“We saw no indication that their drinking would return to baseline, so we think this epigenetic editing might have a lasting effect,” Pandey says. “I think a lot more work needs to be done in terms of how this can be translated into people for a therapy, but I have high hopes.”
To test that Bow the gene was really responsible for this result, the researchers also designed a Crispr injection intended for reduce its expression. They tested it on rats that were not exposed to alcohol in their teens. After the injection, the rats had more anxiety and consumed more alcohol than they did before.
The study raises the possibility that our molecular memory may be revised – or even erased. “I am deeply moved by this work, which demonstrates the potential to change a gene’s memory of its experience,” said Fyodor Urnov, Professor of Genetics at UC Berkeley and Scientific Director at the Innovative Genomics Institute of UC Berkeley and UC San Francisco. But, he continues, rats are not humans and we should not jump to conclusions. “The distance between curing a rat and injecting a human with alcohol dependence with an epigenetic editor is formidable,” says Urnov. “I think we are a long way from anyone who has developed a mild drinking problem being eligible for a rapid injection into their amygdala.”
That said, Urnov, who is also a co-founder of Tune Therapeutics, an epigenetic editing company, could see an experimental therapy like this being tested among people with alcohol dependence who have relapsed from treatment several times and have no other therapeutic options left.
Yet, as with direct editing of genes, there can be unintended consequences of adjusting their expression. Because Bow is a regulator gene involved in the plasticity of the brain, changing its expression can have effects in addition to alcohol dependence. “We do not know what other behaviors are altered by this change,” said 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 is effective and something that does not interfere with everyday life.”
Another complicating factor is that the expression of dozens, perhaps hundreds, of genes is altered by alcohol use over time. In humans, it may not be as simple as screwing up the expression of Bow, which is only one of them. Although it may seem like the solution would be to fine tune all of these genes, manipulation of the expression of many at once can cause problems. “Knowing that behaviors, including alcohol use behaviors, are regulated by a number of genes is really a challenging problem to solve,” Ferguson says.
And it is not clear how long the effects of such editing can last. Epigenetic changes that occur naturally can be temporary or permanent, Ferguson says. Some may even be passed on to future generations. Overall, she finds the idea of using epigenetic editing to treat alcohol dependence 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 launched to commercialize epigenetic editing. At San Diego-based Navega Therapeutics, researchers are studying how to treat chronic pain by turning down the expression of a gene called SCN9A. When strongly expressed, it emits many pain signals. But it would be a bad idea to simply delete this gene because a certain amount of pain is helpful; it signals when something is going wrong in the body. (In rare cases, persons with a SCN9A mutations that effectively inactivate it are immune to pain, making them vulnerable to damage they are unable to sense.) In experiments on Navega, epigenetic editing in mice appeared to suppress pain for several months.
Urnov’s Tune Therapeutics, meanwhile, plans to use epigenetic editing for a wide range of conditions, including cancer and genetic diseases. Although Urnov does not see epigenetic editing as the antidote to overeating, he believes that this proof-of-concept study shows that it may be possible to recreate the experiences of our genes to reverse some of the harms of early alcohol abuse. “It’s honestly empowering to consider the fact that we now have genome editing to combat the harmful action of a drug right at the point where the drug inscribes its memories in the brain,” he says.