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Xenotransplantation: First pig-to-human heart transplant and its implications

On 7th January, 2022, Dr. Bartley Griffith and his team transplanted a heart from a genetically modified pig into a human at the University of Maryland Medical Centre, Maryland, Baltimore. The surgeons are closely monitoring the patient, 57 year old David Bennett, who appears to have not rejected the organ till date. The patient is currently on immunosuppressants and a new experimental drug to prevent his body from rejecting the donor pig’s heart. This surgery has further deepened the conundrum surrounding the practice of xenotransplantation in the medical fraternity. 

Physicians and scientists worldwide have for decades been pursuing transplanting animal organs into people, known as xenotransplantation or xenograft transplantation. Xenotransplantation helps to deal with the global organ shortage but there are several risks associated with using animal organs. The chances of the human body rejecting an animal organ is much higher than rejecting a human organ. The animal organs, naturally, are not catered to the human body hence it might grow more or less than what is required.  Many animal support groups also raise questions on the ethical nature of xenotransplantation further adding on to the dilemma. 

One of the first few attempts of xenotransplantation in humans was performed in 1984 on Stephanie Fae Beauclair otherwise known as Baby Fae, an American infant born with hypoplastic left heart syndrome. The surgeons at the Loma Linda University Medical Centre, California, transplanted the heart of a baboon into the baby, making her the first subject in a xenotransplant procedure and infant heart transplant. However, the patient died within 21 days of the procedure due to organ rejection. Hence the experiment was abandoned. 

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Scientists and medical researchers have since then performed xenotransplantation in other animal models such as non-human primates. However, non-human primates tend to have antibodies that humans don’t, which attack proteins on donor organs, so a lot of work has gone into making the organs suitable for the non-human primates, not people. This is one of the biggest limitations of animal models. Genetically modified donor animals is a safer, more plausible solution as the scientists could modify the genome of the donor animal to make it more compatible with the human body and minimize organ rejection. 

The pig is the most commonly used animal for making genetically modified organs for humans. Various genome editing techniques such as CRISPR–Cas9 technology are used to add or remove genes to make genetically altered pig cells which grow into pig embryos. These modified pigs are raised in a controlled bio-sealed environment. Once they have grown, the organs are harvested from the pigs to be transplanted into humans. The FDA had approved the use and rearing of genetically modified pigs for medical and agricultural purposes in December, 2020. 

Several companies are engineering pigs for solid organ transplants with different genetic modifications, although none yet has medical-grade facilities, except United Therapeutics. eGenesis in Cambridge, Massachusetts, is making pigs that cannot pass on retroviruses that are present in all pig genomes. NZeno in Auckland, New Zealand, is breeding miniature pigs whose kidneys remain human-sized without growth-hormone modifications.

In 2021, surgeons at New York University Langone Health transplanted kidneys from the same line of genetically modified pigs into two legally dead people with no discernible brain function. The deceased recipients’ bodies (sustained on ventilators) did not reject the organs which continued to function normally. 

The researchers at the University of Maryland Medical Centre had applied to the FDA to do a clinical trial of the pig hearts in people, but were turned down. However, David Bennett gave the team a chance to perform the transplant. Bennett had been on cardiac support (ECMO) for almost two months and was deemed ineligible for an artificial heart pump due to arrhythmia. He did not qualify to be on the transplant list because he had a history of not complying with doctors’ treatment instructions. Given that he otherwise faced certain death, the researchers got permission (compassionate use provision) from the FDA to give Bennett the pig heart.

Three genes, responsible for rapid antibody-mediated rejection of pig organs by humans, were knocked out and six human genes responsible for immune acceptance were inserted into the genome of the donor pig. An additional gene in the pig was edited out to prevent excessive growth of the pig heart tissue, which totaled 10 unique gene modifications made in the donor pig. Revivicor, (United Therapeutics) a regenerative medicine company based in Blacksburg, Virginia, provided the genetically-modified pig to perform the xenotransplantation. 

At the moment, xenotransplantation is limited by the cost of making and rearing the genetically modified animals, the supply of said animals and regulatory hurdles. The question on the ethical nature of using genetically modified animals and the general discomfort of the recipients to have animal organs transplanted into them are some other obstacles of xenotransplantation. 

Note: The article is based on the data available till January 17th, 2022

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