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Japanese Scientists Plan to Create Human-Mouse Hybrids

A mouse embryo on Day 11 of development.

Some unusual embryos may soon be growing in Japan: those of human-mouse and human-rat hybrids, news sources are reporting.

A research group in Japan received approval from a committee in the Japanese government on July 24 to move forward with an experiment that will put a type of human stem cells (cells that can grow into almost any cell) into animal embryos.

Once inside the embryos, the human cells — called induced pluripotent stem (iPS) cells — may grow into specific organs. If all goes well, the researchers plan to eventually grow human organs in other animals, such as pigs. Perhaps these organs could one day be used for organ transplants in people, the researchers said.

“I personally thought it was very exciting” that the Japanese government approved this project, said Ronald Parchem, an assistant professor of neuroscience at Baylor College of Medicine in Houston, who is not involved with the new research. “It has tremendous potential to help many people who are suffering from a broad variety of diseases or in need of different types of tissue or organ replacement.”

There are, however, scientific and ethical questions that may arise as this research progresses.

Japan made headlines in March when the country reversed a ban on growing human cells in animal embryos beyond Day 14 of an embryo’s existence and transplanting those embryos into the uterus of a surrogate animal. This reversal was a big deal for Hiromitsu Nakauchi, a stem-cell biologist at Stanford University and the University of Tokyo, who has been pursuing this line of research for more than a decade, Nature magazine reported.

Now, pending official approval next month from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Nakauchi’s research could be the first approved under Japan’s new guidelines, according to Nature.

If approval is granted, Nakauchi said, he plans to move forward in small steps, first programming mouse and rat embryos not to grow a pancreas. Nakauchi will then transfer the human iPS cells into those embryos, with the hope that the implanted cells will take up the challenge, in effect growing a “human” pancreas in the rodent embryos.

Once the embryos develop and are born as full-fledged rats and mice, the researchers plan to spend up to two years monitoring the little ones. This stage is key, as the government has placed certain nuanced restrictions on the research. For instance, if the scientists find human cells in more than 30% of the rodent brains, the scientists have to stop the experiment. This is to ensure that a “humanized” animal won’t come into being, news site ScienceAlert reported.

The term humanized is a vague one. But, in essence, some scientists and ethicists are concerned that if too many human cells creep into the mouse’s brain, then “that mouse brain might have a change in cognition or mental ability in some way,” Parchem told Live Science. “We don’t actually know what’s going to happen. Our training suggests that it’s very unlikely that you would get a mouse with human qualities … What you might find is that there’s more folding in the brain or there’s more of a [certain] type of neurotransmitter.”

In other words, it’s unlikely that the hybrid mouse would have human behaviors. Rather, the mouse might have certain molecular features that are human-like, Parchem said.

But this scenario is unlikely, too, Nakauchi said. In a previous experiment, he put human iPS cells into a fertilized sheep egg and then transplanted this embryo into a sheep at Stanford University. The transplanted human cells didn’t transform the embryo into a weird human-sheep creature, he said. (The hybrid embryo wasn’t brought to term; it was destroyed after 28 days of development.)

“The number of human cells grown in the bodies of sheep [was] extremely small, like 1 in thousands or 1 in tens of thousands,” Nakauchi told The Asahi Shimbun, a Japanese news outlet. “At that level, an animal with a human face will never be born.”

His team also plans to try the experiment with other organs, including human livers and kidneys, The Asahi Shimbun reported.

Nakauchi’s method is scientifically sound, as it doesn’t involve just inserting the cells of one species into the embryo of another species — something that doesn’t always work. And when it does, the end result is known as chimerism, a mixture of cells from two or more organisms.

“Anytime you take a species and mix it with another, the host species [the one with the embryo] generally does better,” Parchem said. “If you take a rat cell and put it into a mouse blastocyst [an early embryo], the rat cells are at a disadvantage. That’s why, in general, chimerism is very low.”

However, when an entire organ, such as a pancreas, is knocked out in the host, the introduced cells of the other species stand a chance. “They do not have to compete to generate the pancreas,” Parchem said. “And then, these other species of cells can then contribute a large proportion of cells that generate a particular tissue or organ. Otherwise, that’s not very likely.”

Parchem noted that scientists have experimented with chimerism in nonhuman animals — especially those that are closely related to one another, such as quails and chickens — for decades, as it helps researchers learn about developmental biology. But “our ability to make human chimeras is actually very poor,” he said. “All of the evidence says that human cells incorporate very poorly into other species that we’ve looked at, like pig, mouse, rat and sheep.”

Human chimera experiments might have more success if the other animals are nonhuman primates, which are more closely related to people than other lab animals are. But Parchem said he’s never heard of such an experiment, which “is obviously much more fraught with ethical concerns” than testing on mice or sheep, he said.

For now, scientists will have to see how Nakauchi’s experiments progress. As Nakauchi told The Asahi Shimbun, “We don’t expect to create human organs immediately, but this allows us to advance our research based upon the know-how we have gained up to this point.”

In the United States, human-animal hybrids have been made but never brought to term, Nature reported. Moreover, such research must be privately funded in the U.S., as in 2015, the National Institutes of Health put a moratorium on paying for any such research.