July 15, 2020

The Niche

Knoepfler lab stem cell blog

Monkey-pig chimeras pub discouraging for similar human research toward organ transplants

pig-monkey chimera that was born but died
One of the two pig-monkey chimeras that was born but died.

Michael Le Page over at The New Scientist reports on a new paper describing the birth of monkey-piglet chimeras. Unlike most such primate embryo chimeras formed in research in the past, these were allowed to be born. A litter of ten from the new monkey-pig research, two of which were chimeras, all rather quickly died for unknown reasons.

Primate chimeras including humans have been much in the news lately. Back in August unpublished work on human-monkey chimeras was also discussed in the press. I am not sure if that’s been published since, but I haven’t seen it.

In the new study the rate of chimerism at the cellular level was relatively low. Only one monkey cell could be found out of thousands or tens of thousands of pig cells in various tissues of chimeras. The work is from Tang Hai at the State Key Laboratory of Stem Cell and Reproductive Biology in Beijing.

A lot of preclinical work in animals would be necessary first to have a foundation to responsibly try this with human pluripotent stem cells or reproductive cells directly toward the goal of making human organs in pigs via the chimeric embryo route.

In the bigger picture, I do wonder whether this kind of route will be workable because of a variety of technical issues such as no practical way to avoid the human organs being contaminated with loads of xeno-antigens from the host animal such as a pig. There have been attempts to CRISPR out some such antigens, but I’m skeptical that will universally do the trick any time soon. Maybe never. Depending on the nature and extent of that kind of contamination, it’s possible that even immunosuppression of patients getting such organs from chimeras may not be enough to make this approach workable.

You can see more concerns I had discussed in a post from 2017 about a paper on human-pig chimeric embryos here.

Also, so far, these kinds of chimeric embryos tend to have extremely low presence of human cells, light years away from an actual normal, functional human organ composed of billions of human cells all organized properly. You’d also want no animal cells mixed in the tissue of the final organ (e.g. no pig kidney cells mixed in the human kidney made inside a pig) and also what about animal blood circulating through the human organ? Many blood cells like macrophages take up residence in organ tissues.

Then there are ethical issues related to human chimeric embryo research too, which in my view need more discussion. They may not necessarily be deal-breakers, but they need some serious consideration for each study. For example, in any given chimera how many human cells end up in the brain? In the reproductive organs? How many human cells present in brain or gametes or in the chimera more generally would be “too many” and who decides? It’s really complicated.

Given the extremely low chimeric efficiency and the deaths of all the animals in the new study, I don’t see it as particularly encouraging for this line of work or the more ethically complicated work on human embryo chimeras.

For the kinds of reasons discussed above, one starts to wonder if other routes such as bioengineering of organs in vitro may be more promising from a translational perspective, but I can see the logic in continuing multiple routes for a while longer depending on how the preliminary data look. New advances may overcome some of the chimera technical challenges too.

Overall, this is a very challenging area of research technically speaking that also bears the weight of tough ethical considerations, but the need for a new source of human organs for transplant to reduce suffering and death is extremely pressing as well.