Dropping Limits, Pushing Envelopes: Stem cell research organization wants fewer rules

Biopolitical Times
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An organization of scientists is recommending that limitations on several experimental and controversial research procedures – including heritable genome editing, artificial gametes, and growing human embryos in the lab – be loosened or rolled back. Some of the group’s recommendations, which it formulated without any public consultation, run counter to laws or regulations in numerous countries. Others would erase boundaries that are widely observed by scientists around the world.

On May 26, the International Society of Stem Cell Research released its newly revised guidelines on human embryo research. Its last revision was made in 2016. Several commentaries summarizing and explaining the changes were published in Stem Cell Reports, ISSCR’s official journal.

What’s new in the 2021 guidelines? Most widely noted is the lifting of the “14-day rule,” the longstanding prohibition against culturing human embryos in the lab for longer than two weeks. While this boundary was established decades ago, it was only a few years ago that researchers developed the technical ability to breach it. Scientific journals began publishing calls to remove the limit almost immediately.

The new guidelines recommend dropping this rule, but offer no suggestion about an upper limit on how long growing embryos for research should be allowed. They say only that such research should be reviewed by local institutions or jurisdictions on a case by case basis, and approved only after convincing the public of the value of such research.

 

Lifting the 14-day rule and reactions to it

The recommendation to drop the 14-day rule has received the most attention in media coverage of the new ISSCR guidelines.

Some articles treated the recommendations as the new law of the land, overlooking both that ISSCR is a membership organization of scientists rather than a governmental body, and that the 14-day rule is actual law in several countries. Almost none noted that the rule did not originate with the ISSCR.

NPR’s Rob Stein included Stanford bioethicist Hank Greely – who “otherwise praised the new guidelines” – reacting to the lack of a cutoff point in the new recommendations:

"If you don't have any end point, could you take embryos to 20 weeks? To 24 weeks? Is viability the only endpoint? Is viability even an endpoint?"

In response, Robin Lovell-Badge, a stem cell biologist who chaired the ISSCR committee that wrote the guidelines, dismissed any efforts to set a new limit as “difficult and a little pointless.”

In a blog post titled Risks rise as ISSCR drops strict 14-day rule on human embryo growth in the lab, UC Davis stem cell researcher Paul Knoepfler also expressed concern: “[W]ithout a clear limit, I think it’s likely that some researchers are going to go too far utilizing new embryo culture technologies.”

Arizona State University bioethicist Ben Hurlbut called the new guidelines “breathtakingly expansive,”and noted the rapid slide in scientific norms that is written into them:

"What was ethically unthinkable just a few years ago is getting treated as not only permissible but even unproblematic now. Under these guidelines an oversight committee can deliberate behind closed doors and quietly give its blessing to scientists to impregnate a monkey with a partly human embryo, or to see how far into human development scientists can grow artificially constructed synthetic human embryos in bottles."

In NatureRice University legal and policy scholar Kirstin Matthews noted the absence of public involvement in the revision process, despite the guidelines’ repeated statements about the importance of public support.

“[G]iven the public scrutiny of studies of human embryos, the ISSCR should have engaged the public while considering changes to the guidelines.”

 

Expansive and Permissive

Though not widely discussed in the coverage of the revised ISSCR guidelines, other changes are also significant. The new guidelines give significantly expanded attention to heritable genome editing and several other speculative research practices that were mentioned only briefly by the 2016 guidelines. These include the creation of certain kinds of human-animal chimeras (for example, as NPR put it, “allow[ing] a human-monkey embryo to develop inside a monkey's womb”), creating and culturing “embryo-like entities,” and so-called mitochondrial replacement techniques.

The ISSCR’s expanded focus on human genome editing is particularly puzzling since two other bodies are currently dedicated to that task, and since ISSCR’s recommendations are more or less the same as those published late last year by a committee convened by the US National Academies (NAS) and the UK Royal Society (RS). That group is controversially promoting a "translational pathway" to using heritable genome editing for human reproduction.

The new ISSCR guidelines also have new categories. Previous guidelines placed research practices into three categories, designating practices permissible after standard research review (Category 1), permissible after review by a specialized embryo research oversight process (2), or prohibited (3).

The revision splits the first and third categories in two, which effectively facilitates moving practices into more permissible zones. In fact, every one of the ISSCR’s changes from its earlier guidelines involves a category move toward a green light.

