Our understanding of the human body has sky-rocketed in recent decades, opening doors for everything from brain-controlled prosthetics to world-changing mRNA vaccines. But there are still some secrets about the body (and the diseases that plague it) that we just might never know due in large part to ethical barriers they present.
But a U.S. and Chinese research team has just taken a huge step toward unlocking these previously unknowable secrets by developing robust monkey-human chimera (hybrids using genetic material from two different species) embryos that may sidestep ethical dilemmas using human cells with a clever loophole to explore such questions.
The research was published Thursday in the journal Cell and senior author Juan Carlos Izpisua Belmonte, a professor in the Gene Expression Laboratory at the Salk Institute for Biological Sciences, says that its findings could be a huge step forward in how scientists study and understand human disease.
“Human-macaque chimeras reveal invaluable information about how human cells develop and integrate, and how cells of different species communicate with one another,” Belmonte tells Inverse.
What’s new — Even though scientists have been studying and developing part-human chimeras since the 1970s, a problem that continues to plague this research is developing robust enough chimeric embryos that can survive past the first few days of growth. In this new study, researchers have demonstrated the creation of robust macaque-human embryos ex vivo (or, outside an organism) using multi-purpose human stem cells that survived 19 days.
These embryos were grown in lab trays (not unlike ice cube trays) and monitored using genomic sequencing throughout their incubation to monitor the human stem cell proliferation. By using chimera embryos like these in the future, scientists can explore disease progression and treatment much quicker (and potentially less ethically) than they ever could on human beings.
Why it matters — While 19-days is still far from even being considered a fetus (let alone a full-term monkey-human chimera,) Belmonte says this research offers a step forward for researchers to better understand the evolution of both humans and macaque to determine who well-matched they truly are for hybridization.
“Generation of a chimera between human and non-human 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,” he says.
Overcoming such evolutionary barriers could open up unprecedented possibilities for organ and tissue harvesting as well as novel paths for understanding human disease.
Belmonte points to a few effects the research might have. “By better understanding molecular pathways involved in this interspecies communication, we might ultimately improve the integration of human cells into hosts such as pigs,” he says. From there they could:
- be used in regenerative medicine
- help decode complex processes in humans, such as aging
But along with it warn ethicists Henry Greely and Nita Farahany in an accompanying Cell review article, are new ethical concerns over the treatment — and potential sentience — of such a chimera if it were ever born to full term.
“Biomedical science increasingly confronts a dilemma,” write the review authors. “We need better models to understand human biology and disease... but as we develop new living models that better approximate humans, we approach the same ethical problems that we sought to avoid.”
In particular, if human stem cells somehow made their way into the sperm or brain of a chimera, would it then too be considered human?
Here’s the background — Chimeras take their name from the Greek mythological monster of the same name that was part lion, part snake, and part goat. In reality, scientific chimeras are much less monstrous and have been under serious scientific investigation since the 1970s.
In short, chimeras are a feat of experimental biology that combines one animal’s cells with another (typically the idea is to combine human cells with another animal) to create a hybrid embryo that contains a bit of both creatures.
Not surprisingly, playing with biology in this way is a hot-button issue for ethicists (and the public) alike. In 2016, the National Institutes of Health lifted a moratorium on chimera research in the U.S. in what some see as a dice roll to support the potential medical benefits of this research over its ethical concerns. Even then, interspecies chimeras aren’t allowed to grow past the fetal stage, so giving birth to a monkey-human baby isn’t in the cards — yet.
But Belmonte says current methods only allow cells that stay alive a few days. “It is very difficult to keep chimeric cells alive in a dish for even a few days, much less the many months that would be required for structures such as complex neural circuits to develop,” he says. “Advancing beyond the current technical limits seems quite remote at this time.”
What they did — In this most recent study, the team set out to create monkey-human chimeras using macaque embryos and an injection of 25 pluripotent human stems.
This type of stem cell is essentially stem cells without specific agendas, meaning they’re just as happy to become a spine as they are muscle tissue. In particular, the line of stem cells used in this research has the potential to provide embryonic and extra-embryonic tissues (e.g. tissue that surrounds the embryo.)
One day post cell injection, the team detected 132 monkey-human embryos. After 10 days, only 103 embryos were still developing. This number would eventually plummet to just three surviving embryos by day 19.
To the untrained eye, this result might seem more like a failure than a success, but Belmonte said the team was able to collect some important information from these short-lived embryos, including the recognition of unique cell pathways that will help inform the next generation of these chimeras.
“We are hopeful that this line of research ex vivo will allow us to obtain enough knowledge that eventually it might be possible to generate human cells and tissues for transplant,” he says.
What’s next — This research is still far away from its ultimate goal — creating chimeras for organ transplant or disease research — but ethicists Greely and Farahany write that now is the perfect time to begin considering the ethical concerns that will meet this science when it does mature.
“It remains altogether unclear whether such [future results] are, or ever will be, possible, write Greely and Farahany. “And yet, those future experiments are now at least plausible. We must begin to think about that possibility.”
As for Belmonte, he said his next line of research will be to continue exploring these novel cell pathways to see which will be most important for the next generation of monkey-human chimeras.
Abstract: Interspecies chimera formation with human pluripotent stem cells (hPSCs) = represents a necessary alternative to evaluate hPSC pluripotency in vivo and might constitute a promising strategy for various regenerative medicine applications, including the generation of organs and tissues for transplantation. Studies using mouse and pig embryos suggest that hPSCs do not robustly contribute to chimera formation in species evolutionarily distant to humans. We studied the chimeric competency of human extended pluripotent stem cells (hEPSCs) in cynomolgus monkey (Macaca fascicularis) embryos cultured ex vivo. We demonstrate that hEPSCs survived, proliferated, and generated several main peri- and early post-implantation cell lineages inside monkey embryos. We also uncovered signaling events underlying interspecific crosstalk that may help shape the unique developmental trajectories of human and monkey cells within chimeric embryos. These results may help to better understand early human development and primate evolution and develop effective strategies to improve human chimerism in evolutionarily distant species.