Primate embryos grown in the lab for longer than ever before

They are the longest lived primate embryos to thrive outside the body. Two groups working in China have succeeded in growing monkey embryos in a dish for 20 days. The work sheds light on a crucial but little-understood phase of early development, and will probably reignite the debate about how long human embryos should be permitted to develop in the lab.

Researchers grow embryos to understand the earliest stages of development. In 2016, biologists in the United States successfully grew human embryos in the lab for 13 days, but then stopped the experiments because of an internationally accepted rule that restricts scientists from growing human embryos past 14 days for ethical reasons. As a closely related species, monkey embryos are a window into early human development, but scientists have previously grown them for only nine days.

The two teams in China report in Science¹,² today that lab-grown embryos from cynomolgus monkeys (Macaca fascicularis) underwent several crucial processes. This includes the process of gastrulation, which is when the basic cell types that give rise to different organs and tissues begin to emerge, around day 14.

“The best part is that there is a system to study gastrulation in vitro in a model very similar to the human,” says Magdalena Zernicka-Goetz, a developmental biologist at the California Institute of Technology in Pasadena. “This is very exciting.”

Although the studies show that early monkey development mirrors many aspects of the first two weeks of the human process, the teams report subtle differences between that species and ours. This suggests that monkey embryos might not be an adequate model for studying some advanced stages of human development, says Pierre Savatier, a stem-cell biologist at the Stem-cell and Brain Research Institute in Bron, France. He predicts that the papers will reinvigorate a push to extend the 14-day policy.

The ability to grow monkey embryos for longer than ever before could also boost research in another hot and controversial field — the generation of hybrid human–monkey embryos, known as chimaeras, with the goal of investigating how human cells differentiate into organs. This research has been held back because researchers haven’t been able to grow monkey embryos for long enough to see how the injected human cells behave. Savatier says he will use the culture technique to grow monkey embryos that will be injected with human stem cells. “This culture system is hugely important for chimaera experiments,” he says.

Embryo bonanza

Both teams grew monkey embryos on a gel matrix that supplied higher levels of oxygen than do cells in the womb. This culture technique was developed by Zernicka-Goetz’s team, which was one of two groups in the United States that succeeded in growing human embryos for 13 days, in 2016^3,4.

In one of the latest two papers, a team led by Juan Carlos Izpisua Belmonte, a developmental biologist at the Salk Institute for Biological Studies in La Jolla, California, and Ji Weizhi at the Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China, reports that 46 of 200 monkey embryos survived to 20 days. The authors of the other paper, led by Li Lei, a developmental biologist at the Institute of Zoology, Chinese Academy of Sciences, in Beijing, say they grew three embryos that long.

The teams tracked the progress of the embryos, which were created using in vitro fertilization, to check whether they grew as they would have in the womb. They examined the timing and shape of structures in the embryos and the structures that support embryonic growth, the types of protein that are expressed by cells at different stages and the primordial germ cells that go on to become eggs or sperm. Then they compared these observations with what is known about development of this species from past experiments, in which embryos were removed from pregnant monkeys at different stages up to 17 days⁵.

Both groups report that embryos in a dish develop in the same way as those in the womb. “It’s ok to assume that the observations made are a representation of what happens in vivo,” says Izpisua Belmonte.

The teams stopped their experiments on day 20, when the embryos turned dark and some cells detached from them — signs that the structures were collapsing. Li says it’s not clear why that happened. He and Izpisua Belmonte say that culturing the cells in an extracellular matrix that better mimics the womb might help them to survive longer. Next, Ji hopes to grow embryos to the point when the primitive nervous system starts to form, around day 20.

Subtle differences

Data presented in both studies suggest there are subtle but crucial differences in the early development of monkeys and humans, so non-human primate embryos won’t replace the need for studies in human cells, says Fu Jianping, a bioengineer at the University of Michigan in Ann Arbor, who has been trying to grow synthetic human embryos. “In vitro cultured human embryos remain the irreplaceable system for us to study and understand human development,” he says.

Savatier says one difference, described in the Ji and Ispizua Belmonte paper, is the genes that are expressed in monkey cells that form the placenta are different from those in humans. But to study these processes in later stages in human embryos, regulators would need to lift the ban on growing them beyond 14 days.

In the wake of the US teams growing human embryos to 13 days in 2016, some scientists and ethicists pushed for a revision of the 14-day policy, and a poll conducted in the United Kingdom in 2017 reported strong public support for extending the limit. Savatier and others think the latest results showing the unique features of human embryonic development will strengthen arguments to change the policy. “No doubt that this work will force the ethical committees and regulatory bodies to reopen the debate over the 14-day rule,” he says.

Researchers are optimistic that the gel matrix could be used to grow human embryos to a more advanced stage if the rules change. Ji says that another group at his institute has developed a protocol specifically for human embryos that will soon be published. “This system could be suitable for human embryos to be cultured to 20 days, but we are not planning to do it,” he says.