It's not much, hardly even noticeable, but the children of parents who drink sway more than normal. This extra sway only turns up in tests done in laboratories like the one at the Western Psychiatric Institute and Clinic, a part of the University of Pittsburgh School of Medicine. The children, ages 8 to 18, stand on a special platform. Feet together, hands at their side, eyes closed. They try to stand as straight and as steady as they can for a minute or so. Then rest. Stand straight again. The platform measures how much they deviate from absolute vertical. The children do not receive any alcohol.
The finding that children born to alcoholic parents sway more than children born to non-alcoholic parents "may have something to do with how these children are neurologically wired," said Dr. Shirley Hill of the Western Institute.
In laboratories across the country, scientists are looking for physiological clues to why certain people seem to be at risk of developing a drinking problem, and the sway study is just one of many emerging pieces of evidence showing the biological footprints of alcoholism.
The current view is that alcoholism arises from a complicated interplay between personality, the environment and the genes. For some individuals, there seems to be a significant genetic component; for others, genes play a minor role. "The question now," said Dr. Boris Tabakoff, scientific director of the National Institute on Alcohol Abuse and Alcoholism, "is what is inherited? What is the biochemical process that determines the behavior that leads to the dependence on alcohol?"
In general, there appear to be two main forms of alcoholism. Type 1, while it may have some inherited aspect, is much more influenced by factors in the environment such as poverty and insufficient education. In a key Swedish adoption study done by Dr. Robert Cloninger at Washington University School of Medicine in St. Louis and others, about three quarters of the alcoholics fell into this category and tended not to develop a drinking problem until after the age of 25 or 30.
Environment alone appears to able to lead to alcoholism since more than 35 percent of the alcoholics have no family history of alcohol abuse.
But genetics, while not explaining everything about the roots of alcoholic addiction, clearly is linked. More than 150 scientific studies -- including studies of identical twins raised independently -- have found higher rates of alcoholism among relatives of alcoholics, regardless of environment.
For example, the other, less common form of addiction, striking a quarter of the alcoholics in the Swedish study, despite environmental factors, appears to be heavily influenced by genetic makeup. Type 2, as it is called, primarily affects men; they are likely to become alcoholics quite young -- by the age of 25.
Although no one has found the gene for alcoholism -- and most researchers believe it will be more than one gene -- a number of scientists have been searching intensely for some genetic clues.
NIAAA's Dr. David Goldman found a genetic marker on mouse chromosome 1, called LTW-4, that seems to be inherited in mice that crave alcohol. "We have no reason to think this is a locus involved in human alcoholism. It is a gene for alcohol preference, not alcoholism," Goldman said. But it's a tantalizing clue.
By studying a carefully selected group of some 250 individuals, either alcoholics themselves or their relatives, representing three generations, Shirley Hill and the group at the Western Psychiatric Institute believe they have found a human genetic marker for alcoholism: a certain combination of the MNS blood types (a blood typing system like the ABO system) seemed to be inherited with the predisposition to become alcoholic.
The MNS genes do not cause alcoholism, but they appear to be inherited with the purported genes that do increase the chances of becoming alcoholic, so both sets of genes will tend to be inherited together. The genes for the MNS system are found on human chromosome 4, which also holds the genes for alcohol dehydrogenase, a liver enzyme central in the metabolic destruction of alcohol.
"We would not want to say that we definitely have it," Hill said. "Within a few more families, I am going to be able to tell the scientific world for sure whether it is there or not."
While intrigued by the data, Dr. Enoch Gordis, NIAAA director, warned that "no one knows what the gene for alcoholism is." ::
To understand the relationship between alcohol and behavior, researchers have zeroed in on the brain. Alcohol physically affects the brain's nerve cells, changing both their external membranes and internal chemistry.
The biggest effect appears to be on various proteins called receptors, found on the surface of cells, that normally determine how a nerve cell responds to its local environment and whether it receives a nerve signal or not.
"Alcohol may cause disordering of certain regions of cell membranes, or around certain proteins, and that may cause intoxication," said Dr. Dora Goldstein of the Stanford University Medical Center in Palo Alto, Calif. "The membrane is sort of like clothes. If the clothes are too loose or too tight, it may change the shape of the wearer slightly. In the membrane, it may change the function of the protein."
