Human embryos embrace asymmetry to form the body

The two cells that make up a one-day-old human embryo might look identical at first glance. But a study¹ published today shows that most of the human body forms from only one of those cells — a finding that could help to increase the success rate of in vitro fertilization (IVF) procedures.

The work shows that the very first division of a fertilized egg primes the resulting cells to seek different fates, paving the way for the intricacies of the fully developed fetus.

“This is a major step forward,” says developmental biologist Ali Brivanlou at the Rockefeller University in New York City, adding that the clinical implications will become clearer as research progresses. “It warms my heart to see we’re now getting to a point where we can ask about human-specific traits in our own development instead of generalizing from model organisms.”

The finding was published in Cell.

Origins of asymmetry

Researchers have long thought that all the cells in mammalian zygotes — fertilized eggs and embryos with fewer than 16 cells — are identical and don’t begin to specialize until later in development. After all, zygotes that split into two separate embryos after several cell divisions have already occurred can still turn into identical twins.

But in 2001, developmental biologist Magdalena Zernicka-Goetz, now at the California Institute for Technology in Pasadena, co-authored a paper revealing that the first two cells in a mouse embryo are distinct². One of the two cells divides into progeny cells that go mainly to make up the majority of the mouse fetus, whereas the other cell’s descendants primarily form the yolk sac.

Zernicka-Goetz has long wanted to know whether the same was true in humans. “My dream was to understand how cells specify their fate and how the complexity of life starts to evolve,” she says. But that has proved difficult to study: embryos donated from IVF clinics typically contain dozens of cells.

Long division

Zernicka-Goetz found an IVF clinic that could provide her lab with 54 fertilized eggs that had not yet fully completed their first division, which yields two cells called blastomeres. The researchers allowed the fertilized eggs to divide in the lab and labelled one of the resulting blastomeres with a fluorescent protein. This allowed them to track each blastomere’s descendants as the embryo developed.

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The researchers grew the embryos in culture for four to five days, until they had started to form distinct structures. Analysis showed that most of the cells in the structure that would become a fetus came from the blastomere that divided faster. The progeny of the blastomere that divided more slowly tended to turn into the yolk sac. The correlation wasn’t exact, Zernicka-Goetz says: these first two cells are only “biased” towards forming one system or the other, and their progenies’ fates aren’t sealed until later in development.

Brivanlou was shocked by the extent of the asymmetry, but says that it makes sense, given how complex the human body eventually becomes. “The more we’re looking at this, the more I appreciate that life is made of continuous symmetry breaking,” he says.

Lopsided development

It’s not yet clear what causes the asymmetry. In mice, the location at which the sperm enters the egg affects how the egg then divides, and Zernicka-Goetz says that other factors, such as the structure of the chromosomes in the egg cell, could also affect the balance.

Knowing which cells are more likely to form the fetus could allow IVF clinics to better screen embryos to find those that are most likely to lead to successful pregnancies, Zernicka-Goetz says. “If we can understand what is so fragile at this time, some losses can be prevented.”

She says that it’s hard to predict how this early asymmetry affects the later human body, but that the effect is probably very long-lasting.