Dr. Kirk Wilhelmsen is an enthusiastic tour guide as he shows his visitors around the various labs where he works in Emeryville. He shuffles through the corridors in fits and starts, stopping every now and again to explain the groundbreaking work being done by his colleagues. He speaks with a deliberate air of whimsy reminiscent of other smart guys like Carl Sagan, often beginning his sentences with the conclusive phrase, "It turns out that..." (While he sounds like Carl Sagan, he looks more like Stephen King.)
"This is Steve McIntire's lab," he says, pushing open the door, heading directly to a nearby microscope. "His group studies C Elegans -- it's a barely visible soil worm. These soil worms are rather phenomenal," he says, the volume of his voice rising slightly. "Every one of them is identical."
On the slide under the microscope, the translucent micro-worms don't seem obviously impressive, but Wilhelmsen is quick to explain their significance. "They're very simple organisms, and you study the genetics [by] how these organisms behave," he explains. "For instance, it turns out that you can isolate the mutant worms that don't get drunk with alcohol."
Mutant lab worms aren't the only critters in the 75,000-square-foot research space inside the two-year-old Emery Station building who are getting soused. Down the hall from the worms, fruit flies residing in glass cylinders are exposed to vaporized alcohol. In earlier experiments, scientists in the lab discovered that some fruit flies can fly under the influence, while others pass out. It turns out that the alcohol-sensitive flies possess something that cheeky researchers label "the cheap date gene."
Upstairs, genetic tinkerers have bred mutant mice lacking an enzyme labeled PKC, the absence of which enhances the effect of alcohol on a particular molecular receptor in the brain associated with inhibition. It turns out that these mutant mice are 75 percent less likely to want a drink than their normal brethren.
If there seems to be a theme running through all of this research, there is: The scientists laboring in this lab are trying to find a cure for alcoholism, and much of their work is centered around the fact that people who demonstrate an early tolerance for alcohol -- the ones who are left standing after the kegger in college -- are more likely to become alkies down the road than their passed-out companions.
Lightweights, you see, tend to get sick when they drink too much and therefore tend to avoid repetitive tokes from beer bongs. That's why the mutant mice didn't drink as much as the normal ones -- they were bred to be extra-sensitive to alcohol.
Back in Wilhelmsen's lab, the genetics expert is pointing out other tools of the alcoholism research trade like a machine that slices and dices DNA extracted from blood samples of alcoholics. For the past five years, Wilhelmsen and his team have been gathering blood and personal information from hundreds of alcoholics and their relatives. He's optimistic that his study will ultimately yield major scientific breakthroughs.
"The biggest jackpot," Wilhelmsen gleams, "would be able to figure out what it is about alcoholism that is inherited as well as find the gene for it. [We know that] there is something that is hereditary [about alcoholism], but we don't know exactly what it is. Is it the ability to learn to like alcohol? Is it the ability to develop a craving for alcohol? There are lots of possibilities. We're not only trying to figure out where the genes are that lead to predisposition, we're trying to figure out what elements of alcoholism are caused by these genes."
"I'm fully expecting," Wilhelmsen adds with a measure of self-satisfaction, "to redefine alcoholism based on the underlying biological process and what it is about alcoholism that's inherited. If there's a gene that's involved, there's a molecule that is involved, and a drug that can be developed for that."
Wait. A drug that could rid alcoholics of the insatiable craving that causes them to turn their livers into liverwurst and call their exes at 3 a.m.? Not only do these researchers think it's possible, so does the state of California. In 1998, the state authorized funding that the lab's director describes as a "Manhattan Project" for alcohol research, to the tune of $143 million. And if that sounds fantastic, get this: The man who made this newfangled effort to nuke alcoholism possible is none other than Central Valley wine tycoon Ernest Gallo.IIf it would seem unusual for any vintner to be mounting an ambitious research project into the causes and treatment of alcoholism, Ernest Gallo is an especially unlikely benefactor.
