The Challenges of Xenotransplantation

Xenotransplantation from genetically engineered pigs to humans is one of the potential approaches that is hoped to provide an arbitrarily large supply of replacement organs. Whether or not this becomes a sizable industry depends on how long it takes for competing researchers to complete the alternative route of generating patient-matched new organs from cell samples. While the production of small functional organoids from patient samples is a going concern, the construction of entire organs continues to be held back by the inability to reliably generate the intricate blood vessel networks that are needed to supply large tissue sections. Not that xenotransplantation is without challenges, as this article illustrates. The problems are largely discovered by running into them, as researchers continue the process of testing transplants between pigs and baboons.

Even though humans can give their hearts to compatible persons with little more than a side of immunosuppressants, cross-species transplantation is not so straightforward. More than 60 percent of attempts to replace a baboon's heart with that of a pig ended in the recipients dying within two days. Two important developments pumped hope into the field over the past few years. First, researchers began using the gene-editing tool CRISPR-Cas9 to remove parts of the pig genome that might harm humans or provoke an immune response. Then in 2016 researchers took this further by showing baboons could survive with a genetically engineered pig heart implanted into their abdomens for nearly 1,000 days - if the baboon was on a certain cocktail of immunosuppressants.

For the new work researchers wanted to see if the same genetically engineered pig hearts and immunosuppressant regime could support the life of a baboon. But the first five animals in the new study did not live long. Three died of heart failure almost immediately. It turns out porcine hearts are more vulnerable compared to human hearts. During the period between removal from a pig and implantation into a baboon the heart will sustain damage similar to that caused by a heart attack. Human hearts can often recover from this damage, but the pig hearts could not.

So researchers tried something new with another group of baboons and repeatedly immersed the pig hearts in an experimental nutrient solution for a couple of hours. The researchers think this formulation, originally designed to help transport human hearts long distances, might have helped keep the pig hearts from deteriorating too much. These baboons hung on for about a month before dying - this time because the pig hearts began swelling inside the monkeys' chests, eventually squeezing against the rib cages and failing. "A pig grows to maturity within four months or so, but a baboon takes about 10 years to grow. So the pig heart was growing in the primate as if it was still in a pig. We were just astonished. Nobody had experienced this before - the heart grew like a tumor."

In the third group of baboons researchers added an immunosuppressant drug called temsirolimus, which could also stop the pig hearts' unwanted growth. With the exception of one baboon that died of mechanical heart failure 51 days after surgery, the transplant recipients in this group survived in good health until the researchers euthanized them at 90 or 180 days, an action required under the study protocol approved by officials. The study is invigorating xenotransplantation researchers who, after decades of sometimes dismal attempts, say human trials are finally in sight.