Published On June 10, 2016
IF HEARTS AND KIDNEYS THAT FUNCTIONED IN HUMANS COULD BE GROWN IN A PIG, the organ shortage would be all but over. More than 120,000 patients in the United States are on donor waiting lists, and 22 of them die every day. But successful xenotransplantation, the science of transplanting tissue from one species to another, has proved as elusive as cold fusion.
The feat seemed just around the corner 10 years ago (“That’s Some Pig,” Fall 2005). Researchers had engineered a pig that lacked alpha-1,3-galactose, or Gal, a sugar in pig tissue that triggered acute rejection in primates. And researchers, including David Sachs at Massachusetts General Hospital, had discovered that they could improve tolerance of a foreign pig organ by the monkey immune system. They used a novel parallel procedure: transplanting either bone marrow or parts of the thymus, the gland that produces T-cells, from the donor animal at the time the organ was transplanted.
But those discoveries were soon followed by a stalemate. Immune systems in monkeys and baboons continued to attack the pig tissue as foreign. There was also concern that PERVs, viruses that pigs carry but aren’t harmed by, might infect human recipients. Xenotransplantation went back on the shelf.
Then last year, the game changed again. A team led by geneticist George Church of Harvard Medical School used CRISPR to modify 87 genes in pig embryos. CRISPR, a new gene editing technology that is derived from the immune systems of certain bacteria, allows researchers to alter genes with unprecedented accuracy. The researchers eliminated all 62 PERVs and modified another 25 genes involved in the immune system response. Separately, a team at the National Institutes of Health shattered longevity records for pig-to-baboon transplants by splicing human genes into the pigs and using new immunosuppressant drugs. The baboon recipient of the pig heart lived for 945 days—more than five times the previous record.
Caution is still the watchword. While PERVs have been eliminated, other viruses might lurk in the pig genome. And more steps may be needed to prevent rejection by primate and human immune systems. Sachs has continued to explore the benefits of simultaneously transplanting bone marrow into the transplant recipient. Inserting the human gene CD47 into pig bone marrow prior to transplant of pig skin into a baboon, he found, appeared to lengthen the survival time of a skin transplant. Hearts, kidneys and lungs are next.
In other good news, private investors are returning to the field after sitting out the long drought. Revivicor, a division of the biotechnology company United Therapeutics, is pouring millions into developing pig organs for researchers using some of the gene-editing techniques developed over the past decade. Meanwhile, a company co-founded by George Church is working to create pigs whose genomes reflect his most recent breakthroughs in gene editing.
“The progress has been slow, much slower than a lot of us would have hoped,” says Sachs, who has been working on xenotransplantation since the 1980s. “But it has been steady. When you look back to when we first started xenotransplants, the survival of the pig kidney in a baboon was measured in minutes. Each decade since then has seen a progression, from minutes to weeks to months. Now, with genetic engineering, it may soon be measured in years, and that’s when I think it will really have an impact on saving people’s lives.”
Stay on the frontiers of medicine
- Progress on Pig’s Organs
The first issue of Proto looked at the promise of transplanting organs from other species. What’s happened since then?
- That's Some Pig
Sugar-free and engineered for tolerance, hogs may one day fill a need for transplant organs.
- The Transplant Trick
An experimental protocol fools the immune system into accepting a new organ without debilitating drugs. Could it become routine?