Scientists recreate virus that killed millions
Oct. 5, 2005
Special to World Science
Scientists say they have made a virus identical, in most key respects, to the Spanish flu virus that killed an estimated 20 million to 50 million people in 1918.
The purpose of the recreation, the researchers said, is to protect humanity from another world outbreak, which may be imminent because the virus is related to bird flu viruses that have been killing growing numbers of birds and some humans.
“This will advance our ability to prepare vaccines” and effective drugs in case of an outbreak, said
Jeffery Taubenberger, chairman of the molecular pathology department of the Armed forces Institute of Pathology in Rockville,
Md. He is the lead author of a paper on the virus to appear in the Oct. 6 issue of the research journal
Researchers have warned that existing bird flu viruses may be on the verge of leaping to humans and killing millions of people. This seems to be exactly how the 1918 pandemic started, researchers involved in the reconstruction
The newly minted virus is being held under close surveillance for testing at the U.S. Centers for Disease Control and Prevention (CDC) in Atlanta, Ga., U.S. health authorities said in a conference Tuesday.
But Taubenberger acknowledged terrorists could theoretically use information from the project to construct the virus themselves, since researchers published the recreated virus’s genetic sequence in a public database. If someone else wants to reconstruct it now, “the technology is available,”
Taubenberger said in a Nature news article.
The researchers and CDC officials said they simply accepted this risk because the potential benefits are much greater. If the virus escaped into the population today it’s “unlikely” to cause a global pandemic, said CDC Director Julie Gerberding, because most people have some built-in immunity to it from exposure to related viruses. Also, effective vaccines and drugs exist. Neither was the case in 1918, she said.
Nonetheless, in testing, the reconstructed virus has turned out to be deadlier to mice than ordinary flu viruses, researchers reported in a separate paper published in the Oct. 7 issue of the research journal Science. This suggests “that this property of the 1918 virus has been recovered in the published sequence,” wrote the journal’s editors in an editorial.
Researchers said they reconstructed the virus by drawing fragments of it from the lungs of a woman who died in the 1918 outbreak, and was buried in the frozen ground of Alaska.
Viruses are packets of genetic material that inserts itself into living cells, hijacking their genome to turn it into machinery that produces more copies of the virus.
The CDC’s Terrence Tumpey led a team of researchers that reconstructed a live virus containing all eight of the genes that the 1918 virus contained, which they described in the Science paper.
In addition to genes, the 1918 virus also contained some genetic material that doesn’t consist of actual genes. Tumpey said his team wasn’t able to reproduce this part of the virus exactly, so they instead used similar material from a closely related virus to complete the reconstruction.
By reconstructing the virus, researchers say they have now discovered at least part of what made it lethal, thus providing essential information for influenza drug and vaccine research.
The Spanish flu virus is more closely related to bird flu viruses than other human flu viruses, according to researchers.
Therapies against a new flu strain would need to disarm the parts of the virus that do the most damage to the body,
Taubenberger said. By studying the reconstructed 1918 virus closely, researchers said they can determine which parts these are.
Tumpey and Taubenberger said their findings may also help researchers assess the potential virulence of future flu strains as they emerge.
The research is beginning to reveal how the 1918 virus changed from its bird form to a human form,
Taubenberger explained. Based on this information, researchers can monitor whether these same changes are occurring in existing bird flu viruses. Indeed, they are starting to, he said, although several more changes would probably have to take place before serious human outbreaks can occur.
“We felt we had to recreate the virus and run these experiments to understand the biological properties that made the 1918 virus so exceptionally deadly. We wanted to identify the specific genes responsible for its virulence, with the hope of designing antivirals or other interventions that would work against virulent pandemic or epidemic influenza viruses,” said Tumpey.
Gerberding said U.S. health authorities had consulted extensively before the publication, and agreed with scientists that the benefits of the project outweighed the risks.
The publication of the sequence will let “the best and the brightest among the scientific community… join the team” of researchers studying the virus, said Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, at the conference. Ultimately this will lead to greater protection of the public, he added.
To reconstruct the 1918 virus from the separate fragments of it they had recovered, the researchers said they used an approach called “reverse genetics.” This involves transferring combinations of he viral genes into living cells, where they combine on their own to form a full virus.
The researchers also produced variations of the virus for comparison, with certain Spanish flu genes replaced by the corresponding genes from other flu viruses. Then they studied the viruses’ effects in mice, chick embryos and human lung cells and identified the constellation of genes that was responsible for the Spanish flu virus’ extreme virulence.
One gene associated with high virulence was the HA gene. This gene creates a protein molecule that goes on the surface of the virus and helps it attach to cells properly so it can infect them. This gene seemed to be responsible for much of the severe lung damage reported in people infected with the Spanish flu, according to the authors of the Science paper.
Three genes that code for the production of viral “polymerase”—enzymes that form the virus’ basic replication machinery—were also found to be important for high virulence, the authors said.
“Given that HA is responsible for so much pathology in the lung, if we could identify the mechanism for how that happens and then block it, perhaps it would be useful for antiviral development. With the identification of the polymerase genes contributing to disease, that represents another set of genes that might also be a good target,” Tumpey said.
Although more research needs to be done on antivirals and vaccines for a future flu pandemic, Tumpey noted some encouraging signs. The FDA-approved flu antiviral drugs, oseltamivir and amantadine, have been shown to be effective against viruses carrying certain genes from the Spanish flu virus. And, vaccines containing the Spanish flu HA gene, as well as another gene from this virus, were protective in mice, he added.
Gerberding said the virus is being held under a security regime known as Biosafety Level 3, the second most stringent level of security under CDC guidelines. The first, Level 4, is reserved for pathogens “for which there is no vaccine and no antiviral treatment,” she said.
Level 3 involves filtering the exhaust air from the laboratory, requiring self-contained breathing apparatuses for lab workers to avoid having them pick up the virus, and showering before leaving the facility, she added. “It is a very, very high level of containment.”
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