The death of a man given a gene-edited pig heart in a landmark transplant operation earlier this year may have had an unexpectedly routine cause: a common and preventable infection in the donor heart, reports MIT Technology Review.

Back in January this year, a man named David Bennett made history: after an eight-hour operation at the University of Maryland Medical Center he became the first human on Earth whose heart came from a member of a different species – a pig, to be specific.

It was a highly experimental surgery, and Bennett knew it was a last resort: “It was either die or do this transplant,” he said at the time. “I want to live.”

And live he did, at first: Bennett started physical therapy to regain strength, was able to spend time with his family, and there were no signs of the heart being rejected. In fact, it was performing like a “rock star,” according to his transplant surgeon, Bartley Griffith of the University of Maryland School of Medicine.

But after about six weeks, things took a turn for the worse – and in early March, Bennett died.

Initially, his doctors were stumped. "There was no obvious cause identified at the time of his death,” a hospital spokeswoman told the New York Times, and any further comment would have to wait until a thorough medical investigation had been performed.

Now, the culprit for Bennett’s death may have been found: the heart used in the transplant was infected with porcine cytomegalovirus.

“It was surprising. That pig is supposed to be clean of all pig pathogens, and this is a significant one,” said 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.”

Speaking at a recent webinar for the American Society of Transplantation, Griffith said the virus “maybe was the actor, or could be the actor, that set this whole thing off.” If so, he sees reason for optimism: “If this was an infection, we can likely prevent it in the future,” he said during the presentation.

But the presence of this virus in the transplant organ highlights a concern that experts have long held over xenotransplantation: the transfer of animal pathogens into human hosts.

In the age of coronavirus, the most immediate thing that comes to mind when we think of zoonotic disease is likely fears of accidentally starting a new pandemic. In this case, though, there is “no real risk to humans,” Jay Fishman, a specialist in transplant infections at Massachusetts General Hospital, told MIT Technology Review.

But evidence does suggest that porcine cytomegalovirus can have devastating effects on transplant recipients. One study from 2020 found that the presence of the virus reduced the survival time of baboons given pig hearts from up to 28 weeks to just one or two.

The researchers behind that paper, a German team led by virologist Joachim Denner, said at the time that they thought it “very likely the same may happen in humans” – and Bennett’s case may have proved them correct. In his presentation, Griffith noted that the damage caused by the illness was similar to that seen in the baboons, adding that he “personally suspect[s] [Bennett] developed a capillary leak in response to his inflammatory explosion, and that filled his heart with edema, the edema turned into fibrotic tissue, and he went into severe and unreversing diastolic heart failure.”

It may be tempting to pass this off as a case of extreme and inexplicable bad luck for Bennett, but the case raises some real and important questions surrounding the field of xenotransplantation.

“It’s a big red flag,” Arthur Caplan, a bioethicist at New York University, told MIT Technology Review. If infections can’t be ruled out, he said, “then such experiments are tough to justify.”

But for Denner, the solution is simple: more accurate testing.

“It’s a latent virus and hard to detect,” he explained. “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.”

But even if the virus is what was behind Bennett’s death – and it should be noted that it’s still too soon for a conclusive cause of death to be known – Denner says the experiment was still a “great success.”

“This patient was very, very, very ill. Do not forget that,” he told MIT Technology Review. “Maybe the virus contributed, but it was not the sole reason.”