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CRISPR's Most Exciting Uses Have Nothing to Do With Gene-Editing

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If CRISPR is a gene targeting system with a pair of scissors attached... you might just want the targeting system, which has come to be called "dead CRISPR". Then you can turn gene expression on and off, light up genes in the cell, or temporarily acquire immunity to viruses that target particular receptor molecules.

The possibilities for medicine are mind blowing.

Most recently, they have started to write more complex “programs” in which several genes are simultaneously activated and others are repressed. George Church, another CRISPR pioneer, used similar programs to transform stem cells into neurons. And Wendell Lim, who was involved in developing CRISPRi and CRISPRa, wants to program customized cells, such as immune cells that attack cancers.

“I hope that the dead-Cas9 platform can one day partially replace the drugs that people have developed for treating cancers or other diseases,” says Qi. Many of these drugs are designed to block specific genes, but the dead Cas9 could do so more accurately, while also targeting many genes at once. “It’s equivalent to using a cocktail of drugs, but with much better specificity.”

This is truly brilliant.

The technique relies on two components: an enzyme called Cas9 that cuts DNA like a pair of scissors, and a guide molecule that directs Cas9 to a specific target like a genetic GPS system. Qi, now at Stanford University, found a way of blunting the scissors, creating a “dead” version of Cas9 that can’t cut anything at all.

This seems perverse, but it’s actually quite brilliant. The dead enzyme can now act as a platform for other molecules, including activator molecules that switch genes on, repressors that turn them off, or glowing substances that reveal their locations. And with the right guide molecules, scientists can now direct these payloads to any gene they like.

Now, instead of a precise and versatile set of scissors, which can cut any gene you want, you have a precise and versatile delivery system, which can control any gene you want. You don’t just have an editor. You have a stimulant, a muzzle, a dimmer switch, a tracker.

This matters because much of biology depends on how genes are used, rather than the sequences of those genes. Think of the genome as a the script of a play: The same text can lead to vastly different productions depending on how lines are delivered, how sets are constructed, or how stage directions are interpreted. Likewise, we can use exactly the same sets of DNA to sculpt a muscle cell, a neuron, or a skin cell. By using CRISPR to finely control the activity of specific genes, we can better understand how our bodies do so naturally.

Scientists could turn on genes that cause heart muscles to expand after a heart attack, or silence genes that fuel the growth of cancers. “Or let’s say you’ve been exposed to a virus,” says Jonathan Weissman from the University of California, San Francisco. Viruses typically begin their invasions by latching onto receptor molecules on our cells, and we know the genes that make many of these receptors. “Turn those off, and now you’re immune to the virus. Your immune system can clear it. Then you turn the gene back on and you’re back to normal.”

These aren’t new concepts; scientists have long tried to perform similar feats using other tools. CRISPR just makes things easier. Its potential was clear right from the start, when Jennifer Doudna and Emmanuelle Charpentier showed that they could use specific guide molecules to point the snip-happy Cas9 scissors at a specific target. “We immediately thought: Well, let’s just break the scissors,” says Weissman.

By the time Doudna and Charpentier published their now-classic 2012 paper detailing CRISPR’s potential as a gene editor, Weissman, Qi, and their colleagues (Doudna included) had already developed the dead Cas9 and were racing to find ways of using it. While the world was chatting about editing, they were working on control.

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