Last March, the first man grafted with a pig’s heart is dead. The medical team had not given any additional information, except that his condition had deteriorated in a few weeks. Recently, the surgeon who performed this first xenotransplantation announced that the heart was carrying a porcine virus which contributed, to some extent, to the premature death of the patient. A look back at this medical feat and the reasons for its failure.
David Bennett Sr., who was on the verge of death in January, had then received a genetically modified pig’s heart in a pioneering cross-species transplant, which was hailed as a hit. A few days following the operation, David Bennett showed no signs of rejection. His surgeon, Bartley Griffith of the University of Maryland School of Medicine, pointed out that ” her new heart was beating wonderfully and [que] [David] acted like a rock star “. He had even been able to watch the very popular final game of the NFL American football championship, the Super Bowl. But regarding 40 days later, Bennett, 57,’s condition deteriorated. After two months, he died. In a communiqué released by the university in March, a spokesperson said there was “no no obvious cause identified at time of death and that a full report was pending.
Nevertheless, during a webinar hosted by the American Society of Transplantation on April 20, B. Griffith explained that Bennett’s heart had been affected by porcine cytomegalovirus, an infection that was preventable but linked to devastating effects on transplants. The issue is now widely discussed among specialists, who believe the infection was a potential contributor to Bennett’s death and a possible reason why the heart stopped.
A virus hidden in the pig’s heart
This transplant is a major step for the xenotransplantations, i.e. organ or tissue transplants between two different species. For this type of intervention to succeed, the pigs are specially bred and selected. Indeed, the biggest obstacle to animal organ transplants is the human immune system, which attacks foreign cells in a process called rejection. To avoid rejection, companies genetically modify pigs — removing and/or adding certain genes — to give their tissues a profile that protects them from immune attack. In the case of David Bennett, the pig had undergone 10 genetic modifications, carried out by Revivicor, a subsidiary of United Therapeutics. Additionally, these pigs, specially bred to provide organs, are supposed to be virus-free.
Unfortunately, it seems here that the experience was compromised by an error at this level. Revivicor has made no public statement regarding the virus, which might compromise future trials.
Indeed, Griffith said during his presentation: “ If it was an infection, we can probably prevent it in the future especially since this type of virus can be detected and easily eliminated from pig populations. If the porcine virus really played a significant role in this premature death, it might mean that a virus-free heart xenograft might last much longer. Some surgeons believe that the genetically modified organs might, in theory, continue to beat for several years – and more rigorous procedures should allow more “filtering” of the viruses.
But indeed, porcine cytomegalovirus is linked to organ and patient damaging reactions. In 2020, a team of German researchers led by Joachim Denner from the Robert Koch Institute in Berlin, found that pig hearts transplanted into baboons only lasted a few weeks if the virus was present, while organs free of the infection might survive for more than six months.
Finally, a fear raised by this kind of transplant is that it might trigger a pandemic, if a porcine virus like the one hidden in the transplanted heart, adapts to the human body. However, experts believe that the specific type of virus present in Bennett’s heart is not capable of infecting human cells. They are then reluctant to fully attribute Bennett’s death to the virus. But what would be the real cause of death?
An inevitable death?
It was the United States Food and Drug Administration (FDA) that issued special permission to try an animal organ in a one-time transplant, on Bennett, at Griffith’s request. He seemed like a good candidate, because not being eligible for a human heart transplant, he was condemned to die. The operation went very well. But despite an encouraging recovery, Bennett’s condition remained fragile throughout, as his surgeon points out in his online presentation. He decompensated very quickly, with all the signs of an infection that had, until then, gone undetected. Even a biopsy at 34 days revealed nothing abnormal.
His doctors monitored the state of health with great rigor, performing a battery of advanced blood tests, looking for traces of various viruses and bacteria. Nevertheless, a very low level of this virus was detected, during an analysis, but was supposed to come from an error, so low the figures were. The test to clarify this point requires 10 days, effectively preventing doctors from knowing if the virus had already multiplied and therefore from intervening early enough to contain it.
The probable cause of Bennett’s death is therefore not necessarily attributable entirely to the virus, but it was at least the trigger for an immune storm, which Bennett’s general state of health might not stem. Faced with signs of infection, doctors found themselves confronted with a dilemma, well known in transplantation: how to fight infections while controlling the patient’s immune system. Eventually, doctors gave Bennett a last-resort drug called Cidofovir, sometimes used in AIDS patients, along with intravenous immunoglobulins. But that wasn’t enough to keep him alive.
Despite this premature end, the experiment has made it possible to accumulate a great deal of valuable knowledge regarding xenografts and the mandatory conditions to be met — such as more sensitive screening of animals for the virus — so that this type of operation can be repeated with more safety and success. The latter carry a certain hope in order to fight once morest the shortage of transplantable human organs.
