More than 115,000 people in the United States are on waiting lists for an organ transplant, and 20 Americans die each day, on average, from a shortage of donated organs.
While scientists have tried to culture organs in the lab from stem cells, the process is slow and biologically fragile. Another option is to grow human organs inside animals like pigs and sheep by implanting their embryos with bits of human DNA. Think of them as four-legged organ farms.
Although the work has been slow and somewhat controversial, scientists recently announced that they reached a new milestone in the quest to grow human organs in animals — a human-sheep embryo in which one out of every 10,000 cells contains human DNA.
Growing human organs in animals sounds exotic, but the process is relatively straightforward. Using the gene-editing tool Crispr, scientists delete the DNA from an early-stage pig or sheep embryo that controls for organ growth, say a pancreas or liver. In its place, researchers inject human pluripotent stem cells into the embryo — undifferentiated cells that can fill the genetic gap and grow a human organ instead.
The resulting hybrid creature, which contains DNA from two different individuals or species, is known as a chimera, a nod to the mythological three-headed monster that was part lion, part goat, and part serpent. But the biology behind modern chimeras is very real.
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Scientists from Japan and the United States have already created fully functional mouse-rat chimeras with the eyes, heart, and pancreas of a rat grown inside mice. One group even grew a mouse pancreas in a rat, then successfully transplanted it back into a diabetic mouse, where the new organ cured the critter’s diabetes. There was no danger of the mouse rejecting the pancreas, because it was made from the DNA of its identical twin.
To grow human organs from chimeras, however, we’ll need an embryonic host a lot bigger than a mouse or rat. That’s why there’s been so much interest in pigs and sheep, which could conceivably grow a genetically matched, human-size heart, kidney, or liver from a chimera embryo in as few as nine months.
But coaxing human cells to grow in a foreign embryonic environment is far more complicated than swapping DNA between a mouse and a rat, which are nearly identical genetically. Plus, there are the ethical questions raised by crossing human DNA with other species. At what point does a human-pig chimera become something more than just an animal?
Pablo Ross at the University of California, Davis is a member of the research collaboration that announced its progress toward a human-sheep chimera at a February meeting of the American Association for the Advancement of Science in Austin, Texas. In previous work with pigs, Ross and his colleagues had created chimera embryos with one human cell for every 100,000 pig cells. The human-sheep embryo represented a 10-fold increase in human genetic contribution.
Still, Ross told Seeker, one human cell for every 10,000 sheep cells is way too low of a concentration to be able to take over organ development in an embryo.
“For organ generation, we’re going to need human cells with the potential to contribute about one percent [of the embryo],” said Ross. “We’re still 100 times short of that goal.”
One of the greatest challenges for increasing those concentrations is that researchers still don’t know what strains of human pluripotent stem cells, or what combinations of different cell types, work best in a chimera embryo.
The problem is essentially an ethical one, explained Ross. With mice, you can take stem cells from one animal, implant them into another mouse’s embryo and see how effectively they propagate. By doing that over and over again, with different types and concentrations of stem cells, scientists now know exactly which mouse stem cells work best in chimeras.
“With human stem cells, obviously we can’t do that kind of experiment for ethical reasons,” said Ross. “We can’t put human stem cells in human embryos and see if we get a chimeric person."
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The result is a much slower trial-and-error process that’s also hampered by a lack of funding. The National Institutes of Health (NIH), which provides research grants to more than 30,000 projects each year, imposed a moratorium on funding for chimera research in 2015. Despite proposing a lift on that ban a year later, the funding freeze remains.
One reason the NIH imposed the original funding ban was concerns over potential “off-target” effects of implanting human stem cells in animal embryos. What if, for example, human stem cells migrated to a pig’s developing brain resulting in a chimera with human-grade cognition? Such a creature would permanently blur the moral and ethical lines between humans and non-humans, calling into question everything from scientific experimentation to raising animals for food.
Ross insists that his human-sheep chimera research is far from unethical and that UC Davis has put careful and thoughtful checks in place to ensure that all research involving human stem cells and animals is approved at multiple stages.
At this point, Ross’s chimera embryos are only grown for three weeks and then destroyed, leaving no possibility that the human-sheep mashups will mature. Although Ross has great hope that he and his colleagues will ultimately find the right combination of human stem cells to grow the organs that will save thousands of lives, he admitted that scientifically we’re just scratching the surface.
“We’re in the very, very, very early stages of trying to make this work,” he said.