The researcher behind base-editing is out with what some scientists are hailing as the biggest advancement in CRISPR technology since that 2016 breakthrough: “prime editing.” The new molecular gadget is capable of erasing any base pair and stenciling in another and cutting or adding long segments of DNA without breaking both strands of the helix.
Luke Dow Dow Lab David Liu, base editing pioneer and founder of Beam Therapeutics, published the findings in Nature alongside Andrew Anzalone. They estimated that the breakthrough “in principle” puts 89% of human diseases in purview — although experts cautioned that human therapies were a long way off.
“This is a big advance,” Luke Dow, a Cornell cancer researcher who was not involved in the study, told Endpoints News. “The evidence in this case for correcting those disease alleles is the first step and that’s a long way off from the last step.”
To pivot the tech into therapeutic applications, Liu also launched Prime Medicine with the backing of Arch Venture Partners, GV, Newpath Partners and F-Prime. That could spell trouble for Beam, which filed for a $100 million in September and may now see some of their science outpaced, although the prime editing tech has been sublicensed to Beam for some fields.
The early CRISPR technology, for all its heralded precision, was something of a blunt force object. It tears open DNA, creating what are called double-strand breaks, and then leaves the DNA to patch itself back up, by knitting the two strands together, taking random nucleotides from within the cell to fill the gap or splicing in patches of DNA supplied by scientists. It’s often loathe to do the latter, a major obstacle in applying CRISPR to diseases that require not only removing faulty genes but putting in the right ones. Even when it does, it can often cause off-target effects.
Liu made a major breakthrough in 2016 when he introduced base editing – the ability to directly rewrite the nucleotides that make up DNA’s 4-letter alphabet. News coverage talked about the potential to cure diseases such as sickle cell, caused by a single nucleotide in the gene for hemoglobin.
The problem was Liu’s first discovery –and Beam Therapeutics, the company he launched around it – had major difficulty attacking sickle cell, because that first gadget could only make four switches: C-to-T, T-to-C, A-to-G, and G-to-A. A sickle cell treatment would require switching T to A on the right gene.
In yesterday’s Nature paper, Liu and his coauthors switched T to A. They also switched every other of the 12 possibilities.
“It doesn’t improve on base-editing,” Dow said. “The original base editing tool the Liu lab described a few years ago with a few modifications became very efficient. What this does is open up a lot of different types of mutations that weren’t available previously.
Liu described the new tech as a “search-and-replace” tool – essentially control F for the human genome. That’s probably overselling where the tech is today – Dow said they only tested it on four human cell types, leaving questions on how it will fare in the rest – but it gets at the potential. In addition to sickle cell, researchers spliced out the 4-letter sequence that causes Tay-Sachs. Overall, they made 175 edits in mouse and human models.
The authors reported being able to do 44 insertions and said more was possible. They also were able to edit in non-dividing such as neurons and liver cells.
Rather than breaking the cell DNA on both sides and providing another piece of DNA for the cell to incorporate, the new technology breaks only one strand and uses RNA to supply the nucleotides. By not causing double-strand breaks, it limits off-target effects on other parts of the genome – one of the bigger risks of CRISPR technology.