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The stem cells were no more than a week old when scientists moved them from their slick-walled plastic wells into ones lined with a thin layer of human endometrial tissue. But in that time, the cells had multiplied and transformed, organizing themselves into semi-hollow spheres. Per the instructions of the chemical cocktail in which they’d been steeping, they were trying to turn into embryos.

Video cameras captured what happened next: The balls of cells rotated until they were cavity-side-up, before finally touching down and grabbing onto the endometrial layer, a cellular proxy for a human uterus. Days later, when the scientists dipped paper test strips into the wells, pink lines appeared. Their Petri dishes were pregnant.

“These experiments clearly point out the fact that we are able to model in the dish the first touch between the embryo and the mother,” stem cell biologist Nicolas Rivron told reporters at a press conference.

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On Thursday, Rivron and his colleagues at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna reported in Nature that they’ve learned to efficiently manufacture realistic models of human embryos from stem cells. These so-called blastoids aren’t the first successful attempt to recapitulate the developmental stage that embryos reach between four and seven days post-fertilization — when they’re a blastocyst made up of about a hundred cells and ready to implant into the walls of the uterus — but they appear to be the most advanced yet.

These synthetic embryos were made by mixing induced pluripotent stem cells with a brew of biochemical signals capable of coaxing them into forming spherical structures that include the beginnings of three distinct cell lineages — outer layers representing the future placenta and amniotic sac, and an inner clump of cells with the potential to develop into a fetus.

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“This is a very, very close model of a real, complete human embryo,” said Insoo Hyun, director of research ethics at the Harvard Medical School Center for Bioethics, who was not involved in the study. “It’s probably the closest I’ve seen.”

The field of synthetic embryology has exploded in recent years. A parade of increasingly lifelike models that mimic portions of an embryo’s journey to personhood promise to shed light on critical moments of human development while providing a more flexible and ethical alternative to the study of human embryos, which has been historically limited by regulations and the willingness of IVF donors.

As the science of synthetic embryology gets more sophisticated, the models become more useful. But each advance raises a new round of ethical questions about where embryo models end and embryos begin. If it divides, organizes, and develops like an embryo, does it matter how it was made? Should an embryo derived from stem cells get the same legal and ethical rights as one produced when sperm met egg?

“At some point we have to ask, ‘when does an embryo model become so good that it functionally becomes an embryo?’” said Hyun. “And for me, that question starts to get raised here.” It’s not that the latest work on blastoids was unethical, he clarified. On the contrary, it met all the guidelines issued by the International Society for Stem Cell Research (ISSCR), which Hyun helped write. The latest version, issued in May, prohibits scientists from transferring blastoids, which contain all the cell types necessary for development, into a human or animal uterus. “It was a really well-done paper, I thought it was kind of stunning actually,” said Hyun. “It just opens up these other questions.”

Already this year, five other groups around the world have independently reported methods for making blastoids, with varying degrees of efficiency and complexity. Two teams — one at Monash University in Australia, one from the University of Texas Southwestern Medical Center in Dallas and Kunming Medical University in China — published their results in Nature in March. Both teams also showed that their artificial structures formed similarly to real blastocysts. But both reported that only about 10% of the reprogrammed cells made the transition, and some of the structures contained cells not typically found in human blastocysts. Two other teams, one based in China and one based in the U.S. and the U.K., showed similar results while working with extended pluripotent stem cells. Another group, from the U.K., reported in Cell Stem Cell in June achieving much higher efficiencies — between 30% and 80% of their stem cells expanded into blastoids. The Austrian group’s blastoids were even more efficient, forming more than 70% of the time.

“It’s been a big year for blastoids,” said Jianping Fu, a bioengineer at the University of Michigan whose lab created some of the earliest human embryo models from stem cells in 2017.

In 2018, Fu and Rivron joined Hyun and several others in writing an editorial urging lawmakers to ban the use of stem-cell based synthetic embryos for reproductive purposes while preserving their use for some types of research. They encouraged regulators to treat embryo models in the same way many nations dealt with cloning in the late 1990s and early 2000s. “We think that the intention of the research should be considered the key ethical criterion by regulators, rather than surrogate measures of the equivalence between the human embryo and a model,” they wrote.

Hyun said he still stands by those recommendations, to a point, even if it makes the slippery-slope crowd nervous. “The further along you get in modeling pregnancy, the harder it is to justify those experiments on the grounds that there’s no other way to answer your research question,” said Hyun. Scientists have been able to glean insights into the earliest stages of development by studying human embryos donated by families who’ve undergone IVF. Tissue from aborted fetuses has provided clues about later stages of pregnancy. But from the time an embryo implants until the time a person realizes they’re pregnant, scientists have virtually no way of knowing what’s going on.

“It’s a total black box,” said Hyun. “But it maxes out at about 28 days. And what most people don’t realize is that means there’s a natural limitation on how long you could justify an experiment with synthetic embryos. Once you traverse the black box of development, there’s no need to keep going in the dish.”

Although it’s not required by law or the latest ISSCR guidelines, which relaxed the long-held “14-day rule” barring research on embryos older than two weeks, the Austrian researchers did not allow their artificial embryos to develop past 13 days. But Rivron said he does not expect any of the blastoids to have the ability to develop into a complete embryo, even if allowed the chance.

A few years ago, his team successfully grew blastocysts in the lab from mouse stem cells. Ever since, they’ve been implanting the blastoids into the uteruses of living mice and crossing their fingers. But they’ve never successfully made any mice pups. Rivron said he’d expect the same thing for their human blastoids if they were implanted into a functioning uterus (an experiment the ISSCR’s guidelines, as well as laws in a handful of countries, expressly forbid). After implantation on the uterus-in-a-dish, the blastoids didn’t grow or organize as well as what you’d expect from real embryos in a real womb, said Rivron. “These are very nice models, but we are far from any potential of using them for reproduction.”

So how does he expect scientists might use them instead? A logical application would be to use them for drug discovery and screening — a process that would require large numbers of these embry(ish)os. “Now that we have formed a reliable embryo model, we can uniquely understand the molecules at play, and I believe that these molecules will actually become tomorrow’s medicines to enhance fertility or to be used as contraceptives,” said Rivron. His group is already working with collaborators to test an FDA-approved drug that prevented the innermost cells of the blastoid from forming. Because those cells instruct the outer cells to become sticky, disrupting them could offer a hormone-free way to prevent embryos from implanting.

Other as-yet-discovered drugs could possibly enhance the implantation process, thereby improving the odds of getting pregnant. Compared to creating a fully competent synthetic embryo, using existing models to find and develop drugs is achievable on a relatively short timescale, said Rivron. “This is not something that requires 10 years.”

Other scientists have other ideas. Fu said an obvious immediate application would be to use large numbers of blastoids to systematically figure out better recipes for the medium that IVF clinics use to culture embryos prior to implantation. “There are a lot of unknowns in how culture medium conditions affect the growth and development of human embryos, including successful implantation,” said Fu. “Those are questions that can better be answered now.”

To Martin Pera, a stem cell researcher at the Jackson Laboratory, an even more powerful application would be to use these models to better understand how organisms precisely alter the expression of genes in different types of cells during early development. “It’s a very dynamic time, epigenetically,” said Pera.

Since the 1990s, some scientists have argued for the fetal origins of adult disease; that the intrauterine environment, especially during times of bodily stress, may predispose a developing fetus to worse health outcomes later in life. “We need models to replicate that, and this is an important start,” Pera said.

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