Scientists have created a life-threatening virus that closely resembles the 1918 Spanish flu strain that killed an estimated 50 million people in an experiment labelled as "crazy" by opponents.
US researchers said the experiments were crucial for understanding the public health risk posed by viruses currently circulating in wild birds, but critics condemned the studies as dangerous and called on funders to stop the work.
Scientists at the University of Wisconsin-Madison used a technique called reverse genetics to build the virus from fragments of wild bird flu strains.
They then mutated the virus to make it airborne to spread more easily between animals.
"The work they are doing is absolutely crazy. The whole thing is exceedingly dangerous," said Lord May, the former president of the Royal Society and one-time chief science adviser to the British government. "Yes, there is a danger, but it's not arising from the viruses out there in the animals, it's arising from the labs of grossly ambitious people."
Influenza viruses circulate freely in wild bird populations. Most remain in chickens, ducks and other birds, but occasionally strains mutate into a form that can infect humans. The H5N1 bird flu strain has killed at least 386 people since 2003, according to the World Health Organisation. The Spanish 1918 flu is also thought to have come from birds.
Writing in the journal Cell Host and Microbe, Yoshihiro Kawaoka describes how his team analysed various bird flu viruses and found genes from several strains that were very similar to those that made up the 1918 virus. They combined the bird flu genes into a single new virus, making a new pathogen only about 3 per cent different to the 1918 virus.
The freshly-made virus - the first of several the team created - was more harmful to mice and ferrets than normal bird flu viruses, but not as dangerous as the 1918 strain. It did not spread between ferrets and none of the animals died. But the scientists went on to mutate the virus, to see what changes could make it spread. Seven mutations later, they had a more dangerous version that spread easily between animals in tiny water droplets, the way flu spreads in humans.
Kawaoka, who led the research in a high-security lab, said the work highlighted how viruses found in wild bird populations had the potential to adapt to humans and cause a pandemic.
Marc Lipsitch, professor of epidemiology at Harvard School of Public Health, said: "I am worried that this signals a growing trend to make transmissible novel viruses willy-nilly, without strong public health rationale.
"This is a risky activity, even in the safest labs. Scientists should not take such risks without strong evidence that the work could save lives."
In an article published last month, Lipsitch argued that experiments like Kawaoka's could unleash a catastrophic pandemic if a virus escaped or was intentionally released from a high-security lab.
But Kawaoka defended the work, saying critics failed to appreciate the impact of his and others' work on dangerous viruses. "There were discussions on the usefulness of stockpiling H5N1 [bird flu] vaccines until our H5N1 papers were published. Similarly, this paper strongly supports stockpiling anti-influenza drugs. If this is not a 'lifesaving benefit', what is?"