Chimeric Human-Monkey Embryos Kept Alive for a Record 19 Days

Chimeric Human-Monkey Embryos Kept Alive for a Record 19 Days
A chimeric human-monkey blastocyst.

Building on previous experiments, an international team of scientists has created chimeric human-monkey embryos, which were kept alive for nearly three weeks. The breakthrough could lead to new ways of testing drugs and generating organs for transplant, but this line of research is raising some ethical concerns.

New research in Cell details the experiment, in which human stem cells were injected into primate embryos belonging to macaque monkeys. Most of these chimeric embryos were dead by the 10th day, but several developed for 19 days. Juan Carlos Izpisua Belmonte, the lead author of the new study and a biologist at the Salk Institute, had previously kept human-monkey chimeric embryos alive for 14 days.

Chimeras are animals with genetic information from more than one species. Experiments on chimeric mammals started in the 1970s, including chimeric rodents used for studying early developmental processes. In 2017, Izpisua Belmonte and his colleagues created human-pig chimeric embryos, which were implanted into sows, but these cells only managed to stay alive for three to six weeks. The limitations of this experiment compelled the team to turn to primates.

“These and other studies using mouse and pig embryos suggested that human cells do not robustly contribute to chimera formation in species evolutionarily distant to humans,” explained Izpisua Belmonte in an email. “Generation of a chimera between human and nonhuman primate — a species more closely related to humans along the evolutionary timeline than all previously used species — will allow us to gain better insight into whether there are evolutionarily imposed barriers to chimera generation and if there are any means by which we can overcome them.”

This research has an undeniably Frankensteinian quality to it, but the potential benefits are many. These experiments could improve our understanding of early embryonic development, both for humans and nonhuman animals, while at the same time offering fresh insights into evolutionary changes and process that occur at the molecular scale. It could also introduce new ways of studying disease, including age-related disorders and cancer, and the testing of drugs.

All these important benefits aside, the primary purpose of the new research is to pave the way toward the development of transplantable organs — a laudable goal, given that the 130,000 organ transplants performed each year represent a mere 10% of the total global demand. Ultimately, Izpisua Belmonte and his colleagues envision chimeric pigs capable of growing human organs and tissue for transplantation.

As for creating half-monkey, half-human hybrids, that’s most certainly not the goal. But by experimenting on chimeric primate embryos, the researchers hope to acquire the requisite insights needed to create pigs capable of growing human kidneys, livers, pancreases, hearts, and other organs.

The new research was made possible owing to a key breakthrough made last year. Weizhi Ji, a biologist at the Kunming University of Science and Technology in Yunnan, China and a co-author of the new study, developed a technique that allowed monkey embryos to stay alive and grow inside a petri dish for an extended period of time — around 20 days. For the new experiment, the scientists applied this same technique to chimeric human-monkey embryos.

To make it happen, the researchers took human stem cells and tagged them with a fluorescent protein, allowing them to identify and track the human cells after transplantation. A total of 25 human stem cells were implanted into six-day-old monkey embryos; specifically, the team used human extended pluripotent stem cells (hEPSCs), which work nicely in both embryonic and non-embryonic tissue. Stem cells are ideal for these types of experiments because they’re undifferentiated, meaning they’re still capable of turning into any other type of specialised cell.

The scientists detected human cells in 132 monkey embryos one day after the transplants were performed. By day 10, 103 embryos were still alive and developing inside their petri dishes, but survival rates dropped dramatically beyond this stage. Only three embryos survived to day 19.

That’s still a record, and, just as importantly, the team “demonstrated that hEPSCs survived, proliferated, and generated several…cell lineages inside monkey embryos,” said Izpisua Belmonte. What’s more, the experiment helped to identify some communication pathways involved in “interspecies cross-talk,” which may contribute to the “unique developmental trajectories of human and monkey cells within chimeric embryos,” he added.

As to why so few chimeric embryos survived past the 10-day mark, Izpisua Belmonte said it was likely on account of the experiment being done in petri-dishes, as opposed to in a live animal. This likely had an effect on the development of both the monkey embryos and the donor human cells, he said.

This experiment uncovered several promising communication, or molecular, pathways between the cells of the two different species. Looking ahead, the researchers are hoping to identify which pathways are enabling this interspecies cellular communication. Izpisua Belmonte said he’s hopeful that this line of research will allow his team to “obtain enough knowledge that eventually it might be possible to generate human cells and tissues in a more evolutionarily distant species like the pig, that for various reasons, including social, economic, and ethical, might be more appropriate for regenerative medicine translational therapies.”

Which finally brings us to the ethical side of the discussion.

Izpisua Belmonte said his experiments were reviewed at the institutional level and by independent bioethicists “with experience in state and national policies in this area of research.” To which he added: “All of our work is always directed by existing ethical and legal guidelines and will undergo review and approval by all relevant committees.”

Indeed, there’s not much to nit-pick here from an ethical perspective. These embryos aren’t developing past the blastocyst stage, and they certainly don’t turn into anything that approximates a living organism capable of experiencing pain, or anything else for that matter.

Alan Regenberg, a bioethicist at Johns Hopkins University, offered a similar take.

“I don’t have serious ethical concerns about this specific study,” he explained in an email. “The researchers appear to have paid close attention to the ethical challenges and carefully designed their work.”

What’s more, the work “was conducted in a dish and was limited to early embryonic development, so there was no real risk of this study resulting in the live birth of human-nonhuman animal chimeras,” said Regenberg. To which he added: “We can learn a lot from these experiments.”

Where the ethics does get tricky, however, is when we think about the end goal: pigs capable of growing human organs. Should we ever advance to that stage, it would represent yet another way for us to exploit and harm nonhuman animals. For people who eat bacon and pork chops on a regular basis, this may not seem like a big deal, but for advocates of animal rights, this research could reasonably be construed as immoral.

Regenberg said he’s concerned about this line of research in terms of where it might be headed, particularly if the work involves species closely related to humans.

“First, we need sufficient evidence that the animals that would be created through experiments, or for clinical use, would not experience an unacceptable amount of pain and distress,” he said. “We don’t have a great understanding of the suffering of the nonhuman animals that we currently know, so just imagine how difficult it will be to build a body of evidence regarding the inner life and suffering of a new chimeric animal that doesn’t exist yet.”

A second challenge, he said, has to do with the pending moral standing of chimeric animals. If, for example, “being human is the key to having moral status, we need to know how we should think about the moral status of animals that are partly human,” said Regenberg.

Which is a very good point, and it has me thinking about a famous quote from the Enlightenment philosopher Jeremy Bentham, who said, “The question is not, Can they reason?, nor Can they talk? but, Can they suffer? Why should the law refuse its protection to any sensitive being?” Hear, hear. And if I may paraphrase Bentham, the looming question here is not “are they partly human” but “can they suffer?” Something to keep in mind as this line of research continues to move forward.