When humans regularly drink alcohol, only 15 percent or so become dependent on the stuff

From A Landmark Study on the Origins of Alcoholism by Ed Yong. The article primarily focuses on the prospect of genetic treatment of alcoholism. I empathize and hope that the new insights do indeed lend themselves towards treatment of this longstanding scourge.

What I find interesting is the illustration of how blind we often are when considering whether we are examining something on a like-to-like basis. Most of our sociological findings to which we initially react with outrage, later end up failing to replicate and very frequently they fail to replicate because they were failing to compare like-to-like. The classic example is the refuted claim that men and women are paid differently for the same work. If you start with a postmodernist belief set in group identity and patriarchy, then this claim is self-evidently true.

And yet when researchers began to test it thirty or forty years ago, that is not what they found in the data. Sure, for any given individual there might be instances of +/- 5 or 10% deviance from the market but that was true for men and women, whites and blacks, whatever group identity you were interested in. That was the path dependency/circumstantial noise in the system and it applied to everyone. It was not bias at play but circumstance. Some men were underpaid; some women were overpaid. But more pertinently, at the system level, when you control for all the relevant factors that drive variance such as years of experience, field of endeavor, education attainment level, hours worked per week, years worked continuously, etc., men and women are paid exactly the same. Which is what you would expect in a competitive labor market and what economic theory predicts.

The original postmodernist claim was facially plausible but was untrue and it took a long time to reveal the untruth because it took a long time to eventually compare like-to-like.

Which is exactly what happened here, as explained in the article, in an area of consequential research but without the ideological/political overtones.

Many researchers, independent of one another, and without bias, over a long duration, failed to examine rats under the same circumstances as they examined humans. When they finally did so, they found an avenue of research which might actually lead to some positive results. By comparing like-to-like for the first time, they obtained new insights for the first time.

Emphasis added.

For Markus Heilig, the years of dead ends were starting to grate.

A seasoned psychiatrist, Heilig joined the National Institutes of Health in 2004 with grand ambitions of finding new ways to treat addiction and alcoholism. “It was the age of the neuroscience revolution, and all this new tech gave us many ways of manipulating animal brains,” he recalls. By studying addictive behavior in laboratory rats and mice, he would pinpoint crucial genes, molecules, and brain regions that could be targeted to curtail the equivalent behaviors in people.

It wasn’t to be. The insights from rodent studies repeatedly proved to be irrelevant. Many researchers and pharmaceutical companies became disillusioned. “We cured alcoholism in every rat we ever tried,” says Heilig, who is now at Linköping University in Sweden. “And at the end of every paper, we wrote: This will lead to an exciting treatment. But everything we took from these animal models to the clinic failed. We needed to go back to the drawing board.”

Heilig doesn’t buy that mice and rats have nothing to teach us about addiction. It’s more that researchers have been studying them in the wrong way. Typically, they’ll let the animals self-administer drugs by pressing a lever, which they almost always learn to do. That should have been a red flag. When humans regularly drink alcohol, only 15 percent or so become dependent on the stuff. Why them and not the other 85 percent? That’s the crucial question, and you won’t answer it with an experiment in which every rodent becomes addicted.

Eric Augier, who recently joined Heilig’s team, tried a different approach—one pioneered in his former laboratory to study cocaine addiction. After training rats to self-administer alcohol, he offered them some sugary water, too. This better mimics real life, in which drugs exist simultaneously with other pleasurable substances. Given a choice between booze and nectar, most rats chose the latter. But not all of them: Of the 32 rats that Augier first tested, four ignored the sugar and kept on shooting themselves up with alcohol.

“Four rats is laughable,” says Heilig, referring to the study’s small size, “but 620 rats later, no one’s laughing.” Augier repeated the experiment with more rats of various breeds, and always got the same results. Consistently, 15 percent of them choose alcohol over sugar—the same number as the proportion of human drinkers who progress to alcoholism.

Those alcohol-preferring rats showed other hallmarks of human addiction, too. They spend more effort to get a sip of alcohol than their sugar-preferring peers, and they kept on drinking even when their booze supply was spiked with an intensely bitter chemical or paired with an electric shock. “That was striking to me, as a clinician,” says Heilig. “Embedded in the criteria for diagnosing alcoholism is that people continue to take drugs despite good knowledge of the fact that it will harm or kill them.”

Many lab studies treat animals as if they were identical, and any variation in their behavior is just unhelpful noise. But in Augier’s work, the variation is the important bit. It’s what points to the interesting underlying biology. “This is a really good study,” says Michael Taffe, a neuroscientist at the Scripps Research Institute who studies drug addiction. “Since only a minority of humans experience a transition to addiction, [an approach] such as this is most likely to identify the specific genetic variants that convey risk.”

That is exactly what the team did next. They compared the alcohol-preferring and sugar-preferring rats and looked for differences in the genes that were active in their brains. They focused on six regions that are thought to be involved in addiction, and found no differences in five. “But in the sixth, we did,” says Heilig. “And it made me smile because I started out doing my Ph.D. on the amygdala.”

The amygdala is an almond-shaped region that sits deep within the brain, and is heavily involved in processing emotions. When Augier looked at the amygdala of alcoholic rats, he found signs of unusually low activity in several genes, all of which are linked to a chemical called GABA.