Ernest and his brother, Julio Gallo, became big-time wine retailers in the mid-'50s when they switched their marketing focus from table wines to fortified wines that have a twenty percent alcohol content. Their first big seller was Thunderbird, a combination of white port and lemon juice, which quickly caught on in African-American communities like Oakland, where consumers previously used to mix lemon with their port to cut the acidity.
If you believe Ellen Hawkes, author of Blood and Wine: The Unauthorized Story of the Gallo Empire, Thunderbird caught on with a little help from Gallo's marketing luminaries. According to Hawkes, Gallo salesmen threw empty bottles of Thunderbird in the gutters of skid row to increase product awareness in the ghetto.
The notoriously reclusive 92-year-old vintner doesn't provide much insight as to why he helped launch Emeryville's Ernest Gallo Clinic and Research Center with a reported $6.5 million endowment in the early '80s. [Even Gallo's spokesman, Lou Friedman, refused to answer any questions for this story.] In the 1994 book, Ernest & Julio: Our Story, Gallo briefly mentions his donation to the cause after ranting about teetotalers he condemns as "neo-Prohibitionists." "The neo-Prohibitionists would have people believe that a drink is a drink -- and therefore bad," Gallo grouses. "I'll bet that no one has ever gone into a bar and ordered a double-shot of Cabernet. Wine historically has been a beverage of moderation to be enjoyed with food. It still is. The dangers of alcoholism have been common knowledge for centuries. It is possible, however, that progress can still be made toward the prevention and cure of this disorder." To that end, Gallo goes on to say, he magnanimously chose to establish his cutting-edge clinic where scientists would use "space-age techniques" to cure alcoholism.
The idea that Gallo would have an altruistic motive for starting the center strikes alcohol industry critics as transparently absurd. Andrew McGuire, who chaired the failed 1990 Alcohol Tax Initiative that Gallo opposed, dismisses Gallo's generosity as a PR ploy. He points out that although Gallo has tried to increase his company's snob factor, the winery still produces Thunderbird and Night Train, fortified drinks not usually enjoyed with a plate of veal parmigiana and garlic bread. Those drinks, he says, are aimed squarely at the ten percent of the adult population that qualify as alkies. Gallo doesn't want to lose those alcoholic customers -- they mean money, McGuire argues.
In her book, Hawkes notes that Gallo established the research center at a time when consumers had become more health-conscious. Ernest had also become more conscious about his company's lowbrow image. The famous "All the best from Ernest and Julio Gallo" ad campaign soon followed. "Whether he was trying to improve his image or was acknowledging the new attention to health with which the wine industry had to deal ... [it] was one of the few major charitable contributions of the Gallo family that was publicized."
Researchers at the Gallo Center are aware of the criticism, of course; they have gone to great pains over the years to establish the legitimacy of their work. Although it is technically an independent nonprofit entity, the Gallo Center operates under the auspices and direction of UCSF's department of neurology; the program boasts two Nobel Prize winners on its scientific advisory board, and any research findings the center publishes are submitted to normal scientific peer review. And although Gallo scientists have assisted on at least one study showing the positive health benefits of moderate drinking, the Gallo Center's undisputed focus has been on the physiological roots of problem drinking.
Dr. David Smith, the president and founder of the Haight-Ashbury Free Clinic, regularly interacts with Gallo Center director Dr. Ivan Diamond. Smith agrees that the center's scientific reputation is beyond reproach. "I believe it's the top alcohol research facility in the nation," Smith gushes. As for Gallo's involvement, Smith says that doesn't bother him because the winemaker isn't dictating the research. Gallo Center genetics expert Wilhelmsen agrees. "The fact is," Wilhelmsen says, "there are no restrictions on anything we publish. There are no restrictions on anything we say. They [Gallo and company executives] might have control in the sense that they could say, 'We're not going to support you as well,' but in fact people from this institution have said alcohol is bad for you."
Whatever his motives, the businessman behind Thunderbird could also go down in history as the businessman who helped revolutionize medical treatment for some of his best customers. But will it actually result in a cure?GGallo was indeed right when he said in his book that we've long known the dangers of alcoholism -- perhaps we've always known them. But our understanding of alcoholism has steadily and dramatically evolved over the hundred years.
