Reacción a "Reactions: First chimeric monkey born from embryonic stem cell lines"

In 1984, British researcher Allan Bradley demonstrated that it was possible to generate chimeric mice with a high contribution of embryonic pluripotent cells injected into pre-implantation embryos, in blastocysts. The resulting chimeric mice were also able to transmit the genome of the injected cells to their offspring after colonisation of the gonads. This experiment triggered a series of advances that led to the birth of the first mutant mouse in 1989, generated from mutations introduced into embryonic pluripotent cells. This technology, which made it possible to understand the function of thousands of mouse genes (and, by comparison, our genes), was awarded the Nobel Prize for Medicine in 2007, and the winning researchers were Mario Capecchi, Martin Evans (Allan Bradley's boss) and Oliver Smithies. For years, this technology could only be used in mice. In 2008, embryonic pluripotent rat cells with the ability to colonise chimeras were obtained, but for all other species, including primates, this technique was not technically possible.   

Nearly 40 years later, a large team of researchers in China has just demonstrated that they can repeat Bradley's experiment in macaques—with a very modest, but still remarkable efficiency. They generated the first chimeric macaques by microinjecting pluripotent macaque embryonic cells, obtained from embryos and maintained under very specific culture conditions. These cells, labelled with a gene that fluorescently colours the cells derived from them green, have managed to colonise all the organs of the resulting chimeric monkey. Between 20 and 90% of the cells in each organ have developed from the original injected embryonic pluripotent cells. This includes the gonads, the testes (the two chimeric monkeys they have been able to analyse, one aborted and one that survived birth, were both male). This suggests that this chimeric macaque is likely to be able to transfer the genome of the injected embryonic cells to its offspring, something the researchers will have to undertake soon.  

This is an experiment that is not novel in the animal world (we have known how to do this very effectively in mice for forty years) but it is novel in primates, such as the macaque used here, which brings this methodology closer to its possible use in humans—which ethically, scientifically and technically would neither be feasible today, nor justified. Reviewing the research team's figures gives us an idea of what might happen if this experiment were attempted in another primate species, such as humans. They obtained 206 macaque embryos at the morula stage and injected them with pluripotent embryonic cells. Of these morulae, 91 reached the blastocyst stage and 74 could be implanted into (no less than) 40 females, experimentally prepared to accept and maintain gestation to term. They obtained 12 gestations of which 2 aborted early, 4 during foetal development and 6 went to term. Of these, only one macaque survived with a high chimeric contribution of embryonic cells. One chimeric macaque out of 206 embryos: a very low efficiency of about 0.5%.   

The relevance of this experiment opens the door to the possible generation of chimeric monkeys that carry specific mutations, initially introduced in pluripotent embryonic cells, and that serve to investigate diseases that affect us humans. However, this technology comes ten years too late. Since 2013, we have known how to use CRISPR gene editing tools, which are very useful to mutate genes in a very precise and specific way directly in embryos of any animal species. In 2014, they were already used to generate mutant macaques without the need to use chimeric monkeys or pluripotent embryonic cells. In other words, biologically it is a significant advance to be able to generate these chimeric macaques from embryonic pluripotent cells, but in practice, almost everything we could do with this technique has been possible for years thanks to CRISPR tools.  

The very low efficiencies in the generation of chimeric macaques are very similar to those obtained when 21 years after the birth of Dolly the sheep, the first mammal cloned from adult cells, the first cloned macaques were obtained in 2018, with an efficiency similar to that reported for the most famous sheep, again around 1%.   

Finally, it is important to note that this experiment, which is published in the prestigious journal Cell, could not have been carried out in Europe, since our European legislation on animal experimentation prevents the use of non-human primates such as these macaques in scientific experiments—unless it is to investigate very serious, fatal diseases that affect us. Since this experiment is a first proof of concept and is not intended to investigate any disease, it would not have obtained the necessary permission to be carried out in any EU country. This explains why all the advances in non-human primate reproductive biology that we have seen in recent years have come from experiments in China, the United States, Japan and Korea—not from Europe.