Mythology meets science; human-animal chimeras are coming
According to Greek mythology, Chimaera was a monstrous fire-breathing hybrid creature, a lion with a goat head on its back and a snake as its tail. With such creative and fascinating story background, the term “chimerism” came to describe anything composed of very disparate parts.
Technically, many crosses humans undertook in the last 10.000 years would come close to chimerism, animals such as mules (crosses between horses and donkeys) or the liger (lion/tiger); yet these hybrids would commonly be non-fertile (thus unable to procreate). Hybrids have been studied by biologist for decades to investigate speciation, the process of how biological populations can become different species over time.
However, until recently, more elaborate inter-species crossings have been strictly in the realm of science-fiction and mythology.
That was before Nobel-price winner and field pioneer Shinya Yamanaka discovered how to reprogram mature cells back to pluripotent stem cells (PSC) in 2006. In short, pluripotent stem cells have enormous potential for regenerative therapy, as these cells can give rise to all other cell types in our body. In nature, embryonic pluripotent stem cells are literally the first cells that develop into all other more specialized cell types that make up our body. Shinya and his colleagues discovered that cell fate and pluripotency is guided by a complex cocktail of transcription factors (= proteins that control gene expression networks) and can be influenced by us through manipulating these proteins.
Fast forward 10 years to today, where stem cell research has not only significantly enhanced our understanding of development, but also opened up a whole new avenue of therapeutic possibilities. The underlying idea being that if one can control how cells develop, genetically identical organs can be re-grown from stem cells for each patient in need of a transplant, just by taking a small skin sample from them.
Yet, as many things in life, matters are more complex then they first appear. In order for stem cells to grow into organs, a intricate interaction of signalling molecules from surrounding tissue as well as less understood genetic and epigenetic mechanisms are required over weeks and months to produce a functioning organ. A task yet too complicated to be performed outside of a host body.
Enter Jun Wu and his colleagues and collaborators from California, Spain and Japan. Since years, they have been trying to introduce rat stem cells in the earliest stages of development; the fertilized and dividing mouse blastocyst. Finding the right timing to add stem cells during development is incredibly hard even for rat and mouse, since even quite similar species have different developmental times.
Interestingly, one of the most prominent differences between rats and mice is the fact that rats lack a gallbladder. However, mouse-rat chimeras do not only possess a gall bladder, but the rat stem cells even contributed to gall bladder formation.
This is amazing news because it:
(…) suggests that the mouse embryonic microenvironment was able to unlock a gallbladder developmental program in rat PSCs that is normally suppressed during rat development.
For stem cell and development researchers this insight alone is incredibly potent.
After thinking about these experiments, some might feel a certain unease. Now at this point it might be necessary to mention that in modern research, all kind of animal experimentation is under strict rules and guidelines regarding animal welfare, which includes minimization/avoidance of animal suffering; as well as ethical oversight by an ethics committee to judge whether the proposed research is in accordance with ethical standards. An ethics committee has the responsibility to decide whether insights gained from animal experimentation can be obtained by any other means (in which case they would reject research proposals) and whether the knowledge gain justifies the methods used (otherwise it will be rejected as well).
While animal experimentation in general might be seen as inhumane, the welfare of lab animals is regulated especially considering animal dignity, it is small in scope and way more advanced than e.g. norms for maintaining or slaughtering farm animals for food production. Short of experimenting directly on breed humans, animal experimentation is the best we can do for now to gain insights on development and disease biology. These insights are not solely important for understanding and counteracting human disease, but ultimately will help us get biology to a point where we can help human and animal alike.
Coming back to chimerism research; Jun Wu and his colleagues were not done yet.
While mice and rats still belong to the same order (rodents), the real mythological chimera was a mixture of different animal classes or even phyla. Rodents are still quite different from humans as well, so it is very unlikely to ever use human stem cells in rodents or vice-versa; also it is unclear that this would have any applications apart from basic research. However, an animal that is way closer to human physiology, anatomy and size is the common domestic pig. One of the great medical successes of the past century was the discovery and subsequent usage of pig insulin, a peptide hormone that closely resembles human insulin and was used to treat diabetic patients.
So the researchers reasoned that human pluripotent stem cells (hPSC) could in theory be added to pig blastocysts to generate a chimeric pig.
It turns out that trying to generate pig chimeras is a complicated and sophisticated task. The engineering of the stem cell background alone would have been impossible without the recent CRISPR-Cas9 gene editing revolution. The delivery of the human stem cells into the pig blastocyst is also no small feat; to make microinjection possible they had to induce damage to the protective outer layer (trophectoderm cells) with a precise laser. Finally, in the end it came down to finding the right timing as well.
In the end, the researchers had to conclude that generating inter-species chimerism using human stem cells is possible but inefficient.
This is typical for science; huge efforts have to be invested just to go from the “impossible” to the “barely possible but still useless”. However, as history shows, once that bridge is finally crossed, once things become possible, there is no going back.
The procedures and observations reported here on the capability of human pluripotent stem cells to integrate and differentiate in a ungulate (e.g. pigs and cattle) embryo, albeit at a low level and efficiency, when optimized, may constitute a first step towards realizing the potential of interspecies blastocyst complementation with hPSCs. In particular, they may provide a better understanding of human embryogenesis, facilitate the development and implementation of humanized animal drug test platforms, as well as offer new insights on the onset and progression of human diseases in an in vivo setting. Ultimately, these observations also raise the possibility of xeno-generating transplantable human tissues and organs towards addressing the worldwide shortage of organ donors. — Wu J. et al.
In the overall arch of reported history, scientific advance and with it human capabilities seem to be only limited by our imagination. This research is another example that there is enormous potential but also disquieting dangers associated with science, and only scientific literacy within the general public can steer us into a more prosperous future.
Source: Wu J. et al., Cell, 2017
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