In the spring of 1983, James Isaacson, 33, an aspiring Hollywood recording engineer, fell asleep at a party. He never woke up. A combination of alcohol and other drugs killed him. Isaacson's mother already had been under treatment for various addictions.
His grief-stricken father, Omaha businessman Fenton G. Isaacson, decided to do something. Last summer, after consulting with scientists and treatment experts, he organized the National Foundation for Prevention of Chemical Dependency Disease in Omaha, Neb., to promote genetic research on alcoholism. Part of its goal is the development of a "simple biochemical test" that will reveal a predisposition to addiction, particularly alcoholism.
A decade ago, such a project might have been dismissed as absurd. It has been observed for more than a century that alcoholism runs in families -- but then, so does poverty. Through most of its history, alcoholism has been regarded as a character failing. With the development of psychiatry, mental health professionals sought to find its causes in emotional traumas of childhood.
Now, however, many scientists believe that research will one day identify specific biological factors that lead to alcoholism. The stakes are high: Alcoholism afflicts at least 10 percent of the drinking population, and experts estimate it costs the nation about $80 billion a year in lost productivity, health problems and social and emotional disruption.
The intensified interest in biological cause began when researchers discovered that boys inherit a tendency to alcoholism from their biological fathers even when they are adopted at birth.
The first studies, conducted in Denmark and Sweden in the early 1970s, showed that adopted sons of alcoholic fathers were four times more likely than sons of nonalcoholic fathers to develop the disease. An adoption study in Iowa confirmed the evidence that heredity seemed to have a much stronger role than childhood environment.
Studies of twins provided further confirmation. Identical twins -- who have identical genes -- share the same alcoholic fate more often than fraternal twins, who have only half their genes in common, just as nontwin brothers and sisters do.
These studies started research to differentiate between "familial" and "nonfamilial" alcoholism. Nonfamilial alcoholism depends largely on environmental influences. In Norway, for example, the alcoholism rate shot up as the discovery of North Sea oil caused economic and social changes.
But familial alcoholism, say researchers, doesn't have much to do with individual circumstances, and is usually a more severe, fast-developing form of the disease. Familial alcoholics also show more brain abnormalities, as revealed by CAT scans.
It's difficult to search for biological causes in established drinkers, Dr. Enoch Gordis of Mount Sinai Medical Center in New York observes, because when "you look for signs of genetic vulnerability, you don't know if you're looking at the results of drinking or the predisposition." For example, one researcher says alcoholics have less serotonin in their brains, as measured indirectly by blood tests. The only way to find out if such a deficiency preceded drinking is to examine prealcoholics.
Prealcoholics can most easily be found among male children of alcoholic fathers, since about 25 percent of the sons will develop the disease. Female alcoholics, outnumbered by about 3 to 1, have not been studied extensively, but father-daughter transmission seems to be weak. Instead, girls seem to inherit the disease from their mothers.
It has taken many years to develop animal models for alcoholism because rats and mice, the classic test animal, have such fast-acting metabolisms that it's hard to get them drunk. Besides, Gordis says, "it's very difficult to make an alcoholic by force." But several strains of animals now exhibit some of the characteristics of alcoholism such as preference for an alcohol solution over water, tolerance (ability to hold the stuff) and dependence (addiction and withdrawal).
This work has shown there are large, genetically based differences among individuals that govern their preferences as well as how their bodies handle alcohol. Many Orientals, for instance, get red faces, palpitations and nausea after a few drinks. This is caused by a deficiency in a certain enzyme involved in alcohol metabolism that acts as a built-in preventive. About 5 percent of Caucasians also have this trait.
Since the discovery that alcohol metabolism varies with individuals, experts S now believe that these metabolic differences are innate, and that the changes in metabolism are effected by the drinking itself.
But researchers are still looking for some subtle, preexisting metabolic abnormality. Dr. Marc Schuckit of the University of California at San Diego thinks he may have identified such an abnormality among his high-risk subjects.
When the body absorbs alcohol, it changes alcohol to acetaldehyde, a toxic chemical. In most people, acetaldehyde levels remain so low they can't be measured after one drink. But Schuckit's young men developed acetaldehyde levels two or three times higher.
Confirmation of this finding could lend support to one controversial theory: that excess acetaldehyde leads to the formation of morphine-like substances that plug into the brain's morphine receptors and lead to an opiate-like addiction.
Most researchers now doubt that there are specific brain receptors for alcohol but instead suspect that addiction results from more generalized effects on the central nervous system.
At present, says one, "the hottest research in town" is in brain waves. Subjects are hooked up to machines that trace the electrical pattern emitted from a specific part of the brain in response to a visual or aural stimulus.
The hottest wave in town is the "P3" wave, a well-studied wave that relates to attention and learning. Dr. Henri Begleiter of Downstate Medical Center in New York measures this wave in children of alcoholics, aged 7 to 13, who have never been exposed to alcohol. He says that although normal people rarely show any abnormality in this wave, about 70 percent of alcoholics do. Some 35 percent of his high-risk children show the same abnormality.
Begleiter's subjects will have to be tracked for years to see if their brain waves have anything to do with alcoholism. But many researchers are gearing up to repeat this experiment because it has, for the first time, identified a biological trait, governed by genes, in a high-risk group untouched by alcohol.
In more indirect attempts to assess brain function, Oscar Parsons of the University of Oklahoma is looking at how groups of alcoholics and nonalcoholics perform in tests of reaction time, spatial awareness and problem solving. Within each group, it turns out, the people with a family history of alcoholism do more poorly than the rest, particularly in more complex intellectual functions. Tests such as these have led many researchers to believe that familial alcoholics suffer from mild, preexisting neurological anomalies.
Some investigators believe there is a large subgroup of alcoholic men who also have genetically influenced behavior problems. Dr. Robert Cloninger of Washington University in St. Louis has identified a "male limited" form of alcoholism in the Stockholm Adoption Study. The fathers of these subjects were both alcoholic and criminal. Other research suggests that not only are alcoholism and antisocial personality often found together, but both are frequently preceded by childhood hyperactivity or "conduct disorders."
Long-term personality studies also lend some weight to the notion of a psychological predisposition to alcoholism. Analysis of the youthful personality tests of alcoholics in treatment clinics has uncovered a disproportionate number of traits such as rebelliousness and poor socialization.
"The psychosocial people have had their day," says T. Edward Reed, a pharmacologist from the University of Toronto. Current research may culminate in a new, "biobehavioral" definition on the potential alcoholic.
Alcohol affects every system in the body, making it difficult to spot the beginning of the chain of mechanisms that leads to addiction. Even if a reliable marker were found -- color-blindness was once a candidate -- it would not necessarily have any relation to the disease. It could just be on one of the same genes, like a rider attached to an unrelated legislative measure.
In any study, says Dr. Peter Martin of the National Institute for Alcoholism and Alcohol Abuse (NIAAA), "you have to have something very, very impressive" if it is to show up amid all the static. He believes that "the study that offers the greatest hope is longitudinal" -- tracing a group of adolescent pre-drinkers for a couple of decades. Such studies are just beginning.
Researchers may eventually find that there are "different genetic pathways to the same problem," says Boris Tabakoff, director of intramural research at NIAAA. Tabakoff, who is on the scientific board of Isaacson's new foundation, says it is possible that susceptibility could be detected either through chemical or neuropsychological tests. But "in the end, it's all chemistry."