After a human sperm and egg unite, a new embryo spends its first few weeks looking blobby. There’s no obvious top or bottom, and it is unclear which cells will give rise to which body parts. After about 14 days, the embryo elongates and forms layers, revealing a rough plan for the body. But this dramatic transformation, called gastrulation, has never been directly observed in human embryos: Growing them to this stage in a lab is technically difficult and ethically fraught. Now, researchers have made structures from human stem cells that mimic some features of embryos after gastrulation, an advance that could reveal how genetic mutations and chemical exposures can lead to miscarriages and birth defects.
“This is really the first … model that allows us to study postgastrulation development of the human embryo,” says Jianping Fu, a bioengineer at the University of Michigan, Ann Arbor, who was not involved in the new work. “It’s a very important step.”
Researchers have few windows into the first weeks of human life. They can observe surplus embryos created for in vitro fertilization procedures, but widely adopted ethical guidelines prohibit growing these in a lab beyond 14 days. Embryos from mice and other animals offer glimpses of how cells organize and signal to each other early in development, but they differ structurally and genetically from human embryos.
To turn human stem cells into something embryolike, researchers in the lab of developmental biologist Alfonso Martinez Arias at the University of Cambridge and collaborators modified a method they developed for mouse cells. In 2018, they showed they could create elongated, embryolike structures—so-called gastruloids—by exposing clusters of mouse embryonic stem cells to a chemical that activates a developmental signaling pathway known as Wnt.
In the new study, the researchers applied a similar treatment to a line of cells, originally derived from a human embryo, which has the potential to develop into any of the body’s cell types. In just 3 days, the cells self-organized into a structure that resembled a human embryo that is roughly 18 to 21 days old, the team reports today in Nature. Genetic analysis revealed that, like an embryo, these gastruloids have cells belonging to three main “lineages” that will go on to form the body’s many tissues. And the gastruloids stretched out to create distinct front and back ends.
This is the first model in to clearly show human cells spontaneously organizing along a body axis, says Aryeh Warmflash a stem cell biologist at Rice University. Studying the gastruloids could reveal how signaling between cells drives this self-organization, he adds. However, patterns of gene expression in cells at different points along the gastruloid are somewhat disorganized, he says. For example, genes that are expected to be expressed more in the back show up in the front. “It’s not as clean as what’s been shown for the mouse.”
Meanwhile, some cells are missing altogether. The new gastruloids don’t have cells that would go on to form the brain, for example. And unlike real embryos, they don’t produce “extraembryonic” cells that would allow them to implant in a uterus and would eventually form a placenta. (Such cells are also thought to enable brain development by shielding the embryo from certain chemical signals in the uterus.) After about 3 days, the gastruloids stop developing and curl up, possibly because they buckle under their own weight, says Cambridge developmental biologist Naomi Moris, a co-author on the study.
It’s clear these gastruloids are not embryos and won’t develop into embryos, says Jeantine Lunshof, a philosopher and ethicist at Harvard Medical School. But by mimicking embryo features, such models could “resolve a lot of problems” she says, allowing researchers to study developmental stages that the 14-day limit on in vitro embryo research currently puts out of bounds.
Nothing about the method is obviously ethically concerning, agrees bioethicist Insoo Hyun of Case Western Reserve University. “But it does raise further questions that I think have to be dealt with.” For example, he says, the desire to validate these gastruloid models by comparing them to natural human development could inspire challenges to the 14-day rule. And if other researchers want to include extraembryonic cells or the precursors of brain cells in gastruloids, “What’s to stop somebody from trying to model the whole thing?”
Moris, for one, says she has no such ambition. Future studies will look in more detail at how cells of the embryo self-organize—for example, how they form somites, the blocks of tissue that go on to form structures in the torso such as muscles and vertebrae. To understand how this and other developmental processes go awry, sometimes ending a pregnancy or leading to birth defects, her group aims to introduce mutations in the stem cells used to make gastruloids, and to create gastruloids out of “reprogrammed” cells from people with congenital disorders.
For those studies, “having a simplified model system is actually beneficial,” she says, “and I think that there are still more questions than I could possibly answer in my lifetime.”