In the early part of the 20th century, mainstream society oscillated between viewing compulsive drinking as a character flaw, and viewing it as a mental illness. Drunks often found themselves coming to in the morning strapped down to beds in sanatoriums. It was then that Bill Wilson (himself a regular at his local nuthouse) and Dr. Bob Smith forever changed the way people think about alcoholism when they founded Alcoholics Anonymous in the 1930s. In the "Big Book," the AA bible, they described alcoholism as both a mental obsession and a physical allergy. More importantly, the two sober drunks pioneered the concept of alcoholism as a disease.
Characterizing chronic alcohol abuse as a disease removed the stigma that had humiliated so many wake-and-drinkers. A disease was something beyond human will -- it was a fact of life. And like other diseases such as diabetes, alcoholism could be treated, Wilson and Smith suggested, if not actually cured. The treatment they prescribed was the now-famous twelve-step model in which newcomers admit their powerlessness over alcohol and turn their lives and will over to God or a Higher Power. After that, one just had to "let go and let God" and stay sober one day at a time. There simply is not, the AA founders insisted, an "easier, softer way."
Though AA popularized the notion of alcoholism as a disease, the program didn't spawn much research into the actual physiology of the body's "allergy" to alcohol. (In the sixty years after AA was founded, the Food and Drug Administration approved only one drug specifically for the treatment of alcoholism. That drug, which hit the market in 1948, was called antabuse, and it worked by making drinkers violently ill.) Addiction experts blame a variety of factors for the lack of research into the physiology of alcoholism: that deep down, policymakers and the public in general still deemed alcoholism a personality disorder; and that pharmaceutical companies were not willing to take the risk of trying to develop a drug general physicians were not treating. Nonetheless, over the years the body of evidence continued to steadily grow, suggesting that alcoholics were born, not made (or at least both born and made).
In the early 1970s, Danish scholars released a study that examined adopted kids with alcoholic biological parents, who were raised by adoptive parents without drinking problems. Their research showed that children with the hereditary link were at least three times more likely to become alcoholics than kids with normal biological parents who were also raised by nonalcoholic parents. Other studies of twins raised separately also strongly suggested a genetic component to alcoholism.
Soon scientists like Dr. Ivan Diamond, a neurological specialist at the University of California at San Francisco, were taking it as a given that genes and other biological factors played a crucial role in whether someone becomes a problem drinker. The challenge for Diamond and other researchers has been to find exactly which genes, cell signaling pathways, and neurotransmitters were involved. With that knowledge, scientists might finally be able to develop something to treat or even prevent alcoholism.IIt was sometime around 1980 when Diamond first met Ernest Gallo. As the story goes, the two began discussing alcoholism and the need for more study of the disease so drug treatments could be developed. "[Gallo] told me that as far as he is concerned, [alcoholism] is a blight on his industry," Diamond would recall several years later in an interview with the Modesto Bee. "He didn't feel this kind of research was being addressed anywhere."
And for the most part, it wasn't. Back then, alcohol and addiction research was the territory of psychiatrists and social scientists who focused on behavioral treatments. When the Gallo Center opened, it had only six employees and an annual budget of $400,000 (today it has 160 employees and a budget over $30 million).
Still, the center made do, and in 1988 Diamond announced an important discovery: He had found strong evidence for genetic differences between cells of alcoholics and cells of nonalcoholics.
According to news accounts at the time, Diamond and his team took the cells from identified alcoholics and those of nondrinkers and reproduced them over several generations without exposing them to alcohol at first. When they did feed them booze, the cell descendants from nondrinkers and the ones from alcoholics reacted differently, even though neither had been exposed to alcohol for generations. The alcoholic cells clearly adapted to booze more quickly and at lower doses than the cells of teetotalers.
