Scientific panel loosens ’14-day rule’ limiting how long human embryos can be grown in the lab

An influential scientific panel cracked open the door on Wednesday to growing human embryos in the lab for longer periods of time than currently allowed, a step that could enable the plumbing of developmental mysteries but that also raises thorny questions about whether research that can be pursued should be.

For decades, scientists around the world have followed the “14-day rule,” which stipulates that they should let human embryos develop in the lab for only up to two weeks after fertilization. The rule — which some countries (though not the United States) have codified into law — was meant to allow researchers to conduct inquiries into the early days of embryonic development, but not without limits. And for years, researchers didn’t push that boundary, not just for legal and ethical reasons, but for technical ones as well: They couldn’t keep the embryos growing in lab dishes that long.

More recently, however, scientists have refined their cell-culture techniques, finding ways to sustain embryos up to that deadline. Those advances — along with other leaps in the world of stem cell research, with scientists now transmogrifying cells into blobs that resemble early embryos or injecting human cells into animals — have complicated ethical debates about how far biomedical research should go in its quest for knowledge and potential treatments.

Now, in the latest updates to its guidelines, the International Society for Stem Cell Research has revised its view on studies that would take human embryos beyond 14 days, moving such experiments from the “absolutely not” category to a “maybe” — but only if lots of conditions are first met.

“We’ve relaxed the guidelines in that respect, we haven’t abandoned them,” developmental biologist Robin Lovell-Badge of the Francis Crick Institute, who chaired the ISSCR’s guidelines task force, said at a press briefing.

The change is not expected to unleash a torrent of such research. In some countries, including Australia and the United Kingdom, it would require a change in law. The ISSCR also said that such experiments would first require national academies, academic institutions, funders, and regulators to hold discussions about the research — focusing on the scientific, societal, and ethical issues at play — and to earn public support. A project should be allowed to move forward only if there is a justified scientific rationale, and if no other research models can answer the question scientists want to study, a review that would fall to “a specialized scientific and ethical oversight process.”

“This is not a green light for groups to go ahead with extending human cultures beyond 14 days,” biologist Kathy Niakan of the University of Cambridge, one of the experts who worked on the guidelines, said at the briefing. “It would be irresponsible, and in many jurisdictions it would be illegal, to do so. What we’re doing instead is, the guidelines are a call to proactively engage in a two-way dialogue with the public to review the 14-day limit on human embryo culture.”

The guidelines, last updated five years ago, do not delve into what those public discussions should look like or what levels of public support should be required before an experiment is authorized. But Niakan said the process could look different country to country depending on local perspectives on this type of research. “It shouldn’t be led by one country’s comfort with this,” she said.

Scientists say that studying human embryos a bit longer could let them peer into the “black box” of days 14 to 28 of development, a time when different cell types emerge, the body’s tissues tilt toward specialization, and the placenta begins to take shape. It could help researchers understand what goes wrong in miscarriages or what causes congenital abnormalities. It could also validate whether the models scientists use to mimic human embryonic development, such as animal embryos, are legitimate stand-ins, and, if not, in what ways they’re lacking. (Past 28 days is when women typically find out they’re pregnant, so researchers can obtain tissue from abortions and miscarriages beyond this point to study those phases of development.)

There are perhaps some people who tolerate culturing embryos up to 14 days who would balk at, say, 18 days. But many scientists view the 14-day mark as an arbitrary cutoff, the result of a compromise made four decades ago. There are some steps an embryo undergoes around the 14-day mark — like starting to orient itself, with a front and a back, and no longer being able to split into twins — but to many researchers, it’s not as if a 15-day embryo all of a sudden takes on recognizably human qualities.

But the rule has had other purposes as well, in effect establishing a sort of compact between researchers around the world and the public, said Josephine Johnston, a bioethicist at the Hastings Center, who was not involved in the ISSCR’s updated guidelines. Researchers could point to the rule to show they were abiding by a certain code of ethics and transparency when using these cells and tissues and to assure the public that they weren’t, for example, secretly creating a baby in a Petri dish.

“The rule has served a really important function for assuring the public that there are significant limits on scientists, especially around growing early human lifeforms in the lab,” Johnston told STAT.

