H5N1 Paper Published: Deadly, Transmissible Bird Flu Could Be Closer than Thought

After an epic debate over whether to release research detailing how scientists created H5N1 in the lab, Nature finally published one of the two controversial papers on Wednesday.

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You might not have noticed, but the influenza world has been in a bit of an uproar since late last year, when news leaked out that two teams of researchers had purposefully tweaked H5N1 bird flu in the lab to potentially make it more transmissible among human beings. (H5N1 spreads like wildfire among birds — and usually kills them — but the virus only rarely seems to jump to human beings, though when it does the infections are often fatal.)

The two scientists — Yoshihiro Kawaoka of the University of Wisconsin–Madison and TIME 100 honoree Ron Fouchier of Erasmus University in the Netherlands — had submitted their research to Nature and Science, respectively, with the expectation of swift publication. In December, the National Science Advisory Board for Biosecurity (NSABB) did something unprecedented: they ruled that the two papers should be censored if published, that they should be scrubbed of the complete methods and viral mutations that the researchers studied, in order to head off the risk that terror groups could use the information to craft a deadly bioweapon.

(PHOTOS: The Bird Flu Outbreaks in 2008)

That led to intense fighting within the scientific community. Some researchers wanted the papers published in full, both because they believed the work could help arm us against a future flu pandemic, and because they worried about the chill of government censorship on science. Other scientists were against publication and even the experiments themselves, believing that nothing gleaned from the work could be important enough to offset the risk of creating a potentially deadly flu virus.

In the end, Fouchier explained that his man-made flu virus wasn’t the merciless killer that early media reports had made it out to be — Kawaoka’s man-made virus was always believed to be less dangerous — and in March the NSABB took a look at revised papers submitted by the two research teams and voted to recommend that they be published.

On Wednesday, Nature finally published Kawaoka’s research. (We’re still waiting for the Fouchier paper, though the Dutch scientist was recently granted an export license for his work, so it should appear soon.) The sobering takeaway: avian H5N1 flu viruses in nature may be only one mutation away from spreading effectively between mammals, likely including human beings. If that happens — and if H5N1 retains its apparently sky-high mortality rate — we could be in for serious trouble.

For all the controversy, the research itself is actually quite fascinating. Kawaoka and his team mutated H5N1’s hemagglutinin (HA) gene — the H in H5N1 — which produces the protein the virus needs to attach itself to host cells. They produced millions of genes, mimicking the effect of random mutation in nature, and found one version of H5N1 hemagglutinin that seems particularly effective at invading human cells.

(MORE: Dangers of Man-Made Bird Flu Are Exaggerated, Its Creators Say)

The genes for that protein contained four new mutations, three of which altered the shape of the gene, while the fourth one changed the pH level at which the protein attaches to the cell and injects the virus’s genetic material inside. (It’s a bit reminiscent of Alien, if the virus is the face-hugger and this poor guy’s face is the cell.) The team combined the mutated HA gene with seven other genes — flu viruses have eight genes in all — from the highly transmissible if not highly deadly H1N1 strain, which caused the 2009 flu pandemic. The result was an H1N1 virus with mutant H5N1 hemagglutinin proteins on the outside.

Kawaoka and co. then introduced the hybrid flu virus into the noses of ferrets — an animal that has long been used in flu research as stand-ins for human beings — and the bug replicated within the test subjects. Later the researchers discovered that the mutant flu also spread from ferret to ferret relatively easily, something the real-world H5N1 isn’t yet able to do. It’s not clear whether the mutant virus would spread as easily among human beings as it does between ferrets, however, and the new virus remained vulnerable both to the antiviral Tamiflu and a prototype vaccine against H5N1.

Still, it’s possible that the H5N1 bird flu might naturally be able to hit upon the same mutations that Kawaoka created in the lab, while still retaining its current virulence. In any case, as the virologist Jeremy Farrar of the Oxford University Clinical Research Unit in Vietnam told Ed Yong for Nature News: “This work reminds us just how vulnerable we potentially are to relatively small changes.” It didn’t take much for this virus to change completely.

Bigger news will likely be made when Fouchier’s paper comes out. That’s because Fouchier introduced mutations directly into an H5N1 virus, then let the new strain spread and evolve inside the ferrets. Those changes eventually turned what had been a bird flu into a mammal flu, albeit one that ended up not to be deadly to the ferrets. But Fouchier’s work would provide a much more direct formula for terrorists to alter H5N1 viruses themselves.

(MORE: A Bus Driver in Southern China Dies of Bird Flu. Could the Deadly Virus Strike Again?)

That’s still not terribly likely, though — it would require a lot of work on the part of any terrorists, and there’s no guarantee they’d even be able to create anything particularly dangerous. (A bigger threat, in mine and other people’s views, is the possibility of an accidental release of a mutated virus from the lab — something that has happened in the past.) But the debate goes beyond security concerns. The Nature paper marks a new era in science, as Carl Zimmer wrote on Wednesday for Discover:

This episode is just the start of something much bigger. Roger Brent, a biologist at the Fred Hutchinson Cancer Research Center, put it into history of modern biology. In the 1970s, biologists discovered how to move individual genes from one organism to another. The power to rewrite the book of life caused a lot of consternation, and led to a gathering called Asilomar in 1975, where scientists tried to work out a system for ensuring that no monstrous new creatures would escape a lab and wreak havoc on the world. At the time, just about everyone on Earth who had the wherewithal to perform genetic engineering could get together at Asilomar. Over the past 37 years, these manipulations have become democratized. A far broader group of researchers now have far more power than anyone did in 1975.

All of the furor over Kawaoka and Fouchier’s research came well after the research had already been completed, the mutant flus created and cooling in the lab. Our ability to manipulate life — even the those sub-microscopic, sometimes deadly forms of life known as viruses — grows by the day, but there’s been no concurrent development in how we, as a world, should govern those abilities. It turns out that may be an even bigger challenge then inventing a killer flu from scratch.

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