At present, due to a worldwide shortage, 17 people die every day while waiting for an organ transplant—nearly a third of the people on a waiting list. Xenotransplantation (transplantation of animal organs into humans) could greatly reduce this shortage if fully actualised—with a significantly in-demand and crucial donor organ being the heart.
Studies suggest the animal organ donor would likely be a pig. Baboons have been considered, but are more impractical as potential donors given their smaller body size, experience infrequent occurrence of blood group O (the universal donor), their long gestation period and small number of offspring. This affects their overall availability. Pigs, on the other hand, have a decreased risk of cross-species disease transmission due to their phylogenetic distance from humans and are more readily available. Even still, with the advent of CRISPR-Cas9 genome editing, replacement hearts can be genetically edited with human genes to deceive the patient’s immune system into accepting it.
Heart xenotransplants have been attempted many times before with little success. However, recent novel advancements have led to an overview of its scope and potential, as well as what hurdles still remain. If heart xenotransplantation truly is an option, they are a potentially more effective and readily available alternative to allotransplants, that could become safe, accessible and truly life-extending.
Trials, Failures and Successes
There have been multiple attempts at animal heart-to-human transplants in the past. One of the earliest attempts was in 1984, when an America infant girl, Stephanie Fae Beuclair or “Baby Fae”, was born with hypoplastic left heart system in which the left side of the heart is severely underdeveloped and unable to support the system circulation. The procedure performed at Loma Linda University Medical Centre involved a baboon heart and was the first successful infant heart transplant ever. However, three weeks later, Baby Fae still died of heart failure due to rejection of the heart transplant. This is thought to have been caused by an unavoidable humoral response due to an ABO blood type mismatch. Type O baboons (universal donors) are very rare, and all the baboons involved were type AB. the rarity of type O baboons.
The first transplant of a non-genetically modified pig heart xenotransplantation happened in India in December 1996. The patient was Purno Saikia, a 32-year-old terminally ill man who died shortly after the operation due to multiple infections. The procedure was condemned by medical institutions due to the unethical conditions and malpractice. The instance was accepted by the scientific community because the findings were never scientifically peer-reviewed.
In more recent years, researchers have successfully transplanted pig hearts into baboons and saw them survive for 945 days. However, these transplanted hearts were not essential to the life of the recipients, and life-supported pig-to-baboon transplants have only lasted about two months. Nevertheless, researchers found that organ survival after transplantation could be improved by intermittently pumping (perfusing) a blood-based, oxygenated solution containing nutrients and hormones through the hearts at a low temperature. (Fig. 1).
This optimised protocol was tested in five more baboons. First, they reduced the baboons blood pressure to resemble that of pigs, before giving the baboons temsirolimus (a drug that combats heart overgrowth by stifling cell proliferation). Finally, they modified the standard hormone-treatment regimen. Out of five, two baboons lived healthily for three months, another two lived for over six months before being euthanised for non-health related reasons, and one died after 51 days. The survival rate was highly impressive and a cause for hope.
Finally, in the most recent occurrence, in January 2022, doctors led by surgeon Bartley Griffith at the University of Maryland Medical Center performed a heart transplant from a genetically modified pig heart into a terminally ill patient, 57-year-old David Bennet Sr., who was ineligible for a standard allotransplant. Bennett had been on cardiac support for almost two months and could not receive a mechanical heart pump because of an irregular heartbeat. He could not receive a human transplant, because he had a history of not complying with treatment instructions. Since he otherwise faced certain death, the researchers received special permission from the FDA to carry out the procedure under compassionate use criteria.
The pig involved had undergone ten genetic modifications. The company who owned the pig, Revivicor, removed three pig genes that would produce enzymes responsible for producing sugar antigens that would lead to hyperacute organ rejection. They also added six human genes to help the body accept the organ. To modify the pig heart used in the transplant, the company removed three pig genes that trigger attacks from the human immune system, and added six human genes that help the body to accept the organ. A final modification aimed to prevent the heart from responding to growth hormones, ensuring that organs from the 400-kilogram animals remain human-sized.
The surgery initially succeeded and the patient was well. The heart was not immediately rejected and continued to function for over a month, surpassing a critical milestone for transplant patients. However, two months after the transplantation, the recipient died. The exact cause of death is currently unclear, but there are many limitations inherent to xenotransplantation that could be the cause.
Limitations & Setbacks
The most prevalent and reoccurring limitation of xenotransplantation is organ rejection and immune system response. Some degree of rejection is inevitable, but can be limited with drugs that suppress the immune system. ‘Xenozoonoses’ are the biggest threat to rejection, as they are xenogenetic infections which can lead to fatal infections and then rejection of the organs. There are several types of rejection organ xenografts face, including hyperacute rejections, acute vascular rejection, cellular rejection and chronic rejection.
Hyperacute rejection is rapid and violent and occurs within minutes to hours from the time of the transplant. Strategies to overcome it include interruption of the immune system response of the complement cascade by the use of cobra venom factor. However, the toxicity of cobra venom factor could be harmful and could potentially deprive the individual of a functional complement system. Transgenic organs in which the enzyme that could for immune system ‘flags’ and express human complement regulators instead are also an option. Even if this is surpassed, there is still acute vascular rejection, which can occur with 2 to 3 days and can be dreamed with immunosuppressive drugs, and cellular rejection, due to the response of the humoral immune system, are still highly likely to occur.
Furthermore, if all these stages of organ rejection have been surpassed, there is still the poorly-understood prospect of chronic rejection, which David Bennet Sr. is likely to have suffered from. Chronic rejection is slow and progressive, and scientists are still unclear on how precisely it works. It is known that XNAs and the complement system are not primarily involved. Chronic rejection leads to pathologic changes of the organ, and why transplants must often be replaced after many years. It is likely that chronic rejection will be more aggressive in xenotransplants than allotransplants.
There is one final major risk: porcine endogenous retroviruses, or PERVs. These are pig-viruses which could be transmitted to humans. While the risk of PERV-related complications are considered to be small, regulatory authorities worldwide view the possibility with caution. However, on this front, genome-editing technology such as CRISPR-Cas9 has led to researchers being able to produce live, healthy pigs in which PERVs and their related genes have been deactivated, indicating one way in which PERV-transmission can be circumvented. Regardless, there are still many hurdles before heart xenotransplantation is fully realised.
The journey of animal-to-human heart transplantation is a long and convoluted one, and one that is likely to continue facing challenges and setbacks. Nevertheless, promising advancements have been made in the past few years alone. Even in the most recent case of David Bennet Sr.’s unfortunate death after his pig-heart transplant, there is the consideration that he multiple pre-existing health conditions may have had just as much to play in his untimely death as the transplant itself. Researchers and doctors alike will have many things to take into account, from informed patient consent to the possibility of disease transfer from animals to humans, but consideration of risks should not stop safe research into a field with much power to help those in need.
Ishika Jha Youth Medical Journal 2022
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