All of grrl_nrg's Comments + Replies

We don’t actually know that JK He accomplished what he said he did.  He may have tried.  But the results have not been independently verified.  That would require genotyping the parents and children.  So, premature to say that germline editing appears safe in humans.

2GeneSmith
I'm not saying his experiments show germline editing is safe in humans. In fact He Jiankui's technique likely WASN'T safe. Based on some talks I heard from Dieter Egli at Colombia, He was likely deleting chromosomes in a lot of embryos, which is why (if I recall correctly) only 3 out of about ~30 embryos that were transferred resulted in live birth. Normally the live birth rate per transfer rate would be between 30 and 70%. It's also not entirely clear how effective the editing was because the technique He used likely created a fair degree of mosaicism since the editing continued after the first cell division. If the cells that ended up forming hematopoietic stem cells DIDN'T receive the edits then there would have been basically no benefit to the editing. Anyways, I'm not really trying to defend He Jiankui. I don't think his technique was very good nor do I think he chose a particularly compelling reason to edit (HIV transmission can be avoided with sperm washing or anti-retroviral drugs to about the same degree of efficacy as CCR5 knockout). I just think the reaction was even more insane. It doesn't make sense to ban germline editing just because one guy did it in a careless way. Yet in many places that's exactly what happened.

Thanks for the response.

I thought the following article does a good job of outlining some of the limitations of PRS for embryo selection:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9527452/

Like any new (medical) technology, I think that it's important to consider the ethical implications.  This doesn't mean that we shouldn't do it or allow it, but just that we should be thoughtful about it.

As for clinic success rates, I didn't mean to imply that "they don't mean anything".  It's just that prospective patients should be aware that they can't alwa... (read more)

5GeneSmith
The paper you linked outlining the limitations of polygenic embryo screening mostly rests its conclusions on the supposed impossibility of showing that embryo screening actually works. Again, I refer back to tests of polygenic risk scores in siblings. If predictors work in that population, they should be considered clinically validated. This kind of validation is standard practice in other areas of data science. I'd appreciate it if you or someone else questioning PGT-P could outline exactly why they believe sibling validation of polygenic scores is insufficient evidence to justify its clinical use. It is literally a randomized control trial for genes. My response to other criticisms in the paper: "Furthermore, statistical manipulation of genetic data may limit the detection of rare pathogenic gene variants" De novo mutations are exceedingly rare. The average person has about 70. The expected effect from missing these mutations is so low that it's barely worth considering, especially compared to the expected benefits of simply improving predictors and adding more traits to the selection index used in PGT-P. not only is it difficult to assess the clinical validity of PRS-ES in terms of the outcomes in question, it is also possible that clinical validity would be limited by the different effects of future environment on gene expression, compared to the past. Yes, I agree that this is a fair critique of embryo selection, particularly for the diseases of old age. But the obvious solution here is just to apply some time discount factor; weight traits like depressive tendency, obesity, and intelligence more heavily than prostate cancer and heart disease, since the former will have an impact much sooner. Mathematical modelling of PRS-ES has been attempted and indicated extremely limited utility in terms of non-pathological trait selection (Karavani et al., 2019), such as height and intelligence quotient (IQ). The Karavani study used predictors that were already
grrl_nrg11-14

Great post.  Thank you.  Fertility doctor here and a supporter of ART (assisted reproductive technologies) in general.  A few thoughts (although you touched on a few of these below, worth emphasizing in my opinion):

  • PGT-P has not been validated yet, which may take decades to do, if ever.
  • The science in terms of GWAS isn't quite there yet IMHO - we don't know all the genes that are important for most traits and we may be inadvertently selecting against some desirable traits, for example.
  • Comparing clinic success rates using CDC data is imperfect
... (read more)
2GeneSmith
I made my reply to your comment into a standalone post