Need to revisit cross-species transplantation

Dinesh C. Sharma

Science Commentator

IN the last week of March, the medical world reached a new milestone. The Massachusetts General Hospital announced the transplant of a genetically edited pig kidney into a person suffering from kidney failure. Seven decades ago, the same hospital had carried out the world’s first human kidney transplant. The pig kidney was genetically edited to remove potentially harmful pig genes and to add certain human genes to improve its compatibility with the recipient. Some pig retroviruses were also inactivated to eliminate any risk of infection after the transplant. The pig kidney underwent 69 genomic edits before being transplanted into a living patient.

The transplant brings a glimmer of hope for millions of patients with end-stage kidney disease who are waiting for cadaver kidneys for transplant. It is difficult to predict how long it will take for the technique to become a routine procedure. It all depends on how well the donor’s body copes with a pig organ and for how long. The patient was on dialysis for many years, and would not need it any more if his new kidney performs well.

The medical world is keeping its fingers crossed given the experience of another such transplant in recent years. In January 2022, a genetically modified pig heart was transplanted into a human patient suffering from total heart failure at the University of Maryland School of Medicine. The recipient suffered a sudden heart failure and died two months after the transplant. A detailed analysis found several reasons for the pig’s heart failing. The patient was given a drug that contained antibodies to prevent infection, but these antibodies may have damaged heart muscle cells. In the heart tissues recovered from the recipient after his death, doctors found the presence of a latent pig virus, PCMV, in the pig heart that could have contributed to heart failure, though there was no evidence of the virus infecting the heart or other organs of the recipient.

For more than half a century, medical scientists and clinicians all over the world have been experimenting with the transplantation of animal organs into humans — a branch of science known as xenotransplantation. They have been experimenting with mainly hearts and kidneys drawn from chimpanzees, baboons and pigs. The preferred animal is a pig because it is similar to humans in organ size and physiology. Before human organ transplantation became possible, scientists tried transplanting animal organs into humans. The difference now is that the advances in the gene-editing technology, CRISPR-Cas9, have helped make animal organs seemingly more compatible with the human body. Early experiments with gene-edited pig organs involved transplanting a pig kidney into a deceased man who was maintained on a ventilator to study the functioning and acceptance of the new kidney. Another long series of studies involved identifying infectious agents in pigs.

India has had a fair share of experiments and controversies in human as well as xenotransplantation. Dr PK Sen, a pioneering surgeon in Mumbai, started experimenting with transplantation in animals first in the 1950s. His team performed experiments on hundreds of dogs to study immune rejection and different techniques of heart transplantation. These studies helped him prepare for the transplantation of a human organ — India’s first ever human kidney transplant using a kidney from a cadaver donor done in May 1965. The patient died after 11 days because of acute myocardial infarction. Dr Sen carried out the second kidney transplant in April 1966 using a cadaver donor kidney, but the recipient died three days later. Encouraged by these transplants and his experiments with dog hearts over the decade, Dr Sen carried out the first heart transplant using a cadaver heart in a heart failure patient. The transplanted heart worked only for three hours. Dr Sen, however, did not attempt any animal-to-human transplant. His transplant surgeries were criticised as he had used organs from ‘brain-dead’ persons when no such condition was legally recognised in India then.

The first animal-to-human transplant was done by Dr Dhani Ram Baruah at his hospital at Sonapur in Assam’s Kamrup district on January 1, 1997. He transplanted a pig heart — and other organs — into 32-year-old heart patient Purno Saikia in an operation that he claimed was successful. Saikia died on January 7 after a second surgery during which it was discovered that he had infarction of organs as well as infection. Dr Baruah was arrested, but he claimed that the detention was illegal since the Transplantation of Human Organs Act passed in 1994 had still not been notified in Assam. The scientific details of the surgery too remained a mystery as Dr Baruah never published them in any scientific journal. Since he did not subject his work to peer scrutiny, the world never recognised him as a pioneer of pig heart transplantation.

Cross-species organ transplantation is a serious matter concerning human health and medical ethics though the advancements in immune-suppressive medicines and gene editing have made xenotransplantation a distinct possibility. We need to move cautiously and develop robust scientific, bioethical protocols and regulatory systems. Regulators and bioethicists will have to develop ways to deal with transplantations involving animal organs. For now, the US Food and Drug Administration permits such transplants on a case-to-case basis on humanitarian grounds.

When Dr Sen performed human transplantation surgeries in the 1960s, hardly any regulations existed in India. The ethical and regulatory system was hazy and still developing in the mid-1990s when Dr Baruah carried out arguably the world’s first pig heart transplantation. In a knee-jerk reaction, the Indian Council of Medical Research shut the doors on xenotransplantation by imposing an outright ban. In retrospect, it was a wrong move. Subsequently, animal experimentation rules were made extremely tough for biomedical research under pressure from animal rights groups. Today, when xenotransplantation technology is gaining ground and showing promise in the decades to come, India has no experience in it even though it has developed great strengths in CRISPR-Cas9 technology. It is time for course correction.

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