The 14 day rule might need to be readdressed in the near future to account for synthetic human entities with embryo-like features (SHEEFs) according to an article written by John Aach, Jeantine Lunshof, Eswar Iyer, and George M. Church. The article was published in eLife, and argues that simply adjusting the 14 day rule as it stands will not solve the fact that the underlying framework of the rule does not adequately describe SHEEFs.

The 14 day rule was first formulated in 1979 when the US Ethics Advisory Board outlined guidelines for the creation and usage of human embryos in scientific research, based on the ethical complications. The basic premise of the ruling was that an embryo could not be maintained in vitro for longer than 14 days, the point at which the primitive streak (PS) appears in development. While a contentious issue, with some people arguing that ‘life’ and therefore moral rights begin at conception, the rule has since been widely adopted internationally. In the past, the ruling has been assured because of the difficulties researchers have had in maintaining an embryo for so long without a host; even today, the longest confirmed period an embryo has been sustained is 13 days.

However, the legality and ethics of maintaining SHEEFs is not so clear cut. SHEEFs were first successfully created in 2016 (after similar entities were created with mice two years prior) using human pluripotent stem cells (hPSCs). Previous work had shown that PSCs were capable of differentiating into other cells within the body, but they had not been recognised as being ‘totipotent’; that is, they had not been shown to be capable of self-organising and executing a ‘body plan’ to create a new organism. However, multiple papers published in 2016 were able to show that hPSCs were capable of mimicking the early stages of pro-amnionic cavity development even in the absence of maternal tissues. These entities could not develop later epiblastic features and so could not be considered true embryos, but the similarities between them are sufficient to call ethics into question.

As SHEEFs are not embryos, the 14 day rule does not apply to them. This is actually one of their most appealing factors to researchers, allowing them to investigate stages of development not possible with embryos because of the rule. However, it has been observed by some that with further development and research, SHEEFs may eventually become sufficiently developed to be considered as ‘synthetic embryos’. Should this be the case, they may need to be regulated with the same rules as true embryos.

There has been some interaction among the regulation community on the matter already, but nothing has been confirmed. While many researchers appear to accept the idea of regulation for SHEEFs, there is also concern that they will lose the opportunity to examine later stage development that SHEEFs have allowed them. As a result, there is currently an on-going discussion about whether the 14 day rule itself needs to be revised to accommodate more recent developments in embryonic studies.

Church et al. argue that this revision would be insufficient to account for SHEEFs.

“Through their enhanced engineerability, SHEEFs offer a possible way of escaping the dilemma above by enabling generation of human entities that recapitulate aspects of embryonic development potentially very precisely, but that are different enough from non-synthetic embryos to justify their exemption from research limits on such embryos,” the authors wrote. “But to achieve this will require deep consideration of the conditions under which SHEEFs might develop features that are morally concerning, and a framework that allows research limits to be specified for them.”

They start by discussing the potential synthetic biology has in adapting SHEEFs for research purposes. While we might be able to make them more similar to non-synthetic embryos in time, this would also give us the ability to make them less like a true embryo to study different aspects of biology that might not be possible with non-synthetic tissue. To simply consider all SHEEFs as true embryos, we would be treating these novel structures that are very unlike embryos with the same ethical rights as natural organisms.

The article continues by considering the way SHEEFs could be engineered to ‘bypass’ selected stages of development. One of the main considerations of the 14 day rule was to prevent an embryo from feeling pain or developing sentience during the research process, factors which would begin with the neurulation that immediately follows the appearance of the PS. With SHEEFs, the development process would not necessarily be so linear.

“A research limit based on canonical development that works in embryos to avoid the concerning situations might be ineffective for SHEEFs because they need not develop canonically,” the authors wrote. “For instance, through the methods described above, researchers could soon find ways to generate SHEEFs that proceed through neurulation without having first gone through a PS.”

Because of the possibility of non-linear development, the central concept of the 14 day rule – that the embryo should not be developed enough to feel pain – falls apart. Using SHEEFs, it could be possible to have an organism that is 20 days old which has not undergone neurulation, or one which is 5 days old which has.

The authors argue that because of the uncertainty that SHEEF development presents, any guidelines to restrict them should not focus on the stages of canonical embryogenesis. Instead, they believe that they should be based as directly as possible on the development and appearance of the features and capacities we associate with the emergence of moral status, such as neurulation.

“On our proposal, the research limit would be set at the first entry into the condition that directly raises moral concern—in this case, the appearance of neural substrates and functionality required for the experience of pain—rather than at a canonical preemptive stage (the PS) that, as noted earlier, is not seen as intrinsically morally significant,” they wrote.

While a logical concept, the proposal then raises the question of what stages of development constitute morally significant events in embryos. When considering natural embryos, it is only necessary to consider the earliest point at which moral status can be assigned – the emergence of the primitive streak. For this proposal to be effective, any and all stages that denote consciousness will need to be identified and agreed upon. The difficulties seen in creating the initial draft of the 14 day rule are testament to the fact that this is not a decision which will easily achieve unanimous consensus.

The authors acknowledge that this is a discussion that needs to be spread across the genomics community as a whole. They conclude the piece by saying, “It is our hope that the analysis and proposals we have presented in this article will encourage these and like-positioned bodies to discuss the ethical issues raised by SHEEFs, both individually and collectively, and also serve as an initial concept for addressing them that they can debate, develop, organize about, and ultimately undertake.”

SHEEFs are a prime example of science moving more quickly than legislation. Through ethical assessments of peer-reviewed journals and open discussions within the community, researchers frequently work to police themselves to ensure that research is both correct and morally sound. For now, SHEEFs continue to be managed by such protocols, but in the near future it is likely that firm legislation will need to be put into place.

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