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Genetic study links 1918, '97 flu outbreaks
Clues indicate virus leaped from animals

Sabin Russell, Chronicle Medical Writer Friday, September 7, 2001

Using the latest tools of genetic engineering, researchers have discovered tantalizing clues to explain two outbreaks of influenza nearly 80 years apart.

The first epidemic was the Spanish flu of 1918, which killed at least 20 million people, and the second, just four years ago in Hong Kong, might have been just as deadly -- but was stopped by the slaughter of a million chickens that may have harbored the virus.

In each case, changes in the genetic makeup of an influenza virus apparently allowed the disease to jump from animals to people, exposing them to a microbe that the human immune system had not encountered before.

Both investigations are chronicled in today's issue of the journal Science. While the discoveries described by scientists are different and apparently unrelated, they underscore how researchers are gaining valuable -- and potentially dangerous -- knowledge about one of the most threatening diseases on the planet.

'MOLECULAR WHODUNIT'
"This is a molecular whodunit," said Robert Webster, a virologist at St. Jude Children's Research Hospital in Memphis, who wrote a commentary accompanying the articles in Science. "We've got some of the clues, but there's a few more clues to come in."

With new insights, however, comes a caution. Scientists are learning so much about the inner workings of the deadliest flu viruses that it is now possible to create them in the lab.

"When the complete sequence of the 1918 virus is obtained, it may be possible to create the virus anew," Webster wrote. "Such a study should be attempted only if its benefits warrant the risk, and if high-level biosafety laboratories are used."

The Science articles are the latest evidence of a growing fascination with the 1918 flu, which study author Mark Gibbs and colleagues at Australian National University describe as "the most severe recorded outbreak of acute human disease."

AUSTRALIAN RESEARCH
In their article, the Australian researchers presented a new and highly controversial theory that the Spanish flu was triggered when a gene segment from pig influenza somehow swapped with a gene segment in a flu virus infecting humans -- an event called recombination.

The new virus, according to the Australian team, was a natural version of the kind of recombinant viruses that can be crafted in a modern gene-splicing lab. The hybrid gene would have produced on the surface of the Spanish flu virus a docking protein that resembled human influenza at its roots, but a pig variant at the top where it grabs onto a target cell.

Gibbs' findings are based on a re-examination of gene fragments of the 1918 flu virus extracted from preserved tissue of two soldiers who died of it and from an Inuit woman who also died from the flu and was buried in the Alaskan permafrost. They used computers to compare genetic signatures of the fragments with those of more recent human and swine flus, and plotted the likely evolution of the 1918 strain.

Their conclusion: the gene segment from the pig flu virus entered the human flu lineage just prior to the outbreak of Spanish flu in 1918.

Gibbs said via e-mail that pathologists who discovered the old viral fragments did not spot the spliced gene in their initial analysis because there was no reason to look for such a major shift. "It was believed that influenza viruses couldn't recombine in this way," he said. "It took special software to spot the changes," he added.

Skeptics are not convinced. "There is absolutely no evidence for recombination in influenza," Webster said. He called Gibbs' conclusions "a stretch."

HONG KONG CHICKEN FLU
The evidence uncovered by studies of the Hong Kong chicken flu virus, Webster contends, are much more compelling.

Veterinarians at the University of Wisconsin at Madison obtained two different strains of the Hong Kong virus that killed six of 18 infected people in 1997. One was found to be lethal to laboratory mice, and the other was not. Using a new laboratory technique called reverse genetics, they were able to pinpoint two mutated genes in the lethal strain.

To scientists trying to find out why some flu viruses are so much more virulent than others, this is an exciting discovery. "Now, the tools are beginning to get into place that can work out what makes a virus mild, and what makes it nasty," Webster said.

E-mail Sabin Russell at srussell@sfchronicle.com