As NIAAA Ends Anniversary Celebration, New Research Efforts Abound

Research Efforts Abound After more than a year of commemoration, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) this week concludes its 25th-anniversary celebration at the annual meeting of the Research Society on Alcoholism in Washington, D.C. NIAAA was signed into existence in 1970 by President Richard Nixon ironically-or, perhaps, fittingly-on New Year's Eve, a holiday marked by excessive alcohol consumption. The institute initially was charged with developing health, education, research, and planning programs for the prevention and treatment of alcohol abuse and alcoholism as part of the National Institute of Mental Health. DIRECTOR: Enoch Gordis notes a shift in NIAAA's research focus. NIAAA became an independent institute in 1974 but did not receive specific authorization to conduct research until 1976. By 1981, research had become the institute's sole focus. Today NIAAA supports approximately 90 percent of all alcohol-related research in the United States, according to its director, Enoch Gordis. Technological and methodological advances in genetics, neuroscience, and treatment research have vastly increased the potency of NIAAA's work, while causing shifts in focus, Gordis says. "Some research issues that were very popular in the early '70s, such as intermediary metabolism [of alcohol] and studies of certain vitamin functions, are less so now," he states. "But the seeds of our current genetic research were being planted by virtue of early adoption studies and half-sib studies [of alcoholics and their relatives]." NIAAA historically has promoted a multidisciplinary approach to the study of alcohol abuse and alcoholism. Since its inception, that field has broadened to include neuroscience, quantitative genetics, and molecular biology as well as psychology, sociology, medicine, epidemiology, and biochemistry, among other disciplines. ALCOHOL ABUSE AND ALCOHOLISM RESEARCH RESOURCES National Institute on Alcohol Abuse and Alcoholism: Scientific Communications Branch 6000 Executive Blvd., Suite 409, Rockville, Md. 20892-7003 (301) 443-3860 Fax: (301) 443-6077 World Wide Web: http://www.niaaa.nih.gov Journal: Alcohol Health and Research World Professional Societies: Research Society on Alcoholism 4314 Medical Parkway, Suite 300, Austin, Texas 78756 Phone and fax: (512) 454-0022 E-mail: debbyrsa@bga.com 1,200 members President: Ivan Diamond Executive Director: Debra Sharp Journal: Alcoholism: Clinical and Experimental Research International Society for Biomedical Research on Alcoholism 33 Russell St., Toronto, Ontario, Canada M5S 2S1 (416) 595-6033 Fax: (416) 595-9997 E-mail: vcabral@arf.org 725 members President: Kinya Kuriyama Executive Assistant: Val Cabral Journals: Alcohol research includes many different disciplines. For information on journals that cover the broad spectrum of alcohol studies, consult the Science Citation Index/Journal Citation Reports, Barbara Nagy-Teti, Institute for Scientific Information, 3501 Market St., Philadelphia, Pa. 19104 (215) 386-0100, Ext. 1290. Fax: (215) 387-4706. E-mail: bnagy-teti@isinet.com. The institute continues to encourage multidisciplinary research in areas of current emphasis, such as the genetics of alcoholism and alcohol's effect on the developing fetus. For example, through the extramural Alcohol Research Center program, NIAAA provides five-year grants totaling $21 million in 1996 to 14 centers for interdisciplinary studies on topics such as the neurobehavioral aspects of fetal alcohol exposure and the genetics of neuroadaptation to alcohol. The centers are located in universities and hospitals across the United States. "Our job here is to try to find answers to a few straightforward questions," says Gordis, who has led NIAAA since 1986. First, he asks, why do people drink alcohol at all? What goes on in the brain as it shifts from moderate drinking to alcoholism? Why does this happen to only a subset of drinkers? What are alcohol's medical effects? And finally, he adds, how can alcohol-related problems best be prevented or, failing that, treated? Further, Gordis explains, NIAAA is "interested in both alcohol abuse and alcoholism, which are not quite the same thing. Alcoholism involves a long list of diagnostic features that involve dependence." These include the requirement for increasing amounts of alcohol to achieve intoxication, physical dependence, and the neglect of other activities in favor of drinking or as a result of its effects, he says. On the other hand, Gordis defines alcohol abuse as "the hazardous use of alcohol short of dependence," a more severe affliction than the colloquial "problem drinking," and one that sometimes leads to full-blown alcoholism. The institute estimates that more than 13 million U.S. adults-more than 7 percent of the population-meet standard diagnostic criteria for alcohol abuse or dependence. The notion that alcoholism is a disease sharpened the focus of alcohol research as it helped to lift the stigma of a chronic disorder "no more inherently immoral than diabetes or heart disease," Gordis wrote in a retrospective of NIAAA's achievements last year (Alcohol Health and Research World, 19:5-11, 1995). While this disease concept closely resembles models of addiction to drugs such as cocaine and heroin, Gordis is quick to point out that alcoholism is a far more complex disorder than is addiction to illegal drugs. "The commonalities we see [between alcohol and other addictive drugs] are in certain [neurological] reward pathways, but even there the receptor systems involved are more complex," he says. Moreover, "alcohol is a food as well as a drug: It has caloric value and is metabolized by the liver. There's a whole range of research about the consequences of that metabolism." One such consequence, cirrhosis of the liver, causes 25,000 deaths a year in the U.S., according to NIAAA. In addition to studies