WHAT A PIECE OF WORK WE ARE!

 I love genes. I can’t get enough of them.

Forty years ago when I was working with James Milam on my first book, “Under the Influence,” I spent hundreds of hours in libraries searching for answers to my questions about the biochemical and neurogenetic processes underlying addiction.

I’ll never forget my excitement when I came across psychiatrist Donald Goodwin’s research on the genetics of alcoholism. Goodwin studied children of alcoholics who were separated from their parents at birth and adopted by nonrelatives. 

Despite having no exposure to their alcoholic parents, the children of alcoholics had a four times higher risk of becoming alcoholics – and they were more likely to develop the disease earlier in life, usually in their twenties.  The children of nonalcoholic parents, on the other hand, had relatively low rates of alcoholism even if reared by alcoholic foster parents.

Alcoholism, in other words, is a genetically-influenced disease – the children of alcoholics inherit, through the genes passed from parent to child, a physiological susceptibility to addiction.

We humans have between 20,000-25,000 genes. For the genetically influenced disease of alcoholism, dozens, even hundreds of different genes interact, many in as-yet unmapped ways to determine how, where, when, why, and what we drink (or snort, swallow, smoke, or inject) and who is most likely to get hooked once they start.

In the late 1980s researchers Kenneth Blum and Ernest Noble teamed up to search for genetic mutations (also called alleles) that might be involved in addiction.

Noble, it turns out, had access to a large collection of brains of deceased late-stage alcoholics and non-alcoholics, along with complete medical records.  Using more than fifty gene probes that allowed them to search inside the DNA, Blum and Noble found a genetic mutation in the q22-q23 region of chromosome 11, which they dubbed the A1 allele. 

Sixty-nine percent of the alcoholic brains contained the gene mutation.  By looking at this one gene mutation, Blum and Noble could predict with 75 percent accuracy whether the brain belonged to an alcoholic or nonalcoholic.

This is the kind of stuff that gets me all worked up.  I’m not a scientist and if I took a course in biochemistry, I’d fail it.  But the genetic research, dumbed down into lay language, fascinates me. 

Whenever I think about genes, my brain latches onto the song from the musical “Hair” (lyrics taken directly from Shakespeare’s Hamlet): “What a piece of work is man!  How noble in reason!  How infinite in faculties, in form and moving how express and admirable!”

How express and admirable is the intricate lacework of genes that influence alcoholism and addiction!

Take the gene 9A, for example, which produces an enzyme that switches other genes on and off.  In the brains of mice given repeated doses of cocaine, researchers discovered that gene 9A was repressed, causing the “pleasure circuits” (I prefer to think of them as faucets) to get stuck in the open position which, in turn, enhances craving for the drug.

Scientists have linked over 276 genes with nicotine addiction, many of which affect smoking initiation, persistence, and amount. Smokers with extra copies of the CYP2A6 gene, for example, tend to inhale their cigarettes “with greater intensity.”   

The PAV gene variant makes people sensitive to the bitter taste of cigarette smoke while people with the AVI gene don’t find the taste so nasty. 

A variation in the gene ADAM33 is more common among smokers with chronic obstructive pulmonary disease (COPD), which may explain why 25 percent of smokers develop COPD while the rest aren’t afflicted.

People with the gene variant ALDH2, which metabolizes alcohol in the liver, experience a severe flushing reaction, nausea and dizzinness when they drink; thus, this enzyme variant is considered “protective” against alcoholism.  But if people with this genetic variant drink heavily, they are more likely to deveop colon and other GI cancers. 

A gene called RASGRF-2 stimulates the brain to release the brain chemical dopamine, which triggers pleasurable feelings.  People with genetic variations in this gene feel happier and “higher” when they drink, possibly increasing the risk for heavy drinking and addiction.

The serotonin transporter gene SLC6A4 significantly influences the level of drinking intensity among heavy drinkers.

Mutations in the MAOA (monoamineoxidase A) gene have some really nasty effects.  People with highly active versions of the MAOA gene are more likely to become violent when they drink.

The research is constantly evolving as more and more gene variants and their myriad interactions are discovered.  I think researchers must feel as if they are on a treasure hunt to find at least a piece of the puzzle that explains our entirely human, often unpredictable, and seemingly inexplicable behaviors.

I’m running out of room (in other words, I’m over my word limit), but I can’t stop here.  So in my next column I’ll regale you with more tales from my ever-expanding Gene Vault.  Just wait until you hear what mice, rats, and fruit flies have to teach us about getting hooked on alcohol and other drugs.