“We did not see any indication of their drinking coming back to baseline, so we think that maybe this epigenetic editing will produce a long-lasting effect,” Pandey says. “I think a lot more work needs to be done in terms of how this can be translated into humans for a therapy, but I have high hopes.”
To test that the Arc gene was truly responsible for this outcome, the researchers also designed a Crispr injection meant to decrease its expression. They tested it in rats that weren’t exposed to alcohol in adolescence. Following the injection, the rats had more anxiety and consumed more alcohol than they did before.
The study raises the possibility that our molecular memory could be revised — or even erased. “I’m struck deeply by this work showcasing the feasibility of changing a gene’s memory of its experience,” says Fyodor Urnov, a professor of genetics at the UC Berkeley and scientific director at the Innovative Genomics Institute of UC Berkeley and UC San Francisco. But, he continues, rats aren’t humans, and we shouldn’t leap to conclusions. “The distance between curing a rat and injecting a human being with addiction to alcohol with an epigenetic editor is a formidable one,” says Urnov. “I think we are quite a way away from somebody who has developed a mild drinking problem becoming eligible for a quick injection into their amygdala.”
That said, Urnov, who is also the cofounder of Tune Therapeutics, an epigenetic editing company, could see an experimental therapy like this being tested among people with alcohol addiction who have relapsed from treatment several times and have no other therapeutic options left.
Yet, as with direct editing genes, there could be unintended consequences of tweaking their expression. Because Arc is a regulator gene involved in brain plasticity, modifying its expression could have effects beyond alcohol addiction. “We do not know what other behaviors are altered by this change,” says Betsy Ferguson, a professor of genetics at Oregon Health and Science University who studies epigenetic mechanisms in addiction and other psychiatric disorders. “It’s a balance between finding something that’s effective and something that’s not disruptive to everyday life.”
Another complicating factor is that the expression of dozens, perhaps hundreds, of genes are altered by alcohol use over time. In people, it may not be as simple as turning up the expression of Arc, which is only one of them. While it may seem like the solution would be to tweak all of those genes, manipulating the expression of many at once could cause problems. “Knowing that behaviors, including alcohol use behaviors, are regulated by a number of genes, it’s really a challenging problem to solve,” Ferguson says.
And it’s not clear how long the effects of such editing might last. Epigenetic changes that occur naturally can be temporary or permanent, says Ferguson. Some can even be passed onto future generations. Overall, she finds the idea of using epigenetic editing to treat alcohol addiction fascinating, but she’d want to see the results replicated and the Crispr treatment tried in larger animals that more closely mimic humans.
That day may not be too far off, as a handful of companies have recently launched to commercialize epigenetic editing. At Navega Therapeutics, which is based in San Diego, researchers are studying how to treat chronic pain by turning down the expression of a gene called SCN9A. When it’s highly expressed, it sends out lots of pain signals. But it would be a bad idea to simply delete this gene, because some amount of pain is useful; it signals when something is going wrong within the body. (In rare cases, people with an SCN9A mutation that effectively renders it inactive are immune to pain, which makes them vulnerable to injuries they are not able to sense.) In experiments at Navega, epigenetic editing in mice seemed to repress pain for several months.
Urnov’s Tune Therapeutics, meanwhile, plans to use epigenetic editing for a broad range of conditions, including cancer and genetic diseases. Though Urnov does not see epigenetic editing as the antidote to binge drinking, he thinks this proof-of-concept study shows that it may be possible to rewire our genes’ experiences to reverse some of the damage of early alcohol abuse. “It is empowering, frankly, to consider the fact that we now have genome editing to fight a drug’s pernicious action right at the venue where the drug inscribes its memories onto the brain,” he says.