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IN the pub of the future, ask for another drink and you could be told you
need your head examined. As the publican slips a crown of electrodes over your
temples, he quickly scans your brain waves on the monitor behind the bar. If
you’re lucky, the characteristic patterns of alcohol dependence are absent, and
you’re allowed another beer. Anyone who fails the test, however, is legally
obliged to consult the bar’s in-house genetic counsellor.

A fanciful prospect, of course, but it’s not all make-believe. Over the past
decade and more, scores of American scientists have been assiduously mapping the
brain waves of alcoholics and their offspring. OK, so nobody has marketed a bar
brainometer (at least not yet) but researchers do claim to have found telltale
electrical patterns that identify those at risk of alcoholism.

What’s more, those brain waves could be signposts to the big goal: genes that
influence whether someone becomes a “problem drinker”. One day, the researchers
claim, we’ll be able to scan babies’ DNA and determine whether their genetic
inheritance predisposes them to alcoholism. Though that day is probably far off,
geneticists already have some prime suspects in mind, because they have
identified several physical traits that point to an increased risk of
alcoholism.

The brain wave work may aid that search by providing an easily measured clue
to a person’s risk of alcoholism. Henri Begleiter, a psychiatrist at the
Downstate Medical Center in Brooklyn, part of the State University of New York,
says the best predictor is something snappily called the P3 component of the
event-related brain potential. What’s that? Well, crudely put, it’s the third
spike that appears in your brain waves about 300 milliseconds or so after your
sensory system has been surprised by, say, a flash of light. Begleiter and his
colleagues have shown that this P3 spike is lower in alcoholics than in normal
people. And the smaller the spike, the more severe the alcoholism.

P3 deficits turn up not only in the alcoholics themselves but also in many of
their unaffected relatives and in their young offspring. The atypical brain
waves could indicate that these others are at risk of alcoholism in the future,
says Begleiter, who is convinced that the size of an individual’s P3 spike must
have genetic underpinnings. Even rats that have been bred to voluntarily guzzle
alcohol have a P3 lower than that of their teetotal peers, says Cindy Ehlers, a
geneticist at Scripps Clinic and Research Foundation in San Diego.

Begleiter thinks the P3 spike is an index of how inhibited your central
nervous system is. The higher the spike, the stronger the inhibitory processes
at work in your brain. So having a low P3 spike means that you lack normal
central nervous system inhibition, says Begleiter. In other words, your brain is overexcited.
Drinking alcohol helps calm this churning activity, but relief is only temporary
and gradually requires larger and larger amounts of booze. Physical dependence
can quickly result.

But stunted brain waves are just one of several factors that can predispose
you to alcoholism. For instance, an ability to hold your liquor from an early
age could also put you at higher risk. “Alcoholics tell me that early on in
their drinking careers they could consume a lot with little effect,” says Marc
Schuckit of the University of California at San Diego.

Almost 20 years ago, these personal testimonies inspired Schuckit to
investigate young drinkers’ sensitivity to alcohol. He compared 453 sons of
alcoholics, all in their early 20s, with controls matched for age, sex and
religion. Inviting them into his laboratory for a drink or two, Schuckit
analysed their hormones, brain waves, motor coordination and subjective feelings
afterwards. It turned out that 40 per cent of the sons of alcoholics were
relatively insensitive to alcohol’s intoxicating effects, compared with only 10
per cent of the sons of non-alcoholics. In other words, they could have drunk
the controls under the table.

Ten years later, Schuckit tracked down all the men in the previous study. Low
response to alcohol at age 20 turned out to roughly double the risk that a man
would become alcoholic by age 30, says Schuckit. He’s now carrying out the
20-year follow-up, focusing on the original young men’s offspring, who are now
in their early teens. By screening their DNA, Schuckit hopes to find genes
related to the low response to alcohol, and hence, to being at risk of
alcoholism.

“It’s an incredibly exciting time to be in this field,” says Schuckit, who is
both a researcher and a clinician in charge of treatment programmes for
alcoholics. Although a keen gene hunter, he stresses that genes probably account
for only 40 to 60 per cent of the risk of alcoholism. “No one is ever
predestined to become alcoholic,” he says. Environmental factors such as peer
pressure and family stability also play important roles. Begleiter puts it even
more bluntly, noting that genes only predispose people toward
alcoholism—they don’t ensure it. “There are no genes for alcoholism. None
whatsoever,” he says. All the same, though, genes matter. “Understanding the
genetics will tell us that not everyone is predisposed through the same
biological mechanism, and so hopefully enable us to tailor treatments
appropriately,” says Schuckit.

