Killer 1918 Flu Gives Clues to New Virus

Working with scraps of DNA preserved for nearly 80 years in the Alaskan permafrost, scientists have resurrected the virus behind one of the deadliest pandemics in human history -- the 1918 Spanish flu -- and identified key similarities with the current bird flu in Asia.

Two teams reported Wednesday that the 1918 virus had 25 to 30 separate mutations that, cumulatively, allowed it to infect humans, eventually killing as many as 50 million worldwide.

Some of those same mutations are present in the bird flu virus now circulating in Asia, the teams said, bolstering fears that a few more mutations could trigger a similar pandemic.

“Given a few molecular changes in an avian virus, it has the potential to go into a human host and raise havoc,” said biologist Terrence M. Tumpey of the Centers for Disease Control and Prevention.

One important similarity between the two viruses is that both migrated to humans directly from birds, unlike other flu viruses that first require a passage through pigs or other animals, according to two studies released Wednesday by the journals Science and Nature.

Now that researchers know what kinds of changes to look for, they are better equipped to monitor the evolution of the bird flu virus and catch a potential outbreak before it spreads, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and CDC director Dr. Julie Gerberding said at a news conference Wednesday.

If threatening genetic changes were detected in a bird flu virus, experts said, it might be possible to block an outbreak by culling infected birds and treating patients with antiviral agents.

Fauci called the research “a milestone in the scientific approach” to combat bird flu.

But some scientists have questioned the wisdom of publishing the genetic blueprint for such a deadly virus, especially because science is quickly gaining the ability to create such viruses in the laboratory from scratch.

“Just having the sequence in the public domain is troubling,” said Jonathan Tucker, a biological warfare expert at the Monterey Institute of International Studies.

Dr. Jeffrey K. Taubenberger of the Armed Forces Institute of Pathology in Washington pieced together the complete genetic blueprint of the 1918 virus using DNA fragments isolated from soldiers and an Alaskan woman who died during the pandemic.

Over a 10-year period, he painstakingly assembled the fragments and sent them to Tumpey, who then grew the virus and tested it in mice and cultured human tissues.

The virus has eight genes, but two of them proved to be most crucial.

One, identified last year by virologist Yoshihiro Kawaoka of the University of Wisconsin, is the blueprint for hemagglutinin, the protein that allows the virus to latch onto human cells before invading them. The second is polymerase, which helps the virus replicate.

The researchers found that the 1918 hemagglutinin gene has two mutations that convert it into an infectious powerhouse.

Normal flu viruses rely on enzymes in the lung cells they invade to cleave and activate the protein, allowing it to enter cells.

The mutations in the 1918 gene eliminate this requirement so that the virus can enter virtually any cell it encounters.

Studies of the intact virus in mice, for example, showed that it could enter and kill virtually all lung cells, including those deep within the lung that normally escape an infection.

As a consequence, the 1918 virus killed mice within three to five days. Other flu viruses are rarely lethal to the species.

The altered polymerase, they reported, helps the virus grow much faster in human lung cells, allowing an infection to burgeon out of control before the immune system has time to react.

When Tumpey and his colleagues removed the hemagglutinin gene from the 1918 virus and replaced it with the gene from today’s bird flu, the virus no longer killed mice and could not grow in human lung cells.

The two forms of the hemagglutinin protein differ by only two amino acids. Neither of the changes has been observed in the current bird flu virus.

The current bird flu also differs from the 1918 virus in that it passes from human to human only with great difficulty.

In addition, the Spanish flu concentrates in the lungs, though the current virus also infects other internal organs.

Still, Taubenberger said the 1918 virus “might give us some excellent clues” on the possible evolution of the current virus, which has killed 60 people.

Gerberding addressed criticisms about the research at Wednesday’s news conference, saying that the research took place in a high-security laboratory to prevent any inadvertent releases.

She added that it did not require greater security because the Spanish flu virus can be treated with Tamiflu and other antivirals.

Because the 1918 virus is a precursor to many of today’s human flu viruses, she added, the population already has a degree of immunity -- making it highly unlikely to cause a new pandemic even if accidentally released from the lab.