Posted by: Ernst-Martin F?chtbauer on Thursday, October 27, 2016

The new and accelerating technical development of the CRISPR/Cas9 system opens up for the possibility of targeted genetic modifications in germline competent human embryos. This is an avenue, which until very recently has been regarded as absolutely off limits. To cross the border between genetic modifications of somatic cells and germline cells was simply not conceivable, at least in most Western countries. Indeed, the border has not yet been crossed, but we are getting closer.

In two recent papers Chinese scientists used triploid human embryos as a ‘model’ to either treat ß-thalassemia [1] or to recapitulate a spontaneous mutation in the CCR5 gene [2], which results in resistance against HIV infections. Both targets are clearly chosen due to their potential for future therapeutic application.

Shortly after the first of the two papers was published, the Board of Directors of the ISTT posted a statement [3], which among other arguments contains the following sentence:

Uses of genetic engineering in human embryos should be limited to disease mitigation for those diseases where no other option is available; we reject the idea of “designer babies”.

This raises the question whether there are at all diseases where there are no other options (now or in the future). Hereditary diseases are rarely transmitted by homozygous parents, which makes preimplantation diagnostics (PID) an obvious safer and ethically far less disputed alternative. The example, ß-thalassemia reaches in very limited populations, like the Maldives, a frequency that puts about 1% of couples at risk to be double homozygous. But still, is not a CRISPR/Cas9 based hematopoietic stem cell therapy the obvious and much easier developed therapy?

However, the case of targeting CCR5 is fundamentally different. As no one can claim that being wild type for CCR5 is a disease, this is a clear designer approach. Given that we know relatively little about the function of CCR5, one might wonder how we can be sure that it is beneficial to mutate it in a world of ever changing microbial threats. It seems that developing a CCR5 blocking drug or somatic mutations ofCCR5 in HIV patients is the obvious way forward.

It is my feeling that many colleagues, some of whom I greatly admire, are beginning to accept experiments with the obvious goal to modify the human germline ‘if it is the only cure for severe diseases’. However, I have not heard one convincing example of such disease that is not in principle “treatable” or “avoidable”. Finally we should keep in mind that the Hardy-Weinberg equation ridicules all eugenic attempts to clean the population from ‘disease’ alleles.

I am increasingly concerned because the discussion in our community has, within a few months, taken an almost purely technical turn about off target risks and efficiency. We neglect many decades of thorough philosophical and ethical literature on the issue. There is more at stake than the possible treatment of a few rare diseases.

These questions are too important to just wait and see. We as ISTT members are so close to the topic that we need to have an honest and open discussion about our opinions. This blog could be a starting point and I invite/encourage you to add to this discussion.

[1] Liang, P. et alProtein Cell (2015)

[2] Kang, X. et al. J. Assist. Reprod. Genet. (2016)




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Ernst-Martin F├╝chtbauer on December 4, 2018 at 7:06:52 am said:
Now, a little more than 2 years later, it happened. He Jiunkai claims to have modified the genome of two recently born twin girls with an other pregnancy on the way. Unless the identity of the children is disclosed to at least some independent persons, it might not be possible to proof whether his claim is correct, but this does not matter. As long as the hospital involved in the retrieval of oocytes and the transfer of genome-modified embryos is not stating that this never happened, it could have happened. I don't want to elaborate here again on the ethics of germ line gen modification in general and on the choice of the target gene. These aspects are very precisely covered in the statement of the ARRIGE steering committee (
What I want to point out is the general failure of control in the scientific community and the society in general. It has been claimed, that He Jiunkai was not socialized in the scientific community because he has basically no embryological or medical background. This is probably true, but he did talk about his research at international meetings and he found a hospital, which uncritically accepted his ethical claims. So he was not just the lonely wolf that can never be predicted. I'm afraid, that he also took the increasing acceptance of experiments with human embryos in journals with increasing impact factor and the decreasing ethical discussion of these papers as an indication that it was OK to proceed with the 'real' application. His statement 'There will be someone, some where who is doing this. If it?s not me, its some else' actually indicates that he assumed that this was a race on being first. Here I think also our community has a responsibility which we might not have lived up to. In the 40 years I'm involved in mouse embryology and gene modification, every single technical advance was met with the question 'what if this could be done in humans?'. Our standard response was that this will not happen without a broader consensus and only if there was a serious and justifiable application. Apparently, we were too optimistic and not vigilant enough.