First Human-Pig Chimera Is a Step Toward Custom Organs

Every day, 22 people in America die while waiting for an organ transplant. But when scientists can grow replacement livers or kidneys or pancreases inside of animal hosts, medicine's organ shortage may end. That’s the hope anyway---and this week there’s more reason to hope than ever that it might become reality.

The key to producing human organs in other animals is the chimera, a mixture of cells from more than one species growing together as a single animal. For decades, researchers have struggled to coax Petri dishes of stem cells into functional, three-dimensional tissues and organs, hampered by technical challenges and political stonewalling. Now, two milestone papers have taken two big steps toward solving the chimeric riddle. Will you be ordering up a homo-porcine gallbladder on Amazon this time next year? No. No, definitely not. But researchers have done two things they’ve never done before: 1. Combine two large, distantly-related species into one embryo. And 2. Use organs from one species grown in another to actually treat disease.

At the Salk Institute in La Jolla, California, biologists Juan Carlos Izpisua Belmonte and Jun Wu spent four years injecting different forms of adult human stem cells---derived from skin or blood cells and reprogrammed to act like naive, stem cells---into 1,500 pig embryos. They wanted to figure out which ones could survive into the first few weeks of life. The cells that worked the best, they report today in Cell, were “intermediate” pluripotent stem cells, somewhere between a blank slate and a stem cell primed to start developing into different tissues. These cells became the first human colonizers of the pig body: Around 20 days in, fluorescent tagging showed one living human cell nestled within every 100,000 or so pig cells.

“This was a real tour de force,” says Daniel Garry, a cardiologist who leads a chimera project at the University of Minnesota. “What separates them from all the rest of us who do this work is the large number of animals they showed this in.” Izpisua Belmonte and Wu also successfully created human/cow chimeras at the blastocyst stage---a few days following fertilization, but before the ball of about 250 cells implants in the uterine wall---but only pursued pigs because of the animal’s long history in human medicine. Pig valves are still used in heart transplants, and before recombinant DNA technology, that’s where artificial insulin came from.

With other advances, scientists are hoping to do away with artificial insulin altogether. About 30 million Americans have diabetes; more than 3 million of them rely on artificial insulin to stay alive. Chimeras could potentially help those patients make their own insulin---and Hiromitsu Nakauchi, a stem-cell biologist at the University of Tokyo and Stanford, showed you can do just that in a paper published yesterday in Nature. At least, you can in rats. His team used genetic tweaks to prevent rats from making their own pancreases. Then they injected mouse stem cells (complete with all the necessary pancreas-making genes) into the developing pancreas-less rat embryos. The rats grew normally. The only thing different was their pancreases were made almost entirely of mouse cells.

Then they went a step further. From those rat-mouse chimeras, Nakauchi’s team took out tiny clusters of pancreatic cells that make insulin (called islets) and transplanted them into diabetic mice. The islets settled in and made enough insulin to keep the host mice’s blood glucose levels in a normal range for more than a year. In layman’s terms? The mice were cured. It’s the first time a chimera-created organ has ever treated a medical condition.

“What’s really significant here is that a rat pancreas, generated in a mouse background, responded to typical events the way you’d want it to,” says Garry. That’s great news for diabetics. You want your inter-species transplant organ to work inside you like you were born with it, even if it was grown in a pig.

Now, things can get a little bit complicated if your donor animal starts growing organs they aren’t supposed to. Before Izpisua Belmonte and Wu got around to making man-pigs and man-cows, they too worked with mouse-rats. Using Crispr to delete different critical tissue genes, they created mice without the ability to make a heart, a pancreas, or eyes. Then they introduced rat stem cells to see if they would fill those vacant organ niches. They did. Mice grew rat eyes and rat hearts and even a rat pancreas. But some of those rat cells also went on to form gallbladders in the mouse. Why is this weird? Because rats stopped developing this organ about 18 million years ago.

This suggests that rats don’t have gallbladders not because they can’t, but because their rat-specific set of developmental instructions overrides that ability. Change the environment, and those hidden traits come out. Wu says there’s no reason we shouldn’t believe the same might hold true for humans. “We generate organs and tissues now that we see as human, but maybe we have the ability to do something more,” he says. “Those abilities, that have been suppressed during evolution because we don’t need them anymore could be unlocked. You just need a different environment.”

To find out, scientists will have to improve human stem cells' colonization of their animal hosts. The Salk team’s next hurdle is trying to embed one human cell in 1,000, or even 100 pig cells. “That’s when we can start thinking about practical applications,” says Wu. But that’s also when ethical questions start to become more urgent. How many cells do you need for a chimera to be considered more human than pig? Does it matter what kind of cells, what kind of tissues?

“It’s a Goldilocks kind of situation,” says stem cell researcher Paul Knoepfler. “You need the right amount plus the right location.” But Knoepfler says, scientists and policymakers shouldn’t be waiting for that “just right” moment to have these conversations. In August, the National Institutes of Health announced that it was proposing to lift its 2015 moratorium on public funding for human chimera research. Since then, the institute has reviewed 22,000 public comments on the issue. And while neither of these studies were NIH-funded, the excitement over their results has many wondering if more research dollars might accelerate the field. For those waiting on organ donor lists, that money can't come soon enough.