But novel treatments are certainly years away. “We are still at the beginning
of the beginning in finding the genes are involved in alcoholism,” says Kirk
Wilhelmsen, a clinical neurobiologist cum molecular biologist at the University
of California at San Francisco. He works at the Ernest Gallo Institute, funded
in part by Gallo, the world’s largest wine maker. “Alcoholism is such a
prevalent disease that it’s no accident—it tells us something important
about our biology. If this is indeed an ancient trait, then we can probably find
the genes responsible,” he says. But the search won’t be quick or easy. “We’re
not talking about a small number of genes with large effects, but a large number
of genes with small effects,” warns Wilhelmsen.

Geneticists in the field wince when they remember the “false starts”, such as
the hype surrounding the announcement of a putative alcoholism gene, the
dopamine receptor D2, in the early 1990s. Excited researchers believed they had
made a huge genetic breakthrough, and rushed into print with their findings. But
when other teams looked for D2 receptor mutants in other alcoholic families,
they didn’t find them. In the end, it appears, the “alcoholism gene” was just a
genetic quirk of the original small study population. “It’s like comparing the
DNA of alcoholic Eskimos with a population of non-alcoholic pygmies, and jumping
to the conclusion that any difference you find is the gene for alcoholism,” says
Wilhelmsen.

Today’s researchers are determined not to make the same mistake. A
ten-year-old “big science” project called COGA—the Collaboration on the
Genetics of Alcoholism—aims to search as thoroughly as possible for genes
that influence the risk of becoming an alcoholic.

This huge genome fishing expedition, funded by the US National Institutes of
Health and coordinated by Begleiter, focuses on “densely affected families”,
which are most likely to show a genetic predisposition. To count as an alcoholic
in this study, you must have at least three close relatives who are similarly
afflicted.

“I’m very excited and encouraged with progress to date, but I wouldn’t say we
are very close to finding individual genes,” cautions molecular geneticist
Howard Edenberg of the University of Indiana at Indianapolis. “We’ve got
reasonably good signals pointing to particular regions on chromosomes. But these
regions each contain some 20 million base pairs and as many as 600 genes, the
vast majority of which are of unknown function.”

Those regions contain plenty of “candidate genes”—genes like the
ill-fated dopamine receptor that might logically be expected to interact with a
drug such as alcohol that wreaks havoc in your brain-but scientists still need
to find direct proof.

The trouble is, alcohol does not appear to have a single specific target in
the brain. Instead, it alters many aspects of brain chemistry
(see “Jane behaving badly”).
So all manner of brain messengers may interact with
alcohol molecules to somehow fuel our appetite for drink. For instance, George
Koob at the Scripps Research Institute in La Jolla recently showed that brain
levels of corticotropin releasing factor (CRF), a neurotransmitter associated
with stress responses, shoot up when alcohol-dependent rats are prevented from
drinking. This adds weight to the notion that alcoholics keep drinking at least
in part to stave off acute feelings of tension and distress. What’s more,
genetic differences in the action of CRF could play a role in an individual’s
susceptibility to alcoholism, Koob suspects.

Jangling nerves

Another messenger molecule that interacts with alcohol, gamma-aminobutyric
acid, acts mostly to inhibit brain activity. Recent research suggests that
alcohol-dependent individuals have fewer receptors for this
neurotransmitter—again, perhaps because of some underlying genetic
difference. Fewer receptors mean less inhibition, backing up Begleiter’s idea
that alcoholics suffer from a hyperactive central nervous system.

A new player has recently joined the scene, a signalling molecule called
neuropeptide Y (NPY). Mice genetically engineered to lack the gene for NPY
voluntarily quaffed almost twice as much alcohol as control mice and could also
hold their drink better in experiments run by Todd Thiele, Richard Palmiter and
their colleagues at the University of Washington in Seattle.

The altered mice could, for instance, stand up faster than normal mice after
being rolled on their backs when drunk. They also recovered more rapidly from a
drinking bout, even though the alcohol level in their blood was initially
similar to those of normal mice. These results echo Schuckit’s finding that
increased resistance to alcohol is a good predictor of alcoholism in humans. And
in a neat twist, Thiele and his colleagues went on to show that mice genetically
engineered to overproduce NPY were less keen to drink than normal mice and were
quicker to slip into an alcoholic stupor.

It’s intriguing work, but researchers in the field reckon it’s far too early
to regard NPY as the answer to alcoholism. No one yet understands what NPY is up
to in the human brain—it seems to be tied up with everything from eating
and anxiety to pain sensitivity. And because the lack of NPY might conceivably
cause the engineered mice to develop abnormally during fetal life, there’s
always the possibility that their altered alcohol responses are the end result
of defective development, rather than something that starts in adulthood. To
test this, Palmiter is now producing a strain of mice in which the NPY gene can
be turned off later in development. Meanwhile, Thiele is trying to track down
NPY receptors that play a role in the mice’s drinking preferences.

