Scientists have found a way to study early embryonic development without real embryos. Using CRISPR, they programmed stem cells to self-organize into structures mimicking early embryos.
The cells show remarkable, collective behavior, almost as if they instinctively “know” what to do. This breakthrough allows researchers to explore genetic influences on development, reproductive challenges, and potential fertility treatments—all without using actual embryos.
Unlocking the Earliest Mysteries of Life
The earliest moments after fertilization, when a sperm cell meets an egg, remain one of biology’s greatest mysteries.
Scientists from various fields are fascinated by how a single cell develops into a complex organism. In many animals, this transformation occurs inside the protective environment of the uterus, making direct observation difficult. As a result, researchers struggle to fully understand what can go wrong during early development and how external factors might prevent embryo formation.
Engineering Embryos Without Embryos
To overcome these challenges, scientists at UC Santa Cruz have engineered cellular models that replicate the first few days of embryonic development, without using actual embryos. Using CRISPR-based techniques, they guide stem cells to self-organize into “programmable” embryo-like structures, known as embryoids. These lab-grown cell assemblies are not true embryos but closely mimic key aspects of early development, providing a powerful tool for studying genetic and environmental influences on embryonic formation. Their findings were published today (March 20) in Cell Stem Cell, a leading journal in stem cell research.
“We as scientists are interested in recreating and repurposing natural phenomena, such as formation of an embryo, in the dish to enable studies that are otherwise challenging to do with natural systems,” said Ali Shariati, assistant professor of biomolecular engineering and the study’s senior author. “We want to know how cells organize themselves into an embryo-like model, and what could go wrong when there are pathological conditions that prevent an animal from successfully developing.”
Cell Co-Development: A More Natural Approach
Shariati is an expert in stem cell engineering, a field that uses stem cells — unspecialized cells that can form any type of cell such as gut or brain cells — to study and solve biological and health problems.
This project, led by UCSC postdoctoral scholar Gerrald Lodewijk and biomolecular engineering alumna and current Caltech graduate student Sayaka Kozuki, used mouse stem cells that are commonly grown in the lab to guide them to form basic building blocks of the embryo.
Programmable cellular models of embryos, known as embryoids, allow scientists to mimic the first few day of embryonic development. Credit: Ali Shariati/ UC Santa Cruz
CRISPR Technology: A Revolutionary Tool
The team used a version of CRISPR technology known as an epigenome editor, which does not cut DNA but instead modifies how it is expressed. They targeted regions of the genome known to be involved in the development of an early embryo. This allowed them to control which genes were activated, and induce the creation of main types of cells needed for early development.
“We use the stem cells, which are like a blank canvas, and use them to induce different cell types using our CRISPR tools,” Lodewijik said.
This method had the advantage of allowing different cell types to “co-develop,” which more closely resembles the natural embryo formation than the chemical approaches other scientists have used to develop different cell types.
“These cells co-develop together, just like they would in an actual embryo, and establish that history of being neighbors,” Shariati said. “We do not change their genome or expose them to specific signaling molecules, but rather activate the existing genes.”
Self-Organizing Cells: A Remarkable Discovery
The team found that 80% of the stem cells organize themselves into a structure that mimics the most basic form of an embryo after a few days, and most undergo gene activation that reflects the development process that occurs in living organisms.
“The similarity is remarkable in the way the cells organize themselves, as well as the molecular composition,” Shariati said. “[The cells require] very little input from us — it’s as if the cells already know what to do, and we just give them a little bit of guidance.”
The researchers observed that the cells showed a collective behavior in moving and organizing together.
“Some of them start doing this rotational migration, almost like the collective behavior of birds or other species,” Shariati said. “Through this collective behavior and migration they can form these fascinating embryonic patterns.”
“Programmable” Models for Developmental Research
Having an accurate baseline model that reflects a living organisms’ early embryo could allow scientists to better study and learn how to treat developmental disorders or mutations.
“These models have a more complete representation of what’s going on in early stages of development, and can capture the background,” Lodewijik said.
The CRISPR programming not only allows the scientists to activate the genes at the beginning of the experimentation process, but also enables them to activate or modify genes important for other parts of development. This allows the embryo models to be “programmable,” meaning they can be relatively easily influenced with a high level of control to target and test the impact of multiple genes as the embryo model develops, illuminating which have deleterious effects when turned on or off.
As an example, the researchers demonstrated how certain tissues form or are hindered during early development, but their methods could be used to study a wide range of genes and their cascading effects on the cell types.
“I think this is the pioneering work of this study — the programmability and that we don’t rely on extrinsic factors to do this, but rather have a lot of control inside the cell,” Shariati said.
The researchers are interested in how this approach might be used to study other species, allowing for a look into their embryo formation without ever using their actual embryos.
A Window Into Fertility Challenges
This research could allow for the study of the bottlenecks that lead reproduction to fail in early stages. Among mammals, humans have more reproduction challenges in that human embryos often fail to implant or establish the correct early organizational form. Understanding why this is the case could help make progress toward improving human fertility.
Reference: “Self-organization of mouse embryonic stem cells into reproducible pre-gastrulation embryo models via CRISPRa programming” by Gerrald A. Lodewijk, Sayaka Kozuki, Clara J. Han, Benjamin R. Topacio, Seungho Lee, Lily Nixon, Abolfazl Zargari, Gavin Knight, Randolph Ashton, Lei S. Qi and S. Ali Shariati, 20 March 2025, Cell Stem Cell.
DOI: 10.1016/j.stem.2025.02.015
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3 Comments
Wow, this is pretty cool!
This is kind of amazing!
I think this is pretty solid work, Boba