A blastocyst of monkeys – human chimeras.Credit: Weizhi Ji, Kunming University of Science and Technology
Scientists have successfully cultured monkey embryos containing human cells for the first time – the latest milestone in a rapidly advancing field that has raised ethical questions.
In the paper, published on April 15 in Cell1, the team injected monkey embryos with human stem cells and watched them develop. They observed that human cells and monkeys divide and grow together in a vessel, with at least 3 embryos surviving up to 19 days after fertilization. “The general message is that each embryo contained human cells that proliferate and differentiate to a different extent,” said Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute for Biological Studies in La Jolla, California and one of the researchers who led the work. .
The researchers hope that some human-animal hybrids – known as chimeras – could provide better models in which to test drugs and be used to grow human organs for transplants. The members of this research team were the first to present in 20192 that monkey embryos could grow in a vessel for up to 20 days after fertilization. In 2017, a number of other hybrids were reported: human-raised pig embryos, human-raised cow embryos, and mouse-grown rat embryos.3.
But the latest work has divided developmental biologists. Some question the need for such experiments using closely related primates – these animals are unlikely to be used as model animals in the way mice and rodents are. Non-human primates are protected by stricter research ethical rules than rodents and are concerned that such work will provoke public opposition.
“There are more sensitive experiments in this area of chimeras as a source of organs and tissues,” says Alfonso Martinez Arias, a developing biologist at Pompeu Fabra University in Barcelona, Spain. Animal experiments, such as pigs and cows, are “more promising and do not risk challenging ethical boundaries,” he says. “There is a whole range of organoids that we hope can eliminate animal research.”
Sensitive subject
Izpisua Belmonte says the team does not intend to implant hybrid embryos in monkeys. Rather, the goal is to better understand how cells of different species communicate with each other in the embryo in its early growth phase.
Attempts to grow human-mouse hybrids are still preliminary and chimeras need to be more effective and healthier before they can be useful. Scientists suspect that such hybrids may have trouble thriving because the two species are evolutionarily distant, so that cells communicate by different means. But observing cellular conversations in money – chimeras with human embryos – involving two more closely related species – could suggest ways to improve the viability of future human-mouse models, says Izpisua Belmonte.
In the study, the researchers fertilized eggs extracted from cynomolgus monkeys (Macaca fascicularis) and raised them in culture. Six days after fertilization, the team injected 132 embryos with extensive human pluripotent stem cells, which can grow into a range of cell types inside and outside an embryo. The embryos each developed unique combinations of human and monkey cells and deteriorated at different rates: 11 days after fertilization, 91 were alive; it decreased to 12 embryos on day 17 and 3 embryos on day 19.
“This work is a dramatic demonstration of the ability of human pluripotent stem cells to be incorporated into cynomolgus monkey embryos when introduced into monkey blastocysts,” said Magdalena Zernicka-Goetz, a developmental biologist at the California Institute of Technology in Pasadena.. She noted that this team, like others in the past, has not been able to control which cells have grown in which tissues – a key step to master before such models can be used.
Martinez Arias was not convinced by the results. “I expect better evidence,” especially on the later stages of development, he says. The number of embryos fell rapidly as it approached the 15th day of development, suggesting “that things are very sick.”
The combination of human cells with closely related primate embryos raises questions about the condition and identity of the resulting hybrids. “Some people may see you creating morally ambiguous entities there,” says Insoo Hyun, a bioethicist at Case Western Reserve University in Cleveland, Ohio. He says this team has followed existing guidelines. “I think they’ve done enough to pay attention to regulations and ethical issues.”
Research restrictions
Meanwhile, international guidelines are picking up progress in this area – next month, the International Society for Stem Cell Research (ISSCR) is expected to publish revised guidelines for stem cell research. These will address human-primate and human chimeras, says Hyun, who heads an ISSCR committee that discusses chimeras. Currently, the guidelines of this group prohibit researchers from allowing human-animal chimeras to mate. The group also recommends additional surveillance when human cells can integrate with a host’s developing central nervous system.
Many countries – including the United States, the United Kingdom and Japan – at times have limited research on chimeras involving human cells. Japan lifted its ban on experiments with animal embryos containing human cells in 2019 and began funding such work that year.
In 2015, the US National Institutes of Health (NIH) announced a moratorium on federal funding for studies in which human cells would be injected into animal embryos. In 2016, the funding agency proposed lifting the ban, but limiting research to hybrids created after gastrulation, when the early nervous system begins to form. Four years later, the funding ban is still in place. An NIH spokesman said the agency expects the ISSCR to be updated in May “to ensure that our position reflects the contribution of the community,” but did not provide a timetable for publishing the agency’s rules.