Xenotransplantation facts for kids
Xenotransplantation (xenos- from the Greek meaning "foreign" or strange), or heterologous transplant, is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenografts or xenotransplants. It is contrasted with allotransplantation (from other individual of same species), syngeneic transplantation or isotransplantation (grafts transplanted between two genetically identical individuals of the same species) and autotransplantation (from one part of the body to another in the same person). Xenotransplantation is an artificial method of creating an animal-human chimera, that is, a human with a subset of animal cells. In contrast, an individual where each cell contains genetic material from a human and an animal is called a human–animal hybrid.
Patient derived xenografts are created by xenotransplantation of human tumor cells into immunocompromised mice, and is a research technique frequently used in pre-clinical oncology research.
Human xenotransplantation offers a potential treatment for end-stage organ failure, a significant health problem in parts of the industrialized world. It also raises many novel medical, legal and ethical issues. A continuing concern is that many animals, such as pigs, have a shorter lifespan than humans, meaning that their tissues age at a quicker rate. (Pigs have a maximum life span of about 27 years.) Disease transmission (xenozoonosis) and permanent alteration to the genetic code of animals are also causes for concern. Similarly to objections to animal testing, animal rights activists have also objected to xenotransplantation on ethical grounds. A few temporarily successful cases of xenotransplantation are published.
It is common for patients and physicians to use the term "allograft" imprecisely to refer to either allograft (human-to-human) or xenograft (animal-to-human), but it is helpful scientifically (for those searching or reading the scientific literature) to maintain the more precise distinction in usage.
Bioprosthetic artificial heart valves are generally pig or bovine-derived, but the cells are killed by glutaraldehyde treatment before insertion, therefore technically not fulfilling the WHO definition of xenotransplantation of being live cells.
History
The first serious attempts at xenotransplantation (then called heterotransplantation) appeared in the scientific literature in 1905, when slices of rabbit kidney were transplanted into a child with chronic kidney disease. In the first two decades of the 20th century, several subsequent efforts to use organs from lambs, pigs, and primates were published.
Scientific interest in xenotransplantation declined when the immunological basis of the organ rejection process was described. The next waves of studies on the topic came with the discovery of immunosuppressive drugs. Even more studies followed Joseph Murray's first successful renal transplantation in 1954 and scientists, facing the ethical questions of organ donation for the first time, accelerated their effort in looking for alternatives to human organs.
Non-human kidney to a human
In 1963, doctors at Tulane University attempted chimpanzee-to-human renal transplantations in six people who were near death; after this and several subsequent unsuccessful attempts to use primates as organ donors and the development of a working cadaver organ procuring program, interest in xenotransplantation for kidney failure dissipated. Out of 13 such transplants performed by Keith Reemtsma, one kidney recipient lived for nine months, returning to work as a schoolteacher. At autopsy, the chimpanzee kidneys appeared normal and showed no signs of acute or chronic rejection.
Non-human heart to a human
An American infant girl known as "Baby Fae" with hypoplastic left heart syndrome was the first infant recipient of a xenotransplantation, when she received a baboon heart in 1984. The procedure was performed by Leonard Lee Bailey at Loma Linda University Medical Center in Loma Linda, California. Fae died 21 days later due to a humoral-based graft rejection thought to be caused mainly by an ABO blood type mismatch, considered unavoidable due to the rarity of type O baboons. The graft was meant to be temporary, but unfortunately a suitable allograft replacement could not be found in time. While the procedure itself did not advance the progress on xenotransplantation, it did shed a light on the insufficient amount of organs for infants. The story made such an impact that the crisis of infant organ shortage improved for that time.
Non-human heart, lungs, and kidneys to a human
The first transplant of a non-genetically modified pig's heart, lungs and kidneys into a human was performed in Sonapur, Assam in India in mid-December 1996, and was announced in January 1997. The recipient was Purno Saikia, a 32-year-old terminally-ill man; he died shortly after the operation of multiple infections. The Indian cardiothoracic surgeon Dhani Ram Baruah and two of his associates, Jonathan Ho Kei-shing (of the Hong Kong-based Prince of Wales Medical Institute) and C.S. James, performed the surgeries. Baruah claimed that Saikia had failed to respond to conventional surgery, and that the patient and his family had consented to the procedure.
All three involved in the surgery were arrested on January 9, 1997, for the alleged violation of the Transplantation of Human Organs and Tissues Act of 1994. Baruah was dismissed in medical circles as a "mad scientist" and the procedure was dubbed a "hoax". Baruah himself signed a statement saying he had done no transplant, but then alleged that the confession was forced from him. They were found guilty of unethical procedure and imprisoned for 40 days. Dhani Ram Baruah's surgical institute was also found to be without necessary registration.
Critics said Dhani Bam Baruah's claims and medical procedures were neither taken seriously nor accepted by the scientific community because he never got his findings scientifically peer-reviewed. Past complaints of ethics violations during surgeries in Hong Kong by Baruah and Ho had occurred in 1992, when they had implanted heart valves, developed by Baruah, made of animal tissue. A year later, six patients died. The Asian Medical News reported that "grave concerns" were expressed "over the procedure and ethics of the implementation".
