There's a reason why we are afraid of the H1N1 influenza virus: when it spread across the world in the early 20th century, it infected 500 million people and killed at least 50 million of them. All told, somewhere between 3 and 5 percent of the entire human population died from the virus between 1918 and 1920. By comparison, today's flu bugs kill fewer than half a million people every year.

Even as the 1918 flu left behind untold grief and destruction, it also left behind several unanswered questions. "Ever since the great flu pandemic of 1918, it has been a mystery where that virus came from and why it was so severe, and in particular, why it killed young adults in the prime of life," Michael Worobey, a professor in the University of Arizona Department of Ecology and Evolutionary Biology, said this week in a news release. "It has been a huge question what the ingredients for that calamity were, and whether we should expect the same thing to happen tomorrow, or whether there was something special about that situation."

But now Worobey and other researchers from the University of Edinburgh and the National Institutes of Health may have solved that mystery. According to a paper published April 28 in the Proceedings of the National Academy of Sciences, the people who died during the 1918 pandemic were mostly born after 1889, the year of a smaller H3 influenza pandemic that was related to the later H1 virus. Those born earlier than 1889 were exposed to the H3 virus during their childhood. Those born after 1889 were not, and they ended up lacking the necessary immunity to protect them from the 1918 influenza virus. You can see the overlap of death rates and childhood virus exposure in this graph:

"It sounds like a modest little detail, but it may be the missing piece of the puzzle," Worobey said. "Once you have that clue, many other lines of evidence that have been around since 1918 fall into place."

Now that we have this clue – which the researchers documented by tracing the genetics of flu strains back to 1830 – the next step, they say, is to put the lessons learned to use in predicting future pandemics. "What we need to do now," Worobey said, "is to attempt to validate these hypotheses and determine the exact mechanisms involved, then apply that knowledge directly to better prevent people from dying from seasonal flu and future pandemic strains." They suggest that one path might be to develop immunization techniques that would mimic childhood exposure to protect people later in life.

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