It sounds like the plot of a Hollywood disaster movie: scientists tinker with a flu virus to make it more deadly, only for the mutant strain to escape and trigger a pandemic.
Yet flu scientists are currently at loggerheads over experiments to make the H7N9 bird influenza virus that emerged in China earlier this year even more dangerous.
Some argue that "gain of function" experiments to make the virus more infectious, more deadly and drug resistant in ferrets – the best available test animal for human flu – offer up vital information that could help us defend against a pandemic.
Other scientists are concerned that deliberately creating a supervirus could provide a weapon to bioterrorists. What's more, they point out, existing biosafety measures – such as requiring researchers to wear special safety suits and go through decontamination chambers when leaving the lab – may not be enough to prevent the virus spreading.
Now, a team led by Benjamin tenOever, at Icahn School of Medicine at Mount Sinai, New York, has devised a genetic failsafe that would switch off mutant strains if they escaped from the lab and infected humans.
tenOever's team tweaked an H3N2 flu strain, a common cause of seasonal flu, by tagging it with a single strand of microRNA, a sequence of genetic material that when paired with a complementary sequence, can switch genes on and off.
The microRNA put into the virus is chosen so that when it is met by a matching strand in its host organism, the virus's replication genes get shut down.
By using a microRNA that exists in human and mice lung cells but not in ferrets, tenOever and his team developed a modified virus that could replicate in ferrets during their experiments but not in mice or humans, if it ever escaped the lab.
The study comes shortly after a letter was published in Science and Nature by Ron Fouchier of the Erasmus Medical Center in Rotterdam, the Netherlands, and 23 colleagues, defending such research on the basis that the best way to prevent a worst-case scenario is to provoke one.
The letter was intended to prevent a similar furore to the one that erupted in late 2011 surrounding gain of function experiments, which Fouchier also led, on another avian influenza strain, H5N1. It resulted in the publication of the work being delayed by nine months.
tenOever says that Fouchier's H5N1 research was key in identifying mutations that would make the bird virus start to spread between mammals. "This knowledge was critical to focus our surveillance efforts to monitor the virus and predict when the risk of disease justifies vaccine development."
Marc Lipsitch at the Harvard School of Public Health in Boston is unconvinced. He considers gain of function studies highly risky. And the genetic failsafe proposed by tenOever's team may itself be volatile, he says. "Engineering the restrictive sequence is a change with unpredictable consequences, which could make experiments even harder to interpret and also provide a false sense of security".
Michael Imperiale at University of Michigan in Ann Arbor agrees. "My concern is that the microRNA target on the viral genome will just mutate in the same way that a virus develops drug resistance."
tenOever says that the modified viruses grow and infect cells in a similar way to non-mutated strains, suggesting that the biology of the virus has not been altered. On sequencing the altered viruses, they found no mutations.
Yesterday, the first human case of H7N9 since 20 July was reported in the Guangdong province of China. According to the World Health Organization, it brings the total number of laboratory confirmed cases to 135 people, 44 of whom have died.
Last week, the BMJ reported the first probable case of the virus spreading between people – a father and his daughter – although this doesn't seem to be common.
Journal reference: Nature Biotechnology, DOI:10.1038/nbt.2666
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