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Editing the editor: CRISPR gets an "undo" button

How often in life do we wish we had an “undo” feature? A chance to undo a bad decision, or a good decision that somehow went wrong?

Scientists working with the gene-editing technology known as CRISPR, may just have been granted this wish. Findings released this week in Nature Biotechnology  provide mechanisms to either undo a gene-edited event, or calm their spread through a population.

CRISPR, and other similar gene-editing techniques, allows segments of DNA to be snipped and removed or replaced, much like a film reel, giving researchers the ability to remove unwanted characteristics or add desirable ones.

It’s not that CRISPR is imprecise that it warrants an “undo” option – in fact, it’s the precision of gene-editing, along with a reduction in the need to introduce genetic material from other species that makes this technology so incredibly attractive. Venture capital and biotechnology firms were quick to jump on board as well. In less than 15 years use of the technology has exploded, as demonstrated by a simple visualization based on PubMed data (scroll halfway down to see the visual map).

Rather, it’s the concern over just how powerful the technology is that has fueled much of the debate. This fall, UNESCO issued a call for a temporary ban on human DNA editing and in the US, the National Academy of Sciences (NAS) created of an ad hoc committee tasked with reviewing use of the technology in non-humans.

Much of the concern on the human end has to do with ethical questions of whether we should play god with human DNA, even if the change has the chance to remove a devastating illness. On the non-human side, it’s the overriding worry of what can’t be controlled outside the lab that has groups like the NAS on guard.

Many proponents argue that the benefits outweigh the risks. In a way, malaria has become the poster child for CRISPR technology. In this year alone, the World Health Organization estimated that the disease affected 214 million people worldwide and was responsible for 438,000 deaths. Fighting a parasite that has shown an uncanny knack for mutating in response to conventional insecticides has led researchers to look at unconventional approaches – and CRISPR is an enticing fit. If gene-editing could be used to render the malaria parasite sterile (in terms of its ability to infect humans, either by changing the parasite or by making mosquitoes resistant to them), and if that edited organism were to be released into the wild to pass along this disease-free DNA to its offspring, effecting what is called a “gene drive” – a mass, inherited change in the DNA of an organism – we might finally find ourselves on the top end of the malarial fight.

It seems like an iffy business. But it’s very possible. Early experiments with fruit flies have shown an ability to pass yellow pigmentation on to their offspring, and super-muscled pigs were designed with gene-editing just this summer. Experts have predicted that a gene drive to eradicate both malaria and Lyme disease will be ready within the next two years.

But it’s the “what ifs” that put people on edge. What if an experiment escapes into the wild and wreaks unanticipated havoc on an ecosystem? What if the evolutionary response to a gene drive is more devastating than the deleted disease or augmented trait? Yes, this is why an “undo” button will likely be received with great relief by many.

This week’s paper suggests that the ripple effects of a gene drive could be controlled, reversed, or at least minimized. Using a slow-reproducing strain of yeast, the researchers tested two different safeguards. The first involves separating the desired genetic edits into different parts in what they called a “split drive”, where some of the characteristics are changed in the genome, while others were attached to a strand of DNA outside the genome, thereby creating a situation where changes are not always inherited together.

The more dramatic approach, the un-edit or undo feature, would require researchers to develop a second gene drive capable of reversing the effect of the initial edit; the equivalent of having a Band-Aid or skin glue on hand before a cut is made. In this scenario, if an undesirable effect of a gene drive is detected, the hope is that it can quickly be undone.

As was pointed out by the paper’s author, the hope is that having such safeguards at the ready will ensure that unanticipated accidents don’t turn into major events before the necessary conversations and considerations can be made.


Editing the editor: CRISPR gets an "undo" button

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