It’s easy to obey a rule when you don’t have the means to break it. For decades, many countries have permitted human embryos to be studied in the laboratory only up to 14 days after their creation by in vitro fertilization. But—as far as anyone knows—no researcher has ever come close to the limit. The point of implantation, when the embryo attaches to the uterus about 7 days after fertilization, has been an almost insurmountable barrier for researchers culturing human embryos.
Now, two teams report growing human embryos about a week past that point. Beyond opening a new window on human biology, such work could help explain early miscarriages caused by implantation gone awry. As a result, some scientists and bioethicists contend that it’s time to revisit the so-called 14-day rule. But that won’t be welcomed by those who consider the rule to have a firm moral grounding—or by those who oppose any research on human embryos.
“We’re here sooner than we thought,” says Insoo Hyun, a bioethicist at the School of Medicine at Case Western Reserve University in Cleveland, Ohio, and co-author of a commentary in Nature this week calling for a reassessment of the 14-day rule. About 4 years ago, a group led by Magdalena Zernicka-Goetz, a developmental biologist at the University of Cambridge in the United Kingdom, first reported culturing mouse embryos past the implantation stage, and it has been improving its methods ever since.
The latest tricks also work with human embryos, Zernicka-Goetz’s team and a collaborating group led by Ali Brivanlou, a stem cell biologist at The Rockefeller University in New York City, report this week in Nature and in Nature Cell Biology. Both groups initially removed each embryo’s outer membrane and grew the embryos in two different types of culture media, the first containing fetal bovine serum. Together, that allowed embryos to “implant” onto a plastic substrate, which was transparent, enabling the researchers to take images of what followed.
After normal implantation, part of a mammalian embryo reorganizes itself into what will become the placenta and the yolk sac. This is also the stage at which many developmental defects originate. The lab-grown human embryos hit all of the bases expected of one implanted on a uterus. They developed the right shape and generated various cell types, even though they lacked the structure and nutrition that maternal tissues would normally supply. As Harvard University stem cell researcher George Daley puts it, “The embryo is somewhat on autopilot.”
The teams halted their studies when the embryos were 14 or 13 days past fertilization, as U.K. laws require and several U.S. guidelines recommend. But that was enough time for them to see that mouse embryos are imperfect models for human ones. For example, the cells that develop into the fetus and the yolk sac diverge later in human embryos. “You have to study the human embryo to understand the human embryo,” Zernicka-Goetz says.
The 14-day rule prevents researchers from exploring the unique features of human embryos any later in development. But the rule also played a crucial part in making lab studies of embryos acceptable in the first place. Proposed in 1979 by what would later become the U.S. Department of Health and Human Services, it is now enshrined in law in 12 countries and in various guidelines in another five. The rule is pegged to the time at which human embryos develop the “primitive streak”—an easily identifiable group of cells that appears when embryos can no longer fuse or split. That, in the eyes of some religious bioethicists, marks the threshold at which an embryo is a distinct human.
Now that culture methods have finally caught up to the ethics of the 14-day rule, Hyun and his commentary co-authors say it’s time to start a new conversation about whether there is scientific need, as well as a broader consensus, for lengthening the time human embryos can be grown in the lab. The 14-day rule was conceived as a policy tool to enable research, he says. “It shouldn’t be thought of as a hard and fast moral pronouncement.”
Others disagree. “Of course rules can always be reconsidered,” says Marcy Darnovsky, executive director of the Center for Genetics and Society, an advocacy organization in Berkeley, California, that has been critical of human embryo research and modification. “But it was very much intended to be a bright line.” Still others think the 14-day rule should never have been enacted at all—like Reverend Tadeusz Pacholczyk, director of education for The National Catholic Bioethics Center in Philadelphia, Pennsylvania, who calls the rule a form of “lip service to the moral status of the human embryo.”
By culturing human embryos beyond 14 days, Daley says, researchers could address “deeply compelling questions,” such as how the nervous system arises. But he and others who believe there may be value in revisiting the 14-day threshold stress that any alteration to it will require extensive discussion with policymakers and the public. “It was first derived and built upon trust and public dialogue,” Hyun says. “If you even entertain changing it, it needs to involve a wide group of stakeholders.”