The gene-edited pig heart given to a dying patient was infected with a pig virus

The gene-edited pig heart given to a dying patient was infected with a pig virus thumbnail

The transplant of pig hearts into an American patient in a landmark operation earlier this year contained a porcine virus that could have derail the experiment and contributed to his suicide two months later. Transplant specialists say.

David Bennett Sr. was in danger of death in January. He received a genetically modified pig heart as part of a pioneering inter-species transplant. It was hailed a success, and it was.

A few days after his heart was replaced with one from a pig, Bennett was sitting up in bed. According to Bartley Griffith, a transplant surgeon at the University of Maryland School of Medicine, Bennett’s new heart was performing like a rock star and pumping amazing blood.

But about 40 days later Bennett, who was 57, took a turn for the worse. He was declared dead after two months. A statement from the university in March stated that there was no obvious cause of his death and that a full investigation was ongoing.

Now MIT Technology Review has 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. Specialists are now discussing the issue, believing that Bennett died from the infection. This could also explain why Bennett’s heart stopped beating.

” We are beginning to understand why he died,” Griffith said. He believes that the virus “maybe” was the actor or could have been the actor that caused the whole thing to go wrong .”

The heart swap in Maryland was a major test for xenotransplantation (moving tissues between species). It now appears that an unforced error compromised the experiment, even though the organs were donated by special pigs. Revivicor, a biotechnology company, declined to comment on the virus and has not made any public statements about it.

” It was quite 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. “Would Mr. Bennett still be alive if he had not been infected with the virus?” It didn’t help. We don’t know. It likely contributed to the failure.”

10-gene pig

The detection of the pig virus in Bennett’s heart is not necessarily all bad news for xenotransplantation. It could be that a pig virus was involved, which could increase the chances of a successful heart transplant. Some surgeons believe that the gene-modified organs can continue beating for many years. However, more stringent screening should be possible to eliminate 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. Companies have been creating pigs to avoid rejection. They have removed some genes and added others to give their tissue a stealthy profile that protects them 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. New York University and Alabama surgeons each attached pig kidneys in brain-dead patients. However, the University of Maryland took it a step further by inserting a pig heart into Bennett’s chest.

It has been a concern that pig viruses could be transferred to humans. Some fear that xenotransplantation could lead to a pandemic. Patients could need to be monitored for life.

Jay Fishman, a specialist on transplant infections at Massachusetts General Hospital, said that the virus found in Bennett’s heart donor is not believed to be capable of infecting human tissues. Fishman believes there is no risk to human health for it spreading further.

However, pig cytomegalovirus can cause severe reactions in the patient and organs. 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. These researchers reported that they found “astonishingly large” levels of virus in pig hearts taken from baboons. The virus could be transmitted to humans because of the way the baboons’ immune system was suppressed by drugs. However, the immune system of the pigs was not there to stop the virus from spreading. They warned that it was “very likely” that the same thing could happen to humans.

DR. BARTLEY GRIFFITH & DAVID BENNETT JAN 2022
Pig heart recipient David Bennett Sr. with his transplant doctor, Bartley Griffith of the University of Maryland.

UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE

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. Although the US team seems to have tested the pig’s nose for the virus, it is often hidden deeper in the tissues.

“It’s a hidden virus that is difficult to detect,” says Denner. It can be prevented by better testing the animal. Although the virus can be easily detected in pig populations and removed, the test they used didn’t detect it. This was the reason. The donor pig was infected, and the virus was transmitted by the transplant.”

Denner says he still thinks the experiment was a “great success.” For instance, the first human-to-human heart transplant, in 1967, lasted only 18 days and, two years later, one in Germany endured just 27 hours.

Denner claims that Bennett’s death is not due to the virus. He says, “This patient was very very, very sick. Do not forget that.” “Maybe the virus contributed, but it was not the sole reason.”

Cause of death?

Bennett’s cause of death is important because if his heart fails due to immune rejection, researchers may need to go back to the drawing board. Instead, it is expected that companies such as United Therapeutics or eGenesis or academics who work with them will begin clinical trials of their pig organs in a year or so.

Bennett received a pig’s heart after Griffith applied for special permission from the US Food and Drug Administration to transplant an animal organ. He was a good candidate because he was close to death from heart disease and was not eligible for a rare human heart for transplant due to his history of disregarding medical advice.

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On December 31, 2021, the FDA sent Griffith an email saying he could proceed to treat Bennett for “irreversible heart failure” if the patient and ethics monitors agreed.

