Xenotransplantation has long been a dream for humanity. In his classic 1928 novel 'Amphibian Man' Russian writer Alexander Beliaev tells us the tale of a scientist and a maverick surgeon named Salvator, who gives his son, Ichthyander (Greek etymology: 'Fish'+ 'Man') a life-saving transplant - a set of shark gills.
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.
In a fact meets fiction event, University of Maryland scientists and clinicians recently performed the first successful transplant of porcine (pig) heart into an adult human on 7 January, 2022.
In a first-of-its-kind surgery, David Bennett, a 57-year-old man with terminal heart disease, received a successful transplant of a genetically-modified pig heart.
The storied journey of xenotransplantation
According to Dr David K. C. Cooper from the Thomas E. Starzl Transplantation Institute, University of Pittsburgh, between the 17th and 20th centuries, blood was transfused from various animal species into patients with a variety of pathological conditions. Skin grafts were carried out in the 19th century from a variety of animals, with frogs being the most popular.
In the 1920s, French surgeon Serge Voronoff advocated the transplantation of slices of chimpanzee testicles into aged men whose "zest for life" was deteriorating, believing that the hormones produced by the testis would rejuvenate his patients.
Following the pioneering surgical work of Nobel laureate Alexis Carrel, who developed the technique of blood vessel anastomosis, numerous attempts at nonhuman primate organ transplantation in patients were carried out in the 20th century.
In 1963–1964, when human organs were not available and chronic dialysis was not yet in use, transplant surgeon Keith Reemtsma transplanted chimpanzee kidneys into 13 patients, one of whom returned to work for almost nine months before suddenly dying from what was believed to be an electrolyte disturbance.
The first heart transplant in a human ever performed was by Dr James Hardy in 1964, using a chimpanzee heart, but the patient died within two hours. The father of modern transplantation Thomas Starzl carried out the first chimpanzee-to-human liver transplantation in 1966; in 1992, he obtained patient survival for 70 days following a baboon liver transplant.
In 1984, Dr Leonard Bailey transplanted a baboon heart into an infant named Stephanie Fae Beauclair, more popularly known as Baby Fae. She lived for 21 days after the transplant, after which xenotransplants lost steam for a while and was largely limited to the transplantation (implantation) of xenograft heart valves into humans.
The Friday (7 January) pig heart transplant comes right on the heels of surgeons in New York successfully attaching the kidney of a genetically engineered pig to a brain-dead person in October last year.
A historic operation
The US Food and Drug Administration granted emergency authorisation for the surgery on New Year's Eve through its compassionate use provision. It is used when an experimental medical product, in this case, the genetically-modified pig's heart, is the only avenue open for a patient with a serious or life-threatening medical condition.
Dr Bartley Griffith, director of the cardiac transplant programme at the University of Maryland School of Medicine (UMSOM), surgically transplanted the pig heart into the patient. He was assisted by one of the world's foremost experts on xenotransplantation, Dr Muhammad M. Mohiuddin Professor of Surgery at UMSOM.
Revivicor, a regenerative medicine company provided the genetically-modified pig to the xenotransplantation laboratory at UMSOM. On the morning of the transplant surgery, the surgical team, led by Dr Griffith and Dr Mohiuddin, removed the pig's heart and placed it in the XVIVO Heart Box, a device that keeps the heart preserved until surgery.
The doctors also used an experimental drug made by Kiniksa Pharmaceuticals along with conventional anti-rejection drugs, which are designed to suppress the immune system and prevent the body from rejecting the foreign organ.
"The anatomy was a little squirrelly, and we had a few moments of 'uh-oh' and had to do some clever plastic surgery to make everything fit," Dr Griffith said. As the team removed the clamp restricting blood supply to the organ, "the heart fired right up," and "the animal heart began to squeeze," the doctor told The New York Times.
Two newer technologies — gene editing and cloning — have yielded genetically altered pig organs less likely to be rejected by humans. Three genes — responsible for an aggressive rejection response by human immunity response — were "inactivated" in the donor pig. Six human genes responsible for immune acceptance were inserted into the genome.
Lastly, one additional gene in the pig was also inactivated to prevent excessive growth of the pig heart tissue. Pig hearts grow into adult human size in six months. There were 10 unique gene edits made in the donor pig in total.
"It was either die or do this transplant. I want to live. I know it's a shot in the dark, but it's my last choice," said Bennett, the patient, a day before the surgery was conducted. He had been hospitalised and bedridden for the past few months. "I look forward to getting out of bed after I recover," Bennett added, stated the university's press release.
"It creates the pulse; it creates the pressure; it is his heart," said Dr Griffith. "It's working, and it looks normal. We are thrilled, but we don't know what tomorrow will bring us. This has never been done before," reported The New York Times.
The possibilities of xenotransplantation
According to the United Network for Organ, that administers the only Organ Procurement and Transplantation Network in the United States Last year, some 41,354 Americans received a transplanted organ, more than half of them receiving kidneys.
About 1,10,000 Americans are currently waiting for an organ transplant, and more than 6,000 patients die each year before getting one, according to the US federal government's organdonor.gov website.
"This was a breakthrough surgery and brings us one step closer to solving the organ shortage crisis. There are simply not enough donor human hearts available to meet the long list of potential recipients," said Dr Griffith, who surgically transplanted the pig heart into the patient. "We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future."
Cross-species transplantation offers the prospect of an unlimited supply of organs and cells for transplantation, thus resolving the critical shortage of human organs that currently prohibits a significant portion of patients on the waiting list from receiving transplants.
In the US, about 20% of patients on the heart transplant waiting list die while waiting to receive a transplant or become too sick to be good candidates for the complex transplant procedure.
Organs from genetically modified pigs have been a focal point of much of the research in xenotransplantation. In fact, a pig's heart is similar in size, weight, and structure to a human's heart.
UMSOM received a $15.7 million sponsored research grant to evaluate Revivicors' genetically-modified pig hearts.
We're living in an age where whatever the storytellers of the yesteryears dreamed up today's scientists are turning those dreams into reality. Xenotransplantation once imaginable only on the pages of science fiction is now a reality and with it comes the possibility of saving countless lives.
And who knows one day we might be diving into the deep blues in search of pearls with the help of our shark fins just like Ichthyander.