on organ toxicology, NIAAA is researching the possibly cardioprotective effects of moderate drinking and on the nutritional deficits suffered by alcoholics who derive most of their calories from drink. Moreover, Gordis explains, much of the neuroscience research NIAAA supports is unique to studies on alcohol, because unlike other addictive drugs that affect relatively few receptors, its effects appear to be mediated though several different cellular receptors. "There never would have been a true science of alcoholism without the efforts of the NIAAA," reflects Albert Pawlowski, who retired from the institute in 1989. Pawlowski is now vice president of the Alcoholic Beverage Medical Research Foundation in Baltimore. This nonprofit organization, funded primarily by U.S. and Canadian brewing industries, supports scientific studies on alcohol. "Much of the research [that NIAAA has supported] might have been distributed among other institutes, but it wouldn't have had the same impact of knowledge concentrated in one place," Pawlowski says. He would like to see NIAAA fund a greater proportion of behavioral studies as a way of balancing what he sees as a disproportionate emphasis on biomedical research throughout the field. Nevertheless, NIAAA-which ranks among the three smallest NIH institutes with a 1996 budget of $199 million-makes good use of its funds, Pawlowski maintains. "They're small, but they've [brought a lot of] promising scientists into the field of alcohol research." GENETICS STUDIES: Henri Begleiter directs a large extramural project. Over the past decade or so, NIAAA has devoted a substantive portion of its research effort to studying the genetics of alcoholism. The institute's single largest extramural project, the Collaborative Study on the Genetics of Alcoholism (COGA), began in 1989. The project is an ambitious multidisciplinary investigation of the genetic components of susceptibility to alcohol abuse and dependence, according to its director, Henri Begleiter, a professor of psychiatry and neuroscience at the University of New York Health Science Center in Brooklyn. COGA's 1995 budget was $63 million. "Many scientists from different research areas are collaborating to assess hundreds of families and their phenotypes related to alcoholism . . . and to correlate these phenotypes with genetic characteristics," Begleiter wrote in an article describing the project (H. Begleiter, Alcohol Health and Research World, 19:228-236, 1995). COGA researchers at six centers across the U.S. are constructing linkage maps based on polymorphic DNA markers from the sample population. In one project, they are measuring neurophysiological characteristics, such as brain waves, which have been shown to be abnormal in the sons of alcoholic fathers. In another, the researchers are measuring biochemical markers, including the enzyme monoamine oxidase, which they have found to occur at lower levels in alcoholics and their children than in nonalcoholic families. A START: Joseph Jacobson notes initial progress in fetal alcohol syndrome studies. Begleiter and his colleagues are beginning to zero in on sought-after genes. "Expect an announcement shortly dealing with chromosomal regions involved in predisposition to alcoholism," he predicts, adding that researchers are working to produce a fine-scale genetic map of the region. "The next step after that will be to do positional cloning [locating genes for traits based on their linkage to known genetic markers]. With any luck, we'll hit on actual candidate genes." Researchers will examine the genes in more than 2,400 cell lines, then compare their results with follow-up behavioral studies of the cell donors to gauge the predictive value of any genes they identify. In genetic research intended to complement the wide-ranging COGA, several intramural scientists at NIAAA are studying alcohol use in such relatively homogeneous populations as Finns and American Indians, according to Markku Linnoila, who directs NIAAA's Division of Intramural Clinical and Biological Research. About 10 percent of the institute's 1996 budget (about $21 million) supports the work of 90 scientists in four intramural laboratories that focus on molecular and cellular neurobiology, neurogenetics, membrane biochemistry and biophysics, and clinical studies. By contrast, more than 80 percent of the institute's 1996 funds (about $160 million) is earmarked to support extramural research. DNA RESEARCH: David Goldman discovered gene polymorphisms. David Goldman, chief of NIAAA's Laboratory of Neurogenetics, led an effort to collect extensive pedigrees and cell lines in American Indian tribes with both high and low rates of alcohol abuse. In subsequent DNA studies, he and his colleagues discovered abundant polymorphisms in genes that encode neurotransmitter receptors, which the researchers are testing for correlation with alcohol-related behaviors. Two other intramural laboratories are applying their own expertise to extend Goldman's polymorphic receptor research. The laboratory of Norman Salem, Jr., chief of NIAAA's Laboratory of Membrane Biochemistry and Biophysics, is examining how alcohol affects membrane interactions with the various polymorphic receptors. Meanwhile, Forrest Weight, chief of the intramural Laboratory of Molecular and Cellular Neurobiology, and coworkers have expressed several of the receptors and are studying how alcohol affects their function. Linnoila and colleagues are conducting behavioral genetic studies to compare apparent subtypes of alcoholism. Early-onset alcoholism appears to be limited to young men who exhibit antisocial behavior. By contrast, the more common late-onset disease arises in both sexes and is associated with feelings of guilt. Linnoila's team is tracing the development of both versions of alcoholism in high-risk communities in Finland, as well as in controlled studies on the effects of mate selection and child-rearing on