A kidney transplanted from a genetically engineered miniature pig kept a monkey alive for more than two years — one of the longest survival times for an interspecies organ transplant.
The feat brings clinicians one step closer to their goal of relieving the shortage of life-saving human organs, by using animal organs, a practice known as xenotransplantation. The work describes a raft of genome edits that prevent the recipient’s immune system from attacking the new organs, and that also neutralize ancient viruses lurking in the donor’s organs — crucial steps for harnessing porcine organs for human use.
This is a “proof of principle in non-human primates to say our [genetically engineered] organ is safe and supports life”, says Wenning Qin, a molecular biologist at the biotech firm eGenesis in Cambridge, Massachusetts, who co-authored the study published in Nature1 on 11 October.
Researchers say that this study will provide more data to regulators such as the US Food and Drug Administration, which is considering whether to approve the first human trials of non-human organ transplants. But scientists say that it will be important to dig into why there was considerable variation in the success of the newly described xenotransplants, and how feasible it will be to mass-produce pigs with such extensive editing.
From pig to human
In the past few years, researchers have transplanted pig hearts into two living people2, and demonstrated that pig hearts3 and kidneys4 can function in people who have been declared legally dead.
Such research is crucial, given the dearth of suitable organ donors, says David Cooper, a xenotransplant immunologist at Massachusetts General Hospital in Boston, who was not involved with the study but is a consultant for eGenesis. In the United States alone, more than 100,000 people are awaiting an organ transplant, and about 17 of them die each day.
Xenotransplantation research has mainly focused on pigs (Sus domesticus), in part because their organs are of a comparable size and anatomy to that of humans. But the immune systems of humans and other primates react to three molecules on the surfaces of pig cells, causing them to reject unaltered pig organs. So, researchers started using the genome-editing technology CRISPR–Cas9 to disable the genes that encode enzymes that produce those molecules.
Qin and her colleagues edited 69 genes, which is the most extensive editing done in live pigs for xenotransplantation. Three edits target the rejection-related molecules, and 59 edits target retrovirus genomes that became embedded in the pig genome long ago. Previous research5,6 has shown that, in a laboratory setting, these embedded genomes can produce viral particles that infect human cells, but the infection risk to human xenotransplant recipients and their transplanted organs is unclear.
The last seven edits are additions of human genes that help to keep the transplanted organ healthy. Two genes, for example, encode proteins that prevent unnecessary blood clotting.
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Qin and her colleagues created pigs with these gene edits and transplanted a pig kidney into more than 20 cynomolgus macaques (Macaca fascicularis) that also received an immunosuppressive drug cocktail. None of the monkeys that received kidneys without the seven human genes survived for more than 50 days. By comparison, 9 of the 15 monkeys that received kidneys with the human genes did. Five of those monkeys lived for more than one year, and one of the five lived for more than two. An analysis of kidney biomarkers show that the transplanted organs performed just as well as two native kidneys.
Organs transplanted from conventional pigs grow rapidly in the recipients, threatening to compromise the grafts. Some researchers have tried disabling the pig genes responsible for this growth, but this step comes with unintended complications, says Muhammad Mohiuddin, a xenotransplantation surgeon at University of Maryland School of Medicine in Baltimore. He commends the authors of the Nature study for solving this problem by using kidneys from miniature pigs, whose organs grow at a slower pace.
Range in survival time
Although survival times of up to two years are exceptional, Qin acknowledges that the times were more varied than the team had expected. But researchers engineered the pig genomes with people in mind, not non-human primates, so it’s likely that they would fare better in humans, Mohiuddin says.
Still, the jump to humans will not be small, says Jayme Locke, a transplant surgeon at the University of Alabama at Birmingham. Humans weigh much more and have a higher blood pressure than these monkeys, and it’s unknown whether the pig organs will withstand that environment, she adds.
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Not all researchers are convinced that such extensive genetic changes are necessary. Megan Sykes, a transplant immunologist at Columbia University Medical Center in New York City, applauds the researchers for studying the effect of so many genes.
But the survival is not “strikingly better than what has been seen before with many fewer gene modifications”, she says. With each extra gene modification, they become harder to produce, which might make it more difficult to scale up, she says.
In principle, Mohiuddin agrees that some of these edits might be “overkill”, but he is optimistic that one day there will be genetically modified pigs that eliminate the need for immunosuppressive drugs.
“I don’t think we know yet how simple [these gene edits] can be or how complex they need to be,” Locke says. “That’s really where these clinical trials are going to be very important.”