The 1918 flu that killed over 20 million people may have quietly simmered for years, moving back and forth between pigs and humans, until suddenly growing strong enough to become the world's worst influenza epidemic.
That's the latest theory from the Armed Forces Institute of Pathology, whose researchers, for the first time, have completely analyzed a critical gene from the killer virus.
The organism likely "was adapting in humans or in swine for maybe several years before it broke out as a pandemic virus," says molecular biologist Ann Reid, lead author of the study published in the latest edition of the Proceedings of the National Academy of Sciences.
But "we can't tell whether it went from pigs into humans or from humans into pigs," she adds.
Different influenza strains circle the globe annually. Usually, they're fairly similar to viruses people have caught in the past. But every so often a strain tough enough to kill millions emerges, and experts warn that the world is overdue for another epidemic.
To help them react better if such a flu strikes, scientists need to know what made the 1918 strain the deadliest ever and why it the vast majority of its victims young, healthy people.
Most experts believe that genetically stable flu viruses reside harmlessly in birds, but that occasionally one of these bird viruses infects pigs. The swine immune system attacks the virus, forcing it to mutate genetically to survive. If it then spreads to humans, the result can be devastating.
In two other pandemics -- the 1957 Asian flu and 1968 Hong Kong flu -- viruses apparently made a fast jump from birds to pigs to humans. That's because human flu genes from those outbreaks appear very similar to avian flu genes.
But the new study finds no similarity between those bird genes and a key gene in the 1918 flu.
Reid studied lung tissue preserved from the autopsies of two soldiers who died from influenza, and from the frozen corpse of an Alaskan woman. She fully mapped the hemagglutinin gene, which is key to influenza infection taking hold. She discovered that the hemagglutinin closely resembles mammal genes.
So instead of making that fast, usual bird-pigs-people jump, the 1918 virus apparently evolved in mammals -- either pigs or humans -- over many years before suddenly mutating into killer. It could have lain dormant and evolving for as long as twenty years.
But Reid can't tell if pigs developed the mutation that turned the virus into a killer and gave it to people, or if people gave it to pigs.
A huge wave of mild influenza struck people during the spring of 1918, but no pigs became sick. Then the flu struck again in the fall. This time it suddenly killed millions of people, and pigs got sick, too. But people who had had the more mild spring flu were reported to be immune.
Regardless of which species the killer strain evolved in, the long incubation periohas implications for predicting future flu outbreaks. "We may have to expand our concept of where pandemics come from," Reid says. The mystery of the killer flu keeps getting deeper. "The more you study it," she says ominously, "the more perplexing it becomes."