WASHINGTON -- The 1918 flu that killed more than 20 million people may have quietly percolated for several years, maybe even trading back and forth between pigs and people, until suddenly growing strong enough to become the world's worst pandemic.
That's the latest theory from the Armed Forces Institute of Pathology, which reported Monday that researchers for the first time have completely analyzed a critical gene from the killer influenza virus.
The gene likely "was adapting in humans or in swine for maybe several years before it broke out as a pandemic virus," said molecular biologist Ann Reid, lead author of the study published in 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 said.
Different influenza strains circle the globe annually. Usually, they're fairly similar to viruses people have caught in the past. Every so often a strain tough enough to kill millions emerges, and experts warn that the world is overdue for another pandemic.
That's why understanding the 1918 flu's genes are important. Scientists need to know what made that strain the deadliest ever -- and why it struck down mostly young, healthy people -- to better react if similar killer flu emerges again.
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 change 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 pandemics 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 autopsies of two soldiers who died from influenza, at Ft. Jackson, S.C., and Camp Upton, N.Y., and from the frozen corpse of an Alaskan woman. Reid 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 bird-pigs-people jump that scientists expect in a pandemic, the 1918 virus apparently evolved in mammals -- either pigs or humans -- over many years before suddenly mutating into a mass killer. It may have percolated in humans as early as 1900, she said.
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.
Among the evidence: A huge wave of mild influenza struck people during the spring of 1918, but no pigs were sick. Then the flu struck again in the fall. This time it suddenly killed millions of people, and this time pigs were sick, too -- but people who had had the mild spring flu were reported to be immune.
Regardless of which species evolved the killer strain, the long incubation period has implications for predicting future flu outbreaks. "We may have to expand our concept of where pandemics come from," Reid said.
Institute scientists are analyzing other genes from the 1918 virus, but Reid said the mystery so far is getting deeper. "The more you study it, the more perplexing it becomes."