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Monkey human embryo chimera Cell paper: exciting, ethically complex direction

A new Cell paper from an international team led by Juan Carlos Izpisua Belmonte pushes human embryo chimera embryo research further than ever before. It is both exciting work and raises many complex bioethics questions at the same time.

Human embryo chimera.
Example of a human embryo chimera made by putting human stem cells into a monkey embryo. Salk Institute image.

What is a human embryo chimera?

By way of background, chimeric human embryos contain a mixture of human cells and those of other animals. They have the potential to shed new light on early human development. Some proponents of this research also argue that this work could ultimately lead to production of much-needed human organs made within the context of any otherwise non-human embryo in the future.

For instance, you might be able to get a human kidney grown in an embryo that is otherwise entirely a pig or monkey embryo. Then you could transplant that into a human patient who has been waiting for a kidney transplant. Today, many patients waiting for organ transplants do not make it long enough to get an organ. It’s a huge, serious problem. Can human chimeric embryo work help? Frankly, I’m skeptical, but it’s not impossible.

Overview of the new chimera paper

This new paper provides new insights into how human stem cells behave in chimeras.

They report making embryos that are mixtures of macaque and human cells, which are relatively closely related species compared to much of the past chimeric embryo work. This closeness in evolution between human and monkey embryonic cells may also explain why the levels of chimerism achieved were relatively higher than in many previous reports.

The special nature of the one human pluripotent stem cell line that was used likely also played a key role. Past work such as this recent paper found much less chimeric potential of human stem cells in this kind of context.

Human and monkey cells do a developmental dance, influencing each other

What I found most interesting about this paper is the data on the interspecies crosstalk between the human and monkey cells in the developing chimeras. The dynamic interactions between the different cells illustrate how complex chimeras really are not just at the cellular level, but also the molecular level. These different cells are literally reaching out and grabbing each other, and talking to each other with molecules like growth factors.

In that sense, in thinking about human chimeric embryos one cannot strictly speaking just say “oh, these are 10% human cells”, for instance. Those few human cells are changing the other cells in the embryo, in this case the monkey cells. This makes chimera work more interesting, but also more complex.

There are some limitations to the study too. For instance it did not examine the epigenetic state of the human embryonic cells within the chimeras. In addition, the team only studied one main human stem cell line. What they did achieve is remarkable given the technical complexity of this study.

Is it realistic to think this could lead to organ transplants in the future?

However, I’m not sure about the future clinical implications here. Practically speaking with the percent of human cells still in the high single digits, it’s a long way to imagining a future where entirely human organs could be harvested for transplant from chimeras.

There are other technical hurdles as well such as the presence of animal antigens in the human organ taken from a chimera.

Thorny bioethical considerations of human embryo chimera work

At a bioethics level, should chimeric organ harvesting should be a permissible path in any case even if technically doable?

It’s complicated.

For instance, if you can make an entirely human liver in a human-monkey chimera and that chimera also has 5% or 10% human cells in its brain, is that ethically okay? What about 20%?

What if it is a human-pig or human-sheep chimera?

The paper also raises other challenging bioethical questions and considerations moving forward. As chimeric embryo technology likely advances further in coming years yielding even higher rates of human cells within those chimeras, should the 14-day rule on human embryo growth start to apply to the chimeras too? For example, what if a chimera is 1/3 or 1/2 human? Should there be a defined timepoint or percentage of human cells in a chimera at which special guidelines come into play?

If the 14-day rule is dropped entirely, at what point of embryo development should chimeric embryos containing human cells generally be stopped?

Avoiding minefields

These kinds of questions are urgent and need serious discussion right now, aiming for some broad consensus.

With new developments in this area human embryo research needs concrete guidelines that take into consideration the new technologies. Oversight is needed.

The report of entirely lab-produced human embryo models that are remarkably similar to real human embryos raises the stakes. Similarly, the growth of mouse embryos in vials in the lab deep much later into gestation than ever before resonates here. Some are already talking about growing human embryos for 5-6 weeks in the lab. It is too soon for that.

New guidelines should concretely address such ideas.

Even if those guidelines are temporary or not ideal in some ways, they are needed.

We don’t want the stem cell and human embryo research fields to have a He Jiankui kind of moment.

In my view leaving human embryo research guidelines up to every individual researcher or institutional ethics board is likely to cause serious problems.

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