CRISPR research under scrutiny

jim mcnamara

Egli, D. et al. Preprint at (2017).
A critique of: doi:10.1038/nature.2017.22382 (dated Aug 2)

Here is the more news science version of the CRISPR study:
And news science version for the criticism:

This is how Science works. You perform experiments, publish your results, then you may have to answer criticism. This is a good thing. In this case the original claim was to remove a deleterious gene using CRISPR technology. Not completely correct say a second group of researchers.

The 2 August Nature paper2, led by reproductive biologist Shoukhrat Mitalipov at the Oregon Health and Science University in Portland, described experiments in dozens of embryos to correct a mutation that causes a heart condition called hypertrophic cardiomyopathy.

... The team claimed that the CRISPR–Cas9 genome editing tool was able to replace a mutant version of the MYBPC3 gene carried by sperm with a normal copy from the egg cell, yielding an embryo with two normal copies. ...
The criticism deals with the fact that the created embyos had two normal gene copies, but no explainable way (in terms of what was originally reported) for one of those copies to be in the embryo. (Read the the two news articles. In order for me to get everything correct I'd have to plagiarize a lot of text from the articles.) Maybe @Ygggdrasil can do that without plagiarzing.

The important concept is that Science does attempt to self correct: Not always, and not perfectly because humans are involved.


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The main issue seems to be that the researchers assessed the success of their gene editing approach by looking for the absence of the mutated allele rather than the presence of the corrected allele (which is difficult since the corrected allele would be difficult to distinguish from the normal allele on the other chromosome). The authors of the critique point out alternative explanations as to how the Oregon team could observe the absence of the mutated allele without successful gene editing actually occurring. Mitalipov will likely have to revisit their experiments to investigate these alternative possibilities.

A good discussion of the critique can be found on stem cell biologist Paul Knoepfler's blog:
An international team of top scientists led by first author Dieter Egli has responded via a preprint on Biorxiv to that Mitalipov team high-profile Nature paper on CRISPR gene editing of human embryos. Egli, et al. raise the possibility that the CRISPR gene editing as reported in the Nature study may actually not have happened, at least not in every case and perhaps not the way the Ma, et al. paper argued it did (via homology directed repair (HDR)-based CRISPR-Cas9 action specifically depending on interaction between normal maternal and mutant paternal chromosomes).

On one level it isn’t so unusual to see a scientific critique of and technical questions raised about a published paper that made splashy news. However, I see this particular case as a striking turn of events because although the new Egli, et al. piece is very collegial and diplomatic, they convincingly lay out a number of rather compelling reasons why the main conclusions of the Ma paper might be incorrect and the reasons why there may not have been CRISPR gene editing in many of the embryos. To be clear, Egli and colleagues don’t seem to be saying the Ma, et al. paper is definitely wrong, but they describe some quite reasonable ways in which the Ma paper could hypothetically have inadvertently reached incorrect central conclusions. To me these possible alternative explanations just simply make a lot of sense and are things that should have been ruled out as alternative explanations.

Also mentioned here:

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