The controversial idea of growing human organs in host animals has gotten a reality check. Despite recent successes at growing mouse organs in rats, using the same trick to grow human organs in larger animals such as pigs is a long way off, new research shows. The resulting human-animal chimeras don’t grow well, and few human cells survive.
The hurdles are not unexpected, says Joe Zhou at the Harvard Stem Cell Institute who was not involved in the work. But despite the “very severe technical challenges,” he says, “I’m optimistic. I think this particular path is promising.”
Producing human-animal chimeras has been controversial for several reasons, including worries that human cells could boost the host animal’s intelligence or develop into sperm or eggs. In 2015, the U.S. National Institutes of Health (NIH) said it would not fund such work. After holding a workshop to review the scientific and ethics issues, the federal agency said in August 2016 that it planned to lift the moratorium in January. That has not yet happened, however, and it is not clear whether the new Trump administration will influence NIH’s position on the issue.
The idea behind the new work is that if the cells from one animal are unable to form certain tissues—a pancreas, for example—the transplanted stem cells from the other species will take their place during development and form an organ of “donor” cells. The trick works in rats and mice: Yesterday researchers reported in Nature that they had grown a pancreas made of mouse cells inside a rat, and that the tissue could cure diabetes when it was transplanted back into a sick mouse.
That sounds promising, but so far human cells don’t mix as readily with those of other animals. Using nonfederal funding, Juan Carlos Izpisúa Belmonte and Jun Wu of the Salk Institute for Biological Studies in San Diego, California, have now led a group that has conducted a series of chimera experiments, culminating in placing human stem cells in pigs, because their organs grow to humanlike sizes.
Similar to the Nature work reported yesterday, the scientists initially combined rat and mouse cells successfully: They added rat embryonic stem cells to mouse embryos that were lacking different genes crucial for organ formation, producing mice with eyes, hearts, and pancreases that were enriched with rat cells.
Then the researchers tried combining human induced pluripotent stem cells (reprogrammed adult cells that have regained the characteristics of embryonic cells) with pig embryos. After they implanted the chimeras into surrogate mothers, they let the embryos develop for just 3 or 4 weeks, to check whether and where the human cells were contributing. The researchers implanted more than 2000 human-pig chimeric embryos into 41 surrogate sows, resulting in 18 pregnancies and 186 embryos a month later. However, many of the embryos were much smaller than normal and seemed to grow more slowly, the group reports today in Cell. The researchers saw signs of human cells, but they were rare. “It is fair to say they engraft, but the level is low,” Wu says.
One problem may be that porcine pregnancies last just 114 days (just shy of 4 months), compared with 9 months for humans. And pigs and humans are much more distantly related than rats and mice. Tweaking genes in the pig embryos—so that they can’t form certain tissues, for example—might help give the human cells more room to develop, Wu says. Still, that he and his colleagues found surviving human cells at all after 4 weeks of development is “remarkable,” he says. “I think it’s encouraging. Before we dream about all these downstream applications, we need to know if the evolutionary distance [between humans and pigs] prevents human cells from contributing at all.”
Zhou agrees. “A clear barrier has been identified: limited contribution [of human cells to the developing animal]. But this is a technical problem that can be tackled in a targeted and rational way.”