The dubious quest for an alcoholism gene

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From the "demon rum" campaigns of the 19th century to today's freeway billboards soliciting customers for expensive treatment programs, North America has seldom enjoyed a comfortable relationship with alcohol.

The recent report of a gene "significantly associated with alcoholism" is unlikely to make it easier. The scientific conclusions are tenuous at best and the manner in which they were presented shows how medical research can be contorted to satisfy social demands.

The idea that alcoholism is a disease that for inherent reasons threatens some people more than others originated with the Alcoholics Anonymous movement after the repeal of Prohibition. Though the notion gained enormous popular support it had little basis in scientific observation. For years medical researchers have been searching for facts to justify the belief. Like many areas of biomedical research these efforts recently have focused on genetics.

Alcoholism runs in families, but that says nothing about the nature-nurture question. A number of studies have suggested that there could be an inherited predisposition to alcoholism. These include identification of strains of rats that drink more alcohol than other strains, observations of identical twins reared apart, and comparisons of the metabolism of alcohol in people whose parents were alcoholics with people whose parents were not. But none of these studies was by itself conclusive, and many scientists have believed that the issue could be resolved only by finding specific genes, pieces of information on the chromosome, which could lead to alcoholism.

That was precisely what Kenneth Blum and Ernest Noble reported they had found recently.

Alas Blum and Noble have not located the smoking gun. Despite the best intentions, they and their co-workers carried out a study marred by dubious methodology and unwarranted conclusions. But their findings were too appealing not to trumpet to the world. Because so many people want to believe that a tiny bit of DNA inherited from one or both parents can open the door to the devastation of alcohol, The Journal of the American Medical Association (JAMA), the two researchers, and their universities were able to portray the study as far more important than it is.

As Dr. Paul Billings of the Harvard Medical School, who directs the Clinic for Inherited Disease at New England Deaconess Hospital, pointed out: "If this type of genetic analysis was carried out for a disease or a behavior less attractive than alcoholism, it would never get published. It tells you nothing of significance."

Studying the brains of 70 dead people, half alcoholics and half not, Blum and Noble looked for the presence of a particular gene. The gene is common. One out of four Americans carries it. Brain scientists believe it is responsible for part of the "reward" system that makes the brain feel good about activities in other parts of the body. Blum and Noble found the gene in 77 per cent of the alcoholics and 28 per cent of the non-alcoholics. Among the problems with the research are that the sample size is very small and that there is little reason to think that this gene has anything to do with alcoholism. The gene is so common it is possible that it occurs at three times the normal frequency in any group scientists might choose to look at: compulsive gamblers, tomato growers, or readers of The New Republic, for example. "The study,"says Billings, "is from the genetic dark ages."

Scientists often complain that journalists misrepresent their work, and especially that they fail to report caveats of uncertainty. So it is worth noting just how this research was presented to reporters. JAMA featured the study as the lead article in its April 18 edition. (This was three weeks after JAMA pushed back its publication day so that reports from JAMA would appear in the popular media a day ahead of those from its chief competitor, The New England Journal of Medicine.) For reporters who might not read their advance copies of JAMA, the AMA sent out press releases that began, "For the first time, researchers have evidence of a specific gene that may play a crucial role in causing the disease of alcoholism." The AMA's weekly "video news release," transmitted free by satellite to all the television stations in the country, featured a report including interviews with Blum and Noble and a video of their laboratories. The video news release includes a narration from the AMA that the local station is free to broadcast or to replace with the voice of one its own reporters.

In the same issue, JAMA also carried an editorial written by Dr. Enoch Goris, director of the National Institute on Alcohol Abuse and Alcoholism, and three colleagues pointing out that Blum and Noble's research "must be regarded with caution." The editorial detailed a series of technical questions about the research, including the warning that such "research often hinges on subtle, complex, and often controversial statistical considerations." But such subtleties are almost always lost in a wave of publicity.

Blum works at the University of Texas Health Sciences Centre in San Antonio, Noble at UCLA Medical Centre. After a brief discussion, the two universities' press offices decided the two scientists should be made available to reporters in Los Angeles rather than in San Antonio, assuring much wider coverage. UCLA printed up a glossy press package, scheduled a press conference, and lined up individual interviews with most national news organizations.

The researchers began most of their discussions with reporters with the appropriate warnings, including the one that all scientific findings must be confirmed by others. But they were quick to boast of what they believe they've accomplished. "Assuming all of this holds up to be true," Noble told me, "it means that we now have the potential of drawing blood samples from people and looking to see if they have a predisposition to alcoholism." Blum added that "this understanding of the genetics of alcoholism could lead to better treatments."

A blood test that would identify a quarter of the American population as potential alcoholics would create profound ethical dilemmas. In addition to the personal anguish, a person testing positive might be denied a job or insurance. And with genetic tests the question arises: What can be done for those who test positive? It is by no means clear that a simple admonition to avoid drinking alcohol would be much help. As for better treatments, it might help to recall that for most diseases, discovery of the true genetic cause has not led to treatments. Scientists have understood the genetics of sickle cell anemia for two decades and there is still no treatment.

Another question about Blum and Noble's work is, why did they study brains? Genes appear in every cell of the body. Almost all genetic research is carried out with blood samples from living people, not brains or other organs of the dead. Noble had been working with this set of 70 brains for almost seven years, searching for differences in brain chemistry between alcoholics and non-alcoholics. Those endeavors had met with little success, but Noble continued because, he said, "I was sure of the diagnosis."

Each of the 70 individuals had been subjected to what is called a "psychological autopsy." Researchers pored over the medical records of the deceased and interviewed relatives to be certain who was an alcoholic and who was not. The thirty-five in the study called alcoholics were almost all what Noble classified as "virulent" alcoholics. Many died of cirrhosis. But the need for this rigorous methodology points to one of the profound difficulties of alcoholism research: the definitions of alcoholism and alcohol abuse shift continually.

In the past few years scientists have found either the approximate or precise location of the genes for several diseases, including Huntington's, Duchenne's muscular dystrophy, polycystic kidney disease, and cystic fibrosis. These discoveries have already led to clinical tests to determine whether a person is a carrier of the disease. At the same time other groups have claimed to have found the gene for manic depressive illness, schizophrenia, and Alzheimer's disease. But the claims for the last three conditions either have been retracted or are being challenged seriously by other scientists. A major reason for the success in finding genes for physical diseases and the failures with mental ones is that mental conditions are far more difficult to diagnose. The set of behaviors labeled as alcoholism presents an even more difficult target, making it that much less likely that anyone will soon discover its genetic underpinnings.

Common sense tells us that alcoholism, like almost everything in life, results from a combination of genetics and environment. It is surely possible that people can inherit a gene -- or, far more likely, several genes -- that puts them at greater risk of becoming alcoholics. But the possibilities that genetic studies will yield more effective treatments or methods of prevention anytime soon are remote. And scientists and lay people should remain skeptical of any claims to the contrary, no matter how much they may wish them to be true.