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At every party, no matter the occasion, my drink of choice is soda water with lime. I have never, not once, been drunk—or even finished a full serving of alcohol. The single time I came close to doing so (thanks to half a serving of mulled wine), my heart rate soared, the room spun, and my face turned stop-sign red … all before I collapsed in front of a college professor at an academic event.
The blame for my alcohol aversion falls fully on my genetics: Like an estimated 500 million other people, most of them of East Asian descent, I carry a genetic mutation called ALDH2*2 that causes me to produce broken versions of an enzyme called aldehyde dehydrogenase 2, preventing my body from properly breaking down the toxic components of alcohol. And so, whenever I drink, all sorts of poisons known as aldehydes build up in my body—a predicament that my face announces to everyone around me.
By one line of evolutionary logic, I and the other sufferers of so-called alcohol flush (also known as Asian glow) shouldn’t exist. Alcohol isn’t the only source of aldehydes in the body. Our own cells also naturally produce the compounds, and they can wreak all sorts of havoc on our DNA and proteins if they aren’t promptly cleared. So even at baseline, flushers are toting around extra toxins, leaving them at higher risk for a host of health issues, including esophageal cancer and heart disease. And yet, somehow, our cohort of people, with its intense genetic baggage, has grown to half a billion people in potentially as little as 2,000 years.
The reason might hew to a different line of evolutionary logic—one driven not by the dangers of aldehydes to us but by the dangers of aldehydes to some of our smallest enemies, according to Heran Darwin, a microbiologist at New York University. As Darwin and her colleagues reported at a conference last week, people with the ALDH2*2 mutation might be especially good at fighting off certain pathogens—among them the bug that causes tuberculosis, or TB, one of the greatest infectious killers in recent history.
The research, currently under review for publication at the journal Science, hasn’t yet been fully vetted by other scientists. And truly nailing TB, or any other pathogen, as the evolutionary catalyst for the rise of ALDH2*2 will likely be tough. But if infectious disease can even partly explain the staggering size of the flushing cohort—as several experts told me is likely the case—the mystery of one of the most common mutations in the human population will be one step closer to being solved.
Scientists have long been aware of aldehydes’ nasty effects on DNA and proteins; the compounds are carcinogens that literally “damage the fabric of life,” says Ketan J. Patel, a molecular biologist at the University of Oxford who studies the ALDH2*2 mutation and is reviewing the new research for publication in Science. For years, though, many researchers dismissed the chemicals as the annoying refuse of the body’s daily chores. Our bodies produce them as part of run-of-the-mill metabolism; the compounds also build up during infection or inflammation, as byproducts of some of the noxious chemicals we churn out. But then aldehydes are generally swept away by our molecular cleanup systems like so much microscopic trash.
Darwin and her colleagues are now convinced that the chemicals deserve more credit. Dosed into laboratory cultures, aldehydes can kill TB within days. In previous research, Darwin’s team also found that aldehydes—including ones produced by the bacteria themselves—can make TB ultra sensitive to nitric oxide, a defensive compound that humans produce during infections, as well as copper, a metal that destroys many microbes on contact. (For what it’s worth, the aldehydes found in our bodies after we consume alcohol don’t seem to much bother TB, Darwin told me. Drinking has actually been linked to worse outcomes with the disease.)
The team is still tabulating the many ways in which aldehydes are exerting their antimicrobial effects. But Darwin suspects that the bugs that are vulnerable to the chemicals are dying “a death by a thousand cuts,” she told me at the conference. Which makes aldehydes more than worthless waste. Maybe our ancestors’ bodies wised up to the molecules’ universally destructive powers—and began to purposefully deploy them in their defensive arsenal. “It’s the immune system capitalizing on the toxicity,” says Joshua Woodward, a microbiologist at the University of Washington who has been studying the antibacterial effects of aldehydes.
Specific cells show hints that they’ve caught on to aldehydes’ potency. Sarah Stanley, a microbiologist and an immunologist at UC Berkeley, who has been co-leading the research with Darwin, has found that when immune cells receive certain chemical signals signifying infection, they’ll ramp up some of the metabolic pathways that produce aldehydes. Those same signals, the researchers recently found, can also prompt immune cells to tamp down their levels of aldehyde dehydrogenase 2—the very aldehyde-detoxifying enzyme that the mutant gene in people like me fails to make.
If holstering that enzyme is a way for cells to up their supply of toxins and brace for inevitable attack, that could be good news for ALDH2*2 carriers, who already struggle to make enough of it. When, in an extreme imitation of human flushers, the researchers purged the ALDH2 gene from a strain of mice, then infected them with TB, they found that the rodents accumulated fewer bacteria in their lungs.
The buildup of aldehydes in the mutant mice wasn’t enough to, say, render them totally immune to TB. But even a small defensive bump can make for a massive advantage when combating such a deadly disease, Russell Vance, an immunologist at UC Berkeley who’s been collaborating with Darwin and Stanley on the project, told me. Darwin is now curious as to whether TB’s distaste for aldehyde could be leveraged during infections, she told me—by, for instance, supplementing antibiotic regimens with a side of Antabuse, a medication that blocks aldehyde dehydrogenase, mimicking the effects of ALDH2*2.
Tying those results to the existence of ALDH2*2 in half a billion people is a larger leap, several experts told me. There are clues of a relationship: Darwin and Stanley’s team found, for instance, that in a cohort from Vietnam and Singapore, people carrying the mutation were less likely to have active cases of TB—echoing patterns documented by at least one other study from Korea. But Daniela Brites, an evolutionary geneticist at the Swiss Tropical and Public Health Institute, told me that the connection still feels a little shaky. Other studies that have searched for genetic predispositions to TB, or resistance to it, she pointed out, haven’t hit on ALDH2*2—a sign that any link might be weak.
The team’s general idea could still pan out. “They are definitely on the right track,” Patel told me. Throughout most of human history, infectious diseases have been among the most dramatic influences over who lives and who dies—a pressure so immense that it’s left obvious scars on the human genome. A mutation that can cause sickle cell anemia has become very common in parts of the African continent because it helps guard people against malaria.
The story with ALDH2*2 is probably similar, Patel said. He’s confident that some infectious agent—perhaps several of them—has played a major role in keeping the mutation around. TB, with its devastating track record, could be among the candidates, but it wouldn’t have to be. A few years ago, work from Woodward’s lab showed that aldehydes can also do a number on the bacterial pathogens Staphylococcus aureus and Francisella novicida. (Darwin and Stanley’s team have now shown that mice lacking ALDH2 also fare better against the closely related Francisella tularensis.) Che-Hong Chen, a geneticist at Stanford who’s been studying ALDH2*2 for years, suspects that the culprit might not be a bacterium at all. He favors the idea that it’s, once again, malaria, acting on a different part of our genome, in a different region of the world.
Other tiny perks of ALDH2*2 may have helped the mutation proliferate. As Chen points out, it’s a pretty big disincentive to drink—and people who abstain (which, of course, isn’t all of us) do spare themselves a lot of potential liver problems. Which is another way in which the consequences of my genetic anomaly might not be so bad, even if at first flush it seems more trouble than it’s worth.
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Katherine J. Wu
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