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Flipping the repair switch to edit our genes

December 09, 2015


By Jovana Drinjakovic

A new discovery, based on elucidating how cells control DNA repair, may be a key to editing genes directly in the human body as a means to cure or reverse disease.


Cells’ DNA-holding nuclei, with yellow and red dots that show breaks in the DNA where corrected, man-made DNA sequences can be pasted into.


Imagine if we could correct genetic errors inside diseased organs and return them to health? Gene editing, a process by which inherited mutations can be fixed, has become possible, but it only works in cells that are dividing, which are scarce in our bodies. Now a team led by Dr. Daniel Durocher, a Senior Scientist at the Lunenfeld-Tanenbaum Research Institute (LTRI), has discovered a way to perform this kind of precise gene editing in non-dividing, fully differentiated cell types.

The research study comes out December 8 in Nature.

A decade or so ago, study of the processes by which bacteria fend off infection led to the discovery of CRISPR* in which small pieces of nucleotides direct cleavage and repair of DNA. Application of this basic science finding then led to a new generation of gene editing technologies which allow researchers to selectively and precisely change gene sequences.

CRISPR is often described as a “cut and paste” tool because a disease-causing mutation can be cut out from the genome and replaced with a corrected, chemically synthesised piece of DNA. But the “pasting” relies on a cellular process, known as homologous recombination (HR), that is the method by which our cells mend mistakes in DNA caused by copying of the genetic material during cell division. This is why HR only works in dividing cells and is switched off in non-dividing cells.

The problem is that our bodies comprise largely non-dividing cells that are specialized for different roles, such as muscle cells that contract so that we can chew or dance. To correct mutations in our muscles would be extremely difficult, requiring painstaking regeneration of muscle stem cells which are capable of dividing and therefore open to gene editing. Once the defective mutations have been corrected, the stem cells could then be turned into muscle tissue and implanted back into the patient. This would be akin to scanning a film-based photograph to make a digital copy of it, instead of using a digital camera in the first place. Wouldn’t it be easier and more efficient if we could edit genes directly in the muscle?

While studying the mechanisms by which cells control normal DNA repair systems, Durocher discovered a previously unknown switch that keeps HR “off” in non-dividing cells and devised a strategy to toggle this switch back on. Although his work was not initially focused on gene editing, Durocher and colleagues rapidly realized the implications of their findings that could potentially lead to correcting genetic errors in cells that no longer divide. Durocher is careful to warn that their discovery should be seen as a stepping-stone and that additional work will be needed to fulfill its potential.

“The future of therapeutic gene editing may well be in vivo – inside the body. If we want to correct mutations that cause diseases like neurodegeneration, we may not be able to take cells out, fix them and put them back into the brain. Instead, we will have to act upon differentiated cells within the body. That has to be the future and if we are going to go this way then we’ll have to make HR happen in those differentiated cells. We have provided a blueprint for how to start doing that,” says Durocher.

The researchers were able to reactivate HR in cells, and force it to drive gene editing, but the cells they used were not normal – they were cancer cells, a standard initial go-to cell type in the field. Durocher’s team stopped these cells from copying their DNA, a trick that allowed them to work out the HR off switch. But in the future Durocher will work on reversing the HR block in truly differentiated cells, such as neurons or muscle cells. “If their initial findings can be extrapolated to other cell types, and there are no obvious reasons why this shouldn’t be the case, it will have many applications” noted Jim Woodgett, LTRI Director of Research. “Gene editing is still in its early stages but we’re all optimistic about its potential benefits”. For example, doctors believe that for muscular dystrophy, we may need to correct as little as 20 per cent of patients’ muscle tissue to give them a therapeutic benefit.

“I am excited about the potential of this work. It could have true medical implications and I am keen to further develop this technology in collaboration with clinicians and gene editing specialists because I would be crazy not to!” says Durocher.

*  CRISPR is the acronym for “clustered regularly interspaced short palindromic repeats”.







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