cells following transplant. Decellularized pig corneal anterior lamellar grafts for corneal blindness are being successfully performed in China with encouraging results.(5) Tissue heart values, often made from pig heart valves or cow heart-sac tissue can last from 10 to 20 years and have been used in humans for over 50 years.(6)
The biggest issue in transplanting other tissues or organs stems from immunological barriers causing incompatibility between humans and other animals, which leads to organ rejection. Typically, a rapid innate immune response, involving natural anti-pig antibodies, complement activation and an innate cellular response is first activated driving an inflammatory response, followed by the mobilization of the adaptive immune response, which collectively causes organ rejection.(5) In recent years, the use of CRISPR-gene editing technology has allowed for genetic mutations to be introduced that would hopefully eliminate the aggressive human rejection response. Improved immunosuppressive therapies will also allow for prolonged xenograft survival, making xenotransplantation more viable. Since the 1990s, researchers have focused on pigs as the best candidate source animal for xenotransplantation as they have a lot of physiological similarity to humans, with relatively large litter sizes and lower risk of zoonosis than other animals. Although non-human primate (NHP) organs are more physiologically similar, many logistical barriers exist such as ethical concerns, high risk of cross-species infection transfer and difficulties in breeding.(5) Most research and development into the potential of xenotransplants has involved pig-to-NHP preclinical studies to drive discoveries and make this feasible in humans.
Most recently, the first successful transplant of a pig’s heart into a human being was performed in a grueling eight-hour operation at the University of Maryland Medical Centre.(7) The patient, David Bennett Sr. was too sick to qualify for a human heart donor and made the decision to accept the experimental pig transplant as his only chance. Months prior to this, genetically-engineered pig kidneys were successfully transplanted into two brain-dead people at New York University and the University of Alabama.(8)
The pig heart came from a regenerative medicine company based in the US called Revivicor. To achieve this feat, they had to knock out four genes to dampen the rejection response and to inhibit the heart from continuing to grow once transplanted.(7) They also added in six human genes to make the pig heart more tolerable to the human immune system. Although it was a successful heart transplant for the first two months, Bennett eventually passed away. It is still not clear exactly what was the cause of death, but it was discovered that the pig heart was infected with porcine cytomegalovirus and that this may have contributed to his death.(9)
The transmission of animal pathogens to human recipients has been a major concern in the field of xenotransplantation. A key concern has been porcine endogeneous retroviruses (PERVs) because they are integrated into the porcine genome with multiple copies.(10) Although PERV transmission from pig-to-human and human-to-human cells has been detected in vitro, it is not clear whether they would infect primary cells in an actual human, especially because most cell surfaces lack the necessary functional receptor.(11,12) Inactivation of PERVs is possible through RNA interference or CRISPR technologies, but it is not clear if it is necessary for success.(13)
With each new discovery and increasing clinical experience, transplantation success rates and xenotransplantation capabilities are continuously improving. Developing the ideal genetically engineered organ-source pig and a successful immunosuppressive regimen will be critical to be able to realize the full potential of xenotransplantation. Although this first-in-humans transplant did not achieve the desired outcome, further development of this model in preclinical transplants with other animals will be necessary before further attempts to succeed in humans.
- Barker CF, Markmann JF. Historical overview of transplantation. Cold Spring Harb Perspect Med. 2013 Apr 1;3(4):a014977.
- Hume DM, Merrill JP, Miller BF, Thorn GW. Experiences with renal homotransplantation in the human: report of nine cases. J Clin Invest. 1955 Feb;34(2):327–82.
- McDonald JC. The National Organ Procurement and Transplantation Network. JAMA. 1988 Feb 5;259(5):725–6.
- United Network for Organ Sharing. History of Transplantation [Internet]. 2022 [cited 2022 May 6]. Available from: https://unos.org/transplant/history/
- Cooper DKC, Gaston R, Eckhoff D, Ladowski J, Yamamoto T, Wang L, et al. Xenotransplantation-the current status and prospects. Br Med Bull. 2018 Mar 1;125(1):5–14.
- Manji RA, Lee W, Cooper DKC. Xenograft bioprosthetic heart valves: Past, present and future. Int J Surg. 2015 Nov;23(Pt B):280–4.
- Rabin, Roni Caryn. In a First, Man Receives a Heart From a Genetically Altered Pig. New York Times [Internet]. 2022 Jan 10 [cited 2022 May 6]; Available from: https://www.nytimes.com/2022/01/10/health/heart-transplant-pig-bennett.html
- Rabin, Roni Caryn. Kidneys From a Genetically Altered Pig Are Implanted in a Brain-Dead Patient. New York Times [Internet]. 2022 Jan 20 [cited 2022 May 6]; Available from: https://www.nytimes.com/2022/01/20/health/transplants-pig-human-kidney.html
- Regalado, Antonio. The gene-edited pig heart given to a dying patient was infected with a pig virus. MIT Technology Reviews [Internet]. 2022 May 4 [cited 2022 May 6]; Available from: https://www.technologyreview.com/2022/05/04/1051725/xenotransplant-patient-died-received-heart-infected-with-pig-virus/
- Lu T, Yang B, Wang R, Qin C. Xenotransplantation: Current Status in Preclinical Research. Front Immunol. 2019;10:3060.
- Denner J, Specke V, Thiesen U, Karlas A, Kurth R. Genetic alterations of the long terminal repeat of an ecotropic porcine endogenous retrovirus during passage in human cells. Virology. 2003 Sep 15;314(1):125–33.
- Denner J. Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? Retrovirology. 2018 Apr 2;15(1):28.
- Güell M, Niu D, Kan Y, George H, Wang T, Lee IH, et al. PERV inactivation is necessary to guarantee absence of pig-to-patient PERVs transmission in xenotransplantation. Xenotransplantation. 2017 Nov;24(6).