Neurons – Network of neuronal cells (Blue: nucleus; Red: neurons) [Copyright: Institute for Transfusion Medicine, UK Essen]
What is the Japanese research team planning?
Chimeras are organisms consisting of two or more tissues of different genetic origin. To artificially produce chimeras for research, stem cells are introduced into an embryo (blastocyst) from which then an organism develops that is based on cell lines of different genetic origin. Particularly controversial are artificial chimeras, if human cells were used to produce them. Naturally occurring human chimeras, i.e. a person in whom two zygotes are probably fused, are very rare.
The Japanese stem cell researcher Hiromitsu Nakauchi, whose announcement sparked the latest debate, has already been investigating how stem cells of one animal species behave in embryos of another animal species. In 2017, he published the results of an experiment in which he and his team first genetically modified rat embryos so that they did not develop a pancreas. Among other things, the pancreas produces the hormone insulin, which is required to regulate blood sugar levels and plays an important role in diabetes. Stem cells from mice were injected into these modified rat embryos. Since stem cells can differentiate into various cell types, it was hoped that they would develop into pancreatic cells. In fact, mouse pancreatic tissue was formed in the rat embryos. This tissue was then transplanted into mice with diabetes, where it led to a normalization of insulin production. Research on chimeras containing cells from several animal species is thus not new. Nakauchi's current announcements have attracted a lot of attention because, on the one hand, human stem cells are to be used and, on the other hand, new legal regulations have been in force in Japan since spring 2019: Until now, chimeric embryos were not implanted in mother animals, but killed after 14 days at the latest (the gestation period of mice is 19 to 21 days, that of rats 21 to 26 days). The new regulation now allows both implanting and completing the pregnancy. Nakauchi plans to inject human stem cells first into embryos of rats and mice, and later also into monkey and pig embryos. According to Nakauchi, the experiments are to be stopped before birth.
The discussion triggered by the announcement of Nakauchi’s research project gained even more momentum when reports were published about experiments of Spanish researcher Juan Carlos Izpisúa Belmonte, conducted in China. In these experiments, human stem cells were introduced into monkey embryos. However, apart from the statement that the experiment was promising, but ended after a few days, there is hardly any information available.
Why create human-animal chimeras at all?
Research on chimeras with human cells pursues several goals: In the long term, scientists hope to be able to supply patients with urgently needed cells or organs. As in the experiments with rats and mice described above, human stem cells could be implanted in animal embryos so that certain human cells or organs grow there.
Chimera research can also be useful in another way: Numerous scientists are working on producing patient-specific cells or organ-like tissue structures "in the test tube" rather than in living organisms. However, this has only been partially successful so far. If more can be learnt about the development of human stem cells in animal embryos, this development may also be induced more successfully outside the living organism. For ethical reasons, early development of human embryos can only be studied to a limited extent.
Finally, human tissues or organs in animals could enable testing patient-specific drugs or treatments without exposing the patient to the risk of unknown side effects.
What concerns does research on human-animal chimeras face?
Apart from having concerns about animal well-being, critics of research on human-animal chimeras often worry that these creatures can no longer be clearly classified as humans or animals. In particular, they might develop characteristics we associate with the special moral status of humans.
Since stem cells can differentiate into various cell types, it is theoretically conceivable that other than the expected and desired cell type develop. However, according to Nakauchi it is unlikely that the transplanted cells migrate into the developing brain of the animal embryo and form human nerve cells there, especially since previous experiments had shown that the number of human cells introduced into sheep or pig embryos was greatly reduced after only a few days. Should a migration of the cells into the brain nevertheless occur, this could theoretically also alter the specimen’s cognitive abilities. If, for example, its ability to suffer or its intelligence increase, this could affect which ways of treating it are morally justifiable.
Human-animal beings developing morally relevant, human-like characteristics is a potential outcome that needs to be considered. According to Nakauchi's announcements, however, such results are not to be expected for the time being: His team pursues a cautious approach, in which the life span of the embryos is increased slowly and gradually. Since the animal embryos are modified in such a way that they do not develop certain organs themselves, it is assumed that the human stem cells will primarily fill the resulting "gaps". Where and to what extent human stem cells actually integrate into the organism will be constantly observed. In addition, Nakauchi has announced that he will stop the experiments if it is observed that the introduced human cells migrate into other tissues, e.g. the brain.
At present, research is still a long way from producing entire human organs in animals and numerous hurdles have yet to be overcome. For instance, organs produced in mice or rats would be far too small to fulfil their function in an adult human being. In this respect, pigs are better suited host animals. However, in previous attempts to establish human stem cells in pigs or sheep the cells were largely destroyed during embryo development. This might be because pigs and humans are a lot less closely related biologically than, say, rats are to mice. With this in mind, research on human stem cells in closely related species such as monkeys seems promising, but is only just beginning.
In research on human-animal chimeras, fascinating medical outlooks encounter understandable concerns. Therefore, it seems advisable to conduct experiments, but to proceed carefully and in small steps so that animal well-being can be addressed adequately, and new findings constantly monitored not only from biological, but also ethical perspectives.
Newspaper coverage and expert statements:
Scientific publications:
We have listed further press coverage on the subject here.
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