Notably, the ISSCR panel did not propose another maximum timeframe beyond 14 days, arguing that the stopping point should be dictated by the demands of the specific research.

“It really depends on the scientific question, the stage of development, the issue you’re trying to deal with,” said developmental biologist Janet Rossant of Canada’s Hospital for Sick Children, another expert on the ISSCR panel. “Is it a congenital abnormality of the spinal cord when you need to go to a particular stage? If you want to study heart development, a different stage?”

Rossant added: “Every single experiment that is proposed is going to have to be justified in terms of the particular timeline it would be studied under.”

The panel said that experiments that require culturing embryos for longer, as well as those that would need more embryos, should have to clear a higher bar for approval.

Insoo Hyun, a bioethicist at Case Western Reserve University and a panel member, told reporters the experts did not foresee an immediate leap in the length of time scientists could grow an embryo in culture.

“Just because a group may be allowed to go beyond 14 days doesn’t mean that technologically they can go very far,” he said. “They would have to optimize their culture conditions. We think that the scientific approach has to be small steps, has to be a few days at a time, to understand, can you go beyond 14 days? Is that data going to be useful?”

Researchers, however, are making great technical strides in studying different kinds of embryos. Recently, researchers in Israel reported growing mouse embryos outside wombs for half their gestation period.

Groups that oppose research using human embryos have warned against extending the 14-day rule, arguing that scientists blindly want to lift any checks that stand in their way and that any relaxation in the policy will lead the world down a slippery slope. They’ve called for a “zero-day” rule.

“What has our world come to when the scientific ‘experts’ are encouraging growing living human beings in lab dishes?” David Prentice and Tara Sander Lee of the Charlotte Lozier Institute, an arm of the anti-abortion Susan B. Anthony List, said in a statement Wednesday. “Human beings should not be treated as research fodder to be created, manipulated, and discarded at will, no matter their stage of development. Canceling the already unethical and arbitrary ‘14-day rule’ degrades science and opens the door to horrific ‘baby in a bottle’ experiments with no limits.”

The ISSCR guidelines carry particular weight in the United States, in part because Congress, through a 25-year-old policy tied to the Health and Human Services Department’s funding, has prohibited federal dollars from going to effectively all research using human embryos. But that also means that health agencies like the National Institutes of Health can’t impose policies on any such research that it would otherwise fund.

“There’s sort of a vacuum,” Johnston said.

U.S. research institutions often look to the ISSCR guidelines for what should be allowed. With the updated guidelines, it’s possible that researchers could secure private funding, engage in some sort of public discussion about the work they want to pursue, and receive ethical approval from their institutions to move forward with an experiment in which they grow embryos past 14 days.

In a statement, the NIH said, “ISSCR has long been a thoughtful voice for the international stem cell research community, and we will certainly think carefully about their report.”

The ISSCR guidelines also touch on a range of other hot-button research topics that are challenging both technical and ethical frontiers. Among them are embryo models (transforming stem cells into embryo-like structures), chimeras (animals or animal embryos that have some cells from another species, including humans), and organoids (small-scale simulacrums of organs, including brains). Scientists are making technical breakthroughs at a rapid pace and the guidelines aim to both reflect where science stands now and anticipate what kind of progress could occur in the next few years.

The recommendations outline what kind of research falls into different categories, from experiments that can go on without much regulation to those that require permission and oversight to those that should not be pursued, because they’re currently unsafe, scientifically unmerited, or unethical. Experiments that are not allowed under the guidelines include making babies from early embryos that have had their DNA edited (which is listed as currently unsafe), and both trying to start a pregnancy with an embryo model made from human stem cells and transferring a human-animal chimeric embryo into the uterus of a person or ape (which are deemed ethically concerning or lacking scientific rationale).

The guidelines involved an array of experts — lawyers and ethicists in addition to scientists — from 14 countries.

“Some find these scientific advances scary and uncomfortable,” Lovell-Badge wrote in a commentary accompanying the guidelines. “They raise complicated questions around ethics, beliefs, norms, and values. Most scientists want clear boundaries delineating which experiments are acceptable, both legally and to society. And the public wants reassurance.”