Animal-to-human transplantation is having a moment. In January, a man in Baltimore made history when he received a heart transplant from a genetically modified pig—and the heart actually worked. Just a few months before, surgeons in New York attached a pig kidney to a brain-dead person’s blood vessels and kept it alive for three days, and a surgical team in Alabama successfully transplanted a pig kidney into the abdomen of a brain-dead man.
These achievements take us closer than ever to a future that transplant surgeons have been working toward for centuries: one where there are no more organ shortages—just a limitless supply of human-compatible animal parts ready for installation. Xenotransplantation, as scientists call it, has always made some people squeamish, but the idea has persisted through the ages—and many failed attempts—because of its potential to save lives. “People would rather be alive than dead, basically,” David Hamilton, a retired transplant surgeon and author of A History of Organ Transplantation, told me. Organ donors are constantly in short supply; more than 106,000 Americans are on the national wait list, and 17 of them die waiting each day.
Though it seems like something out of science fiction, people have flirted with the idea of human-animal transplants since antiquity, say scholars. Ancient Egyptians had the Sphinx, a human-lion-falcon mashup akin to mythical Greco-Roman centaurs and fauns. Dedalus legendarily played surgeon when he attempted to attach wings to himself and his doomed son Icarus. Inserting a pig organ into a human has the same end goal: to improve and augment human life.
Recorded attempts at xenotransplantation begin with Jean-Baptiste Denis, a physician to the 17th-century French king Louis XIV who dabbled in animal-human blood transfusions to improve health. Animal blood, Denis wrote, “is less full of impurities than that of men because debauchery and irregularity in eating and drinking are not so common in them as in us.” After a couple of dog-dog and dog-calf test runs, he made several attempts to transfuse lamb blood into human patients. “Obviously, that didn’t end super well because of allergic reactions, and the blood wasn’t very compatible,” transplant surgeon Sham Dholakia, chief medical officer of CareDx, a transplant diagnostics company, told me.
Scientists didn’t begin to understand the immune system until the last quarter of the 19th century. Until then, European physicians regularly transplanted skin from animals to cover ulcers and burns. Frogs were popular because of their thin skin, but occasionally rabbits, chihuahuas, and even chickens were used. Surgeons tried “any animal that was around,” said Hamilton. “Monkey skin looked attractive and might have lasted for weeks.” Regardless of the animal, these grafts never became permanent. “The skin is one of the most immunogenic tissues,” Mohamed Ezzalarab, a research associate professor of surgery at the University of Pittsburgh’s Thomas E. Starzl Transplantation Institute, told me.
“Most likely they were rejected after a few days.”
The body’s protestations didn’t deter the infamous France-based surgeon Serge Voronoff from carrying out his “monkey gland experiments” in the 1920s, which consisted of implanting slices of chimpanzee or baboon testicles into their human counterparts. Doing so, he wrote, would lead to all-around “rejuvenation”—sexual and otherwise—because the sex gland stimulated not only “amorous passion” but also cerebral activity and muscular regeneration. He believed that using primate organs led to better results but wasn’t sure why; perhaps, he wrote, it was because apes had a “more robust physical constitution” and didn’t suffer from human ailments like alcoholism and arthritis. Though scientific reporting on these experiments was scarce, the surgeries were a sensation. They even inspired an American named John Brinkley, who in the 1930s offered similar surgeries using goat testicles that he claimed gave his patients ”an astonishing sexual vigor.” (Brinkley was sued for wrongful death multiple times and in 2016 inspired a documentary titled Nuts!)
Scientists continued dabbling in xenotransplantation through the early 20th century, but it didn’t evolve into a credible science until the French surgeon Alexis Carrel came up with a way to stitch together blood vessels. The technique earned him the 1912 Nobel Prize and ushered the era of transplantation in general—agnostic of species.
With the successful transplant of a kidney from a boy to his twin in 1954, it became clear that human-to-human transplants had enormous potential. So why not animals? “Once ordinary human kidneys were possible, it became worth trying again,” said Hamilton.
