Lit from below by the microscope’s soft glow, the translucent mouse embryos looked exactly as they should. On day 3 they began to elongate, from spheres into cylinders. On one end, the neural tube started to fold around day 6, on the other a tail began to bud. By day 8, a beating heart began to circulate blood through vessels forming around the embryo’s yolk sac.
But these embryos weren’t the product of an egg and a sperm. They weren’t even growing in the uterus of a female mouse. They were developed inside a bioreactor, and made up entirely of stem cells cultured in a Petri dish.
The experiments, performed at the Weizmann Institute of Science in Israel and published Monday in Cell, marks the first time researchers have grown fully synthetic mouse embryos — that is without the use of sperm or eggs — outside the womb.
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The advance opens up new avenues for studying how stem cells form various organs in the developing embryo and better understanding how certain mutations drive various developmental diseases. It also raises profound questions about whether other animals, including humans, might one day be cultured from stem cells in a lab.
“As soon as the science starts to move into a place where it’s feasible to go from a stem cell population in a Petri dish all the way through to organ development — which suggests one day it will be possible to go all the way to creating a living organism — it’s a pretty wild and remarkable time,” said Paul Tesar, a developmental biologist at Case Western Reserve University School of Medicine who was not involved in the study.
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Since the 1980s, developmental biologists have been taking apart embryos cell by cell to try to understand how they eventually become all the specialized tissues that allow fish to swim and mice to scurry and humans to walk and talk. In the last decade or so, researchers have learned enough about the signals that send stem cells down these differentiation paths to be able to put them back together into things that resemble organs (organoids), recently fertilized eggs (blastoids), and even embryos (embryoids).
But these balls of mouse and human cells could only be grown in dishes and test tubes for a short amount of time before they’d poop out. They needed a living womb to support their further development, or even better, an artificial approximation of one.
Jacob Hanna, an embryonic stem cell biologist at the Weizmann, spent seven years engineering a tubed system of spinning glass vials housed in an incubator to do just that. Last year, his team reported in Nature that their mechanical uterus could keep natural mouse embryos alive for up to 11 days.
In this latest work, the team combined that system with a novel cocktail of stem cells, some of which had been chemically coaxed to overexpress genes that switched on development of the placenta and yolk sac — tissues that are vital for supporting the healthy growth of embryos.
The synthetic embryos were able to grow to day 8.5, developing the beginnings of a well-shaped brain, a neural tube, and an intestinal tract, as well as a beating heart. Analyses of the synthetic embryos’ gene expression patterns across different tissues showed that they were 95% similar to a natural mouse embryo of the same age.
However, the work has some important limitations. Day 8.5 is still relatively early; the full gestational time for a mouse is 20 days. And the embryos that survived that long were a rarity. Only about 50 of 10,000 cellular clumps self-organized into embryos. The rest failed to develop properly.
“This is just one step, but a very important step for us to be able to study early development,” said Tesar. “We’re crossing into the realm of being able to generate an embryo from scratch, and potentially a living organism. It’s been a really notable switch for the field.”
