Genetically engineered pigs produced in Munich, Germany, were recently used in a record-breaking baboon heart transplant.

Jan-Michael Abicht

Scientists grow bullish on pig-to-human transplants

BALTIMORE, MARYLAND—Add your name to a waitlist for a kidney transplant in the United States today, and you’ll join around 100,000 people, many of whom have already been waiting years. The scarcity of life-saving organs for transplants has raised hopes for substitute organs from pigs, which have a similar anatomy to humans. But decades of scientific setbacks have kept clinical trials of that approach, called xenotransplantation, on the horizon.

Now, a few teams are chomping at the bit. Exhilarated by recent results in monkey experiments, some researchers here at a meeting of the International Xenotransplantation Association are eyeing human testing.

“What we thought was very far away seems to be coming to the near future,” says Muhammad Mohiuddin, a cardiac transplant surgeon at the University of Maryland School of Medicine here. He moderated a premeeting session where scientists discussed advances with officials of the U.S. Food and Drug Administration, which would review any application for a clinical trial.

Teams focusing on kidney and heart transplants now have results they’re eager to share with regulators. In the past couple of years, they have managed to dampen—though not eliminate—the violent immune response that transplanted pig organs normally provoke in monkeys. Earlier this year, a team at Emory University in Atlanta, Georiga, announced that a kidney from a genetically engineered pig had sustained a rhesus macaque monkey for more than 400 days before being rejected, breaking the record by more than 250 days. And today, a group of researchers headed by Bruno Reichart at the University of Munich in Germany announced they had nearly doubled the previous survival record for a life-sustaining pig heart transplant in a baboon, to 90 days.

The study’s experimental design required that the group stop the experiment at 3 months, though the baboon was still “in very good condition,” University of Munich cardiac surgeon Paolo Brenner said after the presentation. It is the first animal to hit a milestone, set nearly 20 years ago by the International Society of Heart and Lung Transplantation, for determining whether a xenotransplantation approach is safe enough to try in humans, Brenner notes. The society’s guidelines are that 60% of animals in a study should survive at least 3 months. Brenner’s team is now working to repeat the results in more baboons, and they hope to launch a clinical trial in 2 or 3 years.

That’s good news for a field that went through a protracted period of hard times. After a flood of optimism and investment in the early 1990’s, the struggle to overcome host immune response and fears that organs could transmit pig viruses to humans scared off pharmaceutical funders. But new immunosuppressant drug regimens and a wealth of new genetically engineered pig varieties have changed the equation, says transplant immunologist David Cooper of the University of Alabama in Birmingham. With gene-editing tools such as CRISPR, scientists can now eliminate immune-provoking sugars from the surface of pig cells, introduce human genes that regulate blood coagulation to prevent dangerous clots, and snip out viral sequences that some fear could infect a human host.

“We feel much more encouraged than we did even 2 years ago,” Cooper says. His group is exploring kidney transplants from another genetically engineered pig variety, and expects to apply for permission to start a U.S. clinical trial by the end of next year.

For all the optimism, researchers are far from being able to offer patients an organ with a lifetime warranty. They are still discovering new mechanisms of immune rejection and debating which genetic changes to pigs are best. And other organs pose bigger challenges. The lung, for example, has proved highly sensitive to inflammation, and experimental animals have survived only a handful of days.

What’s more, any whole organ transplant will for now require a cocktail of immunosuppressant drugs that could leave patients vulnerable to infections. That’s a big obstacle to commercial success, says Martine Rothblatt, CEO of United Therapeutics Corporation in Silver Spring, Maryland. The company has invested in xenotransplantation research focused on lung disease, and owns Revivicor, a major supplier of genetically engineered pigs. To be a commercial hit, xenotransplantation “must touch tens and hundreds of thousands of people,” she says. “I do not believe such a large number of transplants is likely with poorly tolerated organs that need to be beaten down with immunosuppressants.”

But that’s likely to be the state of play for the first pioneering patients, if whole pig organs make it to the clinic. Cooper points to the many people with kidney failure forced to spend hours a week in blood-filtering dialysis treatment. For these patients, even a temporarily functional pig kidney might be valuable as they wait for an available human kidney. “If you offered them a year off dialysis, they would probably think that’s pretty good,” Cooper says. “You have to start somewhere.”