Scientists have learned to change the memory of genes: this is how alcoholism can be treated

Scientists use the Crispr gene editor to cut out problematic DNA to treat diseases. But there are times when it's better to leave the gene intact and tweak it instead, for example by changing the memory of a gene that is responsible for alcohol behavior disorder, reports Wired.

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By now, you've heard of the Crispr Gene Editor, a molecular scissor that allows scientists to make targeted changes to an organism's DNA. Crispr has shown promise as a treatment for sickle cell anemia, a related blood disorder called beta thalassemia, a rare form of blindness and a devastating disease known as transthyretin amyloidosis, in which a malformed protein builds up in the body.

Epigenetic editing

Epigenetics is the study of chemical changes that occur in DNA throughout life, which in turn affect gene expression. These changes can occur as a result of a person's behavior (for example, due to diet or smoking) or environmental influences (for example, toxins or ultraviolet rays). Epigenetics is a kind of molecular memory that reflects the experiences we have had over the years.

It is for this reason that among identical twins with the same DNA code, one can develop cancer, while the other remains healthy.

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While gene editing is based on changing the DNA code itself, epigenetic editing involves increasing or decreasing the expression of individual genes. Genes contain instructions for the production of vital proteins, and their expression is the process by which a gene is "turned on" to produce them. If you think of your genes as volume controls on a deck, epigenetic editing determines how "loud" or "quiet" their settings will be.

Experimenting with these volume controls is a new area, but a study published in May in the journal Science Advances offers an intriguing look at one possible use for the new technology: counteracting how early drinking alters how genes work. In previous studies, scientists have found that excessive drinking during adolescence alters brain chemistry in the amygdala, the small amygdala part of the brain that controls fear and pleasure responses. In both rodents and humans, they found that exposure to alcohol early in life appears to reduce the expression of a gene called Arc. This gene is the main regulator of plasticity, or the ability of the brain to adapt based on experience. When Arc expression is reduced, the change is associated with predisposition to anxiety and alcohol use disorder in adulthood.

For the new study, a team led by Subhash Pandey, professor of psychiatry and director of the Center for Alcohol Research in Epigenetics at the University of Illinois at Chicago, wanted to see if they could reverse this change - in rats - by epigenetically editing Arc in their amygdala.

They created a modified form of Crispr that, instead of editing or deleting a gene, increases its expression. They then injected it into the brains of adult rats that had been exposed to alcohol during adolescence, the equivalent of 10 to 18 years of age for humans. This early exposure meant that Arc expression was already suppressed in adult animals. “We targeted the central nucleus of the amygdala because it is a critical node for processing information going to the brain and also a center for anxiety, fear, and drinking behavior,” says Pandey.

The Crispr injection brought Arc expression back to baseline, in what Pandey calls a “reset” for the brain. After that, these rodents consumed less alcohol and were less restless—something the researchers measured through behavioral testing, including how the rats behaved in the so-called "elevated plus maze." The cruciform maze consists of two open-air branches and two closed branches. The more stressed the rodents are, the less time they like to spend in the open parts of the maze.

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“We didn't see any sign of their drinking going back to baseline, so we think maybe this epigenetic editing will have a long-term effect,” Pandey says. “I think there is a lot more work to be done in terms of how this can be translated into people for therapy, but I have high hopes.”

To test whether the Arc gene was indeed responsible for this result, the researchers also developed a Crispr injection designed to reduce its expression. They tested it on rats that weren't exposed to alcohol as teenagers. After the injection, the rats experienced more anxiety and consumed more alcohol than before.

The study raises the possibility that our molecular memory may be revisited or even erased.

“I am deeply impressed by this work, which demonstrates that it is possible to change a gene’s memory of its experiences,” says Fedor Urnov, a professor of genetics at the University of California, Berkeley, and scientific director of the Institute for Innovative Genomics at the University of California, Berkeley, and the University of California, San Francisco. But, he says, rats are not people, and we shouldn't jump to conclusions. “There is a huge distance between treating a rat and a human with alcohol addiction using an epigenetic editor,” says Urnov. “I think we are a long way from someone who has developed a mild drinking problem being eligible for a quick shot into their amygdala.”

However, Urnov, who is also the co-founder of Tune Therapeutics, an epigenetic editing company, could see an experimental therapy like this being tested in people with alcohol addiction who have relapsed several times after treatment and who are left with no other therapeutic options. .

However, as with direct gene editing, changing gene expression can have unintended consequences. Because Arc is a regulatory gene involved in brain plasticity, changes in its expression may have consequences beyond alcohol addiction. “We don't know what other behaviors were changed by this intervention,” says Betsy Ferguson, a professor of genetics at Oregon Health & Science University who studies the epigenetic mechanisms of addiction and other mental disorders. “It’s a balance between finding something effective and something that doesn’t interfere with everyday life.”

Another complicating factor is that the expression of dozens or even hundreds of genes changes over time under the influence of alcohol. For humans, this may not be so easy. While it might seem like the solution would be to tune all of these genes, manipulating the expression of many genes at once can cause problems. “Knowing that behavior, including behavior associated with drinking, is regulated by a number of genes, it is really difficult to solve this problem,” says Ferguson.

And it is not clear how long the effect of such editing can last. Epigenetic changes that happen naturally can be temporary or permanent, says Ferguson. Some may even be passed on to future generations. Overall, she finds the idea of ​​using epigenetic editing to treat alcohol addiction exciting, but she would like the results to be replicated and the Crispr treatment tested in larger animals that more closely mimic humans.

That day may not be far off, as several companies have recently begun commercializing epigenetic editing. At Navega Therapeutics, based in San Diego, researchers are studying how to treat chronic pain by downregulating a gene called SCN9A. When it is strongly expressed, it sends a lot of pain signals. But it would be a bad idea to just remove this gene, because some pain is good; it signals when something goes wrong in the body. In rare cases, people with the SCN9A mutation, which effectively renders it inactive, are immune to pain, making them vulnerable to injury they cannot feel. In experiments at Navega, epigenetic editing in mice appeared to suppress pain for several months.

Meanwhile, Urnova'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 an antidote to binge drinking, he thinks this proof-of-concept study shows that it's possible to reprogram our genes to reverse some of the damage of early alcohol abuse.

“Frankly, it is very important to consider the fact that we now have the ability to edit the genome to combat the harmful effects of alcohol right at the point where it is written as a memory in the brain,” he says.

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