While the findings strongly suggested a genetic component to alcoholism, they also raised the possibility that science could potentially identify genetically predisposed people. Still, Diamond told reporters, still more research needed to be done before they could pick a drunk out of DNA lineup.
By the mid-'90s, Diamond and other researchers were getting closer and closer to naming specific genes involved in alcoholism. And their studies were repeatedly confirming that the alcoholic brain was different than that of a nondrinker. Alcoholics and addicts, for instance, appear to have a deficiency in a neurotransmitter known as dopamine that is associated with the sensation of pleasure. Thus, a shot of whiskey could be like a shot of dopamine. (Because of this sort of brain chemistry research, the Food and Drug Administration approved a new drug treatment for alcoholism for the first time in nearly fifty years. Unlike antabuse, the new drug, naltrexone, didn't make drinkers sick. It curbed the alcoholic craving for a drink by blocking the abnormal surge in endorphins experienced by the chronic drinker.)
By 1997, the Gallo Center had grown dramatically from where it started. It now had more than forty employees and a budget of over $3 million. But Diamond considered that dollar amount a drop in the barrel for what he really needed to engineer -- a major scientific breakthrough.
He needed a little help from an old friend in the wine business.DDuring the final year of his term as governor, Pete Wilson was chatting on the telephone with his old patron Ernest Gallo. Not everybody gets a one-on-one with the governor of the largest state in the union every day, but Ernest Gallo wasn't everybody. The Gallo family had donated thousands to Wilson when he was a US senator and, more recently, had kicked in $22,000 for his failed presidential bid.
The conversation somehow turned to the heady topic of alcoholism research. As the story goes, the vintner told Wilson about the Gallo Center and his desire to turn its modest accomplishments into revolutionary ones. He told the governor that the center's director, Ivan Diamond, felt that his alcohol research needed a massive influx of resources to make real progress in a short time, like the Manhattan Project, (referring to the World War II effort that produced the atom bomb, not the cocktail made of whiskey and sweet vermouth).
After talking to Gallo, according to his old press aide, Sean Walsh, Wilson stayed up until two a.m. reading about the societal impacts of alcoholism. Apparently impressed, Wilson put a line item in his final budget funding the Gallo Center -- even though it had never gone through a competitive process. A few months later, the governor appeared at the Gallo Center -- then located at San Francisco General Hospital -- and presented Diamond with a $16.5 million check. That was only the first year's installment. The legislature had overwhelmingly voted to give the clinic a total of $143 million over five years (through 2003) from the state's general fund -- an unheard-of amount for such research from a state government. (The feds have traditionally funded such scientific research.) At the press conference, Diamond lauded Wilson for making it possible for the Gallo Center to do in five years what otherwise might take fifteen to twenty years to accomplish: that is, to identify four to six agents that could be developed into treatments for alcoholism.
By the time the state's five-year funding cycle runs out, the Gallo Center expects to have added a total of 100 employees to its payroll. In the first year after the funding kicked in (1999), the center spent nearly $8 million on new equipment alone -- more than twice what it spent on its entire program two years earlier.
Sean Walsh, who still handles press questions for his old boss, defends Pete Wilson's financial support for the Gallo Center, saying the $143 million earmarked for research into alcoholism is "a pittance" when compared to addiction-related costs to the health and criminal justice systems. "He [Gov. Wilson] thought it was a terrific thing and well worth the money," Walsh says.
Nor is Wilson the only politician who's uncorked the public piggy bank for the Gallo Center. Last year, US Senators Barbara Boxer and Dianne Feinstein helped secure $8.5 million for the Gallo Clinic "to study the effects of alcohol on the brain" from an unlikely source: the Pentagon. The military's funding of the Gallo program won a prominent mention in the Center Against Government Waste's 2001 Congressional Pig Book. It also drew sneers from Senator John McCain (R-Arizona), who asked, "What in the world does the Gallo research center have to do with anything that is regarded as defense?"
