Crick scientists crack CRISPR editing

Scientists at the Francis Crick institute have discovered a simple set of rules to determine the precision of CRISPR/Cas9 genome editing.

A system formerly thought to be near-impenetrable, CRISPR has been developed with the hope of targeting DNA to overcome a plethora of biological ailments. Among other things, the successful implementation of CRISPR means scientists could cure HIV or Alzheimer’s disease.

The issue has been coding CRISPR to target DNA in the right way, making sure to avoid the potentially dangerous editing of healthy genes. If carried out incorrectly, the process has the potential to increase the risks of cancer.

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Formerly, the success of CRISPR was believed to be random, leading to widespread scepticism about the use of the procedure. Not only was it potentially costly, but there was no telling what impact it could have on someone’s life if poorly understood – it’s something which edits your DNA, after all.

In an effort to understand the CRISPR process, the Frick team looked at 1491 target sites across 450 genes in human cells. Upon review, the Crick institute research team discovered that the outcomes of CRISPR genome editing actually adhered to a particular set of patterns.

The researchers identified that the use of their synthetic molecules, called guide RNAs, had starkly different success rates dependent on the kind of genes they were combining them with. The guide RNAs come in several forms and should stick like velcro to the appropriate gene. Until this study, however, scientists had significant difficulty in creating the best combitionations.

The guide RNAs are distinguished by four code letters, with each order of letters providing different success in gene binding. The Frick team’s research noticed that it was the fourth letter which has a huge impact on the successful binding of the synthetic molecule.

Project leader Paola Scaffidi says that the process consists of “actually simple, predictable patterns behind it all.” So if it sounded quite simple, that’s because it is. The problematic coding which has been a difficulty for the whole procedure has proven to be a case of overthinking the issue.

The team also found that how ‘open’ or ‘closed’ the target DNA was made a huge impact on the success of the procedure. They discovered that the CRISPR process was much more efficient when the target DNA was open. This means scientists can easily release compounds that force the DNA into an open state, drastically improving likelihood of success.

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Akin to the RNAs, the openness or closedness of the genes was something formerly missed by researchers, with team member and Crick PhD student Josep Monserrat conceding, “we hadn’t previously appreciated the significance of DNA openness in determining the efficiency of CRISPR genome editing.”

Monserrat speaks positively of the future of these findings, stating the team “are excited to observe that distinct cell types share common editing at precise target regions, and hope translation of our findings will be beneficial across disciplines.”

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