Since the first "alcoholism gene," dubbed DRD2, was found in 1990, researchers have hunted for DNA sequences that might predispose someone to a drinking problem. But DRD2's role in alcoholism has remained extremely controversial, and despite many efforts, no better candidates have emerged.

Many investigators are now taking a different tack. Instead of searching in families and populations of alcoholics for genes that might broadly confer a high risk for dependence, they are attempting to understand alcohol's effects and why they differ among people. In an explosion of studies, scientists have used rodents, fruit flies, zebra fish and roundworms to study characteristics such as sensitivity to intoxication and severity of withdrawal. By exploring alcohol's interaction with genes and the associated biological pathways, they hope to find clues to alcohol's addictive qualities.

Such studies are starting to yield intriguing results, including a recent report of a gene that some believe could have an important influence on dependence. Last December neurobiologist Steven McIntire of the University of California at San Francisco, who works with the worm Caenorhabditis elegans at the Ernest Gallo Clinic and Research Center in Emeryville, Calif., described a single gene that seemed to explain for the first time the mechanism of intoxication.

His team examined mutant worms resistant to alcohol's behavioral effects. They all had changes in a gene called slo-1. The gene ordinarily codes for a protein called the BK channel, found in nerve, muscle and gland cells. The channel operates as a gateway to control the flow of potassium ions. The researchers saw that alcohol makes the channel open more frequently, allowing more ions to pour out and slowing neuronal activity. In mouse and human cell cultures, alcohol similarly activated the BK channel, leading McIntire to believe that his group had uncovered the route for alcohol's diminishment of physical and mental control across species.

"Slo-1 might determine sensitivity to alcohol as well as provide a mechanism for intoxication," McIntire says. The gene's influence on alcohol response probably makes it an important factor in dependency among people, he adds, pointing to studies by psychiatrist Marc Schuckit of the University of California at San Diego, who has been following for nearly 20 years 453 university alumni who are sons of alcoholic fathers. Among Schuckit's group, low sensitivity to alcohol's effects at age 20 has correlated with four times as high a risk of alcoholism later in life. Geneticist Raymond White, director of the Gallo Center, has already begun sequencing the genes of several hundred of Schuckit's subjects to investigate the role of slo-1 in this population.

David Goldman, chief of the neurogenetics laboratory at the National Institute on Alcohol Abuse and Alcoholism, praises the efficiency of a simple system such as C. elegans as a way to sift through the genome. His own lab is searching for susceptibility genes in a large-scale analysis of Native American families with both high and low levels of alcoholism, a far more painstaking approach. McIntire's work "is a decisive sort of experiment because it creates immediately testable hypotheses," Goldman explains.

Some researchers, however, wonder if the Gallo Center team may be expecting too much from slo-1. David W. Crabb, director of the Alcohol Research Center at Indiana University, compares the gene with another candidate, cheap date, which makes fruit flies more easily drunk. Discovered in 1998, "it hasn't broken the field open," Crabb remarks.

Evan Balaban, a neuroscientist at McGill University who works on inborn behavioral differences in animals, cautions against using physiological mechanisms to stand in for a complex syndrome. "Social, developmental and personal things all go into our need to use a substance and whether alcohol becomes the substance of choice," he states. A follow-up to Schuckit's study that took into account sociocultural factors, for example, found that low sensitivity to alcohol along with a family history accounted for just 22 percent of later alcohol abuse or dependence.

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