Scientists Turned Monkey Stem Cells Into ‘Synthetic Embryos’

For the first time, researchers transferred them to the wombs of female monkeys, where the embryo-like structures produced a response similar to pregnancy.

The early days of how an embryo develops are shrouded in mystery because it pulls a kind of vanishing act. Once a sperm finds an egg, it begins a roughly weeklong journey to the uterus, becoming a tiny ball of cells along the way. When it reaches its destination, it attaches to the wall of the uterus, disappearing from view. 

To shed light on the process, researchers are trying to create embryo-like structures derived from stem cells, rather than sperm and eggs, so they can observe early development in the lab. These three-dimensional balls of cells could offer clues to how diseases, birth defects, and miscarriages arise, without the practical and ethical concerns raised by using actual embryos. In the latest effort, researchers in China made these structures using stem cells from macaques and tried to establish pregnancies with them in female monkeys. The experiment is described in the journal Cell Stem Cell. Although other researchers have created “synthetic” embryos before, it’s the first time anyone has done it with monkeys—animals closely related to humans—and tried to get them to implant in the uterus.  \

The authors started with stem cells isolated from monkey embryos that were just a few days old. Stem cells have the potential to turn into any and all body cell types, and theoretically can be used to reconstitute something that resembles an embryo. After placing these cells in lab dishes, the researchers exposed them to a cocktail of nutrients and molecules to coax them into different cell types found in an embryo. 

Under a microscope, the structures looked similar to blastocysts—the early stage of an embryo—at days 8 and 9 of development. They also started to form arrangements that looked like a yolk sac, which appears in early pregnancy and nourishes the embryo. 

“They look very convincing,” says Kotaro Sasaki, an assistant professor of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine, who studies primate embryology and human development and wasn’t involved in the study. “It looks like they have all the cell types that are present normally in embryos.” 

The scientists next took some of these embryo-like balls of cells and transferred them into the wombs of eight female monkeys. In three, the structures implanted into the lining of the uterus—the first step of pregnancy. The authors confirmed the pregnancies with ultrasound and also detected the hormones progesterone and chorionic gonadotropin, which arise during pregnancy. The transplanted structures also formed early gestational sacs, fluid-filled cavities that surround a developing embryo. But the pregnancies were short-lived. These sacs disappeared after about a week. No fetuses formed.

The remaining embryo-like structures were cultured in a dish to mimic how they might continue to develop after implantation in the uterus. But at this later stage, Sasaki says, the lab-made embryos became “kind of disorganized and don’t look quite like normal embryos.” They probably failed because of structural or genetic abnormalities, he says.

That the structures didn’t develop normally points to the fact that they’re not the same as natural embryos, says Nicolas Rivron, an embryologist at the Austrian Academy of Sciences. “It’s easy to form a structure that looks like a blastocyst,” he says. “But looks can be deceiving.” 

Rivron’s laboratory was the first to create these embryo-like structures in 2018. His team showed that mouse stem cells can self-organize into structures that resemble a blastocyst, which forms five or six days after sperm fertilizes an egg. They dubbed the balls of cells “blastoids.” 

Then in 2021, several labs showed they could create human blastoids using stem cells. And last year, researchers at the University of Cambridge and the California Institute of Technology reported that they created mouse structures mimicking natural embryos at 8.5 days of development, which even had beating hearts and neural folds, the foundations of the brain.

Scientists behind these experiments insist that these balls of cells are just models, not actual embryos. The International Society for Stem Cell Research, or ISSCR, a scientific group that sets guidelines for stem cell research, prohibits these structures from being transferred into humans for the purpose of trying to start pregnancies. 

For now, scientists want to use them to better understand early pregnancy. “Because monkeys are closely related to humans evolutionarily, we hope the study of these models will deepen our understanding of human embryonic development, including shedding light on some of the causes of early miscarriages,” said Zhen Liu of the Chinese Academy of Sciences in Shanghai, one of the authors of the study, in a press statement. (Liu’s team did not respond to an emailed request for comment by press time.)

Still, trying this in a monkey is the closest approximation to what could happen in a human. “This shows that you can get a pregnancy started, or at least trigger the macaque's hormonal system to think that it's pregnant,” says Hank Greely, director of the Center for Law and the Biosciences at Stanford School of Medicine. “It says there's some evidence that maybe it could give rise to a baby monkey.”

Embryo research is especially controversial in the US, where it has faced religious objections for decades. While most states allow research on human embryos, national law prohibits federal funds from being used to create or destroy them. 

Several countries, including the United Kingdom, Canada, and South Korea, have legal restrictions against growing human embryos in a lab past 14 days after fertilization—when the first signs of the central nervous system appear. (In other countries, the 14-day rule is just a guideline, initially established by the ISSCR.) In 2021, the ISSCR relaxed the 14-day rule to consider experiments that involve growing human embryos past that mark on a case-by-case basis.

Embryo models give researchers an alternative without having to rely on the real thing. But as they get more sophisticated, they are raising concerns of their own. “I think what we’d really like to know is: Can an embryo model give rise to a living organism?” Greely says. “If it can, then it should be treated like an embryo. If it can't, then it doesn't need to be treated like an embryo.” 

To answer that question, Greely is in favor of scientists conducting the kind of experiments that the new paper outlines. He feels it would be unethical to do so in people, because any resulting babies could end up with birth defects or genetic disorders.

Rivron thinks scientists should move slowly with trying to establish animal pregnancies with blastoids, because it’s extremely likely that these structures won’t develop correctly. But at the current pace of research in the field, he thinks the first live mouse born from a blastoid could be a reality within five years. “I think we should do things gradually to make sure we do this right.” 

In their press statement, the team behind the new paper recognizes the work may be controversial. “The researchers said they acknowledge the ethical concerns surrounding this type of research but emphasize that there are still many differences between these embryo-like structures and natural blastocysts,” the statement reads. “Importantly, the embryo-like structures do not have full developmental potential. They note that for this field to advance it’s important to have discussions between the scientific community and the public.”

Scientists Turned Monkey Stem Cells Into ‘Synthetic Embryos’

(May require free registration to view)