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Genome editing in human embryos has unintended side-effects

29 June 2020
Appeared in BioNews 1053

CRISPR genome editing may result in unwanted heritable genetic changes, which could lead to long-term risks in a clinical context.

Three independent studies published on the preprint platform bioRxiv have reported unintended DNA changes adjacent to the target site when using CRISPR/Cas9 in human embryos. These 'on-target' mutations may represent an underappreciated risk, as they can be easily missed by standard assessment methods.

The lead authors of the three studies have declined to comment on their findings before their articles have been peer-reviewed.

The first preprint was published by the research group of Dr Kathy Niakan of the Francis Crick Institute, London. The study intended to investigate embryonic development by creating mutations in the POU5F1 gene using CRISPR/Cas9. They reported that of 18 genome-edited embryos, about 22 percent were left with unwanted DNA changes in the areas surrounding POU5F1, including unexpectedly large DNA deletions and rearrangements. 

Similar changes in chromosomes carrying CRISPR-targeted genes were described in two further preprints. A study led by Dr Dieter Egli of Columbia University in New York, showed that when using CRISPR-Cas9 for the correction of a blindness-causing mutation in embryos, about half of the treated embryos ended up missing sequences on the chromosome on which the gene is situated, and sometimes even lost the entire chromosome. Similar effects were reported in a study by Dr Shoukhrat Mitalipov of Oregon Health and Science University in Portland, while investigating embryos created using sperm known to carry a mutation that causes heart problems.

CRISPR-Cas9 has been praised for enabling precise genome editing through targeted cutting of DNA at regions of interest, followed by repair through the cell's internal DNA repair mechanisms. The repair step is essential for this form of genome editing to function; however, it now appears that may be where shuffling or loss of chromosomal regions can occur, leading to uncontrolled changes to the genome. 

Until now off-target effects – edits at unrelated locations in the genome due to the CRISPR machinery binding DNA in the wrong place – have been one of the major concerns about the use of CRISPR genome editing in humans. However, the newly reported 'on-target' edits, resulting from bystander effects when CRISPR edits the intended genomic sequence, may pose a greater risk.

'What that means is that you're not just changing the gene you want to change, but you're affecting so much of the DNA around the gene you're trying to edit that you could be inadvertently affecting other genes and causing problems,' Dr Kiran Musunuru from the University of Pennsylvania who was not involved in the studies told OneZero.

12 July 2021 - by Dr Dieter Egli 
I recently received a thoughtful letter from a college student I do not know – I'll call her Claudia* – who took the time to reach out to me with her perspective on heritable genome editing in embryos...
19 April 2021 - by Javier Bautista 
Using CRISPR/Cas9 genome editing in human embryos may introduce 'on-target' errors...
2 November 2020 - by Julianna Photopoulos 
A new study has concluded that using CRISPR-based genome editing on embryos makes unintended DNA changes that would be passed on to future generations...
7 September 2020 - by Dr Jennifer Frosch 
Genome editing is not yet safe for creating germline changes in humans, an international commission has concluded...
23 March 2020 - by Dr Jay Stone 
A new CRISPR-based technology can target RNA in human cells, including the RNA-based genome of the coronavirus...
9 March 2020 - by Jakki Magowan 
A novel variant of the Cas9 enzyme may increase the specificity of CRISPR/Cas9 genome editing...
4 March 2019 - by Dr Kimberley Bryon-Dodd 
Two new studies suggest that a form of CRISPR base editing is more error-prone than previously thought...
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