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What is CRISPR?

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University Course Reader · STEM

The trial used CRISPR to disable the gene in the patient's own stem cells before reinfusion.

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Overview

CRISPR is a tool that cuts DNA at one chosen spot. The cell's own repair then usually disables the gene there. If a template is supplied it sometimes rewrites it instead. It has two parts: a guide, a short piece of RNA written to match the target, and Cas9, an enzyme that holds the guide, moves along the DNA with it, and cuts where the letters match. Change the guide and you change the target. It has been used to treat sickle cell disease since 2023.
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Overview

CRISPR is a pair of molecular scissors with a postcode. You write twenty letters of RNA that match the bit of DNA you want; an enzyme called Cas9 holds those letters, moves along the DNA with them, and cuts where they match. The cell then repairs the cut, and that repair is what changes the gene: usually it disables the gene. If you hand over a template it sometimes rewrites it instead. To aim at a different gene you write a different twenty letters. 😎

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Detail

CRISPR is a tool that cuts DNA at one chosen spot, and it has two parts. The first is a guide: a short piece of RNA, about twenty letters long, written to match the stretch of DNA you want. The second is Cas9, an enzyme that holds the guide, moves along the DNA with it, and cuts both strands where the letters match. What is new is the aiming. Before CRISPR, pointing a DNA-cutting tool at a new site meant building a new protein; now it means writing twenty letters of RNA. The cell's repair is what changes the gene. It rejoins the two ends, and the join usually carries a small error that disables the gene. If a template of new DNA is supplied, the cell sometimes uses it as a pattern for the repair, and then the gene is rewritten. The rewrite succeeds in some cells and fails in others. The first approved treatment, Casgevy, has been used to treat sickle cell disease since 2023. Blood stem cells are taken from the patient. In the lab, CRISPR disables the gene that keeps a healthy form of haemoglobin switched off. The cells are then returned to the patient and produce healthy haemoglobin. Cas9 can also sometimes cut at a near-match that is not the intended site, an off-target edit. A treatment's guide is tested for these during development, before approval.
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Detail

CRISPR is a way of cutting DNA at exactly the spot you choose. It has two parts: a guide, twenty letters of RNA that match the target, and Cas9, an enzyme that carries the guide inside it, runs along the DNA, and cuts wherever the letters line up. What is new is how you aim it. Older tools had to be rebuilt for every new target; with CRISPR you write a new twenty letters. The cell's repair of the cut is what changes the gene. Usually it just joins the two ends, the join comes out garbled, and the gene is disabled. Slip the cell a template and it may build the repair from that instead, and then the gene reads differently. That happens in some cells and not others. The first approved treatment is Casgevy, from 2023. Blood stem cells are taken out of the patient, and a gene that normally keeps a healthy kind of haemoglobin switched off is disabled. Put back into the patient, the cells start making healthy haemoglobin. The treatment works because sickle cell disease comes down to a single gene. Conditions that depend on many genes are beyond what one cut can fix. And Cas9 can sometimes cut at a spot that almost matches the guide but is the wrong one, an off-target edit, which is why a treatment's guide is checked for those before it is approved. 😎

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Analogy

CRISPR is an editor who reads down a page for one exact phrase, cuts it out, and sometimes leaves a note on what could go in its place. The original writer then decides what happens at the cut. Usually the writer just leaves it as it stands, and the text there is jumbled: that gene is disabled. Sometimes the writer takes the editor's note and writes something new in its place: that gene is rewritten. The writer, not the editor, decides which of the two happens. The editor is CRISPR, the phrase is the guide, and the writer is the cell doing its own repair. To cut somewhere else you give the editor a new phrase to look for; you do not need a new editor.
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Analogy

CRISPR is a way to find the one exact frame on a three-hour reel plus the scissors that cut there, and the two together are the tool. You can sometimes leave a piece of film beside the cut as a template for the patch. The film's owner, who is the cell, then does one of two things. Sometimes the owner just joins the two ends of the reel, and that stretch plays garbled: the gene is disabled. Sometimes the owner takes your template, builds a piece from it, and joins that in where the cut was: the gene is rewritten. The finder is the guide and the scissors are Cas9. To cut a different scene you describe a different frame, and the same scissors do the job. 😎
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Formal definition — The same term, explained the usual way

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a genome-editing system, adapted from a bacterial adaptive immune mechanism, in which a guide RNA directs a Cas nuclease, most commonly Cas9, to a complementary DNA sequence, where the enzyme introduces a double-strand break. The cell's own DNA repair pathways then act at the break: non-homologous end joining typically produces small insertions or deletions that disrupt the targeted gene, while homology-directed repair, when a donor template is present, may incorporate a specified sequence, with efficiency that varies by cell and cell type. Retargeting requires only a new guide RNA rather than a new protein, which is the principal reason for the system's rapid adoption. The first CRISPR-based therapy, exagamglogene autotemcel (Casgevy), was approved in December 2023 for sickle cell disease and transfusion-dependent beta-thalassaemia.

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