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The entelechy test: embryos and simbryos

29 March 2021
By Julian Hitchcock
Counsel for Bristows LLP
Appeared in BioNews 1089

Over two weeks in March, four teams reported the self-assembly from stem cells of structures resembling human embryos. Following two preprints reporting similar results, Nature published peer-reviewed papers confirming that human blastocyst-like structures (dubbed 'blastoids') could assemble themselves from human pluripotent stem cells (hPSCs) or induced pluripotent stem (iPS) cells

The use of such 'blastoids' could avoid the ethically-problematic demand for, and limited supply of, human eggs and embryos, enabling more researchers to study the underpinnings of infertility and congenital disease in greater detail. These could also perhaps provide sources of more 'natural' cell lines for regenerative medicine. However, this capacity would be limited if the entities were deemed to be human embryos in law.

Blastoids are just one type of mammalian embryo-like structure that could be produced, a 2019 review showed. For brevity, I'll put these various structures and any more developed versions into a class called 'simbryos'.  All these simbryos are objectively distinguishable from human embryos.

In the USA, the absence of federal human embryo research laws has lent weight to the guidelines of the youthful International Society for Stem Cell Research (ISSCR). These include a recommended prohibition on the in vitro culture of simbryos which 'might manifest organismal form, integrated organ system development, autonomous developmental capacity, or full organismal potential as defined by expert review', on the basis of an alleged: 'broad international consensus that such experiments lack a compelling scientific rationale, raise substantial ethical concerns, and/or are illegal in many jurisdictions'.

Whatever our ethical assessments, the embryo/simbryo distinction has consequences under existing laws. Would jurisdictions that forbid embryo research also forbid simbryo research? Would those that permit licensed embryo research require licences to conduct simbryo research? Does the prohibition on cloning human embryos apply to human simbryos? Does the 14-day limit on culturing human embryos apply to human simbryos? Can inventions which exploit iPS cell-derived human simbryos be patented? Would funding restrictions on human embryo research apply to human simbryo research? Plainly, definitions are going to matter.

While embryological inquiry may predate Aristotle, with terms for embryo ('garbha') blastula, gastrula and neurula, legal definitions are a recent phenomenon. The UK's Human Fertilisation and Embryology Act 1990 (HFE Act) originally defined 'embryo' as the product of fertilisation, an assumption dented by a well-known sheep. In 2008, following a ruling by the House of Lords that the literal meaning of the term should be construed to reflect the likely intentions of lawmakers, the definition was amended. Now, in a masterpiece of circularity, Parliament has provided that 'embryo means a live human embryo' and 'references to an embryo include an egg that is in the process of fertilisation or is undergoing any other process capable of resulting in an embryo'.

Nevertheless, English and European law is not silent on the meaning of the term. UK and EU patent law deriving from the Biotechnology Directive and International Stem Cell Case provides that a synthetic cellular entity does not constitute a 'human embryo' if, 'in the light of current scientific knowledge, it does not, in itself, have the inherent capacity of developing into a human being'. The 'mere fact that that organism commences a process of development is not sufficient for it to be regarded as a 'human embryo'. In other words, to be an 'embryo' for purposes of patent law, a simbryo must not only have the potential for continued development, but for development 'into a human being'. Technically, a mere zygote is a human being (albeit not a person), so the legal test appears to rest upon a simbryo's potential to develop full-grown human form and function: Aristotle might have seen this as a sort of 'entelechy test'. 

Whether or not a given simbryo type does have such potential is, in patent law, a matter of 'current scientific knowledge'; and current scientific knowledge suggests that none do. When asked by Nature whether a human blastoid (the most embryo-like of simbryos) is exactly equivalent to a human embryo, Dr Aryeh Warmflash, a stem cell biologist who was not involved in the March simbryo papers told Nature, 'Almost certainly not'. That is certainly the prevailing opinion.

Should we test that opinion empirically? Another ISSCR-recommended prohibition, on 'Experiments whereby human embryos or organised cellular structures that might manifest human organismal potential are gestated ex utero or in any non-human animal uterus', loomed larger when, in the same fortnight as the human simbryo papers, other researchers reported that mouse embryos could be cultured ex utero to the point of organogenesis. We could certainly put a mouse simbryo to the same test, but using human simbryos might breach the guidelines, if not the actual law in the country where the experiments took place. The likelihood is that onward development would swiftly dwindle, but if it were otherwise, the legal effect would be to broaden the definition of 'embryo' (as a function of scientific knowledge) to include such simbryos.

Because the term 'human embryo' is defined according to whether or not the simbryo could develop into a human (the aforementioned 'entelechy test'), IPS cell derived human simbryos would be exempt from restrictions on patenting that are applicable to inventions derived from human embryos. However, taken as a principle of English law, the entelechy test naturally informs the meaning of 'embryo' under the HFE Act. If a simbryo is not an embryo, no licence is required to use it in research, and it can be cultured beyond 14 days, as well as cloned. On the other hand, if an entity emerged that did pass the 'entelechy test', it would be deemed to be an 'embryo' and therefore subject to existing restrictions. The HFEA could helpfully produce directions, on a review of the 'current scientific knowledge', about those simbryo types deemed capable of passing the entelechy test. Those that do not fall under the HFE Act are, however, by no means automatically exempt from standards of best practice, including modes of ethical oversight, but the same may be said of research into certain organoids.

SOURCES & REFERENCES
Guidelines for stem cell research and clinical translation
International Society for Stem Cell Research |  16 May 2016
Lab-grown structures mimic human embryo's earliest stage yet
Nature |  17 March 2021
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