Gene editing tools like CRISPR have the potential to let us change discrete segments of DNA to treat a host of diseases directly at the root. But there is one genetic frontier scientists have yet to break through: the mitochondria. Passed down from mother to child, mitochondria possess 37 genes in which mutations can give rise to around 300 different metabolic illnesses, like Leigh syndrome (which affects the brain’s role in motor movements) or Pearson syndrome (which causes anemia and other blood issues). And unfortunately, we’ve had limited success in using conventional gene-editing methods to study or correct these disastrous mistakes.
But scientists are steps closer to lifting away the mysterious mitochondrial veil. In a new study published April 25 in the journal Cell, South Korean researchers have devised a new gene-editing tool that can precisely swap out the nucleotide adenine for another nucleotide guanine within the mitochondrial genome.
“This is a creative study that has the potential to greatly expand the range of mitochondrial mutations—and thus diseases—that are accessible to genome editing-based therapeutic approaches,” Joseph Mougous, a microbiologist and Howard Hughes Medical Institute investigator at the University of Washington, who was not involved in the study, told The Daily Beast in an email.
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Mitochondria, found in each and every one of the human body’s trillions of cells, are widely-known as the powerhouse of the cell—responsible for converting food and oxygen into usable energy. Scientists believe they were once independent single-celled organisms that got swallowed up by larger cells billions of years ago , which would explain why they have their own (tiny) genomes that get passed down.
“There are some extremely nasty hereditary diseases arising due to defects in mitochondrial DNA,” Jin-Soo Kim, a biologist at the Center for Genome Engineering and the study’s lead researcher, said in a press release. “For example, Leber hereditary optic neuropathy, which causes sudden blindness in both eyes, is caused by a simple single point mutation in mitochondrial DNA.”
And while CRISPR has been a boon to genetics research in the past decade, it’s been a difficult technology to apply to mitochondrial DNA, David Liu, a biologist and Howard Hughes Medical Institute investigator at Harvard University, who was not involved in the study, told The Daily Beast in an email.
In 2020, Liu and Mougous managed to circumvent that roadblock by creating a gene editing tool that could swap out a cytosine for a thymine (which, along with adenine and guanine, make up the quartet of DNA building blocks). This new platform finally opened up the mitochondria for gene-editing business but it could only address one type of mutation—when thymine spontaneously turns into cytosine—and not when guanine mutated into adenine.
Building off of Liu and Mougous’ prior research, the South Korean group built a new version of the mitochondrial gene editor called a TALED, with a broader scope of targets (including reversing guanine-adenine mutations). It uses a protein called a transcription activator-like effector (or TALE) to target specific mitochondrial DNA sequences, and applies an enzyme that makes the desired adenine-to-guanine edit, in addition to cytosine-to-thymine reversals as well.
“Since adenine base editing can, in principle, correct many of the mutations in mitochondrial DNA that cause genetic diseases, [Kim and his] group’s work is a key advance towards the precise correction of pathogenic mitochondrial mutations,” said Liu.
Kim and his team are still working on improving the efficiency and specificity of their tool so that eventually, it could be used to treat mitochondrial diseases, which can strike at any age but especially be fatal and life-threatening if they go undiagnosed in infants and young children. In the U.S., one in 5,000 people has a mitochondrial disease and about 1,000 to 4,000 children are born with one each year, according to the Cleveland Clinic.
"Large investments in nuclear genome editing over the last several years are spilling over to allow researchers interested in mitochondrial genome editing to make progress at a staggering rate,” said Mougous. So while we can’t repair the mitochondria on our own just yet, rest assured we’re riding the swift wave of science.
