Impressions from Stem Cell Models in Embryology

At Keystone Symposia’s conference this year, the embryo model field discussed their next steps forward.

We at e184 are working towards what might be called the holy grail of reproductive medicine, artificial wombs. Artificial wombs constitute an enormously important goal, one that, once achieved, will empower parents around the world, granting new possibilities for forming families and shaping the future.

The road to artificial wombs is a long one, demanding broad scientific knowledge. One area of research that could make a difference is that of stem cell embryo models: assemblies of cells grown to imitate key stages of embryo development. As researchers pursue models of later stages, stem cell embryo models have deepened our understanding, giving us a clearer picture of what it takes to support an embryo as it becomes more complex. By generating embryo-like structures that can be used in the place of actual embryos, embryo models have allowed researchers to directly study development while reducing the need for human embryos.

The growing impact of stem cell embryo models is why we supported Keystone Symposia’s conference last week, Stem Cell Models in Embryology. It’s also why we sent Joseph Owen, the Director of our Program for Artificial Wombs. We wanted to take the pulse of the field, to get an impression both of where the science is, and what researchers feel are the next steps forward. In this post, we’ll talk about what we learned.

The State of the Field

As a research tool, embryo models continue to be powerful. The conference highlighted ways that embryo models have contributed to progress on questions in biology, particularly in the area of gastrulation, where the embryo makes its first steps towards developing the three germ layers necessary for body plan development.

On a more direct level, though, progress appears to be slowing. As blastoids and embryoids have improved, researchers have been able to replicate later and later stages of embryo development with higher and higher fidelity, and it was natural to wonder how far these models could go. Now, though, the field seems to have hit a wall. Blastoids model pre-implantation stages, and are limited in how well they can do beyond implantation. Embryoids, modeling post-implantation stages, can progress to gastrulation, but there is little progress beyond that stage. Organogenesis is still out of reach. Participants discussed why, with several explanations suggested but no common consensus.

While progress in embryo models has moved very little over the past five years, endometrial models have begun to make impressive strides. Three blockbuster results were published in the last month alone, in which several multi-lab teams independently managed to build a 3D co-culture system for embryo and endometrial models, recapitulating key developmental milestones. One group was even able to use their setup to test compounds with the potential to treat implantation failure.

The poster session featured encouraging work by young researchers. One impressive example was the poster, “The Regulation of Human Presomitic Mesoderm Differentiation by the Hippo Signaling Pathway”, which explores how presomitic mesoderm differentiates into what will become the vertebral column, regulated by the HIPPO pathway, and how abnormalities in this pathway could be responsible for severe congenital spine malformations. This work was one of those highlighted by attendees, and we selected it for our $500 Poster Award.

The State of the Conversation

Not all of the discussion at the meeting focused on scientific topics. Any field touching on something as fundamental as reproduction faces ethical questions. How to approach those questions was a major focus of the scientists in attendance, who are well aware that the field faces some tough decisions.

Some of the discussion centered on concrete ethical questions. While some stem cell models use induced pluripotent stem cells, somatic cells from adults reprogrammed into a pluripotent state, others use cell lines derived from human in vitro fertilized embryos and fetal placental cells from aborted tissue. Some members of the public have mixed feelings about this, but it’s not obvious that the alternative, destroying the material rather than using it for research to advance reproductive medicine, is actually an improvement.

For embryo models, a recurring question is how long, and how far, they should be allowed to develop, a topic where there is currently no real consensus. In essence, the question is that of how “realistic” embryo models should be, whether there ultimately ought to be firm dividing lines between them and natural human embryos. This depends crucially on how the models are used, and the motivations for building them. While it is intuitive as a scientist to be curious as to how close embryo models could be to the real thing, the question of whether there is scientific value in reaching a particular stage is one that needs to be actively asked.

There were questions even tougher than these, though. The hardest question is not about any individual ethical issue, but about public understanding of the field.

Fundamentally, the field is conflicted over how these conversations should be carried out. When does it make sense to involve stakeholders from outside the field, or to involve the general public in the conversation? On what timeline do ethical issues need to be addressed, and decisions reached?

There is a worry, a quite justified worry, that the political climate will make these conversations difficult. The field is vulnerable to regulatory shifts or public backlash. For the most part, researchers at the conference seemed pessimistic, expecting a future backlash and not expecting to be able to defuse it. For now, many seem to hope in something akin to security by obscurity, hoping that using the right terminology will forestall public opposition.

We, in turn, are skeptical that obscurity is the right path forward. We see parallels to the early history of IVF, when Robert Edwards had trouble finding funding due to his colleagues’ antagonism to his engagement with the public. Ultimately, the public formed their own opinions, and the fertility community was unprepared for the debate that followed.

Conclusions

There were worrying things about the overall mood at Stem Cell Models in Embryology. Instead of new advances in blastoids and embryoids, much of the discussion focused on comparing and hashing out traits of older models, establishing which existing models are more true to nature rather than working to advance them. This negative focus, coupled with pessimism about conversation with the public, make it natural for researchers to feel that the field is in a difficult place.

At the same time, we see a way forward. The surge of progress in endometrial models is enormously encouraging. It shows not only that science continues to march forward – but that it does so by exploring under-explored questions, in a way that will directly and clearly contribute to reproductive health. In particular, the work identifying compounds to treat implantation failure shows that the areas that are making progress are those with the most potential benefit, the areas that can help families find solutions they desperately want.

In that potential, we see the seeds of a modus vivendi. We can approach ethical questions not with obscurity and worry, but with an eye to the future. We can value research, and decide what we do or do not need to accomplish, on the basis of its potential benefits. And we can bring the public in, tentatively, on that basis: not as opponents whose backlash is inevitable, but as people who can be reassured if they see us focused on goals and values they share, on their survival and flourishing and their hand in the future.