January 17, 2024
4 min read
A genetically modified pig liver successfully filtered the blood of a human who had completely lost brain activity and did so for three days. The achievement offers a potential temporary treatment for people with acute liver failure
For the first time, researchers have successfully connected a functioning liver from a pig to a human body. In a step toward testing the procedure in living people, a team at the University of Pennsylvania externally connected the liver to the body of a person who had suffered brain death. The liver, which came from a pig with 69 genetic modifications, properly filtered human blood for three days without being rejected by the human body.
“This may be a big step forward,” says David Cooper, a transplant surgeon at Massachusetts General Hospital in Boston, who was not involved in the procedure. He says this approach could help treat acute liver failure, which kills thousands of people per year and is fatal in up to 90 percent of cases. Pig livers, he says, could save lives by providing a temporary method of filtering blood until a person’s own liver heals or a human organ donor is found.
Xenotransplantation—transplanting organs from nonhuman species into humans—has seen numerous successes in recent years. Researchers at the University of Maryland School of Medicine have twice transplanted hearts from genetically modified pigs into living people, although both individuals died within a few months of the transplant. Several teams have successfully transplanted kidneys from genetically modified pigs into people kept on life support after they had lost all brain activity. These pigs’ genomes contained 10 or fewer genetic modifications, some of which altered proteins on the surfaces of the organs’ cells to be more akin to human cells. The genome edits helped prevent the recipients’ immune system from attacking and rejecting the organs.
The liver used in the latest procedure came from the company eGenesis, which engineered pigs to contain 69 different genome modifications. Most of these edits eliminated pig viruses that were embedded in the animals’ genome and disguised cell-surface proteins to make them more humanlike. Kidneys from these pigs have kept monkeys alive in lab experiments, but the engineered animals’ organs had never been tested in people.
Livers are particularly challenging in xenotransplantation because they perform more functions than hearts or kidneys. A pig liver must not only filter toxins from blood but also produce thousands of biological compounds such as hormones and blood clotting proteins—any of which could be attacked by the human immune system if they are not similar enough to the human version of these substances. Xenotransplanted livers also tend to recognize the recipient’s blood platelet cells—which are necessary for clotting—as foreign and gobble them up, eventually causing internal hemorrhaging. But these problems might be alleviated if a pig liver is used only temporarily outside of the body rather than permanently transplanted.
Acute liver failure often occurs rapidly when drugs or toxins damage the organ. The liver has the ability to repair itself if it is given enough time, but the condition can quickly lead to death. Rerouting a person’s blood through an external pig liver for even a few days could restore function and buy time, says transplant surgeon Abraham Shaked of the University of Pennsylvania, who led the recent pig liver operation.
To see whether the genetically modified pig organ could survive the human immune system, Shaked’s team tested the liver in a person who was brain-dead and whose body was being maintained on life support. Instead of transplanting the pig liver into the body, the researchers kept the organ in a machine next to it. They used a system of tubes to hook up the recipient’s bloodstream to the liver, allowing blood to flood the organ and return to the body. The liver circulated the recipient’s blood and produced bile—a substance that helps with digestion—for 72 hours, at which point the researchers ended the experiment.
Shaked says that while the number of platelets in the person’s blood dropped in the first 24 hours, the level then stabilized for unknown reasons. He says he was surprised that the liver remained functional for 72 hours without bleeding or losing oxygen and was never attacked by human immune cells in the blood. “It taught me that it’s doable,” he says of the procedure. The group is still testing blood and plasma samples taken during the procedure to determine which functions the pig liver could perform and whether the human immune system showed any molecular signals that it was beginning to react to the organ.
“It sounds encouraging,” says Scott Nyberg, a bioengineer at the Mayo Clinic in Minnesota, who was not involved in the recent operation. His group is working on building artificial livers seeded with pig cells that filter blood through a membrane, as well as drugs that help humans’ liver to repair itself more quickly. Those drugs, he says, could shorten the amount of time a person would need to be attached to an external pig liver. He thinks the temporary system could work, though, because it would likely take weeks for the human body to begin mounting an immune response against proteins produced by the pig organ.
Fully transplantable pig livers may still be years away; it’s not yet known whether a pig liver can support a human body with all the functions it needs. “For now, I think there are so many incompatibilities that we’re not going to look for long-term replacement of the human liver,” Shaked says.
Some experts say the news of the recent pig liver gives promise to future research, however. “This is just exciting,” says Jayme Locke, a transplant surgeon at the University of Alabama at Birmingham, who has done experimental xenotransplants with pig kidneys, adding that she looks forward to seeing the results published. “If they can demonstrate this has the ability to bridge [acute liver failure], it has a real application,” she says.
Shaked says his team is hopeful that it can soon begin trials of the “bridge” livers in people with acute liver failure and has begun designing protocols to use pig livers on an emergency basis in people who are certain to die otherwise. But before then, the researchers want to conduct more tests in people who are brain-dead, including those whose own liver is not functioning, and see whether the pig livers can function for up to one week.