Since 1933, when scientists first isolated influenza A type viruses from ferrets, they have watched it break evolutionary barriers with alarming ease—infecting not only humans, but also birds, pigs, horses, dogs, and other species.

"Really, it's a numbers game," says Robert G. Webster, a virologist at St. Jude Children's Research Hospital in Memphis. "The more that chickens are infected and the broader the virus's geographic range, the faster it all adds up. It's just a matter of time before a new pandemic emerges."

Flu pandemics in 1918, 1957, and 1968 caused millions of deaths. Both strain H2N2 (the cause of the 1957 pandemic) and strain H3N2 (1968's pathogen) are believed to have arisen by the exchange of genes between avian and human flu viruses, possibly following dual infection in humans. The deadliest pandemic, in 1918, was different. It was the result of strain H1N1, thought to be derived wholly from an ancestor that originally infected birds.

Concerned about the likelihood that history will repeat itself—and that it will look more like 1918 than 1957 or 1968—Webster has been sounding the avian influenza alarm for years—to the point that some researchers dismiss him as preachy. "I've been accused of being a Chicken Little," he says. "But someone's got to do it. The H5N1 strain has some very disturbing characteristics."

To scientists, the influenza virus presents a unique opportunity to study evolution in action.

Circulating in Southeast Asia since at least 1997, the highly pathogenic H5N1 has killed more than 150 million birds. And the virus is on the move. Wild waterfowl such as geese have been carrying H5N1 across Asia, along migratory routes where they come in contact with domestic poultry, typically near rivers and lakes. In August, officials in Russia and Kazakhstan confirmed the first reported outbreaks of H5N1 influenza among poultry in those countries.

So far, it's unclear how dangerous H5N1 is to humans. The virus, however, is clearly capable of infecting humans who come in contact with infected poultry—authorities have reported more than 110 confirmed cases, resulting in over 60 deaths, in Vietnam, Thailand, Cambodia, Indonesia, and China. These numbers are likely to be underestimates—with spotty surveillance data, it's impossible to reliably gauge the rates of disease incidence or fatality. But, at least for now, H5N1 does not appear to be easily transmitted from human to human—a basic feature of pandemics.

Many scientists think they're playing a waiting game, however. "H5N1 has been around for 9 years, and I find myself asking, 'Why hasn't a human pandemic happened?'" says Robert A. Lamb, an HHMI investigator at Northwestern University in Chicago. "The fact is, it wouldn't necessarily take much. With these H5 viruses, even a single-point mutation can make the difference between the virus's ability to kill lab mice or not."

Influenza's threat is not limited to this particular avian type. H5N1 belongs to the H5 influenza virus family, just 1 of 16 subtypes. Labeled H1 to H16, each subtype is named for the distinct structural biology of two key influenza surface proteins, hemagglutinin (HA) and neuraminidase (NA). All H5 viruses, for instance, share a similarly shaped HA protein. The influenza viruses within the H5 family as well as in the other families are further distinguished by the shapes of their NA proteins, of which there are nine.

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