Xenotransplantation: A Potential Alternative to Traditional Transplants

January 7th, 2022 marked a monumental moment in the history of medicine. Physicians at the University of Maryland Medical Center transplanted a genetically modified pig heart into David Bennett Sr., a 57-year-old man who was ineligible for a conventional human heart transplant. The pig heart was successfully able to function normally for the first few weeks after the transplant. The hospital reported that Mr. Bennett was able to do physical therapy and watch the Super Bowl from his hospital bed.¹ This procedure was a significant step forward for xenotransplantation, the transplantation of living cells, tissue, or organs from nonhuman donors into human recipients.

Xenotransplantation dates back to the 1660s when French physician Jean-Baptiste Denis performed blood transfusions using lamb’s blood. Unfortunately, his procedures led to a man’s death and the subsequent banning of the practice in France. Xenotransplantation reemerged in the late 19th and early 20th centuries, which primarily included corneal and cell xenotransplantation. In the 1960s, Keith Reemtsa performed 13 kidney xenotransplants from chimpanzee donors for patients with renal failure. Although most failed within 4 to 8 weeks due to rejection or infectious complications, one patient lived for nine months in good health before suddenly passing since chimpanzee kidneys do not function the same way as human kidneys, so the patient suffered from excess urination and electrolyte balances. Nonetheless, Reemtsma’s work inspired other physicians to investigate the potential of xenotransplantation. James Hardy, the surgeon who conducted the first human lung transplant, later transplanted a chimpanzee heart, which failed within hours since it was too small. Hardy received considerable more backlash for the procedure, as he had not obtained informed consent from the patient’s relatives. In 1983, Leonard Bailey transplanted a baboon heart into Baby Faye, an infant with life-threatening congenital heart disease. The transplant failed since the organ was not compatible with the patient’s blood type, and Baby Faye died 20 days later.² Each of these experimental procedures revealed crucial information about xenotransplantation, its physiological barriers, and possible solutions.

Many transplant cases in the 19th century found relative success in nonhuman primate donors since they are closely related evolutionarily to humans. Currently, the only nonhuman primates of sufficient size are endangered, and transmission of viruses poses a considerable problem between closely related species. Pigs are a reasonable alternative since they are readily available, can be bred quickly in controlled environments, and can be genetically modified.² However, immune system complications pose a serious obstacle to xenotransplantation.

Xenotransplantation between different species introduces the risk of immune system rejection and virus transmission. Human bodies produce antibodies that target cells from non-primate species, resulting in hyperacute rejection within minutes to hours of the procedure. Acute vascular rejection, a delayed immune response, can also occur within hours to days of surgery and cause blood clotting in the transplanted organ. Animals also harbor diseases as well, such as retroviruses that can harm the human recipient. Xenotropic organisms can harm non-host species, and retroviruses can insert themselves into the human recipient’s genes and lead to cancer.

Many new technologies and therapeutics are addressing the immunological complications of xenotransplantation. On the recipient’s side, inhibitory agents that prevent the formation of or destroy antibodies can help prevent immune system rejection of xenotransplant organs. CRISPR gene editing can remove the genes that code for proteins that the human body responds to on the donor side. For instance, normal pig cells express the alpha-gal protein on the cell surface, which leads to human xenotransplant rejection and red meat allergies. Gene-editing technologies have successfully removed the gene that codes for this protein, producing alpha-gal-free pigs. Genetically modified animals can also express regulatory proteins that protect their organs from human immune systems.³ In David Bennett’s case, scientists knocked out three genes associated with antibody rejection and inserted six human genes related to immune system acceptances in the donor pig’s genome. Advances in gene-editing technologies and therapeutic drugs provide hope that xenotransplantation could be utilized more widely in the future.

As of September 2021, there were over 100,000 people on the national transplant waitlist. Seventeen people die each day waiting for a transplant.⁵ In its current state, xenotransplantation is still experimental and holds many limitations. Immune system rejection is not wholly understood, and most xenotransplanted organs fail within several weeks. On March 9th, Mr. Bennett passed away two months after the heart transplant procedure. His condition had deteriorated for several days, and he passed away under palliative care.¹ While xenotransplantation cannot currently be considered life-prolonging in the long term, it may mitigate the current human organ shortage.

References

1. University of Maryland School of Medicine | In Memoriam: David Bennet Sr. by Deborah Kotz
2. International Journal of Surgery| A Brief History of Clinical Xenotransplantation by David K. C. Cooper, MD, PhD; Burcin Ekser, MD, PhD; A. Joseph Tector MD, PhD
3. Medscape | Xenotransplantation by Oya M. Andacoglu, MD; Ron Shapiro, MD
4. New York Times | In a First, Man Receives a Heart From a Genetically Altered Pig by Roni Caryn Rabin
5. Health Resources and Service Administration | Organ Donation Statistics