CRISPR Modifications To Mitochondria May Lead To New Biotech

CRISPR Modifications To Mitochondria May Lead To New Biotech

Though the CRISPR / Cas9 system was used in many applications of editing the nuclear genome, altering the mitochondrial genome was a tedious task. The main bottlenecks consisted of a lack of suitable editing sites in the small mtDNA—the extra challenge of importing the guide RNA into the mitochondrial matrix where nucleoids are accessible.

Two new papers on the subject say that notable progress is made on both fronts. The first paper, posted in the journal SCIENCE CHINA Life Sciences, used CRISPR tech to provoke insertion/deletion (InDel) events at various mtDNA microhomologous regions. The InDel events were provoked particularly by double-strand break (DSB) lesions.

The study’s authors discovered that InDel mutagenesis was considerably improved by sgRNA multiplexing and a DSB repair inhibitor known as iniparib, denoting a rewiring DSB repair mechanism to alter mtDNA. In the second study, posted in the journal Trends in Molecular Medicine, the scientists gave a notable overview of recent progress in various forms of nuclear and mitochondrial genome modifications.

To gather some extra insight into the new developments, journalists reached Payam Gammage, an expert in the field of mitochondrial editing with a known history in perfecting a somewhat different editing technology based on zinc-finger nucleases (ZFNs).

The nucleus can eliminate heteroplasmic mitochondria that present faulty nucleoids.

More recently, scientists found out that 25 of the 30 most mutated genes discovered in cancer are also present in mtDNA. The mutations happen at particular loci in approximately 60% of all tumors and, at least in colorectal cancer, increase patient lifespan by approximately nine years in contrast to mtDNA. More than 70% of colorectal cancers have at least on mtDNA, which is found at heteroplasmy levels greater than 5%.

While nucleases can edit out deleterious changes by picking the adequate mitochondria, a technology capable of editing-in new variants that is yet to be perfected.

While the methods used in CRISPR editing described in the previously mentioned papers sound exciting and promising, Payam manifested three main concerns that could decrease the rate of progress of the technological advancements.

First of all, the Life Sciences paper doesn’t wholly address targeting sgRNA to mitochondria. Also, a decreased level of double-strand break religation has formerly been presented in mammalian mitosis. Cas9 protein manifested in high levels without gRNA responses in nonspecific double-strand induction.

Lastly, the DSB repair inhibitor used by research may not do precisely what they thought before.

It was once believed that it inhibited PARP (Poly (ADP-ribose) polymerase), it was finally shown to work in different manners.

Additionally, PARP can’t be found in mitochondria.

A constructive approach to precise, nondestructive mitochondrial editing that doesn’t need CRISPR tech was recently introduced by David Liu from Harvard and MIT’s Broad Institute.

You may not be familiar with his name though he has often been quoted as the true inventor of CRISPR because the Nobel Committee’s higher powers deemed he shouldn’t fit the bill.

Liu’s method is based on a bacterial toxin known as DddA that helps catalyze cytosine deamination within double-stranded DNA.

Adding a uracil glycosylase inhibitor and some TALEN-like proteins helped Liu create RNA-free DddA-derived cytosine base editors (also known as DdCBEs) catalyze C*G-to-T*A conversion in human mtDNA with increased target specificity and product purity.

Further research is needed to perfect the process and make it usable on a larger scale. However, progress is indeed happening, and better results are expected soon, so stay tuned for extra news on the subject!

Asheley Rice

I am a pop culture and social media expert. Aside from writing about the latest news health, I also enjoy pop culture and Yoga. I have BA in American Cultural Studies and currently enrolled in a Mass-Media MA program. I like to spend my spring breaks volunteering overseas.

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