In the 1960s, the Tulane University surgeon Keith Reemstma tried again by transplanting chimpanzee kidneys into six people with kidney failure. Organ shortages were already a problem in the U.S., and dialysis was not yet available. “As this impasse was developing, we decided to explore the use of nonhuman sources for clinical renal transplantation,” Reemstma wrote. Most of his patients died within a few weeks, but one woman survived nine months after the surgery, surprising many in the field. Thomas Starzl, a pioneering transplant surgeon who worked on baboons, called her survival “the one real beacon of hope.”
Surgeons kept chipping away at xenotransplantation, but they didn’t have long-term success. The issue the faced is the same one that plagues the field today: The body rejects foreign organs, especially those of an animal. Immune-suppressing drugs like cyclosporin and tacrolimus “revolutionized immunosuppression for human-to-human transplants” in the 1980s, said Dholakia, but they couldn’t quite convince the body to accept animal organs. And so the research turned toward the animals themselves.
Primates were the donor animal of choice for xenotransplantation as late as 1984, when an infant known as Baby Fae famously received a baboon heart. Chimps and monkeys, the logic went, were similar in size and closely related to humans, so their organs stood the best chance at being tolerated. But primates also take up to nine years to grow to the right size, they’re relatively rare and difficult to breed, and present the obvious ethical quandary of sacrificing close relatives for human gain. While at first Baby Fae’s heart transplant started to “beat spontaneously,” her condition deteriorated after two weeks and she died a few days later. “So people started looking at pigs,” says Ezzelarab. “They are everywhere. People eat pigs more than they eat monkeys … so ethically the public would not feel so bad about using pigs.” One litter of pigs can produce up to 20 piglets, each of which, in six months, can provide a heart, two lungs, two kidneys, a liver, a pancreas, and intestines. “One pig can help eight patients,” said Ezzelarab. Surprisingly, some leaders within Judaism and Islam, which prohibit pork consumption, have been open to pig xenotransplantation. “Saving life is a trump card,” Hamilton said.
But as similar as pigs are to humans, there are still challenges. In the 1990s, scientists found that transplanting a pig organ into a human sets off an angry immune response that largely targets alpha-gal, a sugar molecule found in pigs. After attempts to block or filter it fell short, scientists set out to get rid of it altogether using genetic engineering techniques ushered in by Dolly the sheep. Years of research produced alpha-gal “knockout” pigs, which don’t express the sugar. These pigs have been used in every experimental xenotransplantation attempt this century, including the recent achievements in Baltimore, New York, and Alabama, said Ezzelarab. In December 2020, the Food and Drug Administration approved GalSafe pigs, a line of alpha-gal knockout pigs developed by the regenerative medicine company Revivicor, for consumption and therapeutic use.
So far, there haven’t been any updates on the patient who received the pig heart at the University of Maryland in January. Hamilton is hopeful that the silence is a good thing. “We’ve been waiting for this for 20 years. It’s been going so slowly that people just forget about it,” he said. “I knew it was going to come someday.”
But even if the patient survives, it won’t mean that pig-to-human organ transplants will become common practice anytime soon. We need to know much more about the safety and impact of the procedure. Researchers are still trying to understand the difference between the immune reaction to pig versus human hosts, and it may be that molecules beyond alpha-gal will need to be mitigated in pigs, with different gene combinations for different patients, said Ezzelarab. The medical community will have to decide on the best way to design clinical trials to prove that the procedure is safe, which will be key in gaining the public’s acceptance. “There’s a lot of enthusiasm but also a lot of questions,” said Dholakia.
Already, farms dedicated to growing pigs for human transplantation are being set up, and companies specializing in xenotransplantation are worth hundreds of millions of dollars. The question isn’t if, but when, though Ezzelarab urges caution because he’s concerned that missteps could push the field backward. You don’t want to fly too close to the sun “unless you’re really sure you can protect yourself,” he said. “Use something other than wax.”