“We haven’t seen any indication of their drinking returning to baseline, so we believe this epigenetic modification may have a lasting effect,” Pandey says. “I think a lot more work needs to be done on how this can be translated into humans for therapy, but I have high hopes.”
To test that the Bow gene was really responsible for this result, the researchers also designed a Crispr injection intended to lessen his expression. They tested it on rats that weren’t exposed to alcohol as teenagers. After the injection, the rats were more anxious and consumed more alcohol than before.
The study raises the possibility that our molecular memory can be revised or even erased. “I am deeply struck by this work showing the feasibility of changing a gene’s memory of its experiment,” says Fyodor Urnov, professor of genetics at UC Berkeley and scientific director of UC’s Institute for Innovative Genomics. Berkeley and UC San Francisco. But, he continues, rats are not humans and we shouldn’t jump to conclusions. “The distance between curing a rat and injecting an alcohol-dependent human with an epigenetic editor is formidable,” says Urnov. “I think we’re pretty far from someone who has developed a mild drinking problem and becomes eligible for a quick injection into their amygdala.”
That said, Urnov, who is also the co-founder of Tune Therapeutics, an epigenetic publishing company, could see an experimental therapy like this being tested in alcoholics who have relapsed multiple times after treatment and no longer have other therapeutic options.
Yet, as with direct gene editing, there could be unintended consequences by altering their expression. Because Bow is a regulatory gene involved in brain plasticity, altering its expression could have effects beyond alcohol dependence. “We don’t know what other behaviors are altered by this change,” says Betsy Ferguson, a professor of genetics at Oregon Health and Science University who studies the epigenetic mechanisms of drug addiction and other psychiatric disorders. “It’s a balance between finding something that’s effective and something that doesn’t disrupt everyday life.”
Another complicating factor is that the expression of tens or even hundreds of genes is altered by alcohol consumption over time. In people, it may not be as simple as increasing the expression of Bow, which is only one. Although it may seem that the solution would be to modify everything of these genes, manipulating the expression of several at once could cause problems. “Knowing that behaviors, including drinking behaviors, are regulated by a number of genes, it’s really a difficult problem to solve,” Ferguson says.
And it’s unclear how long the effects of such a montage might last. Epigenetic changes that occur naturally can be temporary or permanent, says Ferguson. Some can even be passed on to future generations. Overall, she finds the idea of using epigenetic editing to treat alcohol addiction fascinating, but she would like 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 away, as a handful of companies have recently moved into the commercialization of epigenetic editing. At Navega Therapeutics, which is based in San Diego, researchers are studying how to treat chronic pain by decreasing the expression of a gene called SCN9A. When strongly expressed, it sends out many pain signals. But it would be a bad idea to simply delete this gene, because a certain amount of pain is useful; it signals when something is wrong in the body. (In rare cases, people with a SCN9A mutation that effectively renders it inactive are immune to pain, making them vulnerable to injury they are unable to detect.) In experiments at Navega, epigenetic editing in mice appeared to suppress pain for several month.
Meanwhile, Urnov’s Tune Therapeutics plans to use epigenetic editing for a wide range of conditions, including cancer and genetic diseases. While Urnov doesn’t see epigenetic editing as the antidote to binge drinking, he thinks this proof-of-concept study shows that it may be possible to rewire the experiences of our genes to reverse some of the damage caused by early alcohol abuse. “It’s frankly empowering to consider the fact that we now have genome editing to combat the pernicious action of a drug at the very place where the drug writes its memories onto the brain,” he says.