Nowadays, you can sequence your genome in a weekend for about a thousand bucks. But would you believe that the first human genome sequenced took 13 years (1990 to 2003) and cost $2.7 billion?
Back in those days, when Harry Potter had just started his on-screen adventures at Hogwarts, getting your genome sequenced was a rare privilege. Among the first people to remove the invisibility cloak from their DNA were James Watson, one of the scientists who helped solve the structure of DNA in 1953, and Craig Venter, who was instrumental in making the Human Genome Project happen. Steve Jobs was also one of the first to have his genome sequenced (which I imagine lab techs referred to as the iGenome). What other luminaries did scientists reach out to for secrets their DNA held? Stephen Hawking? High IQ record-holder Marilyn vos Savant? That guy who won 74 games in a row on Jeopardy?
Nope. Scientists wanted Ozzy Osbourne.
Born in 1948, John Michael Osbourne answers to several names, including “Ozzy,” “Prince of Darkness” and “Godfather of Heavy Metal.” Ozzy rose to stardom with Black Sabbath in the 1970s, and then went on to a wild, and wildly successful, solo career. But Ozzy’s music has often been eclipsed by his legendary drug and alcohol binges. So why would researchers want to peek inside Ozzy’s genes?
Truth be told, Ozzy is a remarkable human specimen. He’s constantly struggled with addiction to multiple vices (cocaine, booze, sex, pills, burritos), tirelessly toured and partied for half a century and survived reality television while taking up to 25 Vicodin pills a day at the time. His immune system was so weakened from drugs and alcohol that he once falsely tested positive for HIV.
Living one week of the Ozzy lifestyle would easily kill most of us, so scientists couldn’t wait to get their latex-gloved hands on this Iron Man’s DNA sequence. What death-defying genes could Ozzy possibly have that would allow someone to survive cocaine for breakfast and four bottles of cognac a day for decades?
In 2010, scientists at Knome Inc. read the DNA diary of a madman and discovered that Ozzy is indeed a genetic mutant. Among some of the more intriguing things spotted in his DNA was a never-before-seen mutation near his ADH4 gene. ADH4 makes a protein called alcohol dehydrogenase-4, which breaks down alcohol. A mutation near ADH4 is likely to affect how much of the protein is made. If Ozzy’s body is built to detoxify alcohol much faster than normal, it might help explain why his liver hasn’t exploded.
Ozzy also possesses variations in genes linked to addiction and alcoholism, as well as how the body processes marijuana, opiates and methamphetamines. All told, his DNA revealed that he is six times more likely than the average person to have alcohol dependency or alcohol cravings, 1.31 times more likely to have a cocaine addiction, and 2.6 times more likely to have hallucinations caused by marijuana.
Ozzy, who claimed that “the only Gene I know anything about is the one in KISS,” was fascinated by the results. And although the variants found in his genome are tantalizing, the truth is, we don’t know enough about these genes yet to build a comprehensive picture that shows us why this man has an addictive personality — or why he is still reasonably healthy after abusing his body for more than 50 years. Addiction is a complex behavior, but research is revealing that our genes, plus other biological factors outside our jurisdiction, can conspire to make life a living hell.
Alcoholism in Your Genes?
Alcoholism includes cravings, loss of control, physical dependence and tolerance. The National Council on Alcoholism and Drug Dependence estimates that 1 in every 12 adults suffers from alcohol abuse or dependence in the United States alone. Americans spend nearly $200 million a day on booze, and about 100,000 people die each year from alcohol-related causes, such as drunken driving, suicide or falling down stairs.
Alcohol addiction is clearly a serious problem, but I’m not trying to cast alcohol as the devil’s nectar. The important question is why some people can’t stop imbibing when they know they should. The National Institute on Alcohol Abuse and Alcoholism says that genes are responsible for about half of someone’s propensity to develop alcohol addiction. But as with Ozzy’s genome, there is rarely a single gene that fully explains this complex behavior.
Indeed, numerous genes have been linked to alcohol dependence. The first one relates to why people like to hit the pub after a stressful day at work. A 2004 study by geneticist Tatiana Foroud at the Indiana University School of Medicine linked a gene called GABRG3 to alcoholism. This gene makes a subunit of the brain cell receptor that recognizes gamma-aminobutyric acid (GABA), a so-called “inhibitory” neurotransmitter that tells the brain to calm down. Without it, a person is more likely to turn to booze to do the same. This discovery gave credence to the theory that the disease is linked to an overactive brain. Due to its sedative properties, alcohol relaxes hyperactive neurons, serving to dam the raging rivers in the mind.
Why Some Just Say No
Genes that govern how the body deals with alcohol or other drugs also influence whether someone is more prone to becoming a substance abuser. For example, some people, particularly those of East Asian descent, experience rapid flushing and a quickening heart rate when consuming alcohol. This is commonly referred to as Asian flush or Asian glow, but the more inclusive name is alcohol flush reaction (AFR). People with AFR possess a genetic variant that impairs production of an enzyme that helps break down alcohol in the body.
