CRISPR and unwanted DNA alterations

jim mcnamara

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@Ygggdrasil is far more qualified to comment on this than I am, but it seems like a good idea to raise the issue. Published today July 16, 2018 Letter in Nature Biotechnology:

https://www.nature.com/articles/Nbt.4192
M. Kosicki, K. Tomberg & A Bradley
Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex
rearrangements.
Abstract:
CRISPR–Cas9 is poised to become the gene editing tool of choice in clinical contexts. Thus far, exploration of Cas9-induced genetic alterations has been limited to the immediate vicinity of the target site and distal off-target sequences, leading to the conclusion that CRISPR–Cas9 was reasonably specific. Here we report significant on-target mutagenesis, such as large deletions and more complex genomic rearrangements at the targeted sites in mouse embryonic stem cells, mouse hematopoietic progenitors and a human differentiated cell line. Using long-read sequencing and long-range PCR genotyping, we show that DNA breaks introduced by single-guide RNA/Cas9 frequently resolved into deletions extending over many kilobases. Furthermore, lesions distal to the cut site and crossover events were identified. The observed genomic damage in mitotically active cells caused by CRISPR–Cas9 editing may have pathogenic consequences.
In plain English this says that DNA gets changed by CRISPR as presented before. It also changes DNA in places/ways that were not intended. This was tested only on cell lines (not people) and some mice.
Obviously a bad change in a human patient has a probability to cause problems for the patient. However I do not understand the scope of the report. For example, most kinds of medical treatments carry risk. So is this article "hype" or reasonable? Clearly, somebody thought it had some merit to be published at nature.com

Insight article on the CRISPR -
https://www.physicsforums.com/insights/dont-fear-crispr-new-gene-editing-technologies-wont-lead-designer-babies/
 
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From an information-theoretic standpoint, "DNA breaks introduced by single-guide RNA/Cas9 frequently resolved into deletions extending over many kilobases", seems rather foreboding.
 
The problem is we have no idea, we are experimenting, getting results that are not expected and have no clue what the end result will be. That said..many good things have resulted from unexpected outcomes of experiments. Push on.!
 

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