Federico Germani, Nikola Biller-Andorno
The recent development of human blastoids calls for a bioethical discussion about the moral status of human embryo models. Here we highlight key ethical challenges and discuss differences between embryo models and embryos in the making, suggesting that limits to the use of embryo models in research should be set considering second order potentiality, which is the potential for a model to become very similar to what is intended to model. These limits will need to define when and why a human embryo model can be developed and used for research.
In two recent studies, researchers formed blastocyst-like structures starting from cultured cells, and called them human blastoids, given their strong resemblance to blastocysts. The authors showed that blastoids were similar in size to blastocysts, with a similar number of cells and a structure containing a cavity and an epiblast-like cluster of cells. Blastoid-derived stem cells were shown to have the ability to differentiate into various cellular lineages once transplanted into mouse blastocysts to form chimeras. Some of the blastoids could attach to culture dishes used to mimic the implantation of blastocysts in the uterus and developed structures that are typically present in post-implantation embryos. With a conceptually similar process, researchers have been able to form human gastruloids, which are embryonic-like structures resembling human gastrulae.
The quick advance of this research field and the increasing requests to revisit existing regulations in embryo research call for an ethical clarification regarding the moral status of a human embryo model. The current uncertainty is reflected in the terminology: Is a human embryo model a “human cell clump”, as Ian Sample referred to it for the Guardian in a recent article, or does it potentially qualify as a human embryo? What are morally relevant differences between human embryos and embryo models, and will the differences between them be maintained with further research and advances in the field? Addressing these questions will be important for understanding how existing regulations for embryo research apply to embryo models and what new regulations might be appropriate.
In an attempt to solve these issues, new International Society for Stem Cell Research (ISSCR) guidelines were recently released, suggesting the study of human embryos beyond current limitations could be discussed on an individual basis and scrutinised by independent ethics review committees. In line with this, the guidelines specify embryo models should be used “only after review and approval through a specialized scientific and ethics review process”, without specifying time limits for their use in research.
Calls advising not to consider restrictions for research with human embryo models rest on two main considerations: (1) currently, embryo models do not have the potential to develop into a fetus, and thus should not be considered as similar to human embryos from a moral standpoint; (2) biologically, human embryos models differ considerably from embryos. For example, transcriptomic profiles of blastoids can be clearly distinguished from transcriptomic signatures of actual embryos.
Even though human embryo models do not currently have the potential to develope into a fully developed human being, it is to be expected that future research will generate embryo models that will be increasingly similar to embryos. This issue could be referred to as “second-order potentiality” (or “potential potentiality”), to account for the possibility that embryo models could acquire the potential to develop into full human beings with further technological advancements. There exists a trade-off between models and what models are intended to model: the more embryo models differ from real embryos, the less the ethical concerns, but also the less revealing research with these models is for human developmental biology and its implications for human health. On the contrary, the closer embryo models’ biology get to an embryo’s biology, the more ethical concerns it raises and the more answers it will produce with implications for human health. The situation is fluid and changes with every piece of research that brings models closer to actual embryos.
We therefore urgently need to define the thresholds we should not surpass with such model systems, including restrictions on the use of partially human, chimeric embryos. These thresholds will importantly depend on the potential to form a viable organism. Research with embryo models, for instance, might be allowed with no restriction if embryo models do not develop structures that could allow for sentience or pain perception and could not develop into a full human being. At the current stage, this can be easily prevented by ensuring embryo models are not transplanted to a uterus, as also specified by ISSCR guidelines. Assuming we may become able to allow embryo models to develop in uterine-like structure in vitro, another technical solution to push research beyond the current limitations could be to engineer them so that their development is interrupted at a specific, pre-defined and agreed stage.
It may well be that embryo models will alleviate some of the moral tension around human embryo research and become a preferred option, similar to the effect that induced pluripotent stem cells (iPCs) had on the discussion around human embryonic stem cell research. Therefore, if embryo models were engineered such that they (1) were and will remain clearly distinct from human embryos, and (2) could not develop into a full human being (including the capacity of sentience), there would be good reasons to negotiate a moral and policy framework specifically governing the use of human embryo models in research.
The 14-day rule chosen by some countries to restrict embryo research was the result of the mediation between a multiplicity of diverging views on the moral status of human embryos in relation to their developmental status. In line with this, calls to set limits on research with embryo models should involve collective moral deliberation. The new ISSCR guidelines, despite calling for a public role in the discussion, were not drafted following a discussion involving the public. Whereas a global public consultation may indeed be beyond the means and responsibilities of an international society of researchers, this does not mean such a step should be forgone. Defining at which stage a human embryo should be granted the moral status of a human being will always be subject to debate and considerations based on different and partly incompatible worldviews. Similarly, this debate should include embryo models, too. Thus, debate on this topic needs to account for the existing pluralism of cultural and ethical values.
Although finding a public consensus on the moral permissibility of research with human embryo models is unlikely, a shared understanding of common no-go zones may emerge from this discussion. Not posing any time limits at all, as the new ISSCR guidelines suggest, seems a risky approach that relies very heavily on a robust ethics review and on evolving clarity on how benefits and harms are to be weighed. We therefore invite those who propose that no limits should be set for research with embryo models to provide arguments for how we can ensure embryo models will continue to differ from embryos in a morally relevant way, even though further research is likely to increasingly close the gap between the model and the embryo. If such morally relevant differences persisted, and if a reasonable agreement between different views emerged, the use of embryo models should be always preferred to the use of embryos.
Federico Germani, Institute of Biomedical Ethics and History of Medicine (IBME), University of Zurich, Zürich, Switzerland
Nikola Biller-Andorno, Institute of Biomedical Ethics and History of Medicine (IBME), University of Zurich, Zürich, Switzerland