Risks rise as ISSCR drops strict 14-day rule on human embryo growth in the lab

Something called the 14-day rule on growing human embryos in the lab helped keep a tough question in check for a long time: when is it ethically wrong or just practically unwise to continue growing a human embryo for research?

There is no good answer based on science or anything else.

ISSCR moves beyond strict 14-day rule

The 14-day rule on human embryo research has placed the limit on lab growth at 2 weeks for many years.

The rule, while arbitrary, has served its purpose of avoiding the minefield of researchers growing human embryos far too long. Until recent years, it wasn’t technically possible to grow embryos to 14-days or beyond, but today the technology makes that doable in some cases. It’s not a moot point.

Now the major global stem cell research organization the International Society for Stem Cell Research (ISSCR) has recommended dropping the strict 14-day rule without any clear replacement. Note that I am a long-time member of ISSCR, but was not involved in this decision.

I believe that entirely dropping the rule without a concrete replacement is a misstep. It has little clear upside and many risks.

In my view the ISSCR should have recommended a new temporary line not to be crossed of something like 21 days for a period of 3-5 years. It’s possible in part that they didn’t because there is no concrete reason that 21 days (or some other time point) should precisely be the cutoff.  How do you pick?

Has 14-day rule outlived its usefulness?

The rule was originally put in place, and in some countries codified into law, because during the earlier days of IVF people realized that embryos potentially could be grown in the lab for much longer periods.

What’s the risk to that?

With advances in technology, such longer-term in vitro grown embryos could become more like fetuses or be actual fetuses.

One can easily see how this gets scientifically, ethically and politically very thorny.

3 new Nature embryo research pubs this week bring the 14-day rule to forefront. It limits growth of human embryos in the lab to <=14 days. What do you think of the 14-day rule? Why? Should it apply to blastoids? #stemcells #embryos #scicomm #bioethics

— Paul Knoepfler (@pknoepfler) March 19, 2021

Where do you draw the line?

There is no particular reason why 14 days is more logical than say 15 or 16 or 21 or so on.

Also, pushing the limit and allowing human embryos to grow even a few more days or a week beyond the 14-day line could in the long run possibly provide helpful new insights into early human development, birth defects, and infertility.

However, now without a clear limit, I think it’s likely that some researchers are going to go too far utilizing new embryo culture technologies.

For instance, in a recent piece, Antonio Regalado reported on stem cell research by a team led by Jacob Hanna where mouse embryos could be grown to midgestation in the lab without a uterus. Midgestation means half-way through pregnancy. The mouse embryos are grown in vials with special nutrients and oxygenation conditions.

In principle it’s possible the same kind of thing with some tweaks could be done with human embryos in the lab or with human blastoids, synthetic human embryo-like structures covered here on The Niche by Ricki Lewis. Complicating this further is the fact that at some point it may be difficult to tell the difference between human blastoids and actual human embryos.

Dropping the 14-day rule opens the door to extremes

From Regalado’s piece on the extended mouse embryo growth in the lab (emphasis mine):

“This sets the stage for other species,” says Jacob Hanna, a developmental biologist at the Weizmann Institute of Science, who led the research team. “I hope that it will allow scientists to grow human embryos until week five.”

Even many proponents of lifting the 14-day rule are likely to get squeamish at the idea of growing human embryos in the lab for 5 weeks. There is good reason for concern here.

Such embryos start taking on more and more human-like characteristics as the weeks go by.

There are likely to be legislative overreactions when scientists continue to make extreme statements. Imagine if photos of lab-grown human fetuses emerge from research well beyond 14 days.

Hanna goes on to say:

“I do understand the difficulties. I understand. You are entering the domain of abortions,” says Hanna. However, he says he can rationalize such experiments because researchers already study five-day-old human embryos from IVF clinics, which are also destroyed in that process.

“So I would advocate growing it until day 40 and then disposing of it,” says Hanna. “Instead of getting tissue from abortions, let’s take a blastocyst and grow it.”

Growing human embryos for 5 days justifies growing them for 40 days? I don’t get it.

Result in scattershot oversight limits?

In my view, you need a clear line if going beyond 14 days like 21 days, even if it is arbitrary.

To be clear, ISSCR’s new recommendations don’t in any way advocate going beyond 14 days with human embryo growth in the lab. Also, many institutions and countries are likely to chose to stick with the 14-day limit despite the ISSCR lifting the strict limit, but others will go into uncharted territory.

From a piece by Kelly Servick in Science covering this development:

“The ISSCR has not abandoned the 14-day rule,” says Amander Clark, a stem cell biologist at the University of California, Los Angeles, and a member of the guideline task force. But the guidelines call for “national academies of science, academic societies, funders, and regulators to lead public conversations” about the “societal and ethical issues raised by allowing such research.”

Those groups will have to decide whether changing current restrictions is “really worth the political capital and the legal battles,” says cell biologist Martin Pera of the Jackson Laboratory. The 14-day limit “has given the public a good deal of reassurance around the boundaries of human embryo research,” he says, “but probably merits a careful reexamination.”

Realistically the practical effect of ISSCR’s relaxation of the rule is a much higher risk of major negative outcomes. I also don’t see a downside to something like a temporary 21-day limit.

Robin Lovell-Badge wrote in Nature about the rationale for dropping the strict 14-day limit. He also reiterates what Amander and Martin said about the institution-by-institution or country-by-country approach to limits:

“The ISSCR’s solution is to require review and approval of proposals to study embryos beyond 14 days. (The approval process, whether by institution or national body, varies by country; all should have representation from specialists and lay members.) Importantly, each proposal should be judged individually, on whether the research is justifiable in terms of the value of the information obtained, whether there are alternative ways to obtain the information and so on. The more embryos that would be used, or the longer they would be kept in culture, the higher the bar.”

He in addition says that the boundary-breaking embryo research should have public support. How would that work?

As I’ve written before, leaving the rules on how long human embryos should be grown up to potential dozens or scores of different institutions or committees seems too risky. Something is likely to go wrong.

More extreme ideas

Regalado’s article that I quoted earlier goes in another, somewhat unsettling direction. The idea of growing human embryos far enough to harvest organs for use as transplants (before discarding the remainder of the embryo) is invoked:

“There may be unexpected practical applications of growing human embryos in jars. William Hurlbut, a doctor and bioethicist at Stanford University, says the system suggests to him a way to obtain primitive organs, like liver or pancreas cells, from first-trimester human embryos, which could then be grown further and used in transplant medicine. Hanna agrees this is a potential direction for the technology.

“The scientific frontier is moving from molecules and test tubes to living organisms,” says Hurlbut. “I don’t think that organ harvesting is so far-fetched. It could eventually get there. But it’s very fraught, because one person’s boundary is not another person’s boundary.”

I can just see a hearing on such ideas and statements in the U.S. Congress or in many other countries. It would not go well.

Yes, it may be difficult to find scientific rationales for specific later timepoint restrictions, but there are good practical reasons to take a stepwise approach. In a Twitter poll I did most respondents favored leaving the 14-day rule place or having a specific later cutoff rather than just dropping the 14-day rule. Yes, it’s just a small social media poll, but it says something.

To me a new 21-day rule would make the most sense for a few years to see how work proceeds and learn from the experiences with the somewhat later embryos. Then revisit the limit.

Given the ISSCR decision, instead we’ll have to see how things proceed moving forward without a clear overall limit.