Though the study leader heralded an operation as providing “new hope for an unlimited supply of organs,” last month’s much-publicized transplant of a kidney from a genetically modified pig to a brain-dead human recipient did little to usher in cross-species organ swaps, others say. Still, the engineered pigs could find less flashy uses today: as donors for skin and nerve grafts, providers of long-lasting heart valves, and sources of allergy-free meat.
The transplant study, performed at New York University (NYU), showed the human immune system doesn’t immediately reject an organ from a pig engineered to lack alpha-gal, a sugar molecule that sends the human immune system into a frenzy. The porcine kidney filtered waste from the blood and produced urine for at least 54 hours. After that, doctors shut off the recipient’s ventilator and ended the experiment.
But those findings are “seriously not a surprise,” says Wayne Hawthorne, a transplant scientist at Australia’s Westmead Institute for Medical Research and president of the International Xenotransplantation Association, a society for researchers who study placing animal organs into human bodies. Monkey experiments had already shown that pig kidneys like the one the brain-dead woman received usually last up to 1 week with no problems. Science could not reach NYU surgeon Robert Montgomery, but at a press conference last month, he defended the study, noting “many other examples of preclinical primate studies that have not translated well into what happens in humans.”
Lacking just one sugar gene, the organs aren’t a viable option for xenotransplants, which need to last for years. Other sugar molecules on porcine cells have similar immune-triggering effects, and experts say they, too, should be genetically purged. Plus, several human genes may need to get added to the pig genome to further temper the body’s immune reaction. But the pigs, engineered at a biotech company now called Revivicor, do have promise for other medical applications with less chance of immune rejection. “Just taking out one sugar, you can make a big difference,” says Thomas Platts-Mills, a clinical immunologist at the University of Virginia.
In the late 2000s, for example, Platts-Mills showed tick bites could provoke an unusual allergic response to alpha-gal. People with this “alpha-gal syndrome” (AGS) develop severe reactions to red meat and many medical byproducts of animal husbandry, including the blood thinner heparin (made from pig intestines) and implantable devices such as bioprosthetic heart valves from cows or pigs. (The antibodies that cause these allergic reactions, elicited only by tick bites, differ from those that attack transplanted pig organs, which everyone carries.)
Revivicor had won regulatory approval for its engineered pigs as a source of meat in December 2020 and although pork chops and sausage patties from the swine aren’t yet commercially available, the company has begun to send free samples to people like Amber Shifflett of Charlotte Hall, Maryland, who has AGS and spent months avoiding red meat. On a Saturday in mid-October, Shifflett, 30, cooked an allergy-safe ham steak for breakfast. Then she had another ham steak for dinner. “I was nervous at first,” Shifflett says. Would her chest tighten, as it usually did after eating meat? “I was completely fine.” Now, she says, “I just want to savor every last bite.”
Beyond meat, Scott Commins, an allergist at the University of North Carolina, Chapel Hill, who treats AGS, hopes to offer his patients allergy-free pharmaceuticals. “Bacon is nice,” Commins says, “but I really believe that there is a broader use of the animals medically that could arguably be more important.” During the pandemic, for example, a safe version of heparin would have benefited AGS patients who developed blood clotting issues from COVID-19.
Some medical products from alpha-gal–free pigs could find uses beyond AGS patients. Replacement heart valves, for instance, are increasingly being made from cow and pig tissues rather than mechanical alternatives. But in part because of immune attack, these bioprosthetic valves deteriorate and must be replaced after 10 to 15 years. To slow that attack, animal-derived valves are stripped of cellular material and chemically treated to mask immune-stimulating remnants. But according to pediatric heart surgeon Joseph Turek of Duke University, alpha-gal remains detectable at “actually pretty astounding” levels—as he, Commins, and others reported in The Journal of Thoracic and Cardiovascular Surgery in April. An alpha-gal–free option might last twice as long as other bioprosthetic valves, estimates Turek, whose work is funded in part by Revivicor.
The alpha-gal–free pigs could also find use as skin donors for burn victims and as a source of neurons to treat peripheral nerve injuries. A company called Alexis Bio (formerly XenoTherapeutics) has already tested skin from the pigs on six people with third-degree burns. Ordinarily, doctors rely on human skin from dead people as a temporary dressing, until patients can get a graft of their own skin. But cadaveric skin is expensive and often in short supply. Engineered pig skin seems to function just as well to help wounds heal for up to 9 days, the longest duration evaluated so far.
“The most striking thing [about the pig skin] is that there is nothing striking,” says trial investigator Jeremy Goverman, a burn surgeon at Massachusetts General Hospital (MGH). Because the graft only stays on the body for a week or two, the immune system doesn’t have time to reject it. “The use of it is intended to be short term,” says Paul Holzer, Alexis Bio’s CEO.
His company and another startup, Axonova Medical, are also developing nerve grafts from the same sorts of pigs. These could supplant the current go-to approach for nerve repair surgery: harvesting nerves from somewhere else on a person’s body, an option that is not always possible and can leave people with sensory problems.
Axonova research director Kritika Katiyar and her colleagues start with neurons from Revivicor pig embryos and grow them into nerves up to 5 centimeters long. Having already repaired damaged leg nerves in rats and facial nerves in pigs, the company plans to move on to monkey studies next. Meanwhile, MGH plastic surgeon Curtis Cetrulo, Holzer, and colleagues reported in September using leg nerves from pigs missing alpha-gal to repair damaged arm nerves in rhesus macaques. In both teams’ studies, over about 6 months, recipient animals’ own nerve cells replaced the pig tissue—eliminating the risk of immune rejection. “It looks like the host tissue has completely taken over, and the graft has been removed from the body naturally,” Katiyar says.
Researchers such as University of Miami xenotransplantation scientist Christopher Burlak await the day when larger organ transplants from pigs—kidneys, livers, or hearts—help saves lives. The NYU study was a “first step in a long road,” he says. Companies are already taking the next ones, designing pig organ donors with three or more genes removed and up to nine added human genes. None of those pigs’ organs have been tested in people. “The next big advance in the field is going to be real transplants,” Burlak says, “not the short-term evaluation of xenografts in dead people.”
Source: Science Mag