May 19, 2021

When does a human embryo model become the real thing & other tough questions for a new field

When does a human embryo model become the real thing & other tough questions for a new field


A human embryo model is a laboratory-produced collection of living cells that has some key things in common with real human embryos. They are made from pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells or iPS cells.

This research is both exciting and ethically complicated, raising some difficult questions.

When does a human embryo model become the real thing & other tough questions for a new field
A human pluripotent stem cell colony differentiated to have three germ layers of an early human embryo. Credit Mukul Tewary.

Embryo models

The technology to make human embryo models is speeding ahead very quickly. The last three years in particular have seen a major jump in this area and related human embryo research.

These models made from stem cells are also sometimes called by other names such as synthetic embryos or blastoids.

The goal of this research is to make models that are as close to real human embryos as possible so as to learn more about human development. Plus this work could have relevance for human diseases as well. For example, data from this research could be transformative for fertility treatments and preventative measures for developmental disorders.

The more similar an embryo model is to real embryos, the better it is as a model. Right? Keep this in mind as you read the rest of the post.

Even as human embryo models have become increasingly similar to the real thing, my sense is that the public is largely unaware of this research.

I would point readers to some very helpful articles I’ve listed in the References section below for more reading. These articles cover both the technology and the ethical/legal/societal considerations.

When does a human embryo model become the real thing & other tough questions for a new field
An ad in the NY Times for an ISSCR meeting on embryo models. Ad was posted on Twitter by Antonio Regalado.

When does a human embryo model essentially become an embryo?

At what point does a human embryo model become so “good” that it is indistinguishable from real human embryos?

Or to put it another way and more bluntly, when does the model become essentially the real thing?

Are we already basically there in some cases?

To really be sure, you’d have to implant the human embryo models in a surrogate mother, see how they develop, and even have the children be born to know if the “embryos” are generally functional like normal embryos. That would be unethical on many levels.

What would be the legal and ethical implications?

If human embryo models eventually are largely equivalent to human embryos, what would the implications and complications possibly be?

It’s not a trivial question.

If those doing human embryo modeling research accidentally make what seem to be real human embryos, then their research could be suddenly regulated in entirely new ways. In fact, their whole experiment may become non-compliant with various institutional regulations and maybe even federal or state laws. However, should we instead consider their research based on their intent rather than what they actually achieved?

In the U.S., what if the team used NIH funding for the work and then accidentally made actual human embryos, which they then “destroyed’ for analysis? Remember, the Dickey-Wicker amendment? It’s still a thing.  Similar scenarios could emerge in other countries.

Ready or not, here we come?

Beyond these practical issues, if the models are basically human embryos then their work becomes much more ethically complex. They and their institutions may not be ready for that.

In the bigger picture, we as a society might not be ready for a time when we can make human embryos from stem cells.

Even though making actual human embryos is not the goal of most of these researchers, it could happen. There could be other consequences of such developments. Could the technology inadvertently facilitate CRISPR’ing of human embryos for more He Jiankui-type efforts? Also, if you can make a human embryo model from stem cells like iPS cells that is a functional embryo, this could be a road to reproductive cloning.

Increased urgency

Some might say we aren’t close to the point of models being close to the real thing, but I’m not so sure. How do we sort this out to make the best decisions about the research and oversight?

More meetings like the ISSCR one advertised in the NYT online (above to Antonio Regalado) are going to be helpful.

The articles I’ve cited in this post at the bottom rightly convey a sense of urgency to have more discussions and debates. The Rivron, Pera, et al. piece has  both four questions and four solid recommendations that I’ve summarized here:

“First, we think that the intention of the research should be considered the key ethical criterion by regulators, rather than surrogate measures of the equivalence between the human embryo and a model

Second, we urge regulators to ban the use of stem-cell-based entities for reproductive purposes.

Third, in our view, current stem-cell models that are designed to replicate only a restricted part of development, or that form just a few anatomical structures, should not have the ethical status of embryos.

Finally, we urge any scientist using human stem cells for research to abide by existing guidelines, such as those of the ISSCR.”

Bringing additional urgency here is the recent development of ex-vivo growth of mouse embryos until mid-gestation by Jacob Hanna. At least as quoted by Antonio Regalado, Hanna seems enthusiastic about applying the prolonged embryo-growth-in-the-lab technology to either human embryos or human embryo models, if that were deemed OK by the field at large. I’m sure some other researchers feel the same way.

14-Day Rule and looking ahead

Another factor to consider here is that the 14-day rule on limiting the period of growth of human embryos in the lab might be effectively dropped without a replacement as soon as this week. I’m going to write more about that in a different post, but to me this possibility adds urgency to have more discussions over tough questions like those raised in this post and the articles I’ve cited.

If you are allowed to grow human embryos for a month or even much longer (which I think is very unwise), then you’re going to be given the OK to do it with human embryo models too. While human embryos from IVF procedures are difficult to procure, it may be possible to make tens of thousands of model human embryos. This scale without a time limit on growth gets thornier and riskier if you consider the models to be nearly the same as the real thing.

How do we constructively engage a diverse audience of people around the world including non-researchers about this area of research?

Also, we should keep in mind that opponents of stem cell research could seize on a few model images of what seem to be human embryos or fetuses to try to hurt the stem cell field overall.

References

  1. Debate ethics of embryo models from stem cells, Nicolas Rivron, Martin Pera, Janet Rossant, Alfonso Martinez Arias, Magdalena Zernicka-Goetz, Jianping Fu, Susanne van den Brink, Annelien Bredenoord, Wybo Dondorp, Guido de Wert, Insoo Hyun, Megan Munsie, Rosario Isasi. Nature, 2018. A good place to start with more reading.

  2. SnapShot: Embryo models. Rivron N, Fu J.Stem Cell Reports. 2021 May 11;16(5):1142-1142.e1. doi: 10.1016/j.stemcr.2021.04.012.PMID: 33979599. This is a nice visual snapshot of research in this area.
  3. All models are wrong, but some are useful: Establishing standards for stem cell-based embryo models. Posfai E, Lanner F, Mulas C, Leitch HG.Stem Cell Reports. 2021 May 11;16(5):1117-1141. doi: 10.1016/j.stemcr.2021.03.019.PMID: 33979598
  4. Biomedical and societal impacts of in vitro embryo models of mammalian development. Moris N, Alev C, Pera M, Martinez Arias A.Stem Cell Reports. 2021 May 11;16(5):1021-1030. doi: 10.1016/j.stemcr.2021.03.023.PMID: 33979591
  5. It takes a village to form embryo models. Rivron N, Fu J.Stem Cell Reports. 2021 May 11;16(5):1011-1013. doi: 10.1016/j.stemcr.2021.04.014.PMID: 33979590
  6. Modelling human embryogenesis: embryo-like structures spark ethical and policy debate, Human Repro Update, 2020.



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