This story contains corrected material, published Oct. 12, 2005.
Government researchers have remade the deadly "Spanish flu" virus responsible for the 1918 global outbreak that killed up to 50 million people, a resurrection they hope will reveal weaknesses of the modern bird flu strains that threaten a new pandemic.
Although the work carries some risk if the virus were to escape from the lab, many experts believe the bug would be less devastating now because people have acquired natural immunity to related strains.
Working under high security at the federal Centers for Disease Control and Prevention in Atlanta, scientists identified many of the genes and proteins that made the old strain lethal, and rebuilt the virus. Mice infected with it died within five days.
The team also concluded that the virus leaped directly to humans from a source in birds--unlike lesser pandemics in 1957 and 1968 in which viruses from animals and humans swapped genes.
Reports on their work Wednesday in the journals Science and Nature come amid signs of increased concern in the Bush administration and among public health experts that avian flu could spawn a new pandemic.
A strain of bird flu that bears similarities to the 1918 virus has killed dozens of people and infected millions of birds across Asia in recent years. The strain cannot yet spread widely among people, though experts fear it will acquire that ability.
By studying how the old virus adapted to people, scientists hope to develop a checklist of key genetic changes and track them as they arise in the new bird flu.
"The point is to understand the implications of what happened in 1918," study leader Dr. Jeffery Taubenberger of the Armed Forces Institute of Pathology said in an interview. "Are there any parallels between 1918 and what's happening now?"
It took Taubenberger's team 10 years to reconstruct the virus by piecing together genetic fragments taken from the frozen remains of an Inuit woman who died in Alaska in 1918. The flu killed 85 percent of the residents of her hometown within five days, Taubenberger said.
As it blazed around the globe, the influenza pandemic exacted a greater death toll in a few months than AIDS has in 24 years--a fearsome history that inspires healthy respect of the virus.
The full genetic code of the 1918 virus will be publicly available to scientists through the GenBank database. That means a knowledgeable virologist in theory could re-assemble the flu bug using the same techniques as Taubenberger's group.
"The concern is that a terrorist group or a careless investigator could convert this new knowledge into another pandemic," Philip Sharp, a molecular biologist at the Massachusetts Institute of Technology, wrote in an editorial in Science.
CDC director Julie Gerberding said several governmental review boards had assessed the risks of bringing the virus back and weighed them against the scientific benefits. One of the review bodies was the new U.S. National Science Advisory Board for Biosecurity, formed last year to guard against misuses of such research.
The board unanimously "voted that in fact the scientific benefit for this far outweighed the risk of this being used in a nefarious manner," said Dr. Anthony Fauci, director of the National Institute on Allergies and Infectious Disease.
Gerberding said the CDC has treated the virus like other "select agents" capable of posing a severe threat to public health. The virus does not warrant the highest level of laboratory containment because antiviral drugs and normal flu vaccines are somewhat effective against it. Gerberding said there are no plans to share the flu virus.
"We have erred on the side of caution," she said.
Merely mapping the virus' genes would not have been enough, many experts said. That's because the genes interacted in the live virus in ways no one predicted, resulting in protein changes that help the flu enter cells. It also was able to take hold deep in the lungs and cause deadly pneumonia.
To make live viruses from the complete genetic sequence, the team enlisted help from researchers at Mt. Sinai School of Medicine in New York. They placed loops of genes called plasmids in animal tissue cultures, where the loops could churn out copies of the viral components.
"What you get at the other end is an infectious flu virus," Taubenberger said.
When researchers modified the 1918 virus by swapping in a key protein from an ordinary flu strain, infected mice no longer developed a virulent form of flu. That suggests a weakness in avian flu that researchers could exploit, said study leader Terrence Tumpey of the CDC.
"It represents an exciting finding where we can pursue potential therapeutic and antiviral measures to target this particular protein," Tumpey said.
In all, the researchers found 10 key amino acid changes that allowed the 1918 flu to make copies of itself and spread among human hosts. The recent strain of avian flu, called H5N1, already has acquired some of those changes.
And although experts had thought bird flu would have to combine with another variety in order to spread among people, the 1918 example shows it's possible for avian flu to adapt directly to a human host. Such an unmixed virus might be more lethal to people, Taubenberger said.
Now that the team has finished the work of deciphering the viral code, the step of creating a live virus would be relatively easy for anyone with a PhD in virology, Robert Lamb, a virologist and influenza researcher at Northwestern University, said (this sentence as published has been corrected in this text).
Yet Lamb, who served on one of the government safety committees that cleared Taubenberger's work, said he is convinced the viral work is safe.
One reason is that the ordinary flu strain called H1N1 is a descendant of the deadly 1918 version, Taubenberger said. So modern vaccines and antiviral drugs like Tamiflu still offer some protection against the old virus.
"It did not actually disappear," Taubenberger said. "Practically everyone on Earth was exposed to this virus. For it to survive in humans it had to rapidly change."
Those essential changes probably also made the modern flu less lethal. But it still carries an echo of the great killer.
"In that sense," Taubenberger said, "it never went away."
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SCIENTISTS HOPE TO LEARN FROM 1918 SPANISH FLU
Scientists recreated the 1918 Spanish flu virus that killed about 50 million people to better understand its origins and prevent a pandemic they fear could stem from a similar bird flu strain that emerged in Hong Kong in 1997.
HOW THE 1918 AVIAN FLU INFECTED HUMANS
The 1918 and current strains are believed to have been directly transmitted through contact with birds:
1 Scientists now say the 1918 flu was likely an entirely avian, or bird, virus that mutated to function in humans.
2 HA and NA proteins line the surface of the flu virus and are necessary to bind the virus to cells, infecting them. Human antibodies usually attach to these proteins.
3 Viral RNA mutates, causing the HA proteins to change. The HA proteins now can attach to the human receptors in a cell. Changes in amino acids, building blocks of proteins, were found in both the 1918 and current strains.
4 A host of changes make the virus deadly and allow for human-tohuman transmission.
MAJOR OUTBREAKS OF FLU
1900 through 2005
1918 Spanish flu
American deaths: 600,000
(About 50 million worldwide)
Transmission: Directly from birds to humans, then among humans.
Most affected: Unusually high death rate among healthy adults ages 15 to 34.
1957 Asian flu
American deaths: 69,800
Transmission: Human and animal viruses swapped genes. Worldwide spread.
Most affected: Young children and the elderly.
1968 Hong Kong flu
American deaths: 33,800
Transmission: Human and animal viruses swapped genes.
Most affected: Adults over age 65.
1997: New bird flu strain H5N1 emerges
Deaths: Six in Hong Kong in
1997. Sixty confirmed deaths so far in Southeast Asia.
Most affected: Like the Spanish flu, the most severe illnesses are
in young adults.
Sources: Nature, Science journals, World Health Organization, Massachusetts General Hospital
Chicago Tribune/Sue-Lyn Erbeck and Marty Bach
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