In early mammalian development, timing is everything.
For healthy development to occur—whether it be three weeks for a mouse or nine months for a human—embryos follow the lead of oscillating genes, which turn on and off in precise cycles and trigger different development milestones. Oscillating genes are conductors keeping time in a symphony of growth.
Scientists at the Morgridge Institute for Research have created a new way to study this virtually unknowable process in humans, using human stem cells in the lab. Their “clock in a dish” not only opens new research avenues, but it also provides a way to replicate developmental disorders to better understand their cause.
Reporting online in this week’s issue of Cell Reports, the team describes growing human stem cells that are programmed into a very early stage, within the first month of development. Then, using CRISPR technology, they edited a specific gene known to be connected to timing so it would illuminate when expressed.
The result: The cells growing in a dish produce a burst of color every five hours, precisely when those faithful oscillating genes are repeating their instructions. This is the first confirmation of the exact timing of oscillating genes in early human development.
Li-Fang Chu, a scientist in the lab of Morgridge and University of Wisconsin-Madison stem cell research pioneer James Thomson, says most major oscillation findings to date have been with model organisms. The landmark paper 20 years ago described the oscillatory system in chickens, and following studies in zebrafish, mice and snakes have all added to knowledge.
“It is so early in the development states that in humans, there is no way you could even approach this process,” Chu says. “That’s why it was attractive for us to use stem cells to see if we can create it in the lab.”
The project focuses on a specific phase of development called somitogenesis—or the development of body segments—which takes place around 20 days of development. It is a period when the 42-44 pairs of somites are forming, and they develop one after the other in a very precise pattern over a period of about two weeks.