WHY THIS MATTERS IN BRIEF

Xenotransplantation relies on organs from other species that can be transplanted into humans to be genetically engineered to be virus free, this one wasn’t and it’s set the field back years.

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The pig heart transplanted into an American patient earlier this year in a landmark operation carried a porcine virus that may have derailed the experiment and contributed to his death two months later, say transplant specialists. David Bennett Sr. was near death in January when he received a genetically edited pig heart in a pioneering between-species transplant that has been hailed as a success – and was, at first.

A few days after his heart was replaced with one from a pig, Bennett was sitting up in bed. His new heart was pumping fantastically and performing like a “rock star,” according to his transplant surgeon, Bartley Griffith of the University of Maryland School of Medicine. But about 40 days later Bennett, who was 57, took a turn for the worse. After two months he was dead. In a statement released by the university in March, a spokesperson said there was “no obvious cause identified at the time of his death” and that a full report was pending.

Now the regulators monitoring the experiment have learned that Bennett’s heart was affected by porcine cytomegalovirus, a preventable infection that is linked to devastating effects on transplants.

The presence of the pig virus and the desperate efforts to defeat it were described by Griffith during a webinar streamed online by the American Society of Transplantation on April 20. The issue is now a subject of wide discussion among specialists, who think the infection was a potential contributor to Bennett’s death and a possible reason why the heart did not last longer.

“We are beginning to learn why he passed on,” said Griffith, who believes that the virus “maybe was the actor, or could be the actor, that set this whole thing off.”

The heart swap in Maryland was a major test of xenotransplantation, the process of moving tissues between species. But because the special pigs raised to provide organs are supposed to be virus-free, it now appears that the experiment was compromised by an unforced error. The biotechnology company that raised and engineered the pigs, Revivicor, declined to comment and has made no public statement about the virus.

“It was surprising. That pig is supposed to be clean of all pig pathogens, and this is a significant one,” says Mike Curtis, CEO of eGenesis, a competing company that is also breeding pigs for transplant organs. “Without the virus, would Mr. Bennett have lived? We don’t know, but the infection didn’t help. It likely contributed to the failure.”

The detection of the pig virus in Bennett’s heart is not necessarily all bad news for xenotransplantation. If a pig virus played a role, it could mean a virus-free heart xenotransplant could last much longer. Some surgeons think the latest gene-modified organs could in theory keep beating for years—and more rigorous procedures should be able to screen out the virus.

“If this was an infection, we can likely prevent it in the future,” Griffith said during his presentation.

The biggest obstacle to animal-organ transplants is the human immune system, which ferociously attacks foreign cells in a process called rejection. To avoid rejection, companies have been engineering pigs – removing some genes and adding others – to give their tissue a stealth profile that hides from immune attack. The version used in Maryland came from a pig with 10 gene modifications developed by Revivicor, a subsidiary of United Therapeutics.

Following promising tests of such pig organs in baboons, three US transplant teams launched the first human studies starting in late 2021. Surgeons at New York University and the University of Alabama each attached pig kidneys to brain-dead people, but the University of Maryland went a step further when Griffith stitched a pig heart into Bennett’s chest in early January.

Transferring pig viruses to humans has been a worry – some fear xenotransplantation could set off a pandemic if a virus were to adapt inside a patient’s body and then spread to doctors and nurses. The concern could be serious enough to require lifelong monitoring for patients.

However, the specific type of virus found in Bennett’s donor heart is not believed capable of infecting human cells, says Jay Fishman, a specialist in transplant infections at Massachusetts General Hospital. Fishman thinks there is “no real risk to humans” of its spreading further.

Instead, the problem is that pig cytomegalovirus is linked to reactions that can damage the organ and the patient – with catastrophic results. Two years ago, for instance, German researchers reported that pig hearts transplanted into baboons lasted only a couple of weeks if the virus was present, while organs free from the infection could survive more than half a year.

Those researchers said they found “astonishingly high” virus levels in pig hearts removed from baboons. They think the virus could go haywire not just because the baboons’ immune systems were suppressed with drugs, but also because the pig immune system was no longer there to keep the virus in check. It “seems very likely the same may happen in humans,” they warned at the time.

Joachim Denner of the Institute of Virology at the Free University of Berlin, who led that study, says the solution to the problem is more accurate testing. The US team appears to have tested the pig’s snout for the virus, but often it’s lurking deeper in the tissues.

“It’s a latent virus and hard to detect,” says Denner. “But if you test the animal better, it will not happen. The virus can be detected and easily removed from pig populations, but unfortunately they didn’t use a good assay and didn’t detect the virus, and this was the reason. The donor pig was infected, and the virus was transmitted by the transplant.”