The History of Transplants and How Xenotransplantation can be Used to Save Human Lives

Doctors performed the first successful human organ transplant, a kidney transplant, in 1954.(1) Earlier attempts had all ended in rejection. Even as technology advanced over the next 15 years, overall survival rates stayed relatively low.(2) The earliest successful kidney transplants happened between identical and dizygotic twins. Immunosuppression through total body irradiation and other chemical suppressants later made successful transplants possible between non-twin recipients too.

Adding chemical immunosuppressants like prednisone and azathioprine dramatically improved 1-year graft survival rates and opened the door to many new transplant centers across the United States. Liver, heart, and pancreas transplants followed in the late 1960s, while lung and intestinal transplants weren’t successfully performed until the 1980s. Better organ preservation techniques expanded the potential for organ sharing across transplant centers, growing the field further.(3) These early successes depended on medical advances in preventing and treating organ rejection.

Today, organ transplant recipients must commit to a lifelong cocktail of immunosuppressants to accept an organ from a donor. In 2021, over 40,000 Americans received a transplanted organ — the largest number of transplants ever performed in a single year.(4) Even with this progress, about a dozen people waiting for transplants die every day because of the organ shortage.

We’re now on the edge of a new revolution in transplant technology: xenotransplantation, which lets us use animal cells, tissues, or organs in human recipients. There’s a strong unmet medical need for tissue and organ transplants, since demand far outpaces the available supply. Xenotransplantation offers a promising way to bridge this gap.(5) Animal heart valves are already used in clinical practice today, but these grafts are mostly structural tissue that doesn’t rely on animal cells — the tissue gets repopulated with the recipient’s own cells after transplant. Decellularized pig corneal grafts for corneal blindness are being performed successfully in China with encouraging results.(5) Tissue heart valves, often made from pig heart valves or cow heart-sac tissue, can last 10 to 20 years and have been used in humans for over 50 years.(6)

The biggest challenge in transplanting other tissues or organs comes from immunological barriers that cause incompatibility between humans and other animals, leading to organ rejection. Typically, a rapid innate immune response — involving natural anti-pig antibodies, complement activation, and an innate cellular response — kicks off an inflammatory reaction, followed by the adaptive immune response, which together cause rejection.(5) In recent years, CRISPR gene-editing technology has made it possible to introduce genetic mutations that could eliminate the aggressive human rejection response. Better immunosuppressive therapies should also help xenografts survive longer, making xenotransplantation more viable.

Since the 1990s, researchers have focused on pigs as the best source animal for xenotransplantation. Pigs are physiologically similar to humans, have relatively large litter sizes, and carry a lower risk of zoonosis than other animals. Non-human primate (NHP) organs are more physiologically similar to ours, but many logistical barriers stand in the way — ethical concerns, a high risk of cross-species infection, and difficulties breeding them.(5) Most research into xenotransplants has used pig-to-NHP preclinical studies to drive discoveries and work toward making this feasible in humans.

Most recently, surgeons at the University of Maryland Medical Center performed the first successful transplant of a pig’s heart into a human, in a grueling eight-hour operation.(7) The patient, David Bennett Sr., was too sick to qualify for a human heart donor and chose to accept the experimental pig transplant as his only option. A few months earlier, surgeons had successfully transplanted genetically-engineered pig kidneys into two brain-dead patients at New York University and the University of Alabama.(8)

The pig heart came from Revivicor, a US-based regenerative medicine company. To pull this off, researchers knocked out four genes to dampen the rejection response and stop the heart from continuing to grow after transplant.(7) They also added six human genes to make the pig heart more tolerable to the human immune system. The transplant succeeded for the first two months, but Bennett eventually passed away. The exact cause of death isn’t fully clear, but researchers discovered the pig heart was infected with porcine cytomegalovirus, which may have contributed.(9)

Transmitting animal pathogens to human recipients has long been a major concern in xenotransplantation. One key concern is porcine endogenous retroviruses (PERVs), which are integrated into the porcine genome in multiple copies.(10) Researchers have detected PERV transmission between pig and human cells, and between human cells, in vitro. But it’s not clear whether PERVs would infect primary cells in an actual person, especially since most cell surfaces lack the receptor they need.(11,12) Inactivating PERVs is possible through RNA interference or CRISPR technologies, though it’s not clear yet whether that’s necessary for success.(13)

With each new discovery and growing clinical experience, transplantation success rates and xenotransplantation capabilities keep improving. Developing the ideal genetically engineered organ-source pig, along with a successful immunosuppressive regimen, will be key to realizing xenotransplantation’s full potential. This first-in-human transplant didn’t achieve the outcome researchers hoped for, but further work in preclinical transplants with other animals will be necessary before doctors attempt this in humans again.

References

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2. 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):327–382.
3. McDonald JC. The National Organ Procurement and Transplantation Network. JAMA. 1988 Feb 5;259(5):725–6.
4. United Network for Organ Sharing. History of Transplantation [Internet]. 2022 [cited 2022 May 6]. Available from: https://unos.org/transplant/history/
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8. 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
9. 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/
10. Lu T, Yang B, Wang R, Qin C. Xenotransplantation: Current Status in Preclinical Research. Front Immunol. 2019;10:3060.
11. 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.
12. 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.
13. 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).