All in all, there’s plenty to keep alcohol researchers busy. After a decade
on the case, the COGA initiative is now gearing up for another five years. With
luck, says Edenberg, “we’ll track down the genes in that time”. After all, says
Ted Reich of Washington University, “we now have hot spots on chromosomes and we
have a range of candidate genes”.

Who knows, the world’s biggest alcoholism research team might just be
cracking open the champagne in 2005.

NO one has yet tracked down genes that drive you to drink, but there are
definitely a couple of genes that can slam on the brakes. In fact, these two
anti-drink genes are the only genes proven to influence whether and how much a
person drinks. These genes are much more common among Asian populations, but
they can pop up anywhere.

You’ll know if you’ve got one. Take a drink of alcohol—and the blood
rushes to your cheeks and ears. You’ve experienced an “alcohol flush reaction”.
In severe cases, your face swells up and you feel nauseous, dizzy and
headachy.

All these horrible symptoms result from an unusually rapid build-up of
something called acetaldehyde, as the body’s enzymes set to work on the alcohol
you’ve ingested. A reactive compound with all sorts of biochemical effects,
acetaldehyde is also a potent vasodilator—a rush of blood to the bowels is
probably what makes susceptible individuals feel sick.

These anti-alcohol genes can conjure up instant hangovers, generating a
strong incentive to stay on the wagon. Such in-built protective factors could be
as important as the much-discussed risk factors in determining an individual’s
chance of becoming an alcohol abuser, says Ting-Kai Li, a geneticist at Indiana
University in Indianapolis.

Individuals with a mild flushing reaction break down alcohol into
acetaldehyde more quickly than unaffected people because they have an overactive
variant of the enzyme alcohol dehydrogenase. Severe flushing afflicts those with
the gene for a slow-acting version of another enzyme, called aldehyde
dehydrogenase. This enzyme—the second step in the breakdown of
alcohol—turns acetaldehyde into acetate, so any sluggishness on its part
quickly leads to an accumulation of noxious acetaldehyde.

One of the most dramatic gene effects on behaviour yet discovered comes from
a variant of the aldehyde dehydrogenase gene known as ALDH2, which may be
present in as many as one out of every two people of Asian descent. If you have
inherited a copy of this gene, “you virtually cannot drink”, says Li.

Despite this, however, he and his colleagues have just encountered the first
case of an alcoholic with this genetic trait. “His drinking behaviour was very
peculiar,” says Li. To cope with his adverse reactions to alcohol, he had to
drink very carefully. In fact, he sipped his tipple. “But if you keep sipping
for 20 hours, as this alcoholic did, you can still consume a fair amount,” says Li.

As Li’s alcoholic demonstrates, determined individuals can overcome their
genes. One study in the 1970s reported that about 80 per cent of Japanese,
Chinese and Koreans have visible facial flushing and increased blood flow to
their ear lobes after consuming small amounts of alcohol, while only the
occasional European or Native American has a similar reaction. Yet rates of
alcoholism in Korea, for instance, are thought to be similar to those in the US.
Culture thumbs its nose at genes again.

• Ethyl alcohol is a colourless, flammable liquid used
  to preserve fish World Bank
• Beer glasses are by far the most common weapon of
  assault in Britain Jonathan Shepherd Surgeon at
  University of Wales College of Medicine and an expert on
  alcohol-related assault
• The most valuable bottle of wine was sold at auction at Christies, London, in
  December 1985. The buyer paid £105 000 for a bottle of 1787 Château
  Lafite claret that was engraved with the initials of Thomas Jefferson. Eleven
  months after the sale, while the bottle was being exhibited, lights dried out
  the cork, which slipped into the bottle and spoiled the wine. Guinness ® World
  of Records 2000
• In the US in 1995, alcohol-related costs in areas such as crime, health care,
  policing and losses in industrial productivity amounted to $167
  billion US National Institute on Alcohol Abuse and Alcoholism
• Troublesome arguments take place in a third of British pubs at least once a
  month and fights break out in 6 per cent of pubs every week. About 5 per cent of
  pub managers are assaulted every month MCM Research, Oxford
• One in every 122 licensed drivers in the US was arrested for driving under
  the influence of drugs or alcohol in 1997 US Department of Transportation
• During 1998, nearly a quarter of Australian men and a tenth of Australian
  women drove while under the influence Australian Institute of Health and Welfare
• The strongest alcohol is an Estonian liquor distilled from potatoes between
  the two world wars. It is 98 per cent alcohol Guinness ® World of Records 2000