Japanese regulators have effectively given the green light to research involving human-animal chimera embryos, which are created by implanting human pluripotent stem cells into animals in early development. The revised guidelines, issued in early March, lift a previous requirement to terminate such embryos after 14 days.

The revisions now pave the way for Japanese scientists to study how to grow human organs in animals as an alternative to organ transplantation, and to produce better models to study human development and disease.

However, they also raise some ethical concerns, as a group of Japanese bioethicists at the Kyoto University note in a letter published today (April 4) in Cell Stem Cell. For instance, the guidelines would allow researchers to create chimeras with human cells populating animal brains—something that concerns the Japanese public. They also don’t explicitly prohibit chimera embryos made from human and nonhuman...

“It’s good that they now allow people to do human-animal [chimera embryos] with species like pigs and sheep,” remarks Sean Wu, a developmental biologist at Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine. Creating human-primate chimeras at this stage may be a step too far, he adds. “There’s just too many things we don’t know about when you try to chimerize two species that are so close to each other, like humans with nonhuman primates.”

Invasive research on great apes isn’t allowed in Japan, notes Misao Fujita, a professor of bioethics at Kyoto University and a coauthor of the new letter. But scientists could theoretically produce chimeras made from human and monkey cells, as long as they can justify there’s “sufficient scientific rationale” for the research, according to the paper. Some US scientists have recently argued that human-primate chimeras could serve as better models of neurological and psychiatric disease than current monkey models. Japanese researchers may someday follow suit, Fujita and her colleagues warn.

The revisions appear to be a welcome change for those scientists researching how to grow human organs in animals for the purposes of transplantation.

It’s the public sentiment towards such research that concerns Fujita and her colleagues, who recently conducted a survey on the matter. They found that the Japanese tend to support the general idea of creating human-animal chimeric embryos with human induced pluripotent stem cells (iPSCs). However, they’re worried about the prospect of human cells contributing to animal brains, or in germ cells that lead to progeny—much more so than if they were only present in heart, blood, or liver tissue.

“The biggest concerns, based on our surveys, is [the] concern that animals could become ‘humanized,’” writes Fujita to The Scientist in an email. “It seems people are concerned that the boundary between humans and animals could become blurred.”

This is an issue that Japan’s Ministry of Education, Culture, Sports, Science and Technology considered when drafting the guidelines. But in the end, they “concluded that there is technically zero risk of producing a new organism mixing human and animal elements under the research,” a ministry official told the AFP-Jiji news agency in March. The revised guidelines don’t allow fertilization of human-animal chimeras with human gametes. However, they neither explicitly allow nor prohibit human-primate chimeric embryos, which could be used to produce models with humanized brains—an ambiguity that concerns Fujita. She and her colleagues recommend that the government undertake public ethical debates before researchers pursue projects that involve chimeric animals with humanized brains or human gametes.  

For many, the idea of chimeric animals with humanized brains raises a number of scientific and ethical questions, explains Laura Cabrera, an assistant professor in neuroethics at Michigan State University. How many human-derived cells does it take for a model organism to develop human-like behaviors or cognitive abilities? How early on in development do they have to be added for that to happen? And if it does, what will the implications be? Could this give them a similar kind of moral status as humans? “I definitely agree that more ethical debates with the public should be conducted,” she says. If not, this could diminish public trust in science, she cautions: “There’s always a possibility to have backlash from the public, and that’s something that scientists don’t want.”

The revisions appear to be a welcome change for those scientists researching how to grow human organs in animals for the purposes of transplantation. On the same day the new guidelines were issued, stem cell pioneer Hiromitsu Nakauchi’s laboratory at the University of Tokyo announced plans for a research project aiming to grow a human pancreas inside a pig, according to Jiji Press. His team had previously succeeded in generating a rat pancreas from a mouse, and growing a pancreas from one species of pig from an embryo of another pig species. Such procedures typically involve the blastocyst complementation technique, whereby stem cells are implanted into a blastocyst that is modified such that it can’t produce the organ in question. The stem cells are added from another organism to populate the empty niche and grow the desired organ. For the new research in Japan, Nakauchi’s team will first have to apply for approval by the university’s ethics committee as well as the Japanese government’s special committee for research ethics. 

Previously, Nakauchi had been doing most of his research at Stanford University in the US, largely because of Japan’s restrictions on chimera research, Wu says. In the US, there isn’t any federal legislation overseeing human-animal chimera research. Although the National Institutes of Health placed a moratorium on the practice in 2015, and hasn’t issued any new guidelines since, human-animal chimera research has been funded by other agencies, such as CIRM, the California Institute of Regenerative Medicine. 

Beyond creating organs for transplantation, human-animal chimera models are valuable for biologists studying human development generally, notes Wu, who coauthored a letter to Science in 2015 opposing the moratorium. “Our argument was really about being able to have this model or system to study early-stage development that we would never have the [opportunity to do with] the human embryo,” he says.

Putting a human cell into an animal embryo allows researchers to observe it go through the very first stages of development. Understanding which mutations disrupt that process may help investigate why certain miscarriages occur, he says. “By not allowing people to do this kind of complementation, then you essentially don’t give any way for people to study how that process is occurring, and potentially trying to figure out what is the biology and what would be useful for helping these people with fertility issues.”

It will probably be a long time before human-animal chimeras are widely used, notes Wu. It’s an extremely costly procedure, and also technically very challenging. For instance, the Salk Institute’s Juan Carlos Izpisua Belmonte showed in 2017 that human pluripotent stem cells could engraft into pig and cattle blastocysts, but the proportion of cells that do is very low. “Very few labs around the world are likely actually able to do things like this,” says Wu.

Correction (April 4): A previous version of this story erroneously stated that the study's authors are affiliated  with the University of Tokyo, whereas they are affiliated with Kyoto University. The Scientist regrets the error. 

T. Sawai et al., “Japan significantly relaxes its human-animal chimeric embryo research regulations,” Cell Stem Cell, doi:10.1016/j.stem.2019.03.015, 2019. 

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