Okay, so the behavior of drunken flies was virtually identical to that of other animals, not to mention humans, but that was just the beginning. Now Heberlein went about looking for a clean experimental apparatus that would allow her to quantify the behavior. "That's when we ran into this device called the inebriometer," she says. "It had been used previously in studies of population genetics to selectively breed flies for alcohol resistance."

Regrettably, inebriometers are not the kind of equipment one can simply buy. Even the population geneticists had built their own. So Heberlein and Carol Singh, her research technician and sole collaborator, had to do the same. "The thing with starting something like this," she says, "is the equipment doesn't exist; you have to build it. The first few months you spend going to the glass shop, going through catalogs, finding fittings and flow meters, trying to engineer this inebriometer. I still remember the day we just turned on the air in the first one and we thought it was going to blow up in our faces."

It didn't however, and they eventually built eight of the devices. Each was a glass column, four feet tall and only about three inches in diameter. Inside the column was a series of platforms on which the flies could perch; the columns were attached to the plumbing needed to diffuse alcohol vapor through the column.

"We put flies into the top of the column, where they will stay in the absence of alcohol," explains Heberlein. "In the presence of alcohol, as they start to become intoxicated, they start losing their postural control. They start falling from one of these platforms to the next, to the next, and they gradually tumble down the column. You put 100 flies in the top for each experiment. At the bottom you collect a pile of flies, and that takes a certain amount of time." In total, Heberlein says, she went through something in the neighborhood of "a gazillion flies, tons of them."

She discovered that it would take about 20 minutes for the average fruit fly, known as the "wild type," to end up unconscious at the bottom of the inebriometer. She also tested huge numbers of mutant flies for their ability to handle alcohol, and she found a handful of these mutants whose behavior was distinctly different. Some had become more resistant to alcohol—one mutant, for instance, could survive for almost 35 minutes in the inebriometer before hitting rock bottom—while others seemed to get drunk right away.

Heberlein called this last group cheapdate. As it turned out, their mutation was in a gene that had already been identified by researchers at the Massachusetts Institute of Technology (MIT). Known as amnesiac, it had been shown to produce memory defects in sober flies when mutated. The gene produces a brain chemical, a neuropeptide also called amnesiac, that seems to activate a messenger system in fly brain cells. "We don't know exactly how alcohol fits into this," she says. "All we know is that the flies that are more sensitive to the effects of alcohol have a disruption in this messenger system."

Now Heberlein is working to clone several of the other genes she's identified that affect the fly's resistance to alcohol. She is a little reluctant to talk about what she's discovered, but she will admit that she has one mutation, called lightweight, that causes flies to be even more susceptible to alcohol than cheapdate. So far, no similar genes have been found in humans and no human genes have been conclusively linked to an increased risk of alcohol abuse. But once the human genome and Drosophila genome projects are complete, says Heberlein, finding the human versions of these genes, if they exist, should be relatively easy.

With the genes in hand, it might be possible to develop drugs that would modulate their function and control alcohol addiction. "If you absolutely knew what the genes were," she adds, "you could also perhaps identify in advance youths who are at risk for alcohol addiction, and you could employ intervention strategies such as counseling to head off the problem."

Late last year, Heberlein moved from the Gallo Center to UCSF's anatomy department. She is continuing her alcohol work in flies but is extending the approach to a search for the genetic basis of nicotine and cocaine addiction. While Heberlein is not surprised that her crazy project in flies has panned out into a career's worth of work, she is surprised by one simple fact: "I'm still amazed that there are so many similarities between the behavior of these little flies and the behavior of humans when exposed to these drugs."

— Gary A. Taubes

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