Starting in the 1960s, doctors attempted transplants of kidneys, hearts, and livers from baboons and chimpanzees—humans’ closest genetic relatives—into people. But the organs failed within weeks, if not days, due to rejection or infection. These efforts were largely abandoned after “Baby Fae,” an infant with a fatal heart condition, died within a month of receiving a baboon heart transplant in 1984. (Her immune system rejected the heart.)
By the 1990s, researchers turned their attention to pigs. Their organs are more similar in size to human ones and take only months to grow to a size suitable for donation. Unlike primates, there’s less concern about them passing on HIV-like viruses to patients (though pigs harbor different kinds of viruses). And scientists thought pig donors would be more accepted by the public, since they are already raised for agriculture.
But biological differences between pigs and humans make transplantation much more challenging. So researchers turned to genetic engineering to make pig organs more suitable for human recipients—deleting pig genes and adding human ones to prevent immune rejection, blood clotting, and inflammation.
All the pig organs used in humans this year had 10 genetic edits—although the exact modifications differed slightly. One they each had in common was the deletion of a gene called Alpha-gal, which is involved in hyperacute rejection, which occurs within a few minutes of transplanting the pig tissue. This meant none of the transplanted organs were immediately rejected. Still, different types of rejection can happen weeks or months afterward, and scientists don’t know which edits, or how many of them, will lead to the best outcomes.
The Maryland team has put forth a few theories as to why Bennett’s heart ultimately failed. Although it didn’t display typical signs of rejection, it did show damage to the capillaries—the smallest and most delicate blood vessels—during an autopsy. Mohiuddin says this may be evidence of a type of immune rejection the team hadn’t seen before in baboons who received pig hearts.
Another possibility is that the patient was infected with a virus found naturally in pigs, and in his immunocompromised state brought on by anti-rejection medication the virus made the heart fail. Scientists were already on the lookout for porcine endogenous retroviruses, which are integrated into the pig genome. These viruses weren’t detectable in Bennett’s heart tissue, but another kind was: porcine cytomegalovirus, or pCMV. The infection could also explain the capillary damage, says Mohiuddin.
The Maryland team has since developed a test to detect pig viral DNA in very small amounts, which they’ve used on the tissue of baboons implanted with pig hearts. In lab tests, they found evidence of the virus in several animals but no correlation between infection and how long the transplanted hearts lasted.
A third explanation is that an antibody therapy Bennett was given attacked his heart. The drug, intravenous immunoglobulin, is for people with weakened immune systems, such as transplant patients. But since it’s made from a pool of antibodies from thousands of donors, it could have contained natural antibodies that may have attacked cells in the pig heart.