1918 Influenza: Coming to a City Near You

[biomat]

Nature 437, 794-795 (6 October 2005) | doi: 10.1038/437794a

Special ReportThe 1918 flu virus is resurrected

Top of page

Abstract

 

The recreation of one of the deadliest diseases known could help us to prevent another pandemic. Or it might trigger one, say critics. Andreas von Bubnoff investigates whether the benefits outweigh the risks.

 

It is thought to have killed 50 million people, and yet scientists have brought it back to life. In this issue of Nature, scientists publish an analysis of the full genome sequence of the 1918 human influenza virus. And in this week's Science, researchers describe how they used that sequence to recreate the virus and study its effects in mice.

 

Some scientists have already hailed the work as giving unprecedented insight into the virus. Working out how it arose and why it was so deadly could help experts to spot the next pandemic strain and to design appropriate drugs and vaccines in time, they say.

 

But others have raised concerns that the dangers of resurrecting the virus are just too great. One biosecurity expert told Nature that the risk that the recreated strain might escape is so high, it is almost a certainty. And the publication of the full genome sequence gives any rogue nation or bioterrorist group all the information they need to make their own version of the virus.

 

Jeffery Taubenberger of the Armed Forces Institute of Pathology in Rockville, Maryland, is the lead author of the sequencing study. He says the work was necessary and the risks were low. The paper on page 889 gives details of the final three genes; the sequences of the rest have already been published.

 

The full sequence is strong evidence that the 1918 flu virus is derived wholly from an ancestor that originally infected birds. In contrast, the viruses that caused the flu pandemics of 1957 and 1968 arose when human and avian flu viruses infected the same person at the same time, allowing their genes to mix.

 

All eight of the genome segments from the 1918 virus differ in important ways from other human flu sequences, suggesting that none of the genome came from a strain that had previously infected people. "It is the most bird-like of all mammalian flu viruses," says Taubenberger.

 

Pinpointing exactly which genetic mutations allowed the virus to jump to humans will enable scientists to recognize other bird viruses that could trigger a pandemic. Taubenberger's team has already identified 25 changes in the protein sequences of the 1918 strain that have been present in subsequent human flu viruses. These mutations are likely to be particularly important, he says. One such change, in the polymerase gene PB2, was found in the virus isolated from the only human fatality in a 2003 outbreak of H7N7 bird flu in the Netherlands.

 

In the paper in Science (T. M. Tumpey et al. 310, 77−80; 2005), Terrence Tumpey at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and his co-workers have used Taubenberger's sequence to recreate the complete 1918 virus (see graphic).

 

They have constructed a virus that is perhaps the most effective bioweapon known.

 

When they used the strain to infect mice they found it was extremely virulent, and after 4 days had generated 39,000 times more virus particles in the animals' lungs than a modern flu strain (see 'How virulent is 1918 flu?'). "I didn't expect it to be as lethal as it was," says Tumpey.

 

The researchers compared the complete 1918 virus with strains in which some genes had been replaced by those of contemporary strains. They found that replacing the haemagglutinin gene, which helps the virus to enter cells, made it unable to kill mice. Replacing all three of the polymerase genes, which allow the virus to replicate, significantly reduced its virulence. The haemagglutinin gene is essential, says Tumpey. "But no single change or gene is the answer," adds Taubenberger. "It's a combination effect."

 

Future research will involve testing reconstructed viruses with and without certain mutations, to see which are the most important for virulence. Information from this type of study will hopefully be of use in vaccine and drug design, but so far the work is more about obtaining a basic understanding of the virus than any immediate health benefits.

 

The studies have been praised as groundbreaking. "It's a landmark," says Eddie Holmes, a virologist at Pennsylvania State University in University Park. "Not only is this the first time this has been done for any ancient pathogen, but it deals with the agent of the most important disease pandemic in human history."

 

The team got permission to do the work from CDC head Julie Gerberding and Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, based in Bethesda, Maryland.

 

But the studies have sparked fears among other researchers. "There most definitely is reason for concern," says Richard Ebright, a bacteriologist at Rutgers University in Piscataway, New Jersey, who serves on biosecurity panels. "Tumpey et al. have constructed, and provided procedures for others to construct, a virus that represents perhaps the most effective bioweapons agent now known."

 

"This would be extremely dangerous should it escape, and there is a long history of things escaping," says Barbara Hatch Rosenberg, a molecular biologist and member of the Federation of American Scientists' Working Group on Biological Weapons. "What advantage is so much greater than that risk?"

 

Ebright agrees that there is a significant risk, "verging on inevitability", of accidental release of the virus into the human population, or of theft by a "disgruntled, disturbed or extremist laboratory employee". And there is the danger that a hostile nation might reconstruct its own version of the virus, he says, pointing out that any of these scenarios could result in a large number of deaths.

 

Ebright also believes that using an enhanced biosafety level-3 lab for the work was inadequate. If the researchers were going to do the work at all, they should have used level 4, the strictest biosafety condition, he says. This requires experimenters to wear full body suits. In 2003, he points out, a SARS virus escaped accidentally from a level-3 lab in Singapore, and in 2004 two further escapes occurred from such labs in Beijing.

 

Tumpey counters that enhanced level 3, which requires upper body suits and respirators, is safe enough. Disgruntled employees aren't a concern either, he says, because he is the only one who works with the virus. The few researchers with access to the lab undergo extensive background checks, and retina and fingerprint scans are used to prevent any unauthorized entry to the lab.

 

He adds that even if the virus did escape, it wouldn't have the same consequences as the 1918 pandemic. Most people now have some immunity to the 1918 virus because subsequent human flu viruses are in part derived from it. And, in mice, regular flu vaccines and drugs are at least partly effective against an infection with reconstructed viruses that contain some of the genes from 1918 flu.

[j_p]

I am far more worried about the current Avian flu mutating to allow human to human transmission.

[tejaswini]

one problem after another please.let's tackle the more fatal ones for now.

[insane_alien]

But aren't some of the current influenza virii decended from that one and still hanging around the cities. influenza is a relatively new virus as in <300 years since we have encountered it. also medicine and hygene have improved now so the chances of surviving flu(if you even catch it in the first place) are very high unless you are old, already seriously ill, or very young. even then there is a good chance that you will pull through.

[prion]

the chances of surviving flu(if you even catch it in the first place) are very high unless you are old, already seriously ill, or very young.

 

This is only true for 'normal' flu, i.e. the ordinary strains of flu that we are familiar with and that do the rounds every winter. The type of flu that causes pandemics is totally different, it is a virus that has mutated so that we have no immunity to it, because our species has never encounted it before. There would be totally different effects, mainly that it would infect many more people and would kill very many people. Also the pandemic flu of 1918 was more likely to kill people who were young and previously healthy, as their inflammatory response was so much more dramatic. I think to a point this was also true of the pandemics in the 50s and 60s - my friends uncle died suddenly of flu in the 60s having been young, fit and healthy. It worries me that in the event of a pandemic people will campaign for the very old and young to be vaccinated/treated when they are not the most vulnerable in those circumstances.

 

It surprises me that people get quite blase about flu when it regularly kills thousands. In the UK a few years ago there was a bad epidemic and every hospital had to have refrigerated trucks outside to hold all the bodies, yet it's been totally forgotten and people can't understand why there so much hype when we are facing a strain that is vastly more dangerous that that.

 

By the way thanks Biomat for drawing attention to the paper - I wasn't aware of that one. Thank goodness it was done at the CDC, heaven knows what precautions they had to take with their containment labs.