In the scientific journal The Lancet, a detailed analysis of the failure of what was, in 2022, hailed as a breakthrough: the transplant into a human being of a heart from a genetically modified pig.
What went wrong with the world’s first in-human heart transplant performed—on a 57-year-old man—using the heart of a pig that had been genetically modified (to increase its compatibility)?
“Patient 1”, whose procedure was performed in January 2022 by surgeons from the University of Maryland School of Medicine (United States), managed to survive for 47 days, earning him a front-page spot in media across the world (see an in depth article of ours on the subject). The result was hailed as a watershed event for heart surgery, because, after decades of research, a barrier that, for a very long time, had seemed insurmountable—that of being able to transplant animal organs into humans, or xenotransplantation—appeared to have been overcome, opening the door for important developments in this field, beginning with greater organ availability.
Then, however, after seven relatively uneventful weeks, “Patient 1”, David Bennett, without having shown any clear signs of acute organ rejection over the previous days, died suddenly of heart failure, taking his doctors by surprise.
Now, 18 months later, the University of Maryland surgeons and researchers involved have published, in the scientific journal The Lancet, an exhaustive account of what they have learned from analysing Bennett’s tissue and reviewing the results of the numerous tests he underwent following the procedure, in an attempt to understand what may have occurred. First and foremost—they write—we must bear in mind that the patient, who suffered from severe cardiac insufficiency, was at end stage, meaning that he was bound to die soon in any event. As such, he could not receive a “traditional” transplant, which is precisely why the Food and Drug Administration (the U.S. body that regulates trials of pharmaceuticals and other treatments) granted the authorisation, defined in technical terms as “compassionate,” to perform this first transplant using a pig heart. The fact that Bennett was in a desperate condition to begin with was certainly of consequence.
Impaired immune defences
What’s more, his body's immune defences were extremely compromised, to the point that it was not possible to provide him with the standard immunosuppressant treatment or even the very powerful one that had been used to prevent the risk of rejection in all previous xenotransplantation trials using animal models.
This situation, in all probability, led to the progressive development of rejection that, although non-acute, was not, as such, less dangerous. Bennett’s body did, in fact, produce all of the antibodies that usually form after a transplant. What’s more, twice in two months he was administered an infusion of another type of antibody, called IVIG, in order to minimise the risk of infection, but these antibodies may actually have damaged the heart.
An "undetected” virus
Lastly, one of the unexpected effects that came to light as soon as the analysis was undertaken was a porcine cytomegalovirus infection. This virus, undetected during testing, had found fertile ground to reproduce in the patient's debilitated body, despite his having received an antiviral therapy. The cytomegalovirus may have caused an inflammation that, in turn, damaged the heart tissue, although no evidence was found of it having spread to any other organs beyond the transplanted heart.
The death of David Bennett, most likely due to the sum of these concurrent causes and to his condition prior to the procedure, was not, however, in vain. It has served to highlight a number of factors for improvement and more in-depth consideration. Hence, the work on xenotransplantation continues, even if, for the moment, there is no word regarding any new patients.
“We were determined to shed light on what led to the heart transplant dysfunction in Mr. Bennett, who performed a heroic act by volunteering to be the first in the world,” said Bartley Griffith, co-author of the study, and Alice Marie Hales, Distinguished Professor in Transplantation at the University of Maryland. “We want our next patient to not only survive longer with a xenotransplant but to return to normal life and thrive for months or even years.”
