Huge breakthrough could change medicine forever

MIT and Harvard scientists have developed a new gene editing tool that can rewrite the mutation in the genome that causes inherited diseases like cystic fibrosis

DNA Edits, Without All the Cutting

This method helped researchers to make precise changes in RNA at different points of the cell.

As CRISPR gene editing marches closer to the clinic, several researchers have been tinkering to unleash the DNA editor on another nucleic acid: RNA, the intermediary messenger between DNA and proteins. No molecular scissors required. Gaudelli started with an enzyme called TadA that's able to convert adenine to a molecule called inosine (which cells treat as guanine), but in transfer RNA rather than in DNA. If DNA is thought of like a blueprint, any edits to it are permanent. Earlier versions of these "base editors", which target typos related to the other half of disease-causing genetic spelling errors, have already been used to alter genes in plants, fish, mice and even human embryos. DNA sequences contain four "base" chemicals that pair up on the molecule's twin-stranded double helix in specific ways. He says a single base pair is like a word in a paragraph of text. The base pairs are found in specific patterns as C pairs with G, and T pairs with A. RNA editors will be valuable instruments for controlling gene expression in the lab, O'Connell says.

"It really tells us that many Cas proteins can truly bind RNA", he said. Mistakes often arise when cellular machinery attempts to fix DNA breaks. Such "permanent irreversible edits at the wrong place in the DNA could be bad", Yeo says. The two are different both structurally and functionally. Within those experimental cells, they used their new type of CRISPR system to fix the mutations at the RNA level.

The work builds on a technique introduced past year that allowed researchers to change C-G base pairs to T-A base pairs.

"REPAIR can fix mutations without tampering with the genome, and because RNA naturally degrades, it's a potentially reversible fix", said co-first author David Cox, a graduate student in Zhang's lab. According to Liu, about half of the 32,000 known pathogenic point mutations in humans can be traced down to mutations that change G-C to an A-T. Until now, there was little anyone could do about it, he says.

Because no enzyme exists in Nature that will turn an "A" base into a "C" - the key step in the "repeal and replace" manoeuver - the scientists had to create one, a feat they had never attempted. Such enzymes chemically convert adenine to inosine (I), which the cell interprets as G. Such RNA editing happens frequently in octopuses and other cephalopods and sometimes in humans (SN: 4/29/17, p. 6).

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Zhang is part of the team who first harnessed CRISPR for mammalian genome editing and has now been instrumental in creating the new system fix.

But this variation slices RNA instead. Zhang and colleagues then bolted the A-to-I converting portion of ADAR2 onto CRISPR/Cas13.

Carroll stated that the gene editing enzyme would be a very useful tool for both research and practical studies in medicine and possibly in agriculture. The researchers did not detect any undesired changes. For example, RNA editing could serve as a short-term therapy during wound healing and inflammation by modulating the activity or levels of RNA that produce proteins involved in those processes.

Prof David Liu of the Broad Institute said: "We are hard at work trying to translate base editing technology into human therapeutics". But that editor couldn't make the opposite change, switching A to G. "I think there is more work to be done, but essentially the idea that any RNA [sequence] could be targeted is pretty exciting". The classic CRISPR system uses an enzyme called Cas9 to cut DNA. The result was a base editor, called ABE, that could switch A-T base pairs into G-C pairs in about 50 percent of human cells tested. He also cautions that the study was done only in cell lines. That mutation is known to confer protection against blood diseases including sickle cell anemia. Researchers can now manipulate the four bases.

Liu's team invented an approach called base editing.

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