Fruit flies that are literally falling-down drunk may provide the first insight into why some humans are able to hold their liquor better than others, San Francisco researchers report today.
The flies have a genetic defect, dubbed "cheapdate" by the scientists, that causes them to display all the characteristics of human drunkenness: hyperactivity, loss of coordination, disorientation and, ultimately, unconsciousness. Moreover, they become intoxicated on 30% less alcohol than is required to produce the same effects in their healthier brethren, geneticist Ulrike Heberlein and her colleagues at UC San Francisco report in the journal Cell.
The gene is the first that has been definitively linked to a propensity for alcoholism, and, experts said, it is not unrealistic to think that the discovery could lead to new ways to reverse the effects of overimbibing.
"It's a very interesting and provocative result," said Bob Karp, director of extramural genetic programs at the National Institute on Alcohol Abuse and Alcoholism. "This is the beginning of the elucidation of a pathway for sensitivity to alcohol."
Perhaps as important, added pharmacologist Adron Harris of the University of Colorado Health Sciences Center, the study shows that the genetic origins of alcoholism can be studied in fruit flies, which are much cheaper and more easily manipulated than the rodents that are now widely used.
"This is a very powerful genetic approach," he said.
Alcoholism is a pervasive public health problem, affecting an estimated 14 million Americans. Although it often strikes victims seemingly at random, researchers have long suspected a strong genetic link.
People who have a brother or sister who is an alcoholic are three to eight times as likely to develop alcoholism themselves as are those with no family history of the disease. The identical twin of an alcoholic has a 60% chance of becoming alcoholic.
Scientists have not linked a single gene to alcoholism in humans, but the new research gives them a good idea about where to look for at least one of them.
Heberlein and her colleagues used a device called an inebriometer to screen tens of thousands of laboratory-mutated flies to see how alcohol effects them. The inebriometer is, in essence, a four-foot tall glass dome with funnel-shaped screens across it at regular intervals.
Fruit flies normally prefer to stay at the top of the dome, but as alcohol fumes are pumped into the chamber, they become intoxicated and fall progressively to lower levels. It takes normal flies about 20 minutes to fall to the bottom and out of the chamber. The cheapdate flies fall through in less than 15 minutes.
Studying the cheapdates' genes, Heberlein's team found that they have a mutated copy of a previously known gene called amnesiac, which produces memory problems. The normal form of the gene stimulates production of a chemical called cyclic AMP, or cAMP. The cheapdate flies do not make as much cAMP in their brains and that, Heberlein said, makes them more sensitive to the effects of alcohol.
But the team found that if they gave the flies drugs that increase production of cAMP in the brain, the flies became more tolerant to alcohol and could last as long as healthy flies in the inebriometer. Presumably, similar drugs could help humans resist the effects of alcohol.
The study provides "compelling evidence that cAMP metabolism plays an important role . . . in the acute response to ethanol in fruit flies," said Dr. Hugo J. Bellen of the Baylor College of Medicine in Houston. "The fruit fly may pave the way for an in-depth study of many of the genes involved in the acute and chronic effects of ethanol" in flies and humans.
Scientists have been searching for alcoholism-related genes for more than a decade, since Karp's institute began a massive project called the Collaborative Study on the Genetics of Alcoholism. The project has received about $6 million a year in funding and has accumulated more than 350 families and collected data on about 10,500 people.
Last month, the team said the search for such genes has been narrowed to small areas on chromosomes 1, 2, 4, 7 and 11--five of the 23 pairs of chromosomes that carry the human blueprint.
"Alcoholism . . . is not due to a mutation in a single gene," said Dr. Enoch Gordis, the institute's director. "In all likelihood, it is a handful of genes" that cause it.
Scientists have not yet found the amnesiac gene in humans, but that may be because they have not been looking. The human genetic blueprint contains an estimated 100,000 genes, and researchers have so far identified fewer than half of them.
But human genes are similar to fruit fly genes "to an astonishing degree," Karp said, and it is likely that amnesiac has a human counterpart. He predicted that scientists will find and test that human gene soon.
Meanwhile, Heberlein and her colleagues have found many other fruit fly strains that have unusual responses to alcohol and are in the process of identifying the genes involved. But hers is the only group studying the genetics of alcoholism in flies.
"We're hoping that, once people see how far and how quickly this has advanced, we will get much more work on fruit flies," Karp added.
Colorado's Harris added an unusual footnote to the research. Flies, he said, seek out alcohol because it leads them to fermented fruit, which is a prime food supply. "So we have to ask, do we like alcohol because we are descended from simpler organisms that sought it out as a source of food?" he concluded.
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Catching a Buzz
Why do some people hold their liquor better than others? Scientists studying fruit flies believe alcohol tolerance is linked to a gene related to production of a chemical involved in memory and responses o some hormones.
1. Before exposure to alcohol, flies stayed near top of dome.
2. Alcohol fumes are introduced into chamber.
3. As they become inebriated, flies slip down, eventually passing out and falling out of chamber.
4. Fruit flies normally take about 20 minutes to fall to bottom. Flies with low levels of the chemical cyclic AMP fall through in less than 15 minutes.
Source: U.C. San Francisco