Mouse and Man - Why is the publishing of the mouse genome
so exciting? Just about all medical advances that benefit human
patients are first studied in mice. (12/4/02)
Buzz - Scientific research gives some insight into what happens
when we drink, which could help keep your night from being one
that youâ€™d rather forget... or canâ€™t remember at all.
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s on Alcohol Abuse and Alcoholism
Number One Health Problem - National Council on Alcoholism
and Drug Dependence
Fruit Flies - The Exploratorium
Beverage Medical Research Foundation
When fruit flies get drunk, they exhibit many of the same behaviors you may
see at New Yearâ€™s parties.
As this ScienCentral News video reports, that's helping geneticists to understand
Heberlein was amazed when she first realized that fruit flies, aka Drosophila,
could become drunk. "They behave just like you or I would," she
says. That was nearly ten
years ago, and Heberlein's lab at the University of California at San
Francisco has become a hotbed of addiction research in drosophila.
In fact, "most organisms have very similar behaviors when they're intoxicated,
and that includes fruit flies," Heberlein says. "We believe that
the same genes are going to be involved in these behaviors in a fly, in a
mouse, and in a human. And the reason for that is that we share about two-thirds
of our genes with flies. And there is a long history of successes in which
genes found in flies have helped understand cancer, sleep disorders and other
complex medical conditions."
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
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
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
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
"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.