If researchers understood how alcohol changed membranes of nerve cells or how alcohol affects receptors, it may be possible to stop or even reverse the process.
Recent evidence suggests that it may be possible to block alcohol's effect on the brain. Alcohol increases the action of a neurotransmitter called GABA, or gamma amino buteric acid, by changing the activity of the GABA receptor, the same one affected by Valium and Librium.
"Alcohol is not binding to the GABA receptor. It is working in an indirect way to affect the shape of the receptor," said Dr. Steven M. Paul of the National Institute of Mental Health. Paul's group can block the GABA receptor with an experimental drug called RO-154513, made by Hoffman-LaRoche, and reverse some of the effects of alcohol, such as intoxication.
The drug has only been used in animal studies and probably will never be used in humans because of side effects, including seizures and causing a rise in anxiety. But by modifying the drug, it may be possible to produce a new compound that blocks alcohol without side effects, Paul said.
Even if such drugs work, researchers do not envision a day when people could go to a bar, get drunk, then take a drug to reverse intoxication before getting in a car to drive home.
Studies with a neurotransmitter called serotonin -- which plays a role in mood and eating and drinking behaviors -- also suggest the uncontrollable craving for alcohol may be chemically based and may someday be turned off. Studies indicate, for example, that alcoholics have reduced levels of serotonin, which scientists have linked to depressed moods in some individuals.
Alcohol has been shown to enhance serotonin function, said NIAAA's Tabakoff. One theory is that alcoholics "learn that if they take alcohol, it will overcome some adverse feeling that they may have."
In a Toronto study -- not yet complete -- scientists are testing a drug that enhances the action of serotonin and may help reduce the craving for alcohol.
Pinpointing the biochemical role of alcohol is difficult because it affects every major system in the brain. "The trouble with the brain is that everything is connected to everything else," said Stanford's Goldstein. "The ideas of what part of the brain are affected keep changing. This week, there is a lot to be said about the cerebellum. It controls balance and walking, and those are obviously impaired. The electrophysiologists can show that alcohol affects neurons in the cerebellum. We may be focusing on that because it is what we can measure." ::
Researchers also have studied alcohol's effects on the liver, the only organ that can break down the potentially toxic drug.
It has been known for some time that people can clear alcohol from their bodies at varying rates. Studies have found genetically caused differences in the enzymes responsible for clearing alcohol from the body, said Dr. T.K. Li of the Indiana University School of Medicine and the Veterans Administration Medical Center in Indianapolis.
In a number of studies, alcoholics are found to metabolize alcohol more quickly, requiring more alcohol to feel an effect and helping them develop a tolerance to quantities of alcohol that would intoxicate others.
Researchers at the City of Hope Medical Center in Duarte, Calif., for example, discovered a genetic defect affecting half of all Orientals, which prevents them from converting alcohol into a harmless substance. When Orientals with this defect drink, a toxic compound quickly builds up in their bodies, causing a hot, flushing sensation and sometimes nausea.
"They get sick, some violently ill," Li said. Orientals with this defect seldom become alcoholic.
The drug Antabuse, given to thousands of alcoholics each year to make them feel sick if they take a drink, works on the same enzyme that is affected by the Oriental genetic defect. Antabuse, however, has had limited success because alcoholics tend to just stop taking the medication to avoid getting sick instead of staying away from alcohol.
Chronic alcohol use causes major damage to the liver, resulting in cirrhosis of the liver, the ninth-leading cause of death in the United States. Researchers have sought ways to protect the liver from alcohol's toxic effects.
On Dec. 3, Dr. Yedy Israel, Dr. Hector Orrego and others at the Addiction Research Foundation in Toronto reported in the New England Journal of Medicine that the anti-thyroid drug called propylthiouracil, or PTU, protected the liver of people who continued to drink heavily and it prevented cirrhosis and death.
"In essence, we are reducing mortality by about 50 percent, independent of the severity of their drinking," Israel said. "This is the first drug we know of that shows this type of protection against mortality for alcoholic liver disease." Protection, however, disappeared when the subjects stopped taking the drug.
This does not mean, Israel said, that people should go out and get the drug to protect their liver while they continue to abuse alcohol. The most effective way to protect the liver, he said, is to stop drinking.