Heritable genome editing, for example, was previously in the prohibited category, but is now included under the new category designated “3A”:

Research activities currently not permitted. Research under this category should not be pursued at this time because the approaches are currently unsafe or raise unresolved ethical issues. There may be valid reasons for undertaking the research in the future, but this should not proceed until the safety and ethical issues are resolved. (emphasis added)

This is distinct from category 3B:

Prohibited research activities. Research under this category should not be pursued because of broad international consensus that such experiments lack a compelling scientific rationale or are widely considered to be unethical.

The new category 3A essentially says "not quite yet." It's hard to avoid the impression that it’s meant to be a temporary holding zone – a parking lot on the way to "ok." Moreover, if someone develops a rationale for “gestating human stem cell-based embryo models” (for instance), how long would it take to overcome the ethical concerns and move this from category 3B to 3A?

This impression is strengthened by the fact that several research practices, including experimentation on human embryos beyond 14 days and in vitro gametogenesis, are explicitly justified by their usefulness to developing heritable genome editing. A commentary accompanying the new guidelines says: “It follows that preclinical research to optimize methodologies and minimize potential harms associated with any heritable application is encouraged.”

Also relevant is that the “prohibited” category in ISSCR’s 2016 guidelines included experiments that “lack a compelling scientific rationale, raise substantial ethical concerns, and/or are illegal in many jurisdictions” (emphasis added). Had ISSCR maintained those criteria, several types of research now in more permissive categories would have to be solidly prohibited. Heritable genome editing, for example,  is prohibited in at least 70 countries. Many jurisdictions also have laws or policies that preclude so-called “mitochondrial replacement” and creating human-animal chimeras – not to mention culturing human embryos past 14 days.

 

Building “consensus” in an echo chamber

An article accompanying the release of the new ISSCR guidelines justifies its more permissive recommendations by invoking "building pressure" to change the 14-day rule. The source, nature, and extent of that pressure are not explained or identified except by references to an article written by a bioethicist who is a member of the ISSCR committee, and two others proclaiming that “the time has come” and advocating for “adapting the 14-day rule.” In other words, the "building pressure" seems to be coming  from the same institutions that house the scientists eager to do the research in question.

ISSCR’s explanation for moving heritable genome editing to a more permissive category is similar. In support of its claim that “there are  valid  reasons for pursuing” heritable genome editing, ISSCR points to the recent NAS/RS report, Heritable Human Genome Editing. But that report’s assertion remains deeply controversial. It is far from a settled fact.

ISSCR seems to be going out of its way to toe what can be seen as the party line on heritable genome editing. This is perhaps unsurprising since it's more or less the same party: Nearly all the NAS/RS and ISSCR authors and committee members are from the same professional circles, and most hold similar views; in fact there are numerous key overlapping personnel.

 

Paying lip service to public engagement

On the 14-day rule as well as on heritable genome editing, ISSCR says it wants public and international support and discussion. (Again, the National Academies / Royal Society committee says the same.) Unfortunately, it's hard to take these calls seriously, if only because after years of repeating this mantra, there has been little or no attention given to how such public conversations will be organized and supported – other than noting that public conversations should be led by scientists or scientific academies, and bemoaning, in Lovell-Badge’s words, “the cost and time involved.”

Some of the media coverage did dig into the implications of these vague calls for public engagement. At STAT, Andrew Joseph noted:

"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."

Further, the ISSCR guidelines and the NAS/RS report all but ignore the strikingly widespread policy agreements that already exist. On heritable genome editing, more than 70 countries have put legal prohibitions in place (see Human Germline and Heritable Genome Editing: The Global Policy Landscape). Surely those established policies represent public perspectives and international views that should be taken into account.

But ISSCR seems to hold its own pronouncements in much higher regard. In comparison with dozens of existing policies with the force of law, its advice is “more complicated but more valuable,” as Lovell-Badge states in his commentary in Nature:

"Blanket bans enshrined in law appeal in their simplicity, yet leave the public worse off, and are more vulnerable to dogma or instinct rather than evidence. Guidelines from international scientific societies can offer leadership in reassuring scientists and the public."

One risk of this approach for eager scientists was expressed by Manchester University embryologist Daniel Brison in comments to The Guardian:

"As scientists it is essential that we are seen not to be changing this rule simply because we now have the technical ability to work beyond 14 days, but instead because we can demonstrate that the public support the aims of the research… Without this clear public backing, we risk being accused of changing the rules out of expediency."

Maybe what it really comes down to is the sentiment expressed by David Baltimore in reference to proposals by fellow scientists for a moratorium on heritable genome editing – a point of view that is perhaps more widely shared:

"To make rules is probably not a good idea."