Is genetic editing producing unwanted changes?

(Stem Cells News image)

Recent debate over the safety of CRISPR/Cas9 genome editing following a study that suggested it can cause hundreds of unexpected mutations left me puzzled. The research (see BioNews 903), published in Nature Methods and carried out in three living mice, could indeed be criticized for the lack of stringent controls and technical errors.

In addition, a number of sloppy mistakes suggested a misinterpretation of the data and therefore incorrect conclusions. It is hard to believe the assertion that CRISPR-Cas9 editing caused so many mutations. And it is also hard to believe how such sloppiness passed the scrutiny of one of the most highly-ranked scientific journals.

In defence of the authors, they did the right thing – they used whole-genome sequencing to assess possible effects of CRISPR-Cas9-mediated genome editing in their experimental system. What they found – from their point of view – was quite alarming, and by publishing the study they wanted to make the data available to the public and warn the scientific community.

The puzzling part to me is the reaction of the companies Intellia Therapeutics and Editas Medicine and their calls for the paper to be retracted on the grounds of flawed design and interpretation (see BioNews 905). Intellia is working on permanently editing disease-associated genes in the human body with a single treatment course, whereas Editas Medicine is dedicated to treating patients with genetically defined diseases. The base technology used by both companies is CRISPR-Cas9.

Why did they get so upset? The notion that CRISPR-Cas9-mediated genome editing may not be flawless brought down the share values of the companies. If they are so cocksure that the technology is flawless, the companies must have proof of that from their own pipelines. Instead just launching an attack to put minds of the investors at peace, they could make available a few examples of whole-genome sequencing data sets before and after CRISPR-Cas9 gene editing from their own work. This would show (I assume) that the technology is indeed in their hands very precise and, therefore, safe.

Failure to do that, makes me question whether they do whole-genome sequencing before and after CRISPR-Cas9 gene editing. I cannot help but ask the question, what is their quality control? (…)

Such an approach is standard in other fields of emerging therapies. If you, for example, work in cellular therapy with pluripotent stem cells, either human embryonic stem cells (hESCs) or human iPSs (induced pluripotent stem) cells, you would have to demonstrate the efficiency of your differentiation protocol by showing that not a single cell remained in a pluripotent state afterwards (which can lead to teratoma formation) – even though the probability of this happening is very low.

The field has been struggling for years with the challenge of validating a hESC/hiPSC-derived cell dose for the absence of pluripotent stem cells.


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