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Cure or Carcinogen? CRISPR-Cas9 May Cause Cancer

ByTim TreuerNOVA NextNOVA Next

A promising vehicle for gene therapies may have just popped a flat tire. Two new studies on the DNA editing tool CRISPR-Cas9 reveal that it may indirectly trigger new cancers—even when used to replace cancer-causing genes.

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The independent studies from Novartis and Sweden’s Karolinska Institute both appeared yesterday in the journal Nature Medicine and point a finger at the same cause, a switch that turns off cancer fighting molecular machinery. When this switch is off, gene therapies more readily take hold. But it also means that the potential for cancer is higher among tweaked cells.

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A cell undergoing apoptosis, a form of self-destruction that can prevent cancer.

In normal cells, a cellular watchdog known as p53 is on the lookout for DNA breakages like those caused by marauding UV radiation or, in this case, CRISPR-Cas9. p53 calls to arms a range of tools that either repairs the DNA or causes the cell to self-destruct. In either case,

p53 stymies gene therapies.

When p53 is disabled or absent, gene therapies take hold, which means those cells are wildly over-represented at the end of the gene editing process. But it also means that those cells lack p53 ’s cancer fighting skills.

Experimental CRISPR therapies are already undergoing clinical trials, which means the potentially fatal flaw somehow slipped through rounds of testing in mice and human cells.

The new technology makes gene editing faster, cheaper, and easier than ever before. Here’s how.

Here’s Sharon Begley, reporting for Stat:

Karolinska’s Haapaniemi said the effect shows up in large-scale experiments like hers and Novartis’ “but can be missed in small-scale studies where people only focus on editing one gene in one cell type.” In speaking to other scientists, she said, “it seems that other teams have noticed the effect of p53 on editing,” but have not highlighted it.

Begley continues:

As for why no one has reported CRISPR’d mice getting cancer, Haapaniemi said, “This is a good question.” One reason might be that “laboratory mice are killed early,” perhaps leaving too little time for them to develop cancer.

The good news is that not all gene-editing therapies trigger p53 and cause it to undo the therapy. When CRISPR is used only to remove problematic DNA rather than insert new code, the watchdog appears to stay quiet. Ditto when only individual letters of DNA code are changed without cutting both strands of DNA. These more limited techniques underpin treatments for a variety of genetic conditions, from sickle-cell anemia to cystic fibrosis.

A revolution in gene editing enables scientists to create and edit DNA like never before.

Still, numerous promising CRISPR gene therapies waiting in the wings may have to be sidelined until a solution to the p53 problem can be found. These two studies also underscore just how far scientists are from fully understanding the tool that had promised to give us control of our own genetic destiny.

Image credit: NIH

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