Reengineering Life

Scientists Can Now Grow ‘Synthetic’ Early Human Embryos in a Dish

The research reignites a debate over embryo research

Reengineering Life is a column from Future Human about the ways humans are using biology to reprogram our bodies and the world around us.

Under a microscope, the little balls of cells look like five-day-old human embryos, known as blastocysts. They’re similar in size, shape, and structure. They even have the three distinct cell types that exist in real blastocysts — the kind that forms the embryo itself, another that makes the placenta, and a third type that gives rise to the sac in which the embryo will develop.

But there’s one key difference between these embryo look-alikes and natural ones: They weren’t made with human eggs and sperm.

In two papers published March 17 in the journal Nature, researchers report that they created living structures that resemble early embryos using human skin cells and stem cells. Scientists have previously made “synthetic” mouse embryos and even used them to grow a mouse fetus. And last year, scientists described making versions of later-stage human embryos. These, however, mimic an embryo at an even earlier stage and are among the most complete models of a human embryo to date.

Currently, scientists who study early human development must rely on difficult-to-obtain embryos donated from patients undergoing fertility treatments at in vitro fertilization clinics. These new models could provide a way to investigate how healthy embryos form without the use of actual embryos. Scientists say these embryo-like structures will help them better study the causes of birth defects and genetic diseases, as well as the impact of chemicals, toxins, and viruses on early embryos.

“They will allow us to study now, at scale, the very early steps of human development without having to use blastocysts donated from IVF,” said José Polo, PhD, a developmental biologist at Monash University in Australia and lead author of one of the papers, in a March 16 call with reporters.

In one paper, Polo and his team made the embryo-like structures by converting human skin cells into an intermediate type of stem cell. In the other paper, researchers led by Jun Wu, PhD, a molecular biologist at the University of Texas Southwestern Medical Center, made their models with a mix of stem cells — some from IVF embryos and some made from skin cells reprogrammed into an embryo-like state. When they put the cells into a dish and fed them a cocktail of chemical signals, the cells organized into 3D clumps that resembled blastocysts after six to eight days. The groups dubbed their models “blastoids.”

The potential to create human embryos in the lab without sperm and eggs raises the question of whether they could one day be used to make babies. But the researchers say we’re still far from that possibility.

Images of the embryo-like structures, known as blastoids, with different cellular staining. Image: Monash University

“I don’t consider them to be the equivalent of a human blastocyst that comes from an in vitro fertilization clinic,” said Amander Clark, PhD, a stem cell biologist at the University of California, Los Angeles and one of Wu’s co-authors, to reporters.

For one, these structures don’t have a membrane called the zona pellucida, which interacts with sperm during the fertilization process and later disappears. The lab-grown blastoids also contain cells not found in natural human embryos.

Wu says it’s highly unlikely that they could be used to establish a pregnancy, given that blastoids generated from mice were not viable in previous studies. “Based on the current technology, we still don’t have the tools and technology to make it exactly like a blastocyst,” he said during the press briefing.

Whether blastoids could eventually develop into fully formed embryos is a big unknown, says Magdalena Zernicka-Goetz, PhD, a developmental biologist at the California Institute of Technology. On March 12, Zernicka-Goetz posted a paper to the preprint server bioRvix describing similar blastoids that her team created. Her paper has yet to be peer reviewed.

She says one application of the blastoids would be to study the causes of miscarriage and infertility. Many embryos fail to implant in the womb, the key first step in pregnancy, and the reasons why aren’t well understood.

“Many, many embryos do not survive the process of implantation,” she says. “These models would allow us to address that.”

But making the blastoids is a frustrating and often fruitless process. To grow, they require just the right mixture of cells and nutrients at the right temperature, says Zernicka-Goetz. Polo’s group reported that they were successful at generating them just 6–18% of the time, depending on the batch.

Even though the blastoids aren’t real embryos, the researchers all stopped their experiments at 14 days, respecting an internationally accepted rule that limits scientists from growing human embryos in the lab for more than two weeks. In the United Kingdom and many other countries, this “14-day rule” is enshrined in law. In the United States, it’s a self-imposed rule that scientists follow.

“Clearly the authors wished for public approval of their work before crossing this line,” said Martin Johnson, PhD, emeritus professor of reproductive sciences at the University of Cambridge, in a statement to journalists.

The 14-day rule dates back to the late 1970s, when the first IVF babies were born. It was meant to provide a clear boundary for embryo research and to ensure the public that scientists wouldn’t try to grow babies outside the womb. The rationale for the rule is that, at around 14 days, an embryo attaches to the uterus and starts to develop a nervous system.

When this limit was put in place, scientists couldn’t culture embryos in the lab for nearly that long. But in 2016, Zernicka-Goetz and her team succeeded at keeping embryos alive in a dish for 13 days — longer than anyone had before. And it’s likely possible to grow them beyond that time.

Some scientists and ethicists think it’s time to visit the 40-year-old rule. Growing embryos past 14 days could yield insights into human health and fertility, they say. In 2017, I reported that support was growing for the rule change but scientists feared political blowback under the Trump administration.

Now, the International Society for Stem Cell Research, which sets guidelines for stem cell and embryo research, seems poised to do away with the 14-day rule, according to a March 16 report by MIT Technology Review. In a press release, the organization said it will “update guidelines for stem cell research” in May but didn’t specifically address the 14-day rule.

Eric Siggia, PhD, a physical biologist at Rockefeller University, thinks 28 days would be a reasonable limit for embryo research. At that point, an embryo measures about six millimeters and starts to develop organs.

He says scientists aren’t making these embryo-like blastoids with the intention of using them for IVF but to study the very earliest stages of human development. “The reason to do synthetic embryology is not because we want to be Dr. Frankenstein,” he tells Future Human. “If you want to make a child, there are more pleasurable and reliable ways to do that.”

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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