The research could lead to new sources of organs for transplantation, but ethical and technical hurdles must be overcome.

A Japanese stem cell scientist is the first to receive support from his government to create animal embryos containing human cells and transplant them into surrogate animals since a ban on the practice was lifted earlier this year.

Hiromitsu Nakauchi, who leads teams from the University of Tokyo and Stanford University in California, plans to grow human cells in rat and mouse embryos and then transplant those embryos into surrogate animals . Nakauchi’s ultimate goal is to produce animals with organs made from human cells that can eventually be transplanted into people.

Nakauchi’s ultimate goal is to produce animals with organs made from human cells that can eventually be transplanted into people.

Until March, Japan explicitly prohibited the growth of animal embryos containing human cells after 14 days or the transplantation of such embryos into a surrogate uterus. But as of this month, Japan’s education and science ministry has issued new guidelines allowing the creation of human-animal embryos that can be transplanted into surrogate animals and carried to term.

Human-animal hybrid embryos have been manufactured in countries such as the United States, but have never been carried to term. Although the country allows this type of research, the National Institutes of Health has had a moratorium on funding such work since 2015.

Nakauchi’s experiments are the first to be approved under Japan’s new rules, by a committee of experts at the science ministry. Final approval from the ministry is expected next month.

Nakauchi says he plans to proceed slowly, and will not attempt to bring any hybrid embryos to term for some time. Initially, he plans to grow hybrid mouse embryos until 14.5 days , when the animal’s organs are mostly formed and it is near term. He will do the same experiments in rats, growing the hybrids in the short term, about 15.5 days. Later, Nakauchi plans to apply for government approval to grow hybrid embryos in pigs for up to 70 days.

“It is good to proceed step by step with caution, which will allow dialogue with the public, which feels anxious and has concerns,” said science and policy researcher Tetsuya Ishii of Hokkaido University in Sapporo, Japan.

Ethical concerns

Some bioethicists are concerned about the possibility that human cells could stray beyond the developing target organ, travel to the developing animal’s brain, and potentially affect its cognition.

Nakauchi ensures that these concerns have been taken into account in the design of the experiment. “We’re trying to do targeted organ generation, so the cells go only to the pancreas ,” he says.

The strategy that Nakauchi and other scientists are exploring is to create an animal embryo that lacks the gene needed for the production of a certain organ, such as the pancreas, and then inject human-induced pluripotent stem (iPS) cells into the animal embryo. iPS cells are those that have been reprogrammed to an embryonic-like state and can give rise to almost all cell types. As the animal develops, it uses the human iPS cells to make the organ, which it cannot make with its own cells.

In 2017, Nakauchi and colleagues reported injecting mouse iPS cells into the embryo of a rat that was unable to produce a pancreas. The rat built a pancreas made entirely of mouse cells. Nakauchi and her team transplanted that pancreas into a mouse that had been engineered to have diabetes. The rat-produced organ was able to control blood sugar levels, effectively curing the mouse of diabetes 1 .

In 2017, Nakauchi and colleagues reported injecting mouse iPS cells into the embryo of a rat that was unable to produce a pancreas. The rat built a pancreas made entirely of mouse cells . Nakauchi and her team transplanted that pancreas into a mouse that had been engineered to have diabetes. The rat-produced organ was able to control blood sugar levels, effectively curing the mouse of diabetes 1 .

But getting human cells to grow into another species is not easy. Nakauchi and his colleagues announced at the 2018 American Association for the Advancement of Science meeting in Austin, Texas, that they had placed human iPS cells into sheep embryos that had been engineered not to produce a pancreas. But the hybrid embryos, grown for 28 days, contained very few human cells, and nothing resembling organs. This is probably due to the genetic distance between humans and sheep, Nakauchi stated.

“It doesn’t make sense to make human-animal hybrid embryos grow into evolutionarily distant species such as pigs and sheep, because human cells will be removed from host embryos early on,” said Jun Wu, who researches human-animal chimeras at the University of Texas Southwestern Medical Center in Dallas. ” It will be necessary to understand the molecular basis and develop strategies to overcome this barrier to move the field forward ,” Wu added.

Nakauchi’s approval in Japan will allow him to attack this problem. It will be experimenting with iPS cells at subtly different stages, and will be testing some genetically modified iPS cells to try to determine what limits the growth of human cells in animal embryons.

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