Scientist Wenning Qin holds up a Petri dish, carefully sloshes around the pink liquid inside, and slides it under a microscope. Some identical tiny slashes come into focus. These cells, she explains, are derived from the ear of a pig. And they may contain the future of animal to human organ transplantation. Researchers in South Korea are expected to transplant pig corneas into humans within a year. A handful of groups across the US are also working toward pig organ clinical trials in the next few years, including a group at Massachusetts General Hospital in Boston that is starting a six-person clinical trial using “blankets” of pig skin to temporarily protect the skin of burn victims. At the University of Alabama at Birmingham’s (UAB) medical school, researchers are planning to transplant pig kidneys into adults and hearts into struggling new-borns. And in Cambridge, Massachusetts, at a start-up called eGenesis, scientists like Qin, the company’s Director of Genome Engineering, are gene editing pig cells in preparation. Their goal – shared by a handful of other biotech companies in the US and Europe working on genetic engineering – is to create pigs whose organs can be safely transplanted into people. “I think this is a magical point in the field of [animal transplants],” says William Westlin, eGenesis’ Executive Vice-President for Research and Development. “It’s no longer a question of if. It’s just a question of when.”
Scientists have long pursued the idea of keeping people alive by using parts from animals – a process referred to as xenotransplantation. But it was long believed to be impossible; early experiments showed that the body takes about five minutes to reject an organ from another species. “Nobody would dare speak” about running clinical trials for xenotransplantation, says Leo Bühler, President of the International Xenotransplantation Association. For a pig kidney, heart or lung to keep a person alive, the human immune system has to be tricked into not recognising that it comes from a different species. That’s where CRISPR gene-editing technology comes in, enabling researchers to make targeted changes to a complete set of genes in many places simultaneously. CRISPR – short for clustered regularly interspaced short palindromic repeats – has been used by eGenesis to eliminate from the pig genome a group of viruses that some worry could jump to humans after a transplant. Now they’re also working to remove markers that identify cells as foreign so the human immune system won’t reject them.
In unrelated research, other scientists have tested bioengineered pig organs in non-human primates, a crucial step toward a clinical trial in humans. In a recent Nature study, baboons lived for six months with hearts transplanted from pigs that had been gene-edited in a few spots to reduce rejection – the longest any animal has depended on an organ from another species. In another advance published in late 2017, researchers at the National Institutes of Health showed that baboons could live up to three years with a pig heart beating alongside their own. Improvements in immune suppression drugs have also made rejection less likely, says Jay Fishman, an infectious disease and immunology specialist at Massachusetts General Hospital and Harvard Medical School.
Animal rights activists are opposed to all research with primates, and such research can be done only under very limited circumstances, and at very few facilities. It would be too risky, researchers say, to try such transplants in humans without first testing them in primates. Primates have different immune systems to people, but testing in baboons is nevertheless challenging. There are no major remaining scientific hurdles to xenotransplantation, and pig organs will eventually be able to keep people alive and healthy, believes Bruno Reichart, a heart surgeon who led the Nature study. Reichart, Chief of the Xenotransplantation Collaborative Research Centre at the hospital of the University of Munich, says he now needs to extend his baboon experiments with the aim of consistently keeping 60% or more alive with a pig heart, and for longer periods of time. He’d like to try to sustain some for a year. But it isn’t simple to convince a baboon to take immunosuppressive medication every day. And it isn’t reasonable to keep an animal tethered to an IV for that long, he says.
The potential for such technology is vast. Right now, 75,000 people in the US are awaiting an organ transplant, and about 20 die every day because they couldn’t get one. Another 6,000 are awaiting organs in the UK. Unlike human organs, where patients have to wait for someone else to die, the supply of pig organs and cells would be virtually unlimited. Devin Eckhoff, a liver transplant surgeon at the University of Alabama at Birmingham Medical School, says if he got the green light today, he could be producing 50 pigs for transplant within nine months. (Animals that are gene-edited for transplantation would not be allowed to enter the food supply, so they pose no risk to the public, Eckhoff noted.) He says it’s frustrating to watch his patients get critically ill and then die for want of replacement organs. “I’ve devoted my life to transplants,” he says. With organs available from pigs, “think of how many more lives we could save”.
Transplant-ready pigs could do far more than just provide organs. Eventually, they could be used to produce the islet cells – clusters of hormone-producing pancreatic cells – needed by people with diabetes. Pig blood could be used to give transfusions to trauma patients and people with chronic diseases like sickle cell anaemia, who often develop antibodies against human blood cells because they have had so many transfusions. Even dopamine-producing cells could be made by pigs, and transplanted into patients with Parkinson’s disease, says David Cooper, who co-directs the xenotransplantation programme at UAB. “It’ll revolutionise medicine when it comes in,” Cooper says. “You’d have these organs available whenever you want them … If somebody’s had a heart attack, you could take their heart out and put a pig heart in on the spot. There is huge potential here.”
Even if a pig organ can’t last forever in a person, it should be able to buy someone time. At the moment, new-borns can wait on the organ transplant list for more than three months for a new heart, often facing a mortality rate above 50%, says David Cleveland, a heart surgeon at UAB. Cleveland wants to use xenotransplantation to save babies born with congenital heart defects. “There’s such a great need,” he says. Artificial hearts can keep adults alive while awaiting a transplant, but no such device exists for infants. There are clearly difficulties in using a pig heart permanently for a baby, but at least the pig heart could be used as a bridge, Cleveland says, keeping the baby healthy until a human heart becomes available. He’s also hopeful that infants’ immature immune systems would make it easier for them to accept pig hearts. Pigskin could also help burn patients, says Jeremy Goverman, the principal investigator of Massachusetts general’s skin trial. Now, he often can’t find swatches of human skin big enough to cover large wounds. He believes a patch of skin from a pig would be more cost-effective than one from a cadaver. For countries that can’t maintain human tissue banks, pigskin might be a life-saving alternative, he says.
The road ahead
Researchers at UAB are aiming to scale up breeding at their sterile facility this year. They plan to raise enough 150lb animals for a pilot trial and small clinical trial in people. But money is, as always, a problem. Researchers are also anxious about how the public will perceive xenotransplantation, although early polling suggests people are open to the concept. Of course, some will baulk at the idea of sacrificing animals for experiments and organs, even if they are used to save human lives. Researchers won’t identify the locations of their animal research labs for fear of animal welfare activists. But Americans already eat about 120m pigs a year– and no one has to accept a pig organ, Cooper notes, with human organ donation continuing for the foreseeable future. He thinks his desperately ill patients would be happy to get a pig organ as long as it works, just as he has seen people’s ideas about becoming an organ donor evolve when they need one themselves. “When it hits you personally and you are going to die, I think your attitude changes,” Cooper says. The final hurdle – the only way to really know whether xenotransplantation will work – will be testing with people, says Fishman. “I think all of us are waiting for the first clinical trial.”
Credit: Karen Weintraub for The Guardian, 3 April 2019.