In a bid to make organs for patients in need of transplants, scientists have created embryos that were hybrids of humans and pigs and grown them until they were on the verge of developing the body parts that might one day save lives.
Researchers reported Thursday in the journal Cell that they injected pig embryos with human stem cells that were capable of developing into a wide range of tissues. Those composite embryos were then transferred into the wombs of mother pigs.
By the time the scientists harvested the embryos after four weeks, the human stem cells had established beachheads throughout the developing pigs. As a blob of fetal pig tissue reached the cusp of developing into a cluster of distinct organs, human cells appeared throughout the tiny organism, ready to contribute to the generation of organs.
Each of these embryos held the promise of becoming a true chimera: a creature half-human, half-beast that has inspired myths and science fiction fantasies through the ages.
In a future that is now a bit closer, such chimeric creatures could become incubators for replacement organs that are in seriously short supply. Each day in the United States, 22 people who need a new heart, lung, kidney or liver die while waiting for a suitable organ to become available.
Though scientists have tried to nurture transplantable organs in the lab, such efforts have proved disappointing, said Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute in La Jolla and senior author of the new report.
“There has been some progress but by and large these cells are not the same as nature generates,” Belmonte said. “The idea we had was, ‘We scientists don’t know how to do this, but nature does it every day, starting with the embryo form. Why don’t we let nature do its thing?’”
In a separate study published Wednesday in the journal Nature, a group of scientists led by Stanford University’s Hiromitsu Nakauchi reported the results of an experiment that took a similar approach. The team took pancreatic stems cells from mice and inserted them into embryonic rats that had been genetically engineered not to develop a pancreas of their own. When the scientists harvested the resulting pancreatic cells from the rats and transplanted them into mice with diabetes, the cells took over the job of producing insulin. The mice were cured for over a year.
That research used small animals to demonstrate the potential of chimerism to advance the science of transplantation. But Salk’s scientists were keen to explore chimerism as a means to develop organs for potential human use.
The domestic pig has long been seen as animal that could incubate replacement organs for humans. They are fellow mammals whose organs grow to about the same size as those of an adult human in the span of about two years.
But if the human immune system is to be tricked into accepting a pig’s organ, scientists know that human cells — in fact, cells specific to the transplant recipient — would need to be well represented in that organ.
Making that happen seemed like a science-fiction dream only four years ago, when the Cell study began, said developmental biologist Jun Wu, the paper’s lead author.
But human stem cell technology has advanced to the point that scientists can turn back the clock on mature skin cells and render them capable of becoming any one of a wide range of specialized tissues. And scientists have a better understanding of the processes by which such stem cells begin to differentiate and become distinct tissues.
The team set out to create chimeras with both cows and pigs, but ended up proceeding only with pigs — approximately 3,500 of them.
The result was fetal tissue that was mostly pig and just a little human, Wu said.
In the tissue that would soon develop into the embryonic pig’s heart, one out of every 1,000 to 10,000 cells was human.
In the embryo as a whole, human cells probably accounted for about one in every 100,000 cells. But with millions of cells in a developing pig embryo, that’s still a lot of human cells, Wu and Belmonte said.
In future research, Wu said, Salk scientists will explore how to increase the concentration of human cells in certain organs (such as the heart). They also want to glean assurances that human cells are not going to organs, such as the brain and gonads, that raise deep concerns among ethicists.
If human cells enter the gonadal tissue of pigs, they could introduce profound genetic changes that would be passed on to future generations. And if human cells enter the pig’s brain tissue, there is the remote but very frightening prospect of “endowing the resulting creature with some kind of humanesque brain or cognitive capacity,” he said.
With both concerns in mind, the National Institutes of Health have placed strict limits on the creation of chimeric organisms involving human cells. (In recent months, NIH officials have proposed loosening some of those limits.)
The findings in Cell are somewhat reassuring on that front. Wu and Belmonte report that, at least at the early stage of fetal development they studied, human cells had not made their way into the pigs’ gonadal or brain tissue, although they were found in peripheral nervous system tissue.
Robert suggested that future research might introduce human cells into the embryonic tissue of even higher-order animals, including primates. If so, the bioethical debates could be fierce.
But for now, he said, scientists and ethicists have time to wrestle with the issues raised by chimeric organisms. Though the accomplishment reported is dramatic, he said, it offers “a very technically competent illustration that we’ve got a long way to go” before truly chimeric creatures are a reality.
Wu and Belmonte agreed. For now, such experimentation can shed light on early cellular differentiation, and perhaps on how and when some genetic diseases take hold.
“It gives us a glimmer of hope” that organs for human transplantation can be made this way someday, Wu said. “But it is still far away. There are still a lot of challenges.”
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