Science · Biology

CRISPR

1987 observed; 2012 adapted for gene editing

Biology — genome editing

CRISPR — Clustered Regularly Interspaced Short Palindromic Repeats — is a bacterial immune system that stores fragments of viral DNA between repeated sequences and uses them as a memory to recognise and cut returning invaders. In 2012 Jennifer Doudna and Emmanuelle Charpentier showed that the CRISPR-associated nuclease Cas9 could be programmed with a single guide RNA to cut any chosen DNA sequence, turning it into a cheap, precise gene-editing tool. They shared the 2020 Nobel Prize in Chemistry — the first science Nobel won by two women alone.

How to spot them

▸An acronym for repeated palindromic sequences separated by spacers of viral DNA
▸A bacterial adaptive immune system, repurposed as molecular scissors
▸Works with the enzyme Cas9, guided to its target by a short RNA
▸The subject of the 2020 Nobel Prize in Chemistry, won by two women
▸Used in Casgevy, the first approved therapy of its kind, for sickle cell disease

Key facts

First seen in 1987 by Yoshizumi Ishino as a set of odd repeated sequences in the genome of Escherichia coli (1987)

He had no idea what they did; the acronym was coined years later by Francisco Mojica in Alicante.

A bacterial immune memory: fragments of past viral invaders filed between repeats and used to recognise them again

Yoghurt companies confirmed the function in Streptococcus thermophilus while protecting cultures from phages.

Doudna and Charpentier's 2012 Science paper showed a single guide RNA could aim a bacterial nuclease at any chosen sequence (2012)

Lead author Martin Jinek; the paper turned a curiosity into a tool.

The 2020 Nobel Prize in Chemistry, the first science Nobel awarded to two women and no man (2020)

A long patent dispute ran in parallel between Berkeley and the Broad Institute's Feng Zhang.

In 2018 He Jiankui used it on human embryos in Shenzhen and was jailed for three years (2018)

Twin girls known as Lulu and Nana; the work was condemned worldwide.

Casgevy, approved in the UK in November 2023, was the first medicine of its kind licensed anywhere (2023)

For sickle cell disease and beta thalassaemia; US approval followed in December 2023.

Its cutting enzyme will only act next to a short signature called a PAM, usually the three letters NGG

The protospacer adjacent motif, which stops the bacterium cutting its own stored copies.

Key ideas

The guide RNA base-pairs with a 20-letter target sequence; Cas9 makes a double-strand break and the cell's own repair machinery does the editing — error-prone end joining to knock a gene out, or homology-directed repair to write a new sequence in.
Later refinements avoid cutting both strands at all: base editing chemically converts one letter to another, and prime editing writes short sequences using a reverse transcriptase.

Quick-fire facts

•The acronym stands for Clustered Regularly Interspaced Short Palindromic Repeats; Cas means CRISPR-associated.
•The workhorse nuclease Cas9 comes from Streptococcus pyogenes; Cas12a (Cpf1) and the RNA-targeting Cas13 are alternatives.
•Jennifer Doudna has her own GoDeep entry as a scientist; Emmanuelle Charpentier is a French microbiologist who was at Umeå in Sweden when the key work was done.
•Francisco Mojica, who named it and first proposed its immune function, has never shared in the Nobel Prize.
•The 2020 prize was the first Nobel in any science awarded to an all-female pair.
•The first therapy, exagamglogene autotemcel (Casgevy), edits a patient's own blood stem cells to switch fetal haemoglobin back on.
•It is cheap: guide RNAs cost a few tens of pounds, against months of work for the older zinc-finger and TALEN methods.
•Common misconception: it does not itself rewrite DNA. It cuts, and the cell's repair pathways determine the edit.

Drill it — 9 cards

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Sources

Walter Isaacson — The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race
Jennifer Doudna and Samuel Sternberg — A Crack in Creation: The New Power to Control Evolution
Martin Jinek, Krzysztof Chylinski, Ines Fonfara, Michael Hauer, Jennifer A. Doudna and Emmanuelle Charpentier — A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity (Science, 2012)