the development of alcoholism in nonhuman primates. "There's a debate in the field as to whether early-onset alcoholism is simply [a manifestation] of anti-social personality," Linnoila says. "I believe that the methods of molecular genetics applied to these groups will provide an answer to that question." Another major theme uniting several NIAAA-sponsored projects is the study of alcohol's mechanisms of action. "For almost a century, scientists believed that alcohol produced its behavioral effects by acting on membrane lipids, which in turn altered the function of membrane proteins, such as receptors and ion channels," notes Weight. "Thus, the alteration of protein function was a secondary effect. But what we've been finding recently is that alcohol can bind directly to neurotransmitter-gated ion channel proteins, such as the NMDA [N-methyl-D-aspartate] receptor," which is thought by researchers to be involved in controlling learning and memory. That well-characterized receptor, Weight says, is a likely candidate for an intoxication-producing site. He and coworkers are now using molecular biological techniques to characterize alcohol-binding sites on neurotransmitter receptors. Beyond intoxication and addiction, alcohol has also been linked to permanent damage in several organ systems and to developmental deficits. The latter were first identified in their most extreme form, fetal alcohol syndrome (FAS), in the 1970s. Today, approximately 10 percent of the institute's 1996 extramural research budget (about $15 million) is committed to studying alcohol's teratogenic effects. "Nobody knows what 'fetal alcohol effects' means," comments Joseph Jacobson, a professor of psychology at Wayne State University in Detroit. He also is a member of Wayne State's NIAAA-supported Alcohol Research Center on the neurobehavioral effects of fetal alcohol exposure. "At what level of exposure do you see children with neurological deficits? What is their functional significance? No one knows yet, but we're beginning to figure it out." Jacobson and coworkers are studying patients at an inner-city maternity hospital in hopes of learning whether moderate to heavy drinking during pregnancy-three to four drinks at a time-produces subtle developmental deficits in children. Other research projects at the Wayne State center include genetic analyses of maternal alcohol metabolism, positron emission tomography studies of adults who sustained fetal alcohol exposure, and experiments to test whether raising exposed animals in stimulating, socially rich environments mitigates the effects of fetal exposure to alcohol. LINKAGE: Michael Charness has connected fetl alcohol syndrome and L1 protein mutation. On the molecular level, Michael Charness-an associate professor of neurology at Harvard Medical School and chief of the neurology service at Brockton/West Roxbury Veterans Administration Medical Center-and coworkers recently discovered a mechanism by which alcohol may produce developmental damage (R. Ramanathan et al., Journal of Cell Biology, 133:381-90, 1996). "What we've done is link two disorders that were not previously associated," Charness says. In experiments on cultured cells, his team found that alcohol specifically interrupts cell adhesion mediated by the protein L1. Alcohol's effect on L1 mimics mutations in the protein that abolish its adhesion. Fetal alcohol syndrome and L1 mutations are both characterized by mental retardation and certain brain malformations. According to Charness, alcohol concentrations equivalent to a single drink significantly inhibited L1 adhesion. "It's scary how little alcohol it takes to interrupt L1 adhesion," he says, "but it's also possible that the effect only lasts for a few hours. Whether or not low alcohol concentrations influence the actions of L1 in nervous-system development may be a matter of timing." GOOD MODELS: James West says animal sutides have been productive. Eventually, possible mechanisms of fetal alcohol effects will be evaluated in animals. Animal models have served researchers in the field well, according to James West, an extramural grantee and chairman of the department of human anatomy and medical neurobiology in Texas A&M's Health Science Center. "Over the years, we've found there's been a good correspondence between animal and clinical findings on FAS," he points out. West has developed rat and sheep models that led him to suspect that binge drinking during pregnancy might be riskier than consuming the same amount of alcohol spread over the entire course of pregnancy. Based on his findings in animal models, psychologist Edward Riley of San Diego State University, also an extramural grantee, moved his research into the clinic. There, he uses magnetic resonance imaging to study brain development in children with FAS. He also studies development in children who had heavy fetal exposure to alcohol but don't have the classic facial features of FAS. These include short eye openings and drooping eyelids; small, flattened noses; and the absence of a groove between the base of the nose and the upper lip. Like West, Riley describes alcohol studies as an arena in which basic research and clinical studies effectively complement each other. "There's a constant interplay between the two," he says. "I think the NIAAA is primarily responsible for that. They've actively encouraged interchange between clinical and basic researchers." That interchange should continue and intensify during the institute's next quarter-century, Gordis believes. "The impact of our basic research on the prevention and treatment of alcohol abuse and alcoholism is going to become greater and greater," he forecasts. "Our futures are linked, as they are in many other areas of medicine." Alison Mack is a freelance science writer based in Wilmington, Del. )

As NIAAA Ends Anniversary Celebration, New Research Efforts Abound

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