Bennett’s condition was still fragile. Griffith said that Bennett’s condition was still fragile after the operation. However, Griffith says that his new pig heart was working hard and looked “super normal” afterward. Even a biopsy taken on day 34 showed no signs of the feared immune attack. It was amazing. Talk to this gentleman, he has a pig heart. Griffith stated that he literally has a pig heart. Griffith admitted that although the result was miraculous, Griffith was concerned about whether the medical team was doing the right thing. In a way, Griffith describes them as a “blind team of squirrels” who had to manage Bennett’s unusual condition as the days passed. To keep an eye on the health of the heart of the pig, Griffith explained that the team was constantly testing their patient with a variety of cutting-edge blood tests. A DNA sequencer was used to scan Bennett’s blood for floating fragments pig genes. Any increase would indicate that the heart cells are dying. Karius developed a novel test that screened Bennett’s blood for hundreds of bacteria and viruses.

It was that test, run on a blood draw taken from Bennett 20 days after his surgery, that first returned “a little blip” indicating the presence of porcine cytomegalovirus, according to Griffith. Griffith stated that the team was concerned about the results because the pigs were supposed to be free from the virus.

The doctors faced another problem–the special blood test was taking about 10 days to carry out. They didn’t know Bennett had a pig virus. This was causing Bennett to become more and more ill. Griffith now believes that this was a “cytokine explosion”, a surge in immune-system molecules.

Even without up-to-the-minute tests, a serious problem became apparent around day 43 of the experiment. Bennett was warm to the touch and he was breathing hard that day. He looked really funny. He was infected. Griffith said that he looked infected. “He lost his focus and wouldn’t talk with us,” Griffith said.

The doctors were then faced with a common problem in transplant medicine: how do you fight infections while keeping the patient’s immune systems in check? They were also handicapped because they didn’t know. Griffith’s account states that they were still unsure of the extent of the infection and that no one had ever treated a person for this particular pig virus.

They ended up giving Bennett a last-resort drug called cidofovir, sometimes used in AIDS patients. And since his immune system was so weak, they also gave him intravenous immunoglobulin–antibodies collected from blood donors.

Bennett looked better 24 hours later and was sitting up in a chair, “so we were all kind of relaxing–we dodged that bump,” says Griffith. The relief didn’t last very long. Bennett’s condition worsened a week later and his heart began to fail.

Now Griffith wonders if Bennett was affected by the same syndrome that was seen in infected pig hearts. The virus causes swelling and other side effects.

Mass General’s Fishman said that he believes Bennett died from a combination of [the virus].”

. However, it’s too early to know why Bennett died. Researchers are still trying to find contradictory clues. The doctors also worry they made a mistake by giving him human antibodies–something they did twice. Later tests revealed that the blood products contained anti-pig antibodies, which could have also damaged the organ.

Even so, Griffith stated that a biopsy taken from Bennett’s pig heart during the experiment did not reveal any signs that it had been rejected. This was the biggest fear Bennett had, and what the gene-edited special pigs were meant to avoid. According to Griffith, the damage pattern was similar to that in the German baboons. Griffith presented a picture of the viral syndrome that might have caused the heart failure. It started with an unexpected “blip” in the test results, then escalated to a larger infection and finally released a damaging cascade. I believe he had a capillary leak as a result of his inflammatory explosion. This edema then turned into fibrotic tissue and he suffered severe and unreversible diastolic failure. The researchers involved said that the procedure was worthwhile because of the “invaluable insight” they gained. Bennett’s son also expressed similar sentiments in a March statement by the university. “We also hope that what was learned from his surgery will benefit future patients and hopefully one day, end the organ shortage that costs so many lives each year,” he said.

However, the presence of the virus–whose risks were already well documented–could now factor into some people’s questions over whether the experiment should have taken place at all. Arthur Caplan, a New York University bioethicist, said that it was a red flag. “If doctors can’t prevent and control infection, then such experiments are difficult to justify,” Caplan said. Bennett was trying to live, and it isn’t clear if he will be able to consent to the procedure or not.

Bennett was described by his doctors as a brave volunteer who showed a lot of fight. Griffith stated that “these losses are difficult.” “This was a patient. It was not an experiment for us. He wanted to live. He was a very funny person. On the way in to get his pig heart transplant, he looked at me and he said squarely, ‘Are you sure I can’t get a human heart?'”

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