In the liver, alcohol is broken down to acetaldehyde, which is toxic, and then to acetate, which is non-toxic. In those with AFR, alcohol is converted to acetaldehyde just fine, but then the acetaldehyde is not broken down efficiently and builds up in the body. This buildup causes blood vessels to dilate, which produces the redness and heat we call flushing. Excessive acetaldehyde can also cause headaches and nausea. The uncomfortable sensations associated with drinking prompt some to lay off the sauce, making people with AFR less likely to suffer from alcoholism.
The same principle underlies the use of the medication disulfiram as a treatment for alcohol abuse. Disulfiram causes drinkers to experience the same unpleasant reactions of AFR when they consume alcohol, discouraging them from hitting the bottle.
Drugs have different effects on different people, largely based on what users have in their genetic toolbox to process the substance in question. For example, about 20 percent of Americans have a mutation in a gene called fatty acid amide hydrolase (FAAH). This gene makes an enzyme of the same name that breaks down anandamide, the so-called bliss molecule. Your body produces anandamide naturally to decrease anxiety by binding to your cannabinoid receptors. People with the mutated FAAH have more anandamide in their brain all the time; they not only tend to be calmer and happier than others, but they are also less likely to use marijuana because it simply doesn’t do much for them.
Why It's Hard for Some to Stop
Alcohol and other drugs are foreign chemicals that are processed by the body. If the body keeps seeing alcohol over and over, it reacts by making the liver work overtime to increase the number of enzymes to get rid of it. The body’s attempt to resume normalcy is why drinkers build up tolerance to alcohol, which means they must ingest more and more to get the same feeling of satisfaction. To novice drinkers, one shot may produce a buzz. But after a few weeks of drinking, it will take two or three shots to reach that buzz, because their liver is processing the alcohol more efficiently.
After prolonged drinking, people need to consume alcohol just to feel normal. To compensate for alcohol’s sedative effects, our brain chemistry adapts to make more neurotransmitters that activate neurons to excite them again. If alcohol intake suddenly stops, the brain is no longer being sedated, but those excitatory neurotransmitters are still cranked up to 11. This is why people undergoing withdrawal experience the shakes, anxiety and restlessness.
Because the brain takes time to recalibrate to the lack of alcohol, many people with withdrawal symptoms resume drinking just to calm down. The excess alcohol that needs to be consumed starts to wreak havoc on other bodily systems including the liver, kidneys and stomach. Benzodiazepines like Xanax and Valium are sometimes administered to people undergoing alcohol withdrawal as a means to replace the effects of alcohol with a medicine that increases the anxiety-reducing neurotransmitter GABA. The administration of benzodiazepines can be better controlled than alcohol intake and often helps restore the proper balance between excitatory and inhibitory activities in the neurons.
Alcohol interacts with numerous other systems in the brain, and genetic variations can exist in any of them, explaining why responses to alcohol and the tendency to become addicted vary so widely. Traditionally, scientists have uncovered genes associated with increased drinking, but a 2016 study led by Gunter Schumann at King’s College London revealed a gene that may explain why some people know their limits. A variant in the gene that makes a protein called beta-Klotho was found in about 40 percent of study participants who show a decreased desire to drink alcohol.
The beta-Klotho protein is a receptor in the brain that catches a hormone called FGF21, which the liver secretes when it is processing alcohol. Schumann and his team believe that beta-Klotho may be involved in cross-talk between the liver and the brain, a type of SOS that there is too much alcohol in the liver. When the team genetically engineered mice without beta-Klotho, these mice drankmore alcohol. Such a feedback mechanism is analogous to how the satiety hormone leptin tells the brain when the stomach is full. Studies like these suggest that people’s ability to know their limits with alcohol may be because they were lucky to be born with a more effective liver-brain communication system.
What a Long, Strange Trip it's Been
You may never have thought about it this way, but just about everyone is or has been addicted at one point to caffeine. Sure, caffeine is mild compared with hardcore drugs, but the fundamental principles are the same.
We enjoy the jolt of energy that caffeine brings, but soon we can’t seem to function without it. We get tired and cranky. Many people are complete ogres until they have had their morning coffee. After a little while, we find ourselves having a second or third cup because one just doesn’t cut it anymore. Try to stop, and you will be tortured with fatigue, headaches and irritability. It’s easier just to brew another pot and keep the habit going. If asked to give up the coffee pot, many would say you’d have to pry it from their cold, dead hands.
It’s the same basic cycle for those with other addictions, but the substances involved are much more difficult to quit. Perhaps we can use this common ground to reshape our approach for helping people with addiction issues. The addiction is punishing enough, and further punitive action has proven to be an abysmal failure that has needlessly ruined the lives of many good people. The true crime of people with addiction is having the wrong genes in the wrong place at the wrong time. With better education, we might prevent more people from doing drugs in the first place. With a better understanding of the biology behind addiction, we can develop effective treatments. With a better idea of the genes predisposing people to an addictive personality, we can screen for people who may be at risk. We need a war on addiction, not a war on drugs, and certainly not a war on those who are addicted.
Excerpted from Pleased to Meet Me, originally published by National Geographic Partners, LLC, on August 6, 2019. Copyright © 2019 by William J. Sullivan. This story originally appeared in print as "Addicted, More or Less."
