The Emergence of Embryo Models in Research: Ethical Considerations

Melissa Lopes & Robert Truog

The names are many: embryoids, synthetic embryos, artificial embryos, embryo-like entities, but the central issues remain the same. Should we grow replicas of embryos in a dish? And if so, how exact is too exact? Last month, Yue Shao of the University of Michigan, and a team of researchers reported the self-organization of human pluripotent stem cells into an amniotic sac embryoid that appeared to mimic a human embryo ¹. In an ethics statement accompanying the article, the researchers clarified that the embryoid model did not have “human organismal form or potential,” as it was missing key elements of a naturally occurring embryo. Earlier this year, Magdalena Zernicka-Goetz , a developmental biologist at the University of Cambridge, led the work that resulted in the creation of an artificial mouse embryo, an achievement they hope to replicate with human cells ² . Last year, the Harvard Embryonic Stem Cell Research Oversight Committee convened a symposium of national and international bioethicists, policy analysts and scientists to examine the 14 Day Rule, an ethical guideline applicable to developing embryos in a dish, in the context of emerging technologies such as the creation of synthetic embryos. A recent MIT Technology Review article may have summed it up best: “Artificial Human Embryos are Coming and No One Knows How to Handle Them .” ³

So, how should we think about these emerging entities that develop outside the natural process of embryogenesis? Generally, when ethical oversight committees are reviewing emerging research technologies that raise ethical concerns, they begin with the why and the how. The question of why is in two parts: Why is this scientific inquiry necessary and why is this approach necessary? Would another pathway answer the scientific questions while avoiding the ethical concerns? There appears to be a number of reasons for the first part of the why here. The replicating of a human embryo in a dish provides insight into what Magdalena Zernicka Goetz has likened to “a developmental black box ,” shedding light on the very early stages of human development that are inaccessible to observation and therefore shrouded in mystery ⁴ . What may be learned from such study could prove useful, if not invaluable, to the broader understanding of pregnancy and its complications, human development, and perhaps even the early origins of human disease.

As to the second part of the why, the creation of embryo models for use in research may be viewed as far preferable to studying actual embryos in a dish. Modeling human form and function has long been part and parcel of scientific inquiry. Models have been used historically as a tool by researchers and clinicians to test theories out and perfect methodologies before moving to actual research participants and/or patients. Embryo models developed through application of engineering techniques and the use of human pluripotent stem cells may be seen as a next iteration of such modeling to better approximate human form and function.

Beyond the why, there arises the need to address the thornier issues of how. How should research involving embryo models be ethically undertaken? Do we map the existing ethical framework applicable to naturally occurring embryos onto these new entities? Both the Shao and Zernicka Goetz labs appeared to instinctively apply the 14 Day Rule to these embryo models. This presumes that the same ethical framework that applies to embryos may apply to these models. However, it is unclear whether embryos created artificially should be imbued with the same moral status as naturally occurring embryos. A better approach may be to tie ethical guidance surrounding such models to what is known or knowable about the developmental capacity of the entity and other characteristics that may confer moral status.

If another ethical framework applies, what informs our decision-making? Does it turn on the exactitude of such models? Does exactitude in replicating a human embryo suggest something about the developmental capacity or the moral status of the entity? Should a structurally and functionally complete embryo model be imbued with a higher moral status and treated differently than a structurally and functionally incomplete model? As a general proposition, one could imagine that the more exact the replica or the model, the more useful it is for study and understanding. Exactitude in modeling is certainly the goal of some of the researchers working this area. The MIT article cites Ali Brivanlou, a leading embryologist, as stating that his “goal is to maximize the modeling, in vitro, of human development,” and thus he “would like to be as accurate as possible and as complete as possible.” Others argue that such exactitude leads to moral ambiguity and therefore should be avoided. They believe that “purposefully incomplete ” embryo models do not raise the ethical concerns of more biologically complete human embryo models, and the use of such incomplete models may eliminate the need for the creation and use of exact models. Without understanding more about these emerging entities, however, it is unclear where the line would be drawn to ensure the model is “purposefully incomplete” and whether such line drawing is even ethically relevant. ⁵ Where on the continuum of exactitude do ethical concerns arise and how do we tie measures of exactitude to what we regard as morally relevant features?

Another potential approach would be to frame the ethical analysis for this work in terms of the proposed goals or uses of such models. For instance, if the goal is to model early development and not to implant the embryo into a uterus for further development, we might conclude that it is ethically irrelevant whether the embryo model is considered structurally and functionally complete.

Our scientific understanding of early embryo development is moving forward at a very rapid pace, and the recent literature shows that those engaged in this research have strikingly different views about what should count as an ethical stop sign and where it should be placed. Further deliberation is urgently needed to establish common ground around the ethical guideposts for this exciting new area of discovery.

References

1. Shao, Y., Taniguchi, K., Townshend, R.F., Miki, T.,Gumucio, D.L., and Fu, J. (2017). Nat. Comm. 8, 208.
2. Harrison, S.E., Sozen, B., Christodoulou, N., Kyprianou, C., and Zernicka-Goetz, M., Science 356, eaal1810 (2017)
3. Regalado, A., Artificial Human Embryos are Coming and No One Knows How to Handle Them, MIT Technology Review, September 19, 2017.
4. Hannah Devlin, “Cambridge scientists create first self-developing embryo from stem cells,” The Guardian, 2 March 2017.
5. Hyun, I. Engineering Ethics and Self-Organizing Models of Human Development: Opportunities and Challenges, Cell Stem Cell 21, December 7, 2017.