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10-05-2005, 01:40 PM
Deadly 1918 Epidemic Linked to Bird Flu, Scientists Say


By GINA KOLATA

Published: October 5,

Two teams of federal and university scientists announced today that they had resurrected the 1918 influenza virus, the cause of one of history's most deadly epidemics, and had found that unlike the viruses that caused more recent flu pandemics of 1957 and 1968, the 1918 virus was actually a bird flu that jumped directly to humans.

The work, being published in the journals Nature and Science, involved getting the complete genetic sequence of the 1918 virus, using techniques of molecular biology to synthesize it, and then using it to infect mice and human lung cells in a specially equipped, secure lab at the Centers for Disease Control and Prevention in Atlanta.

The findings, the scientists say, reveal a small number of genetic changes that may explain why the virus was so lethal. The work also confirms the legitimacy of worries about the bird flu viruses that are now emerging in Asia.

The new studies find that today's bird flu viruses share some of the crucial genetic changes that occurred in the 1918 flu. The scientists suspect that with the 1918 flu, changes in just 25 to 30 out of about 4,400 amino acids in the viral proteins turned the virus into a killer. The bird flus, known as H5N1 viruses, have a few, but not all of those changes.

In a joint statement, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and Dr. Julie Gerberding, director of the Center for Disease Control and Prevention, said, "The new studies could have an immediate impact by helping scientist focus on detecting changes in the evolving H5N1 virus that might make widespread transmission among humans more likely."

The work also reveals that the 1918 virus is very different from ordinary human flu viruses. It infects cells deep in the lungs of mice, and infects lung cells, like the cells lining air sacs, that normally would be impervious to flu. And while other human flu viruses do not kill mice, this one, like today's bird flus, does.

But Dr. Jeffery Taubenberger, chief of molecular pathology department at the Armed Forces Institute of Pathology, notes that the bird flus have not yet spread from human to human. He hopes the 1918 virus will reveal what genetic changes can allow that to happen, helping scientists prevent a new pandemic before it starts.

Scientists said the new work was immensely important, leading the way to identifying dangerous viruses before it is too late and to finding ways to disable them.

"This is huge, huge, huge," said John Oxford, a professor of virology at St. Bartholmew's and the Royal London Hospital, who was not part of the research team. "It's a huge breakthrough to be able to put a searchlight on a virus that killed 50 million people. I can't think of anything bigger that's happened in virology for many years."

The 1918 flu showed how terrible that disease could be. It had been "like a dark angel hovering over us," Dr. Oxford said. The virus spread and killed with terrifying speed, preferentially striking the young and the healthy. Alfred C. Crosby, author of "America's Forgotten Pandemic: The Influenza of 1918," wrote that it "killed more humans than any other disease in a similar duration in the history of the world."

But the research, and its publication, also raised concerns about whether scientists should publish the genetic sequence of the 1918 virus. And should they actually resurrect a killer that vanished from the earth nearly a century ago?

"It is something we take seriously," said Dr. Fauci of the National Institute of Allergy and Infectious Diseases, which helped pay for the work. The work was extensively reviewed, he added, and the National Scientific Advisory Board for Biosecurity was asked to decide whether the results should be made public. The board "voted unanimously that the benefits outweighed the risk that it would be used in a nefarious manner," Dr. Fauci said.

Others are not sanguine.

Richard H. Ebright, a molecular biologist at Rutgers University, deplored the publication of the viral gene sequence and the reconstruction of the virus. "There is a risk verging on inevitability of accidental release of the virus and a risk verging on inevitability of deliberate release," he said. And the 1918 flu virus, Dr. Ebright added, "is perhaps the most effective bioweapons agent ever known."

But Dr. D. A. Henderson, a resident scholar at the Center for Biosecurity at the University of Pittsburgh and a leading expert on bioterrorism, said he agreed with the decision to reconstruct the virus and publish its genetic sequence.

"This work is of the greatest importance," he said, "and it is very important that it be published."

The story of the resurrection of the 1918 flu began in 1995, when Dr. Taubenberger had an idea. He knew about the 1918 flu and the horrors of that pandemic. Medical authorities at the time found it hard even to describe the devastation. At Fort Devens, wrote one doctor, Victor Vaughan, they saw young soldiers' "bodies stacked like cordwood," dead from the flu. The epidemic, he added, "visited the remotest corners, taking toll of the most robust, sparing neither soldier nor civilian, and flaunting its red flag in the face of science."

It had seemed hopeless, though, to discover what that virus looked like. Viruses had not been discovered in 1918 and so no one had isolated and saved the one causing that flu. But Dr. Taubenberger recalled that his institute had a warehouse of autopsy tissue, established by President Abraham Lincoln, who had ordered that every time a military doctor examined a patient and took a tissue sample, a sample must also be sent to and stored at the pathology institute. Dr. Taubenberger wondered if he could find lung tissue from soldiers who died of the 1918 flu and, if so, if he could extract the virus.

He found tissue from two soldiers, snips of lung soaked in formalin and encased in little blocks of wax. And in that tissue was the virus, broken and degraded, just a few molecules of virus, but there.

One of the patients was Roscoe Vaughan, who got the flu when he was 21 years old and training at Camp Jackson, S.C. On Sept. 19, 1918, he reported to sick call. He died on Sept. 26, unable to breathe, the air sacs in his lungs filled with fluid. The other patient was James Down, age 30, who died on the same day at Camp Upton, in New York. The snippets of their lung tissue had remained untouched for nearly 80 years.

Then Dr. Taubenberger got a third sample, from a woman who had died in Alaska when the flu swept through her village, killing 72 adults, leaving just 5. The dead were buried in a mass grave in the permafrost, and a retired pathologist, Johann Hultin, hearing of Dr. Taubenberger's quest, traveled from his home in San Francisco to the gravesite in Alaska at his own expense, dug up the grave with the villager's permission, extracted the woman's still frozen lung tissue, and sent it to Dr. Taubenberger.

Dr. Taubenberger and his colleagues spent nearly a decade carefully extracting and piecing together the viral genes, like putting together a jigsaw puzzle. Along the way, they published findings that they and others used to try to understand the 1918 flu, but until now they had only published the sequences of five of the eight genes. The last three, which make up half the virus's length, are published in their paper, in Nature.

In August, Terrence M. Tumpey of the Centers for Disease Control and his colleagues used that information to reconstruct the 1918 virus and ask what would happen if they infected mice and if they infected tissue from human lungs. And, they asked, would the virus remain as lethal if they switched some of its genes with genes from today's influenza viruses?

The scientists took great precautions, the director of the C.D.C., Julie Gerberding, said at a news conference, using special labs that were designed to protect the researchers and prevent the spread of the viruses. "We have erred on the side of caution at every step of the process," Dr. Gerberding said.

And now, the scientists say, they are starting to unmask that virus's secrets.

In gene-swapping experiments, for example, they put the hemagglutinin gene from the 1918 virus for one from a more recent human virus. Suddenly, the reconstructed virus could no longer replicate in the lungs of mice and no longer killed the animals. It also could not attach itself to human lung cells in the lab. Yet the 1918 virus' hemagglutinin protein differs in just two critical amino acids from the protein of a typical avian flu virus.

"Now we've shown experimentally that those two changes are crucial for human adaptation," Dr. Taubenberger said. So far, he added, they have not been seen in the Asian bird flus.

The ultimate goal, he says, is to make a checklist of changes to look for in the bird viruses.

"Now you have all these viruses going around and we don't know, Is it going to adapt to humans? Is it going to cause a pandemic? We don't understand the rules," Dr. Taubenberger said. "There is a lot of science to go."


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