Potential DNA damage from CRISPR has been ‘seriously underestimated’ study finds

Note that this study covers 'on-target' effects.

As often covered in the news, CRISPR-mediated gene editing can be used to edit a DNA sequence to another, desired sequence. In these applications, it's very important that no other mutations besides the desired mutation are introduced. Such additional mutations would be 'off-target' mutations.

In a second kind of experimental approach, researchers can use CRISPR technology to make arbitrary mutations at a desired site in the genome. This approach cares less about the resulting damage; the goal is simply to destroy the existing gene.

The referenced article[1] seems to characterize the types of mutations that arise when people use CRISPR to ablate a gene (i.e., the second approach). It would be interesting to see if the range of DNA damage is restricted when CRISPR is instead used to change the sequence of a targeted DNA segment into another, desired sequence.

[1] https://www.nature.com/articles/Nbt.4192

>Academic scientists were less dismissive of the new study, in Nature Biotechnology. One leading CRISPR developer called it “well-done and credible,” “a cautionary note to the [genome-editing] community,” and consistent with other research showing that the DNA cuts that CRISPR makes, called double-stranded breaks, “can induce the types of genomic DNA rearrangements and deletions they report.” He asked not to be identified so as not to jeopardize business relationships with genome-editing companies.

no. no. no. no. that is not good for scientific integrity

Here's another good writeup (imho better than OP's) on this study with some potential ways forward:

https://theconversation.com/crispr-cas9-gene-editing-scissor...

It's from Gaetan Burgio, who runs his own research group using CRISPR

CRISPR is a revolutionary research tool that enables researchers to efficiently study the effect of changing genes, commonly by "knocking them out". CRISPR basically cuts a specific piece of DNA from the genome, so you can study how a cell / animal / disease model is different with and without the gene -- testing causality of gene and phenotype

when CRISPR knocks out a gene, the cell tries to repair the DNA using its natural dna repair mechanisms. this can lead to unexpected insertions or deletions of DNA. researchers are widely aware of this risk and have studied it

however, this paper exposes shortcomings of prior assessments of this risk. specifically, prior studies thought that the unexpected insertions or deltions of DNA were usually small, less than 20 nucleotides. there were observations of larger "indels" but these were thought to be rare. there are a few other shortcomings of the research into "crispr induced lesions", the article lists them in detail

the scientists suspect that prior research has significantly underestimated the level of genomic alteration induced by crispr, and that some of this alteration could cause disease like cancer

the authors first tried to delete a gene with crispr by targeting the protein coding part of the gene, and also non protein coding parts. the crispr targeting the protein coding part of the gene showed significnat knockdown of the gene (over 97%). however, so did the crispr targeting the non protein coding part of the gene (up to 20% of cells did not express the gene). some crispr constructs targeted sites that were over 2,000 base pairs from the nearest protein coding site, and 5-7% of those cells did not express the gene. they determined that loss of the gene was due to loss of the protein coding region, not just regulatory elements in the non protein coding part. they did similar experiments in other cell lines and with other genes

so this suggests that researchers may have wildly underestimated the amount of genetic chaos induced by crispr. it is more possible than we thought that people receiving crispr therapies may also have pathogenic crispr induced dna damage

the paper references six studies, all in China, currently using crispr to treat humans. 3 of the studies use crispr to "knock out" PD1, a molecule that blocks the immune system from attacking cancer, 2 use CRISPR to make cells express CD19 to attack cancerous blood cells, and one study tests an HIV therapy. anti PD1 antibodies and anti CD19 cell therapies using other gene editing techniques are approved and highly effective. anti pd1 antibodies are expected to generate over $20B in sales in the next few years. so these treatments have strong scientific basis supporting their potential effectiveness, but we may have drasticlly underestimated the risks

This isn't exactly surprising, in that CRISPR is a bacterial anti-bacteriophage defense system.

No treatment can ever be proven to be safe. It can only be shown that you have yet to observe harm.

Another interpretation could be that the study found just how much our DNA deteriorates over time when replicated..

IMO it will be hundreds or thousands of years (if ever) until humans will fully understand the intricacies of DNA...the complexities are just enormous.

I ran into Liz Parrish at a longevity convention last year and she looked pretty damned good for being 2 years into CRISPRing herself. I cannot begin to fathom how wildly disruptive widespread modification of somatic cells would be to medicine and the drug industry. They'll just have to do it in China first I guess.