Scientists plan to drop the 14-day embryo rule, a key limit on stem cell research

As technology for manipulating embryonic life accelerates, researchers want to get rid of their biggest stop sign.

March 16, 2021
stem cell researchIn 2016, Magdalena Zernicka-Goetz grew human embryos in a lab dish for longer than anyone had before. Bathing the tiny spheres in a special broth inside an incubator, her team at the University of Cambridge watched the embryos develop, day after day, breaking all prior records. The embryos even attached to the dish as if it were a uterus, sprouting a few placental cells.

But on day 13, Zernicka-Goetz halted the experiment.

Zernicka-Goetz had hit up against an internationally recognized ethical limit called the “14-day rule.” Under this limit, scientists have agreed never to allow human embryos to develop beyond two weeks in their labs. That is the point at which a spherical embryo starts to form a body plan, deciding where its head will end up, and when cells begin taking on specialized missions.

For the last 40 years, the rule, which is law in some countries and a guideline in others, has served as an important stop sign for embryonic research. It has provided a clear signal to the public that scientists wouldn’t grow babies in labs. To researchers, it gave clarity about what research they could pursue.

Now, however, a key scientific body is ready to do away with the 14-day limit. The action would come at a time when scientists are making remarkable progress in growing embryonic cells and watching them develop. Researchers, for example, can now create embryo-like structures starting even from stem cells, and some hope to follow these synthetic embryo models well past the old two-week line.

By allowing both normal and artificial embryos to continue developing after two weeks, the end of the self-imposed limit could unleash impressive but ethically charged new experiments on extending human development outside the womb.

The International Society for Stem Cell Research has prepared draft recommendations to move such research out of a category of “prohibited” scientific activities and into a class of research that can be permitted after ethics review and depending on national regulations, according to several people familiar with its thinking.

A spokesperson for the ISSCR, an influential professional society with 4,000 members, declined to comment on the change, saying its new guidelines would be released this spring.

Artificial embryo

Because embryo research doesn’t receive federal funding in the US, and laws differ widely around the world, the ISSCR has taken on outsize importance as the field’s de facto ethics regulator. The society’s rules are relied on by universities and by scientific journals to determine what kinds of research they can publish.

The existing ISSCR guidelines, issued in 2016, are being updated because of an onrush of new, boundary-busting research. For instance, some labs are attempting to create human-animal chimeras through experiments including mixing human cells into monkey embryos. Researchers are also continuing to explore genetic modification of human embryos, using gene-editing tools like CRISPR.

Many labs are also working on realistic artificial models of human embryos constructed from stem cells. For instance, last week, Zernicka-Goetz posted a preprint describing how her lab coaxed stem cells to self-assemble into a version of a human blastocyst, as a week-old embryo is known.

Though scientists are keen to explore whether such lab-created mimicry can be pushed further, the 14-day rule stands in the way. In many cases, the embryo models must also be destroyed before two weeks elapse.

The 14-day limit arose after the birth of the first test-tube babies in the 1970s. “It was ‘Oh, we can create human embryos outside the body—we need rules,” says Josephine Johnston, a scholar with the Hastings Center, a nonprofit bioethics organization. “It was a political decision to show the public there is a framework for this research, that we aren’t growing babies in labs.”

The rule stood unchallenged for many years. That was in part because scientist couldn’t grow embryos more than four or five days anyway, which was sufficient for in vitro fertilization.

Tetsuya Ishii, a bioethics and legal researcher at Hokkaido University, says some countries, including Japan, have put the 14-day limit into law. So has the United Kingdom. Others, like Germany, ban embryo research altogether. That means a guideline change could do most to open up new fields of competition between countries without federal restrictions, particularly among scientists in the US and China.

Scientists are motivated to grow embryos longer in order to study—and potentially manipulate—the development process. But such techniques raise the possibility of someday gestating animals outside the womb until birth, a concept called ectogenesis.

According to Ishii, new experiments “might ignite abortion debates,” especially if the researchers develop human embryos to the point where they take on recognizable characteristics like a head, beating heart cells, or the beginning of limbs.

During the Trump administration, embryologists endeavored to keep a low profile for the startling technical advances in their labs. Fears of a presidential tweet or government action to impede research helped keep discussion of changing the 14-day rule in the background. For instance, the ISSCR guidelines were complete in December, according to one person, but they still have not been published.

Alta Charo, a professor emerita at the University of Wisconsin and a member of ISSCR’s steering committee, declined to comment on the content of the new guidelines. However, she says scientists now have to consider what discoveries could come from studying embryos longer. “Before, you didn’t have to measure a loss in knowledge against other concerns, because we didn’t know how to culture things that long,” she says. “That is what has changed. It’s easy to say no when it can’t be done.”

Going too fast?

People familiar with ISSCR processes say there is not unanimous support for withdrawing the 14-day rule, with objections coming from bioethicists and some scientists. But they are in the minority: most agree that it needs to be eased.

“I agree the rule has to be changed, but it should be done in an incremental manner, on a case-by-case basis,” says Alfonso Martinez Arias, a developmental biologist at Pompeu Fabra University in Barcelona, who thinks researchers should ease their experiments forward a day or two at a time so they don’t lose public support. “My view is opening up too fast could allow very poor science,” he says. “I do worry about getting a flood of experiments that do not help us.”

The ISSCR is not going to set a specific new time limit, like 28 or 36 days, according to one person familiar with the rule change. While hard limits may be reassuring, they are likely to be overtaken by science again, which is why the society wants to move to a more flexible approach.

Many scientists justify their bid to study embryos longer by saying the research could improve IVF or give clues to the causes of birth defects. Johnston, however, believes the primary motives are curiosity and scientific competition. “I don’t think it is driven by a concern for infertility or early miscarriage. It’s driven by an area that is still unexplored,” she says. “The embryo is a bit of a black box, and they would like to chart that territory.”

Others believe the long-term growth of normal embryos, or embryo models, would create a platform to explore the genetic engineering of humans. More fully developed embryos could be used to study the consequences of gene editing and other types of modification. That is, if genetically modified humans are to be created in the future, the modifications should first be tested for safety on lab embryos.

“We would have to ensure they develop normally, and to do that you have to study them beyond 14 days,” says Insoo Hyun, a bioethicist at Case Western Reserve University, who has argued in favor of easing the rule. “You need to study that embryo as long as you can.”

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