Only a handful of scientists have security clearance to access the laboratory at 1600 Clifton Road in Atlanta, Georgia, home to the US government's Centres for Disease Control and Prevention. Before entering, they must pull on a protective hood, don breathing apparatus and pass through electronic fingerprint and retina scanners to prove their identity.
Inside the lab lies a batch of a virus, designated a "select agent", that more than justifies the extreme level of security. Resurrected nearly 90 years after it spread around the globe, leaving an estimated 50 million people dead, it is a replica of the 1918 Spanish flu virus.
The recreation of the virus, which was driven by an urge to unravel why the 1918 pandemic was so devastating, has raised as many fears as it has hopes. While the researchers argue the work will hugely improve protection against natural flu viruses, critics say there is a real danger the virus will escape, with potentially disastrous consequences.
The recreation process was laborious. Scientists collected fragments of the virus from lung tissue taken from victims at the time and preserved in formalin or, in one case, isolated from the lungs of a woman victim whose body had later become frozen in the Alaskan permafrost. Using the fragments, they painstakingly pieced together and read the complete genetic code before using the sequence to rebuild the virus from scratch.
By injecting it into mice, the team led by Dr Jeffery Taubenberger at the Armed Forces Institute of Pathology in Maryland was able to establish just how ferociously effective it was, compared with more common flu strains. All the mice infected died within a few days; all infected with contemporary strains recovered. "I didn't expect it to be as lethal as it was," Dr Terrence Tumpey, a scientist on the project from the US Centres of Disease Control and Prevention, told the journal Nature.
By creating flu strains with only certain parts of the 1918 virus, researchers investigated which of the eight genes that make up the virus were most responsible for its virulence. They discovered that rather than being caused by one or two genes, they all played a part, which suggests that the virus had completely adapted to cause disease in humans, something they say could happen again with avian flu strains.
In a second paper, published in Nature today, Dr Taubenberger and colleagues at the US Centres for Disease Control and Protection analysed the genetic make-up of the recreated virus. Surprisingly, they found it had no similarities to any of the human viruses in circulation, suggesting that the Spanish strain had jumped from birds to humans, and didn't mix with a human virus first, as had been believed.
The finding that Spanish flu came straight from birds has raised concerns among scientists. Previously, a pandemic was only thought likely if an avian strain merged with a human flu virus. "For me, it raises even more concern than I already had about the pending potential of a flu pandemic," said Professor Ronald Atlas, co-director of the centre for the deterrence of biowarfare and bioterrorism at the University of Louisville in Kentucky. "It looks as though an avian strain evolved in 1918 and that led to the deadly outbreak, in much the same way as we're now seeing the Asian avian flu strains evolve."
According to Dr Taubenberger, knowing what mutations gave rise to the 1918 Spanish flu virus will help scientists check viruses to work out which, if any, are evolving to the point where a pandemic is possible. The H5N1 strain of bird flu in Asia is already mutating to make it more suited to humans, he said.
Despite the new insights given by the project, many scientists were alarmed at the recreation itself and particularly that the full genetic sequence was to be made public on an online genetic database.
"Assuming this is a replicant of the 1918 flu strain, if it got out, it could initiate disease in humans and given the work they've done, one had to say it would be infectious," said Prof Atlas.
Viruses have escaped from high-security labs before. During the recent Sars outbreak the virus escaped at least twice, once in Taiwan and once in Singapore, when researchers became contaminated.
Other scientists warned that the 1918 virus's genetic code could easily be misused. Such has been the pace of progress in genetic science that companies now build genes to order for customers who send in details of sequences they want.
"If the genetic sequence is out there on a database, then that is a clear security risk," said Dr John Wood, a virologist at the National Institute for Biological Standards and Control, in Potters Bar.
According to Dr Julie Gerberding, director of the US Centres for Disease Control and Protection, a pandemic is unlikely even if the virus escapes because of most people's natural immunities and the availability of antiviral drugs and flu vaccines.
Publication of the research still raises questions about the powers of academic journals who take ultimate responsibility for publishing the papers, said Dr Wood. "That is some responsibility," he said.
The US National Science Advisory Board for Biosecurity concluded at an emergency meeting last week to discuss the possible publication of the papers that their benefits outweighed their risks.
FAQ: 1918 flu pandemic
Why was the 1918 Spanish flu pandemic so lethal?
The worst pandemic in human history, the 1918 strain killed an estimated 50 million people. Because flu viruses were unknown at the time, no isolates of the pathogen were made, making it impossible for scientists to study. Scientists believe the virus was originally found only in birds but jumped to humans and evolved to become very infectious
Whom did the 1918 flu virus kill?
Most flu viruses kill the very young, the old and the infirm. But the Spanish flu was unusual in striking young, fit people extremely hard. Even with good healthcare, up to one third of those who picked up the infection died, many within days
What is a select agent?
Its designation as a 'select agent' by US Centres for Disease Control and Prevention puts it on a list of controlled pathogens and toxins including ricin, smallpox virus, anthrax and ebola
How secure is the virus?
It is held in a biosafety level 3 enhanced laboratory, kept at a negative pressure to prevent air escaping. Workers must wear protective clothing, breathing apparatus and gain entry via fingerprint and retina scans
