Scientists who re-created the 1918 Spanish flu say the killer virus was initially a bird flu that learned to infect people. Alarmingly, they find that today's H5N1 bird flu is starting to learn the same tricks.

The work involves researchers from the Armed Forces Institute of Pathology (AFIP), the CDC, Mount Sinai School of Medicine, and the U.S. Department of Agriculture. Jeffery K. Taubenberger, MD, PhD, chief of molecular pathology at the AFIP, is one of the study leaders.

"These H5N1 viruses are being exposed to human adaptive pressures, and may be going down a similar path to the one that led to the 1918 virus," Taubenberger said in a news conference. "But the H5N1 strains have only a few of these mutations, whereas the 1918 virus has a larger number."

In 1918-1919, the so-called Spanish flu killed some 50 million people -- including 675,000 Americans. Most of the victims were healthy people in the prime of life.

The researchers’ findings -- published this week in the journals Nature and Science -- come from a remarkable decade-long effort to unlock the secrets of the most deadly flu bug ever known.

To do this, the researchers used a technique called reverse genetics to re-create a living 1918 virus. To do this, they gathered viral DNA from the preserved tissues of people who died in 1918 and 1919 -- including a woman whose body was frozen in the Alaskan permafrost.

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Past Virus, Future Virus

The resurrected virus now lives in high-level containment within the CDC. But that's not what worries public health officials.

The 1918 flu, analysis shows, is a bird flu that learned how to spread among humans. Genetic analysis shows that the deadly H5N1 bird flu now circulating in Asia seems to be learning the same thing.

Like the 1918 virus, the milder pandemic flu bugs of 1957 and 1968 also had bird flu genes. But they picked up the ability to spread in humans by swapping genes with a human flu virus. That could still happen to the H5N1 bird flu. But even if it doesn't, the bug seems to be slowly adapting to humans.

The good news is that the H5N1 flu bug still has a long way to go. The 1918 bug seemed to need several changes in every one of its eight genes. The H5N1 virus is making similar changes but isn't very far along.

"So, for example, in the nuclear protein gene we speculate there are six genes crucial [for human adaptation]," Taubenberger says. "Of those six, three are present in one or another H5N1 strain. But usually there is only one of these changes per virus isolate. That is true of other genes as well. You see four, five, or six changes per gene in the 1918 virus, whereas H5N1 viruses only have one change or so. It shows they are subjected to similar [evolutionary] pressures, but the H5 viruses are early on in this process."

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How Much Time Do We Have?

How long does this process take? Nobody knows. Taubenberger says the 1918 bird virus appeared in humans "a couple of years" before 1918. But how long it took the virus to jump species from birds to humans is unknown.

There is one ominous sign. It's in a flu gene protein called PB2. A single change in this gene makes H5N1 extremely deadly to mice. The same single change helps bird flu to adapt to mammals.

For example, the change in PB2 was seen in six of the seven H5N1 viruses spreading among captive tigers in Thailand. The same change popped up in the only human to die during an outbreak of another bird flu, H7N7, in the Netherlands. And it's present in recent H5N1 viruses from humans in Vietnam and Thailand and from wild birds in China.

"The fact that [gene] changes identified in the 1918 analysis are also seen in highly pathogenic avian influenza strains of H5N1 and H7N7 is intriguing, and suggests that these changes may facilitate virus replication in human cells and increase pathogenicity," Taubenberger and colleagues write in their Nature paper.

New Information to Help Fight Flu

Scary as it is to take a close-up look at killer flu bugs, it's a good thing to do. Knowing the enemy helps us find ways to defeat it, says Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases.

"There are a number of ways one needs to prepare for a flu pandemic. And there is no better way than understanding the issues described here -- particularly the adaptability of the virus in a sense of efficient person-to-person spread and pathogenesis," Fauci said at the news conference.

CDC Director Julie Gerberding, MD, MPH, says the 1918 virus has a lot to teach us.

"We have been able to unmask the 1918 virus and it is revealing to us some of the secrets that will help us prepare for the next pandemic," Gerberding said at the news conference. "Some of those secrets are what led to efficient transmission in people -- and what made it so deadly. This important science does create new information and clues that will ... accelerate development of our antiviral drug stockpile and vaccines to protect against H5N1 or another virus."

Mount Sinai researcher Adolfo Garcia-Sastre, PhD, is one of the developers of the reverse genetic technique used to reconstruct the 1918 virus. He says the genetic changes that help flu bugs adapt to humans appear to be common to all type A flu viruses.

"What is interesting is these genes seem to be involved in the virulence of other flu viruses, not just bird flu," Garcia-Sastre said at the news conference. "So there are common themes involved in the virulence of flu viruses. Now we have good clues for the development of new drugs against flu disease."

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What if It Escapes?

The decision to re-create a living 1918 virus was made only after consultation with several advisory bodies, Gerberding and Fauci said. The bug now lives in a level 3+ containment facility at the CDC. Outside researchers are invited to study it -- but only at the CDC lab, and only with security clearance.

"It is unlikely this virus could emerge and cause a pandemic," Gerberding said. "It is important to emphasize we have erred on the side of caution at every stage. We have no intention of releasing this from the CDC any time soon."

Gerberding says that everything is being done to ensure that the bug stays in the lab. But if it were to escape, she says it probably would not rekindle a 1918-style epidemic. For one thing, it's an H1N1 virus, and the current annual flu vaccine contains an H1N1 virus. Moreover, most people have been exposed to H1N1 viruses, so many people would be immune.

None of this, however, means that a 1918 virus on the loose would be harmless. Natural and vaccine immunity probably would make the bug less deadly but would not offer full protection.

"We do not know the extent this [immunity] would protect people from harm," Gerberding noted. "But a pandemic in this context would be unlikely."

Meanwhile, researchers at The Institute for Genomic Research in Rockville, Md., plan a detailed analysis of large numbers of bird flu isolates. This, they say, will help them track the ongoing evolution of bird flu.

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By Daniel J. DeNoon, reviewed by Louise Chang, MD

SOURCES: Taubenberger, J.K. Nature, Oct. 6, 2005; vol 437: pp 889-893. Tumpey, T.M. Science, Oct. 7, 2005; vol 310: pp 77-80. News conference, American Association for the Advancement of Science. Jeffery K. Taubenberger, MD, PhD, chief of molecular pathology, Armed Forces Institute of Pathology, Rockville, Md. Adolfo Garcia-Sastre, PhD, Mount Sinai School of Medicine, New York. Julie Gerberding, MD, MPH, director, CDC, Atlanta. Anthony Fauci, MD, director, National Institute of Allergy and Infectious Diseases, Bethesda, Md. Terence Tumpey, PhD, influenza branch, CDC, Atlanta.