Genetically engineered non-human kidney to a human
In September 2021, surgeons led by Robert Montgomery performed the first genetically engineered pig kidney xenotransplant to a brain-dead human at NYU Langone Health with no sign of immediate rejection (partly because the pig thymus gland was transplanted as well). The kidney was procured from a pig with only a single gene modification: the removal of alpha-gal.
Genetically engineered non-human heart to a human
In January 2022, doctors led by cardiothoracic surgeon Bartley P. Griffith and Muhammad M. Mohiuddin at the University of Maryland Medical Center and University of Maryland School of Medicine performed a heart transplant from a genetically modified pig to a terminally ill patient, David Bennett Sr., who was ineligible for a standard human heart transplant. The pig had undergone specific gene editing to remove enzymes responsible for producing sugar antigens that lead to hyperacute organ rejection in humans. The US medical regulator gave special dispensation to carry out the procedure under compassionate use criteria. The recipient died two months after the transplantation.
In June and July 2022, surgeons at NYU Langone Health performed two genetically modified pig heart transplants into recently deceased humans. The hearts were from pigs that had the identical 10 genetic modifications used in the University of Maryland Medical Center heart xenotransplantation in January 2022. All three hearts came from Revivicor, Inc., a facility based in Blacksburg, Va., and a subsidiary of United Therapeutics.
Potential uses
A worldwide shortage of organs for clinical implantation causes about 20–35% of patients who need replacement organs to die on the waiting list. Certain procedures, some of which are being investigated in early clinical trials, aim to use cells or tissues from other species to treat life-threatening and debilitating illnesses such as cancer, diabetes, liver failure and Parkinson's disease. If vitrification can be perfected, it could allow for long-term storage of xenogenic cells, tissues and organs so that they would be more readily available for transplant.
Xenotransplants could save thousands of patients waiting for donated organs. The animal organ, probably from a pig or baboon could be genetically altered with human genes to trick a patient's immune system into accepting it as a part of its own body. They have re-emerged because of the lack of organs available and the constant battle to keep immune systems from rejecting allotransplants. Xenotransplants are thus potentially a more effective alternative.
Xenotransplantation of human tumor cells into immunocompromised mice is a research technique frequently used in oncology research. It is used to predict the sensitivity of the transplanted tumor to various cancer treatments; several companies offer this service, including the Jackson Laboratory.
Human organs have been transplanted into animals as a powerful research technique for studying human biology without harming human patients. This technique has also been proposed as an alternative source of human organs for future transplantation into human patients. For example, researchers from the Ganogen Research Institute transplanted human fetal kidneys into rats which demonstrated life supporting function and growth.
Potential animal organ donors
Since they are the closest relatives to humans, non-human primates were first considered as a potential organ source for xenotransplantation to humans. Chimpanzees were originally considered the best option since their organs are of similar size, and they have good blood type compatibility with humans, which makes them potential candidates for xenotransfusions. However, since chimpanzees are listed as an endangered species, other potential donors were sought. Baboons are more readily available, but impractical as potential donors. Problems include their smaller body size, the infrequency of blood group O (the universal donor), their long gestation period, and their typically small number of offspring. In addition, a major problem with the use of nonhuman primates is the increased risk of disease transmission, since they are so closely related to humans.
Pigs (Sus scrofa domesticus) are currently thought to be the best candidates for organ donation. The risk of cross-species disease transmission is decreased because of their increased phylogenetic distance from humans. Pigs have relatively short gestation periods, large litters, and are easy to breed, making them readily available. They are inexpensive and easy to maintain in pathogen-free facilities, and current gene editing tools are adapted to pigs to combat rejection and potential zoonoses. Pig organs are anatomically comparable in size, and new infectious agents are less likely since they have been in close contact with humans through domestication for many generations. Treatments sourced from pigs have proven to be successful such as porcine-derived insulin for patients with diabetes mellitus. Increasingly, genetically engineered pigs are becoming the norm, which raises moral qualms, but also increases the success rate of the transplant. Current experiments in xenotransplantation most often use pigs as the donor, and baboons as human models. In 2020 the U.S. Food and Drug Administration approved a genetic modification of pigs so they do not produce alpha-gal sugars. Pig organs have been used for kidney and heart transplants into humans.
In the field of regenerative medicine, pancreatogenesis- or nephrogenesis-disabled pig embryos, unable to form a specific organ, allow experimentation toward the in vivo generation of functional organs from xenogenic pluripotent stem cells in large animals via compensation for an empty developmental niche (blastocyst complementation). Such experiments provide the basis for potential future application of blastocyst complementation to generate transplantable human organs from the patient's own cells, using livestock animals, to increase quality of life for those with end-stage organ failure.
Related pages
See also
In Spanish: Xenotrasplante para niños
