More than a decade ago Sonia Vallabh, a lawyer, and her husband, an engineer, decided to retrain as molecular biologists. They had an urgent motivation. Dr Vallabh’s mother had died suddenly of a mysterious dementia. An autopsy had revealed the cause to be prion disease, in which the prion protein, the normal function of which is unclear, changes form and spontaneously clumps together and causes the brain to die. Most prion disease is infectious, set off by exposure to an already clumping protein. In this case, it was genetic. “I learned that I’d inherited her mutation,” Dr Vallabh says. They needed to find a cure before the disease came for her, too.
They now run a lab at the Broad Institute in Boston. By 2024 they had created an editor that, in mice, turns off the prion gene in the brain, preventing the disease from taking hold. Next up is making it work in humans. Their editor, however, does not touch the gene at all.
No cell makes all the proteins for which it has genes. A blood cell does not need the same proteins as a neuron. One way cells turn off unneeded genes is by putting locks on them. These locks are chemical changes to the bases that make up DNA or to proteins that store DNA inside the cell. They are known as “epigenetic” marks since the changes are “on top of” the genome, not in the genome itself. What Dr Vallabh and her husband did was put a lock on the prion gene, using what they call an epigenetic editor.
Gene editing can be tough on the genome. Epigenetic editing is gentler. Rather than chopping the DNA in two, it uses an enzyme that installs or removes a chemical lock at a specific place in the genome. Chroma Medicine, an epigenetic editing company in Boston (now nChroma Bio after a merger), examined CAR-T cells, a type of manipulated immune cell showing promise in treating cancer and other diseases. Adding more edits to them could make them more effective. To achieve that several genes must be switched off, a multi-edit which kills off a lot of cells if you use CRISPR-Cas9. But doing the job by epigenetic editing, says Luke Gilbert, who co-founded Chroma Medicine, is “basically non-toxic”.
Although edits are not permanent, they are long-lasting. And because the changes are more easily reversible in theory, epigenetic editing may feel less radical to the public than gene editing. Benjamin Oakes, the boss of Scribe Therapeutics, a Californian biotech firm, sees a future in which epigenetic editing becomes like getting a flu shot, but for protection against heart attacks and obesity instead of viruses. Scribe’s epigenetic editor can block a gene causing unhealthy cholesterol in monkeys. “We can essentially modify your genome so you’re no longer producing risk factors for cardiometabolic disease. And maybe every five years, or every ten years, you need to come back for a booster dose.”
Looking further into the future, epigenetic editing could undo damage accrued during life. Ageing, disease, chemical exposure and emotional trauma all influence the body’s epigenetic marks. Editing might be able to erase such scars. In 2022 researchers from the University of Illinois at Chicago targeted epigenetic patterns, acquired during teenage binge drinking, which are linked to anxiety and drinking problems. They could reverse the changes in alcohol-exposed rats, with the result that they drank less and became less anxious.
Drugs that remove the scars of life, though, are a long way off. ■