As a public policy matter, industry critic Andrew McGuire argues, the government could do other, more cost-effective things to reduce the impact of boozing through education, restricting marketing promotions, and raising taxes on alcohol. Studies have shown that making booze more expensive reduces its consumption, according to McGuire, executive director of the San Francisco-based Trauma Foundation, which, among other things, examines the role alcohol plays in creating trips to emergency rooms and morgues.
Alcohol companies -- including Gallo's -- have opposed tax hikes because, well, they would reduce consumption of their products. Instead of taxation, McGuire says that industry executives have long used the red herring of scientific research into the causes of alcoholism to keep regulators off their backs. The effect: It puts the spotlight on the user instead of the dealer. "As long as policymakers look for a Holy Grail of research to solve alcohol-related problems," McGuire says, "then they'll always be dumping money into a pit that has no bottom.
"They are never going to find the Holy Grail."TTo an extent, McGuire is right. Don't expect the Gallo Center to breed a Brave New World of alcohol-resistant humans if it discovers the exact genes behind alcoholism. For all the hope for new drug treatments, researchers at Gallo concede that whatever they come up with, it won't be a silver bullet that forever eradicates the plague of alcoholism from the earth.
Alcoholism is a very tricky thing. Gallo Center gene-expert Kirk Wilhelmsen says that each new discovery raises complicated issues. Take, for instance, the finding that biological processes associated with alcoholism also are associated with learning and feeling pleasure.
"I've been asked many times if we'd treat alcoholism [by trying] to eliminate it from the population," Wilhelmsen says. "I think that may be a catastrophic idea. Alcoholism is a subversion of the normal biology of our reward system. The things that make us have sex and procreate and learn and fight and do all these things related to survival, those are the same processes subverted by alcohol. If you shut down that system completely, it may be a pretty sad world. And, in fact, if you were to say, 'I'd like to eliminate all the alcoholics in the world,' then you would eliminate some very clever and bright people."
Wilhelmsen's equivocal view begs the question: So then what's the point of this costly Manhattan Project? "What we're doing," he explains, "is trying to understand the biological process and sort it out and take it apart so that we can understand what drives what; how the cells work; how they communicate; how this reward system works so that we can tweak it the right way. It may be that there won't be one pill that treats everyone coming out of this, but maybe we'll learn that there are fifteen types of alcoholics or twenty types of alcoholics. And then the idea would be to sort out what kind of therapy to give to each one of those."
And even if Gallo researchers do come up with new drug treatments, they say that future patients should combine their drug therapy with some kind of psychological therapy or twelve-step program -- for even though we now know that there is a strong biological component to alcoholism, there is clearly also a social and psychological component.
This isn't to say that Gallo and other researchers in the field are not going to produce major medical breakthroughs, says Dr. David Smith of the Haight-Ashbury Free Clinic. Smith argues that hoping for a silver bullet for alcoholism is wrongheaded. Alcoholism is not an acute disease, but, like diabetes, a chronic one that requires both ongoing medical treatment and behavioral modification.
Perhaps the most crucial product of this kind of research, Smith says, won't be a pill -- it will be the promise that alcoholism may finally move onto the treatment map of primary-care physicians. Smith says that most medical doctors now think they can't do anything for an alcoholic because they can't prescribe anything. Thus they often don't even ask their patients how much they drink each week, reducing the potential for early intervention.
Aside from drug treatments, Gallo Center leaders are hoping to use their findings to develop a diagnostic blood test for alcoholics. Smith says if physicians could administer the blood tests, they also would be more likely to screen their patients for drinking problems. "They [researchers at Gallo] are studying the things we need to know," says Smith, "and the reward, if they're successful, will be astronomical."
So, exactly what can we expect from the Gallo Center at the end of its five-year Manhattan Project in 2003? Kirk Wilhelmsen concedes that it would be "optimistic" to say they will actually have helped market a new drug that can be prescribed by then.
"The goal posts are to have drugs that are in trials and that are targets. I think that's possible. I don't think we're going to be able to point to a drug that's advertised in Reader's Digest."
Ultimately, he says, "The commitment is to do good science." And good science is not unlike fine wine -- it takes time.
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