The early beginnings of an embryo as it transforms from a clump of cells to a tiny human is a bit of a mystery — scientifically speaking. We know many of the broad strokes, but there are a lot of intricate steps involved in the transformation that we aren’t privy to simply because we can’t see inside the uterus as everything unfolds.
Not having front-row seats hasn’t stopped scientists from trying to parse together an IKEA instruction manual for embryonic development. Over the last several decades, a variety of studies conducted in animals like zebrafish, mice, and fruit flies have identified some of the genetic switches underpinning embryogenesis — a fertilized egg’s journey to becoming a multicellular organism. There have also been studies using human and human-animal hybrid embryos to various degrees, of which there’s been terse progress due to ethical concerns constraining such research.
The goal, therefore, is to find workarounds and proxies that can mimic a human uterus or resemble human embryonic development. There’s been some effort on that front in recent years when in August 2022, scientists successfully created a synthetic mouse embryo using stem cells instead of the usual mishmash of eggs and sperm and incubated the embryo in a mechanical womb.
Now, in a study published Thursday in the journal Cell Stem Cell, researchers in China have created embryo-like structures from embryonic stem cells taken from the crab-eating macaque. This structure called a blastoid, was similar to a crucial embryonic structure called a blastocyst, and possessed the transformative ability that eventually gives rise to the different cells and tissues in the body. However, when implanted into the uteri of female macaques, the blastoids didn’t survive past a week (nearly three weeks in total from creation), although they did develop gestational sacs.
“I wouldn’t call this a breakthrough study,” Jianping Fu, professor of biomedical engineering at the University of Michigan, who wasn’t involved in the study, tells Inverse. “But it points to an exciting direction to bypass the existing constraints [set] by human and animal models.”
Bathing in a cocktail of growth factors
Stem cells, particularly embryonic and induced pluripotent stem cells (which are derived from adult cells and rewired to resemble their embryonic counterparts), have become a hotbed of interest simply for one reason: They have the potential to change into any cell type in the body, kind of like a cellular Animorph. This means they can be used to generate a wide range of cell types for research and clinical therapies, such as targeting neurodegenerative diseases like Parkinson’s to diabetes and even dental issues.
The embryonic stem cells used in this new study came from crab-eating macaques, a species of long-tailed, brown-gray Old World monkeys native to Southeast Asia. These primates are widely used in medical research due to their physiological and genetic similarities to humans (thus their classification as near-human primates), particularly in areas such as neuroscience, infectious diseases, and reproductive biology.
To get growing and transforming, embryonic stem cells — regardless if they’re human or monkey — need chemicals called growth factors. This jumpstarts and nudges the cell down a certain “career” path (think your high school counselor on career day), which prompts certain genes to turn on and off depending on the desired cell type.
For their study, the researchers across various academic research institutions in China bathed their macaque embryonic stem cells in growth factors known from past studies to be involved in embryonic development. (It’s important to note, though, we don’t have an expansive knowledge of all the growth factors present in an embryo.) After about a week simmering in this chemical cocktail, the embryonic stem cells started to take on the appearance of a blastocyst — a hollow sphere-like structure, parts of which will eventually develop into the placenta — when viewed under the microscope (hence the name blastoid).
Also, under the microscope, these researchers noticed the blastoids appeared to have reached a stage in embryonic development called gastrulation. This is when three cells, or germ, layers — the ectoderm, mesoderm, and endoderm — start to form, ultimately giving rise to all the different types of cells and tissues in the body. This seemed to be corroborated by single-cell RNA sequencing, a technique used to photograph gene expression with resolution down to the single cell (around 6,000 in this study). The gene expression “snapshots” showed that different cells within the blastoid shared a nearly similar gene expression to natural blastocysts or embryos right after implantation, when the fertilized egg attaches to the uterine wall in early pregnancy.
Not quite an embryo
So if it looks like a blastoid, does it act like a blastoid? Specifically, can it become an embryo? Not exactly.
To see how the blastoids fared in a more natural habitat — namely inside a surrogate mama — the early embryonic structures (about two weeks old at this point) were surgically implanted into eight female macaques. Of the eight, the blastoids appeared to successfully tether in three primates. The cells seemed to trigger pregnancy, indicated by the presence of hormones progesterone and chorionic gonadotropin, both crucial for sustaining pregnancy in monkeys as well as humans. This demonstrated that the blastoids were able to mimic some of the critical functions of a developing embryo, albeit on a limited scale.
While the blastoids did form gestational sacs — fluid-filled structures that serve as an early sign of pregnancy — and potentially a yolk sac in one (another early embryonic structure that produces blood and germ cells) seven to 10 days after implantation, these structures didn’t progress any further. Roughly twenty days after they were first created, the blastoids disappeared without a trace.
Research with a long road ahead
Growing these embryo-like structures outside the uterus (at least initially) is among one of many modes of exploration the researchers hope will provide us insight into the molecular mechanisms behind-the-scenes of embryonic development.
“[This research] provides new tools and perspectives for the subsequent exploration of primate embryos and reproductive medical health,” Qiang Sun, the study’s co-author and director of Suzhou Non-human Primate Facility at the Chinese Academy of Sciences, said in a statement.
Especially for reproductive health, this research could lend to a better understanding of why early miscarriages happen, which occur in 10 percent to 20 percent of pregnancies. There’s no exact cause, but there are a variety of reasons, such as random chromosomal abnormalities or structural deficits, whether in the mom’s uterus or in the baby, that prevent implantation or proper embryonic development.
“Such monkey models may be very useful… [for] toxicity screening applications to identify chemicals that have potential toxic effects on pregnancy,” says Fu of the University of Michigan. “There’s also a lot of hope such animal models, especially related to primate development, might guide us to better understand early development so we can [create] better protocols… which might be very useful for [in vitro fertilization].”
But he’s skeptical of exactly how much these findings can contribute to our understanding of early development. Previous studies fusing mouse and human embryonic stem cells show that even these hybrids can develop into blastoids, so demonstrating the same with monkey embryonic stem cells isn’t altogether new. Not only that, he’s not convinced the monkey blastoids actually achieved gastrulation since, judging from the data provided, they still look “very much disorganized.”
Fu warns that a monkey model workaround may still toe the line of what’s ethically permissible since, evolution-wise, macaques are pretty close to humans. This may make their blastoids nearly equivalent to human cells. Ethical concerns about primate models for embryonic development have been raised in the past.
The researchers acknowledge the potential ethical conundrum but note that the blastoids they’ve created are still very different and not functionally on par with human blastocysts.
This research still has a long way to go, and likely many more years before we can completely pick apart the black box that is embryonic development.
