CRISPR-Cas9 — the original gene editing tool that won the 2020 Nobel Prize in Chemistry — works by cutting both strands of the DNA double helix at a precisely targeted location. The cell's natural DNA repair mechanisms then either disable the cut gene or, if a repair template is provided, replace it with a new sequence. This approach is powerful, but it requires the cell to generate a double-strand break — an event that can occasionally cause unintended mutations if the repair process goes wrong.
A new generation of CRISPR tools — base editing and prime editing, developed at the Broad Institute and in academic labs around the world — have changed this fundamental limitation. Instead of cutting DNA, these tools chemically convert one DNA letter into another without breaking the double helix. The precision improvement is enormous, and it dramatically expands the number of genetic diseases that can be corrected.
Base Editing: Single-Letter Precision
Base editing, developed by David Liu's lab at the Broad Institute, uses a CRISPR system that has been deactivated to lose its cutting ability but retains its ability to locate specific DNA sequences, combined with a chemical enzyme that converts one DNA base to another. Current base editors can convert adenine to guanine (adenine base editors) or cytosine to thymine (cytosine base editors) — covering two of the four possible single-letter substitutions in DNA.
This covers an enormous proportion of disease-causing mutations. Approximately 58% of disease-causing single-nucleotide variants are addressable by base editing. Beam Therapeutics, the company David Liu co-founded to commercialise base editing, has multiple programmes in clinical development — including BEAM-101 for sickle cell disease, which appears to show even higher efficacy than Casgevy in early data.
"Base editing and prime editing do not just improve on Cas9. They expand the definition of what CRISPR can treat. The pharmaceutical pipeline addressable by gene editing has grown by an order of magnitude in three years."
Prime Editing: The Search-and-Replace of Genetics
Prime editing, also from David Liu's lab, goes further — it can make any of the twelve possible point mutations in DNA, as well as small insertions and deletions, without cutting the double helix and without needing a separate repair template. If base editing is a pencil that can change two specific letters, prime editing is a word processor that can find any sequence and replace it with any other sequence of similar length.
Prime editing's versatility makes it the most therapeutically powerful CRISPR tool available — but also the most technically challenging to deliver efficiently into cells in the body. Multiple companies are working on delivery systems optimised for prime editing, and the pharmaceutical opportunities unlocked when efficient in vivo prime editing becomes reliable are nearly unlimited.
The Domain That Covers the Full CRISPR Toolkit
CrisprPharma.com covers Cas9, base editing, prime editing, and every future CRISPR tool — the full arc of gene editing pharmaceutical development.
Acquire This Domain →