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CRISPR was not originally a human invention. It is an adaptive immune system of bacteria: when attacked by a virus, bacteria store a segment of the attacker's DNA in their genome to recognize it the next time.
Mechanism
The system consists of two parts:
- Guide RNA — a segment of about 20 nucleotides that is complementary to the target DNA site to be cut.
- Cas9 enzyme — a protein that performs the cleavage of both DNA strands at that exact location.
The 2012 breakthrough by Jennifer Doudna and Emmanuelle Charpentier was demonstrating that the guide RNA could be reprogrammed at will. To cut anywhere, one only needs to synthesize a corresponding 20-nucleotide RNA segment. The two received the Nobel Prize in Chemistry in 2020.
What happens after the cut
The cell repairs the break through two pathways:
- Non-homologous end joining (NHEJ) — fast but error-prone, often creating mutations that disrupt the gene. Used when the goal is to turn off a gene.
- Homology-directed repair (HDR) — more precise, allowing the insertion of a new sequence if a template is provided.
From the lab to patients
Exagamglogene autotemcel (Casgevy) is the first CRISPR-based therapy approved by regulatory agencies. The UK's MHRA approved it in November 2023 for both sickle cell disease and beta-thalassemia. The US FDA approved it on December 8, 2023, but initially only for sickle cell disease; the indication for beta-thalassemia was added on January 16, 2024.
Ethical boundaries
In 2018, He Jiankui announced he had edited human embryos and created two babies—an act widely condemned by the scientific community that resulted in a prison sentence. The key distinction: editing somatic cells affects only the patient, whereas editing the germline is passed down to future generations. Currently, human germline editing is banned or strictly restricted in most countries.
Further reading
References
- [1]MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia — Medicines and Healthcare products Regulatory Agency (UK) (2023)
- [2]FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease — U.S. Food and Drug Administration (2023)
- [3]A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity — Science (2012)
Image: Elena I Leonova — Wikimedia Commons, CC BY 4.0.
