Genetically Engineering Pigs to Grow Organs for People

The idea of transplanting organs from pigs into humans has been around for a long time. And for a long time, xenotransplants—or putting organs from one species into another—has come up against two seemingly insurmountable problems.

The first problem is fairly intuitive: Pig organs provoke a massive and destructive immune response in humans—far more so than an organ from another person. The second problem is less obvious: Pig genomes are rife with DNA sequences of viruses that can infect human cells. In the 1990s, the pharmaceutical giant Novartis planned to throw as much $1 billion at animal-to-human transplant research, only to shutter its research unit after several years of failed experiments.

Quite suddenly, however, solving these two problems has become much easier and much faster thanks to the gene-editing technology CRISPR. With CRISPR, scientists can knock out the pig genes that trigger the human immune response. And they can inactivate the viruses—called porcine endogenous retroviruses, or PERVs—that lurk in the pig genome.

On Thursday, scientists working for a startup called eGenesis reported the birth of 37 PERV-free baby pigs in China, 15 of them still surviving. The black-and-white piglets are now several months old, and they belong to a breed of miniature pigs that will grow no bigger than 150 pounds—with organs just the right size for transplant into adult humans.

eGenesis spun out of the lab of the Harvard geneticist George Church, who previously reported inactivating 62 copies of PERV from pig cells in 2015. But the jump from specialized pig cells that grow well in labs to living PERV-free piglets wasn’t easy.

“We didn’t even know we could have viable pigs,” says Luhan Yang, a former graduate student in Church’s lab and co-founder of eGenesis. When her team first tried to edit all 62 copies in pig cells that they wanted to turn into embryos, the cells died. They were more sensitive than the specialized cell lines. Eventually Yang and her team figured out a chemical cocktail that could keep these cells alive through the gene-editing process. This technique could be useful in large-scale gene-editing projects unrelated to xenotransplants, too.

When Yang and her team first inactivated PERV from cells in a lab, my colleague Ed Yong suggested that the work was an example of CRISPR’s power rather than a huge breakthrough in pig-to-human transplants, given the challenges of immune compatibility. And true, Yang and Church come at this research as CRISPR pioneers, but not experts in transplantation. At a gathering of organ-transplantation researchers last Friday, Church said that his team had identified about 45 genes to make pig organs more compatible with humans, though he was open to more suggestions. “I would bet we are not as sophisticated as we should be because we’ve only been recently invited [to meetings like this],” he said. It’s an active area of research for eGenesis, though Yang declined to disclose what the company has accomplished so far.

“It’s great genetic-engineering work. It’s an accomplishment to inactivate that many genes,” says Joseph Tector, a xenotransplant researcher at the University of Alabama at Birmingham.

Researchers like Tector, who is also a transplant surgeon, have been chipping away at the problem of immune incompatibility for years, though. CRISPR has sped up that research, too. The first pig gene implicated in the human immune response as one involved in making a molecule called alpha-gal. Making a pig that lacked alpha-gal via older genetic-engineering methods took three years. “Now from concept to pig on the ground, it’s probably six months,” says Tector.

Using CRISPR, his team has created a triple-knockout pig that lacks alpha-gal as well as two other genes involved in molecules that that provoke the human immune system’s  immediate “hyperacute rejection” of pig organs. For about 30 percent of people, the organs from these triple-knockout pigs should not cause hyperacute rejection. Tector thinks the patients who receive these pig organs could then be treated with the same immunosuppressant drugs that recipients take after an ordinary human-to-human transplant.

Tector and David Cooper, another transplant pioneer, were both recently recruited to the University of Alabama at Birmingham for a xenotransplant program funded by United Therapeutics, a Maryland biotech company that wants to manufacture transplantable organs.

Cooper has transplanted kidneys from pigs engineered by United Therapeutics to have six mutations, which lasted over 200 days in baboons. The result is promising enough that he says human trials could begin soon. These pigs were not created using CRISPR and they are not PERV-free, though recent research has suggested that PERV may not be that harmful to humans. It will be up to the FDA to decide whether pig organs with PERV are safe enough to transplant into people.

If it happens, routine pig-to-human transplants could truly transform healthcare beyond simply increasing the supply. Organs would go from a product of chance—someone young and healthy dying, unexpectedly—to the product of a standardized manufacturing process. “It’s going to make such a huge difference that I don’t think it’s possible to conceive of it,” says Cooper. Organ transplants would no longer have to be emergency surgeries, requiring planes to deliver organs and surgical teams to scramble at any hour. Organs from pigs can be harvested on a schedule, and surgeries planned for exact times during the day. A patient that comes in with kidney failure could get a kidney the next day—eliminating the need for large dialysis centers. Hospital ICU beds will no longer be taken up by patients waiting for a heart transplant.

With the ability to engineer a donor pig, pig organs can go beyond simply matching a human organ. For example, Cooper says, you could engineer organs to protect themselves from the immune system in the long term, perhaps by making their own localized dose of immunosuppressant drugs.

At last Friday’s summit, Church speculated about making organs resistant to tumors or viruses. When an audience member asked about the possibility of genetically enhancing pig organs to work as well as Michael Phelps’s lungs or Usain Bolt’s heart, he responded, “We not only can but should enhance pig organs, even if we’re opposed to enhancing human beings ... They will go through safety and efficacy testing, but part of efficacy is making sure they’re robust and maybe they have to be as robust as Michael Phelps in order to do the job.”

Xenotransplantation will raise ethical questions, of course, and genetically enhancing pigs might come uncomfortably close to the plot of Okja. These enhancements are hard to fathom for now because scientist don’t yet know what genes to alter if they wanted to make, for example, super lungs. It’s taken decades of research to pinpoint the handful of genes that could make pig organs simply compatible with humans. But the technical ability to make any edits—or even dozens of edits at once—with CRISPR is already here.