Oct. 3, 2022 -- Miscarriages are a devastating, if natural, occurrence. Nearly 1 million pregnant people in the U.S. experience a miscarriage every year, according to the National Advocates for Pregnant Women. New research could lend insight into the causes of some types of early pregnancy loss and maybe one day help prevent miscarriages.
In the bioengineering breakthrough, scientists created a mouse embryo in a lab without using sperm or eggs. The experimental embryo, called a model, was grown out of stem cells and developed further than any earlier experiments, with a beating heart and the foundation of a brain within a yolk sac, according to the researchers.
The experiment, while conducted with mouse stem cells, could help explain why some human pregnancies fail. Miscarriages occur in up to 15% of pregnancies confirmed by doctors, according to some studies, and also for many pregnant people before they even knew of the pregnancy. This experiment gives researchers a glimpse of a critical developmental stage for the first time.
"We are building mouse embryo models, but they have exactly the same principle as real human embryos,” says lead researcher Magdalena Zernicka-Goetz, PhD, professor in mammalian development and stem cell biology at Cambridge University in the U.K. “That's why they tell us about real pregnancy.”
With the new mouse models, the researchers can study implantation, the stage when embryos embed themselves in the mother's body – a stage that’s often difficult for embryos to survive. The same process happens in mouse embryos, which develop very similarly to human embryos at this early stage of life.
Deciphering the Stem Cell Code
Six years ago, researchers from the University of Cambridge and the California Institute of Technology set out to create models that would allow them to study fetal development in three-dimensional form but without the need for human embryos.
"We are trying to understand the major principles of time and space that have to be fulfilled” to form a successful pregnancy, Zernicka-Goetz explains. “If those principles are not fulfilled, the pregnancies are terminated, even before women know they're pregnant."
There are limits on using human embryos for research, and previous experiments have tended to replicate only one aspect of development. That led to two-dimensional experiments: flat cells on the bottom of a petri dish that lack the structural organization of real tissue.
The new models are three-dimensional with beating hearts and the yolk sacs in which embryos feed and grow. The models even progressed to forming the beginning of a brain – a research first.
The scientists used the foundational cellular “building blocks” called stem cells and managed to get the cells to communicate along a timeline that mimicked natural development, simulating those developmental stages, says Zernicka-Goetz. Those “building blocks” are actually three types of stem cells: pluripotent stem cells that build body tissue, and two other types of stem cells that build the placenta and the amniotic sac.
Completing the experiment required the right quantity of each stem cell type. The researchers also needed to understand how those cells exchange information before they can begin to grow. The researchers were able to "decipher the code” of how the cells talk to each other, Zernicka-Goetz says.
Initially, the three types of stem cells combine, almost like a soup, but when the timing is right, they have to recognize each other and sort themselves. Next, each stem cell type must start building a different structure necessary for fetal development. Zernicka-Goetz thinks of this construction as the architecture of human tissue.
With the new technique, researchers can continue investigating the implantation stage and beyond. And they did – tweaking the experiment to create a genetically flawed embryo on purpose.
Goetz and her team eliminated a certain gene known to regulate how cells establish their own identities. Doing so resulted in the same brain development flaws as in human embryos, providing "a proof of concept" that the experimental models can be used to study other genetic mysteries, she says.
Scientists are still in the dark about what some genes do, as well as the point when they become critical to brain development.
“Many genes have very early roles in specifying, for example, the position of the head and also how our brain will function,” Zernicka-Goetz says. “We can now use this model system to assess the function of those genes.”