How does CRISPR work step by step?

1the twist

Here's the twist: scientists didn't invent CRISPR. It's a bacterium's immune system, an old defense against viruses called phages, and we borrowed it.

2the album

A bacterium that survives an attack saves a snippet of the virus's DNA in its own genome, tucked between repeats, like a mugshot album. That album is CRISPR.

CRISPR is the saved album of virus snippets (spacers) between repeats.

3guide plus blade

When that virus returns, the cell copies a snippet into a short RNA, the guide, and hands it to Cas9, a protein that cuts DNA. The guide tells Cas9 where.

4the machine

Scientists borrowed the machine. Cas9 is the blade, and on its own it is blind. The guide RNA, twenty letters we can write to match a gene, is its address.

5find the PAM

Cas9 slides along the cell's DNA checking one thing first: a short tag, N, G, G, called the PAM. No tag, no stopping, which also keeps it from cutting its own album.

Cas9 will only grip DNA that sits right beside a PAM (N-G-G).

6match the guide

Next, the guide unzips the DNA beside the tag and tries to pair with it, letter by letter, all twenty. A full match and Cas9 locks on. A bad mismatch, and it lets go.

7snip

Then Cas9's two blades each cut one strand, about three letters from the tag. The DNA snaps clean through. Notice what Cas9 did: it only cut.

8the cell edits

So where does the edit come from? Not from Cas9. The cell sees a broken chromosome and rushes to repair it, and the repair is where editing happens.

9two repairs

Two routes. Fast, sloppy gluing usually adds or deletes a few letters and breaks the gene. Or, with a template we supply, the cell copies it in and rewrites the gene.

Sloppy repair switches a gene off; repair from a supplied template rewrites it.

10the whole idea

Here's the whole idea. Phage DNA snippets become a guide; the guide steers Cas9 to a matching spot beside a PAM; Cas9 cuts, and the cell's repair does the editing.