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Few people know more about transplanting animal organs into humans than . “I think this is the beginning of a complete revolution in transplantation,” he says.
Cooper, a surgeon and researcher at Harvard Medical School, is referring to the creation of pigs genetically modified to make their organs more suitable for xenotransplantation – the use of organs from other animals in humans. A series of such transplants has made recent headlines. Late in 2021, two teams transplanted pig kidneys into people who were brain-dead in experiments lasting just a few days. Then, in January, a pig heart was transplanted into 57-year-old David Bennett, who is said to be slowly recovering with no signs of organ rejection by his body.
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The next step is to carry out clinical trials – Bennett’s transplant was permitted on compassionate grounds as a last resort, rather than as part of a trial. But Cooper, who wasn’t involved in these recent transplants, is confident that the approach will succeed. In fact, he thinks that with further development, organs from modified pigs will be better than donated human organs.
“This is the first time in 70 years of organ transplantation that we’re able to modify the donor, as opposed to just suppressing the recipient,” he says. “And the more you can do to the donor organ, the less you have to do to the recipient. So I think the day will come, in not too many years, when we don’t need to give the recipient any treatment at all.”
In 1968, Cooper was present at the first heart transplant done in the UK, where he trained as a surgeon. He later worked in South Africa under Christiaan Barnard, who did the first ever heart transplant. Cooper then moved to the US where, since the 1990s, he has focused on developing xenotransplantation to increase the number of available organs.
There is no doubting the need for more organs. In the US alone, there are . Many in need of a kidney will wait more than five years, and nearly half will die while waiting or get taken off the list because they become too frail, he says.
As early as the 1960s, there were attempts to transplant chimpanzee and baboon organs into people. However, primates aren’t a suitable source of organs for numerous reasons, including the ethics. So, instead, most researchers turned to pigs, which multiply rapidly and grow fast enough that organs can be harvested within months of birth.
Unaltered pig organs can’t be put in people because they trigger a strong immune response that destroys the organ within minutes or hours. The main cause of this hyperacute rejection is a sugar on the surface of pig cells known as Gal for short. In 2005, Cooper and his colleagues reported that deleting the gene for the enzyme that attaches Gal when pig organs are transplanted into baboons. So the problem of hyperacute rejection has long been solved, he says.
It isn’t the only issue, however. Biological mismatches between donor and recipient can also lead to transplanted organs being slowly rejected over time despite the use of immunosuppressive drugs. They can also lead to blood vessel damage.
Still some obstacles
To try to prevent these issues, several groups and companies around the world have been making more genetic changes to the pigs they work with. The heart and kidneys used in the recent transplants came from pigs created by a US company called Revivicor. In these animals, four genes have been inactivated, including the gene for Gal, and six human genes have been added. Other teams have made even more extensive changes.
To make further progress, these teams now need to do clinical trials to see if these modified
pig organs can survive for long enough to justify their use.
So why haven’t such trials got the go-ahead? Researchers are stuck in a bit of a catch-22. The US Food & Drug Administration (FDA) wants them to demonstrate consistent survival for at least a year when, for example, a baboon gets a pig kidney transplant, says Cooper. But organs modified to work in humans don’t usually survive this long in monkeys.
“We’ve almost reached the end of the road with the animal models because they’re no longer representative of the human situation,” he says.
Cooper doesn’t think that putting pig organs into brain-dead people for a few days tells us anything new scientifically, because the key questions are now all about long-term survival.
He says he was surprised that the FDA allowed Bennett’s heart transplant to proceed, but he is hopeful it is a sign that the regulator will authorise clinical trials soon. It makes most sense to start with kidneys, because if anything goes wrong people can go on dialysis.
“If we are proposing a small trial in patients with kidney transplants, and they know we have the backup of dialysis if necessary, I think they will probably accept to go ahead with it,” says Cooper.
Another obstacle is setting up a clean facility for raising gene-edited pigs, to ensure they are free from diseases. Revivicor has one, but other groups are only getting started. “Probably the most important thing preventing some groups from going into the clinic now is that they don’t have access to pigs under these clean conditions,” says Cooper. “It’s quite time consuming and expensive to care for pigs under these strict conditions.”
The genetic modifications made to pigs so far probably aren’t enough to prevent their organs being slowly rejected, says Cooper, as already happens with human organs. “Very rarely do you have a patient who, 10 years later, hasn’t got some signs of what we call chronic or low-grade rejection, and it’s a major cause of having to retransplant patients. I think we’re likely to get that low-grade rejection more quickly in a xenograft.”
Even if pig organs initially don’t last as long as human ones, they could still be used to keep people alive and well until a human organ becomes available.
The time that transplanted organs survive might also be extended by new immunosuppressing drugs, developed to treat conditions such as arthritis. “We’re testing one here at Massachusetts General Hospital with very good results in monkeys,” says Cooper.
These drugs aren’t yet approved, but have been shown to be safe in trials. This is why the FDA has allowed one of these experimental drugs, currently called KPL-404, to be given to Bennett.
In the longer term, Cooper thinks further genetic changes can mean immunosuppressive drugs won’t be required at all.
While trials of pig kidney and heart transplants might begin soon, it will be a while yet before it happens with other major organs. “The liver and the lungs are way behind the kidney and the heart,” says Cooper. “We have a pretty good idea what the problems are, but they’re complex. We will certainly need more genetic manipulations of the pig in order to overcome those problems.”
And the possibilities go way beyond organs. For instance, modified pigs could provide an unlimited supply of insulin-producing islet cells for curing diabetes. “Some people say, well, you’re exchanging the need for insulin with the need for immunosuppressive therapy. And that is quite correct,” he says. “But within a few years, you probably won’t have to give any immunosuppression, or very little.”
Other possibilities that look promising include treating Parkinson’s disease with dopamine-producing cells, damaged eyes with corneal transplants and burns with skin grafts. “And we’ve been testing red blood cell transfusions. I think eventually all red blood cell transfusions will be pig red blood cells,” says Cooper. “So xenotransplantation will revolutionise medicine, actually, not just transplantation.”
A history of xenotransplants
1920s French surgeon Serge Voronoff grafts slices of ape testes into those of ageing men, hoping to boost testosterone levels and vigour
1963 Baboon kidneys are transplanted into six people, but none of the recipients survive longer than three months
1963 Chimpanzee kidneys are transplanted into 13 people. One survives for nine months
1964 A chimpanzee heart is transplanted into a dying man, but fails after 2 hours
1966 A chimpanzee liver is transplanted into a child, but the child survives only a few days
1984 A baboon heart is transplanted into Baby Fae, an infant with a severe heart defect. She lives only 20 days afterwards
1997 For three days, until a human liver becomes available, 20-year-old Robert Pennington is kept alive by passing his blood through genetically modified pig livers
1997 Some countries halt xenotransplantation trials because of fears that porcine endogenous retroviruses could infect people, but this moratorium is soon reversed
25 September 2021 A team at New York University Langone Health transplants a pig kidney into a person who is brain-dead in an experiment lasting 54 hours
30 September 2021 A team at the University of Alabama at Birmingham transplants two pig kidneys into a brain-dead person in an experiment lasting 77 hours
22 November 2021 NYU Langone Health does a second transplant of a pig kidney into a person who is brain-dead, also lasting 54 hours
7 January 2022 A team at the University of Maryland Medical Center transplants a pig’s heart into 57-year-old David Bennett
