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Gene Therapy

Modified CRISPR Can Act As A Toggle Switch To Silence Genes

Posted on 14 March 2016

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CRISPR may have burst on the scene as a revolutionary gene editing tool, but it’s proving to be so much more. Tagging the targeting system with a gene silencing component could revolutionise stem cell work and enable a new level of genetic control we’ve never seen before. 

A wonder tool

Efficient and accurate, CRISPR may be in the throes of a patent battle but it’s undoubtedly going down in history as a landmark in biological science. There may be other similar systems out there, but CRISPR makes things quick and comparatively cheap – which tends to revolutionise any industry. 

A new string to its bow

We know the CRISPR system allows you to snip and alter almost any gene you choose. It needs some refining before it’s classed as safe enough for human use, but the associated boom is driving the technology forward exceptionally fast. Lots of teams across the world are now working on various forms of the system; building on the concept, tinkering with it and adding new features. One such team at the Gladstone Institute have now demonstrated that they can selectively silence genes in induced pluripotent stem cells with a modified version called CRISPR interference (CRISPRi).

“We were amazed by the dramatic difference in performance between the two systems. We thought that permanently cutting the genome would be the more effective way to silence a gene, but in fact, CRISPRi is so precise and binds so tightly to the genome that it is actually a better way to silence a gene”

Why is this so cool?

The CRISPRi method was first described by Stanley Qi in 2013, and involves the usual CRISPR targeting RNA. Instead of using the active, DNA snipping enzyme Cas9 however , CRISPRi strings an inactivated Cas9 enzyme and an inhibitor protein called Krab to the targeting system. This means that when the homing CRISPR element locks to your target DNA strand, the Cas9/Krab silencing block can bind to the promoter of the sequence and prevents it being translated into a protein. 

A fast toggle switch

This technology could have therapeutic value in patients with defective and harmful genes, but this new research showed that the CRISPRi system was more reliable than the cutting CRISPR-Cas9 one. It was able to silence a target in 95% of cells, whereas the conventional form only managed 60-70%.

The CRISPRi system may also be safer, as there were no off target effects observed. By removing a certain chemical that activates the silencing mechanism, they could also undo any silencing as well, making any changes reversible. By altering levels of this chemical they could further tune how much or how little they silenced each gene. 

Disease modelling and stem cells

The researchers tested the system on induced pluripotent stem cells and heart cells, silencing a specific gene to create a model of heart disease. Considering each cell behaves differently precisely because of silencing and activating control mechanisms, CRISPRi or a similar technique could change how we program stem cells, and enable us to create new models of disease faster than ever before. 


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