Science1 publisherNot yet confirmed elsewhere2 min readPublished
Fused bacterial proteins insert large DNA blocks at a programmed genome site
A team led by microbiologist Joe Peters fused two unrelated bacterial proteins into a compact tool that inserts large DNA blocks at a chosen genome site. It works in bacteria, and the team is still hunting for relatives that work in human or plant cells.
The Scientist · Science desk
What happened
- The RNA-guided enzymes it uses are thought to be the evolutionary ancestors of today's CRISPR-Cas systems.
- In a separate but related set of experiments the group improved an existing CRISPR-Cas system, cutting wrong-site insertion and raising efficiency over the current method.
- The study appeared Oct. 1 in Molecular Cell, and the team has applied for a patent on the tool.
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Why it matters
- capability Correcting diseases that span long DNA stretches needs whole-section edits, which base editing (one base) and prime editing (a few) cannot make.
- constraint Fewer parts and smaller size ease delivery, since the viruses used to carry gene editors into cells hold only limited DNA.
- constraint A human or plant application is not here yet: the system was shown in bacteria, and bacterial tools need extra parts to work in those cells.
The paper reports two results. The first is the fusion: TldR, an RNA-guided protein that finds exactly where a payload should go, joined to TniQ, which inserts the cargo in a single orientation at that spot. [11][12] "So, we took these vastly different kinds of components and we fused them together," Peters said. [13] The two proteins do not occur together in nature. [2]
The second is a separate set of experiments on an existing CRISPR-Cas system. There the team reports greater efficiency and accuracy than the current method, and a lower chance of the payload landing in the wrong place. [4][5] Those gains belong to that work, not to the de novo fusion.
TldR is one subgroup of a larger family, the TnpB-family named in the paper's title, and the group is now screening many relatives to find any that work in human or plant cells. [14][19] That search matters because the whole system was demonstrated in bacteria. [1] Editing tools borrowed from bacteria need extra specialized parts before they function in a plant or animal cell, and no human- or plant-cell version has been shown. [17]
The size argument is practical. "You want things that are smaller and with fewer components because it makes delivery easier for editing technology," Peters said. [16] The viruses commonly used to carry gene editors into cells hold only so much DNA, and the new system is smaller than CRISPR-Cas. [15]
The gains in accuracy and efficiency arrive without figures: no measured off-target rate, no efficiency number, and no comparison with the current method. [4] The authors' analogy is about scope: base editing changes one letter, prime editing a few words, and this inserts a whole sentence or paragraph. [7] Many diseases involve long stretches of DNA, so changing large sections at once is necessary. [20]
Peters put the draw of a big payload directly. He said the system can be programmed to put a huge block of DNA in a new location, and that this has the field very excited, with a huge amount of competition and other strategies focused on delivering a big payload. [9]
What to watch
- Whether any of the TnpB-family relatives the team is screening turns out to work in human or plant cells.
- Whether the patent application on the RNA-guided transposition system is granted.
- Whether a follow-up reports measured off-target and efficiency rates outside bacteria.