How disease evolves
By David Stipp

(FORTUNE Magazine) – BACK WHEN HE WAS A GRAD STUDENT IN 1977, Paul Ewald came down with an intestinal bug. He'd been doing research at the University of Washington at Seattle on the social behavior of sparrows. But the microbes making him sick proved more interesting. Lying in bed, he wondered, What is diarrhea good for? "I started thinking maybe it is a defense mechanism by the body to get rid of an infectious agent," he recalls. "But in an argument with myself, I realized that it might be due to a microbe manipulating my body in order to spread itself." In other words, diarrhea might be a microbe survival strategy--a way for it to find fresh victims through contamination of hands, objects, and water supplies.

That startling thought eventually led Ewald, now a professor at the University of Louisville, to abandon sparrows and help pioneer a branch of medicine that analyzes disease from the perspective of evolutionary biology. The Darwinians aren't well known among physicians, but they've shed light on many medical riddles, such as why hospital-acquired infections are so deadly. They've also chipped away at stone-writ wisdoms: When you're prescribed antibiotics, it may not always pay to take all of them. Popping painkillers for a sprained ankle could hurt you. And we should probably be a lot more scared of hepatitis C than emerging killers like bird flu.

After recovering from that stomach bug, Ewald set out to learn just who is manipulating whom when it comes to gut infections. What he discovered at the library was a confusing welter of data crying out for evolutionary analysis. Over the next three years he spent countless hours poring over studies on infectious microbes and arguing with himself about their meaning. The fruits of his labor appeared in a landmark paper in The Journal of Theoretical Biology in 1980. Among other things, Ewald laid out a list of tricks that microbes have evolved to exploit hosts, as well as hosts' countermeasures. (Diarrhea can be both, it turns out.)

"I thought the paper was going to have a big effect," he says. "But it didn't." Fellow Darwinians urged him on all the same, including some of biology's biggest names--Britain's Richard Dawkins, Darwin's most renowned living exponent, calls Ewald a "master explainer" who produces "gems of insight." Others followed in Ewald's tracks to gain evolutionary insight on illness, and in the 1990s Darwinian medicine hit the mass media--Ewald's work made the pages of Newsweek, the Wall Street Journal, and other national publications.

Perhaps the new field's most fertile idea is that modern lifestyles sometimes conflict with patterns hacked into our genes by evolution. That may seem tragically obvious to those faced with fudge brownies--our drive to gorge on sweet and fatty foods, a major cause of diabetes and other ills, no doubt evolved to help our ancestors bulk up in order to survive lean times. But other clashes with the past inside us aren't so evident.

Consider taking aspirin to lower a fever. It has long been known that the fever response probably evolved to help fight germs. But in the age of antibiotics, doctors typically regard it as a bad thing. Ewald disagrees. Studies with lizards and rabbits have shown that raising body temperature lowers the risk of death from respiratory infections--many germs can't take the heat. Fever also cuts appetite, and reduced nutrient intake appears to make our infected cells more likely to die, wiping out the germs that have invaded them. (The beleaguered cells actually commit suicide.) And fever-induced lethargy frees energy to fuel our immune attacks on germs. In a study Ewald conducted with his students during the cough-and-sniffle season, those who took to bed as soon they felt a cold coming on recovered within 24 hours. A second group who stayed on the go when they first felt ill took an average of ten days to totally recover.

"You're gambling if you don't let your body take care of an infection" as evolution designed it to, says Ewald. Yet fever isn't always helpful, he adds, for some germs have evolved ways to cope with it. The bug that causes malaria, for instance, even benefits from elevated temperatures in one of its insect hosts.

The pain of muscle strains is another response honed by evolution that we should heed, says Ewald. A sprained ankle's healing involves an exquisite sequence of events that can be bollixed up by putting the ankle back to work too soon--easy to do on painkillers. The crippling injuries professional athletes often suffer by age 40 may largely result from the continually interrupted healing of relatively minor hurts. This doesn't mean we have to forgo painkillers when injured, Ewald adds. We should just act as if we had.

He also urges more thoughtful use of antibiotics. It's well known that their overuse fosters the rise of antibiotic-resistant bacteria, because such strains multiply with greater ease after the medicines eliminate their competitors within the body. (To germs, your body is a banquet with a shortage of seats.) Ewald suggests an unorthodox tactic to lessen the spread of resistant bacteria: Administer antibiotics to infected people only long enough to let their immune systems kick in and knock out the culprits. After all, he reasons, it's much harder for bacteria to evolve resistance to our immune systems, shaped by eons of evolution, than it is to antibiotics.

Unlike antibiotics, public-health measures to block the spread of germs, such as installing water-treatment plants, always make evolutionary sense, Ewald says. Notably, they push virulent microbes to evolve into milder forms. Here's why: The more readily a germ can spread from host to host, the more likely it is to exist in a lethal form. That's because sure-fire transmissibility favors strains that grow like wildfire in hosts, killing them fast--such killers outcompete and displace slower-growing, milder strains. (Picture a gang of Hell's Angels shoving their way into the bodily banquet.) But natural selection doesn't favor very vicious bugs when transmission from sick hosts is difficult, for the hosts literally become dead ends before the bugs can leap to others. In such cases, milder strains tend to become the dominant ones in circulation.

This Ewaldian logic has major implications. It explains, for instance, why water-borne diseases like cholera and typhoid tend to be deadlier in countries with easily contaminated water supplies. In the 1990s Ewald and colleagues tracked a cholera outbreak in South America. Over seven years, strains of the cholera bacterium in Chile, which has good public water systems, evolved toward mildness. In Ecuador, which has less clean water, very virulent strains became the dominant ones.

Similarly, hospitals tend to become hotbeds for highly virulent germs because transmission is so easy there via conduits such as staffers' hands and equipment. (Many hospitalized patients are immune-suppressed, which also abets germ jumping.) Data on staph infections among hospitalized babies, for instance, suggest that strains of the bacterium endemic to hospitals are five to ten times more likely to cause illness than strains whose virulence hasn't been honed by evolution inside the facilities.

Ewald posits that the unequaled deadliness of the 1918 Spanish flu reflects the same phenomenon: Jam-packed wartime hospitals and the rapid transport of very ill troops spread flu more effectively than at any other time in history, causing extremely virulent strains of the virus to evolve. Such conditions aren't likely to be repeated, he adds, making the odds that another 1918 pandemic is on the way smaller than suggested by the alarming headlines about Asia's deadly bird flu.

Far more worrisome, in his view, are growing signs that sexual contact can transmit hepatitis C. The liver-destroying virus, which has been shown to lead to liver cancer and which kills some 8,000 to 10,000 Americans each year, mainly spreads via infected blood--it's often transmitted by addicts' shared needles. But some strains appear capable of spreading via sex. As they evolve, they could trigger a major wave of hepatitis C and, in coming decades, thousands of cases of liver cancer as a result.

Evolution, of course, is at the center of a national debate these days. But for Ewald, there's no argument: His research shows that dissing Darwin could make a lot of people needlessly sick. ■