CRISPR acts like a pair of scissors, cutting whole sections of DNA and then leaving the cell to repair the double helix. Conversely, ABE leaves no collateral damage for the cell to fix. "We developed a new base editor, a molecular machine, that in a programmable, irreversible, efficient, and clean manner can correct these mutations in the genome of living cells," explained Liu.
Since large numbers of genetic disorders, such as cystic fibrosis and genetic blindness, are caused by incorrect base-pairing, ABE’s ability to change just those single base-pairs signals the hope that it may one day be used to treat in embryos, or prevent diseases.
ABE, another step in the CRISPR storyAttached to the same molecule used to identify the target area with CRISPR, Liu said ABE works “at virtually any target site in genomic DNA.” In laboratory tests thus far, ABE has managed to alter the DNA of more lab-grown human cells than CRISPR was able to.
CRISPR is also infamous for creating many off-target edits and randomly inserting or deleting genes. ABE only mistakenly made four off-target edits of the 12 sites provided, whereas CRISPR made nine, and left almost no unintentional insertions, or deletions.
According to Liu, half of the 32,000 known disease-causing, single-letter mutations can be fixed by ABE, including Tay-Sachs disease and cystic fibrosis. ABE was also able to mutate a gene into a form that prevents sickle cell disease, even in individuals who have its disease-causing mutation. This also means that it has the potential to "write in" useful mutations, revealed the scientists.
RNA can be REPAIR’d, too
In a separate study, Feng Zhang from the Broad Institute, one of the scientists credited with the discovery of CRISPR, and his colleagues discovered a genetic tool that can edit RNA. Called RNA Editing for Programmable A to I Replacement (REPAIR), it allows scientists to make temporary, reversible edits to the disease-causing genetic mutations on the molecule that carries genetic instructions to protein-making machinery in cells.
"RNA naturally degrades, it's a potentially reversible fix," explained David Cox, a graduate student in Feng Zhang's lab. “Editing DNA is hard to reverse, but once you stop providing the RNA-editing system, the changes will disappear over time,” highlighted Zhang. It, too, acts like a pencil.
Published in the Science journal, Zhang said “that might make it possible to treat conditions where you don’t need a permanent edit.” Inflammation in the immune system could be one such example.
REPAIR still needs much improvementZhang and his team created the RNA-editor by fusing an enzyme that binds to RNA with another, which changes adenosine (A) to inosine (I), which is similar to guanosine (G).
In the laboratory, REPAIR was tested on human cells that either contained the mutation causing Fanconi anaemia or nephrogenic diabetes insipidus. In the cells with the DNA containing the anaemia mutation, REPAIR was able to correct 23% of them. In the cells containing the mutation causing the diabetes, REPAIR was able to correct 35% of them.
Despite the relatively low score, REPAIR is tipped to be able to correct disorders such as epilepsy and Duchenne muscular dystrophy.
Scientific community posed for the future
Both of the genetic tools have one potential that CRISPR never had – the potential to enter and correct mutations in mature cells such as neurons, which Liu says he has explored in the research he yet to publish. This suggests that treating neurological diseases may one day be a possibility too.
There are still a number of issues to solve. "For example, one has to develop a good delivery approach to getting the machine into the right tissues into the right cells at the right stage of the patient's life," Liu said of ABE.
"A tremendous amount of work is still needed before these molecular machines can be used to treat human disease in patients... but having a machine is an important starting point," he explained.
Harvard biologist George Church, who helped to make CRISPR functional in human cells, said changing a single DNA base meant there would be “fewer worries about the editing enzyme later going rogue or silent.” He also hopes that crops with a single base change will not be deemed “transgenic”, and so can be sold.
Scientists from around the world are excited by the discoveries. “One reason these are so exciting is, they show the CRISPR toolbox is still growing,” said chemical engineer Gene Yeo of the University of California, San Diego. “There are going to be a lot more, and it’s not going to stop anytime soon.” MIMS
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