Barflies

Evidence from human familial studies shows that the risk of developing alcoholism seems to be at least 50 percent genetic. "What we are trying to find is those genes that contribute to the 50 percent that has a genetic component," says Heberlein.

The researchers generate thousands of flies with random single-gene mutations, then test them for variations in how alcohol effects behaviors like locomotion (a sort of "straight line" test) and postural control (how long they can stay standing).

"This genetic approach that we take in flies is completely unbiased," Heberlien points out. "We are making no a priori assumptions of what the genes might be that regulate the behaviors. We're hitting these genes randomly, and then we're just looking: Which of these genes affects the behavior of interest?" That approach would be prohibitively expensive to do in models like mice, she says. "By doing it in this very simple, inexpensive and easy to rear little organism, which has 100 years of genetic analysis to fall back upon, it makes our work a lot easier and faster."

“Cheapdate,” “Tipsy” and “Barfly”

The ingenious devices they've designed, like the "Booz-o-mat" and the "Inebriometer," allow them to test hundreds of flies at a time. "Then, once we find those few mutants that have the behavior change that we're interested in, we can then go in and clone the gene and identify it quite quickly and easily in the fly," Heberlein says.

In 1998, the group reported that a mutant they named cheapdate has a mutation in a gene called amnesiac that's responsible for its alcohol sensitivity. The amnesiac gene also affects memory retention. Humans do not seem to have this gene, but it affects an important biochemical signalling pathway that is also affected in human alcoholics.

Other mutants, like tipsy, which passes out at lower than normal doses of ethanol, and barfly, which take much higher doses than normal, are helping the scientists tease apart the genes that regulate the "activating" effects of alcohol from those that regulate its sedative effects.

Heberlein can't give specific details about any new genes they've identified until that research is published. "We've found quite a few genes lately. We are in the process of characterizing those very carefully," she says.

"What we have found," says Heberlein, "is that several of the genes that we've found in flies have counterparts in humans. And these days, because the human genome has been sequenced and is available to everyone (as is the Drosophila genome) , it's pretty easy to find out whether our fly genes have a human counterpart."

Chasing a Buzz

Do fruit flies show any of the other classic signs of alcoholism, like chasing a drink? Do they show signs of dependence or addiction? As a matter of fact, Heberlein says, they're currently working on ways to measure that. As with the locomotion studies, they need to become experts on what is normal fly behavior, as well as what isn't.

Fruit flies are normally attracted to alcohol. "Flies live on rotten fruit... so they have lived on media containing alcohol for a very long period of time," says Heberlein. "What we'd like to do is measure whether flies like alcohol in the lab, and we're developing assays to do so. But I think it's very obvious that flies do like alcohol, because if you open a beer in our fly room, flies will pretty much jump into the beer. And unfortunately, probably drown in it."

"Dependence is manifested as a withdrawal when you take away the drug, so in that case what you do is you give flies alcohol for a relatively long period of time and then you take it away," she says. "What we have observed is that flies will become extremely hyperexcitable, and they shake, they physically shake for awhile. So I think that we have a response that mimics a physical withdrawal. The question is right now, how can we develop the technology to really measure that accurately? Those are things that we're actively working on, and I think in the near future we'll be able to address."

The group's research is largely funded by grants from the National Institute on Alcohol Abuse and Alcoholism.