H5N1: Bird Flu Pandemic May Be Closer than Thought, Study Finds

It may take as few as five mutations for H5N1 to go from being a bird-only problem to a potentially deadly human pandemic flu, researchers report.

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After a delay of more than six months, a controversial paper describing a virulent, man-made form of bird flu was published in the journal Science on Thursday. The findings suggest that we may be closer than we thought to a potentially deadly influenza pandemic.

Science released in their entirety the details of a series of experiments conducted by virologist Ron Fouchier and his colleagues at Erasmus University Medical Center in the Netherlands, in which they genetically engineered the H5N1 bird flu virus and made it jump easily from host to host. The research, along with another paper submitted to Nature by scientists led by Yoshihiro Kawaoka at the University of Wisconsin-Madison who also created an airborne strain of H5N1, was initially suppressed in December by a U.S. government biosecurity group over concerns that the experiments could pose a bioterror risk. The National Science Advisory Board for Biosecurity (NSABB) asked the editors of Science and Nature to strip the reports of their detailed methods, or withhold them altogether, sparking an intense dispute within the scientific community.

In March, the NSABB reviewed revised papers submitted by Fouchier and Kawaoka and gave them the green light. The release of Fouchier’s paper marks the end of months of bitter debate (Kawaoka’s paper was published in Nature in May) over the risks of government censorship on science versus those of bioterrorists getting their hands on the recipe for deadly flu, but it’s likely just the launching point for continued discussions and yet-to-be formulated policies for dealing with so-called dual-use research that can have both beneficial and destructive consequences.

Fouchier’s intent was to further researchers’ understanding of how flu viruses work — how they adapt to new hosts and how they learn to hop from person to person. H5N1 spreads easily among birds and usually kills them, but it rarely transmits from one person to another, mainly because it isn’t airborne. When it does infect human beings, however, it’s often deadly: of the 606 cases of human H5N1 infection confirmed by the World Health Organization since 2003, nearly 60% have resulted in death. If the virus were to mutate and go airborne — flying from person to person through sneezes and coughs — it could trigger a potentially deadly pandemic. So, Fouchier wanted to know what it would take to make that happen and, by publishing his work, enable scientists to stay one step ahead of the virus by better predicting and preparing for a potential pandemic.

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

In the highly anticipated report published on Thursday, Fouchier describes how he and his team introduced three key mutations to a common H5N1 strain. The team chose genetic changes that had previously appeared in strains of H5N1 that caused pandemic illness among people in outbreaks in 1918, 1957 and 1968. They then introduced their genetically engineered flu virus into ferrets, which because of their anatomy are good models for studying how influenza behaves in people. The virus did not reproduce efficiently in the ferrets, nor did it develop the ability to spread via air droplets from one animal to another.

So the researchers then allowed nature to run its course, repeatedly “passaging” the mutant virus, with its three genetic alterations, in the nasal passages of ferrets and allowing the virus to mutate in its host on its own. The researchers infected ferrets with the original strain, then collected virus samples from the nose and lungs of the animals, and used these strains to inoculate the next set of animals, and so on, thereby mimicking how influenza viruses would naturally circulate and replicate among a group of animals (or people).

Fouchier found that after only four to five such passages, the virus began to mutate, changing to become more efficient at living and thriving in the ferret’s respiratory tract. After 10 passages, the H5N1 became airborne, evolving the ability to jump from an infected ferret and colonize an uninfected neighbor through air droplets; Fouchier’s group confirmed this when three of four ferrets, separated physically from infected animals, became infected by influenza particles released in sneezes by the sick ferrets.

While the virus gained transmissiblity, however, it lost lethality; it wasn’t deadly for animals. More work needs to be done to see how virulent the altered strain might be in humans, but getting airborne is an important first step for a potentially pandemic bug.

(MORE: It’s Back: Bird Flu Returns, and This Time It’s Mutated)

It’s hard to predict how close we are in the real world to a version of H5N1 that would go from being a bird-only problem to one that would pose a serious human threat. But the new paper shows it’s exceedingly possible. “As little as five and less than 10 mutations are sufficient to make H5N1 airborne,” Fouchier told a group of reporters in a teleconference.

The experiments in the ferrets also showed that it wouldn’t take much for these mutations to occur. Some experts believed that H5N1 could become airborne only if it combined genetically with other flu strains, such as those that are responsible for the seasonal flu, in a process called reassortment. That’s what Kawaoka at the University of Wisconsin showed in his report in Nature: his team combined mutated H5N1 genes with genes from H1N1 — which is highly transmissible if not highly deadly — resulting in an airborne version of H5N1.

But Fouchier’s studies proved that H5N1 could mutate on its own to become airborne. And to highlight how easily the virus makes these changes, another group of scientists led by Fouchier’s colleagues at Erasmus, report in the same issue of Science that two of the mutations are already common among circulating H5N1 strains that currently infect birds and fowl. One appears in about 30% of H5N1 strains, while the other appears in half of strains that can infect both birds and people. That means that in order to become airborne, and easily spread from mammal to mammal, all it would take for some H5N1 strains are three additional mutations.

It’s possible that those mutations could evolve in humans, but again, the likelihood is difficult to estimate. “It’s like being in a situation where we would like to predict earthquakes or tsunamis,” says that paper’s senior author, Derek Smith, in the department of zoology at University of Cambridge and a biologist at Erasmus Medical Center. “We now know that we are living on a fault line, and what we discovered is that it’s an active fault line.”

(MORE: Bird Flu: More Common, Less Deadly Than We Thought?)

In January, Fouchier and Kawaoka agreed to temporarily halt work on the H5N1 strains they created, but they’re eager to pick up where they left off and figure out how generalizable the ferret studies are to human populations, and specifically, how virulent the airborne strains might be in people.

To do that, they’ll first need some guidance on how best to pursue such scientifically valuable and potentially life-saving work, while minimizing the risk that such information could be used by terrorists to create a biological weapon. In March, U.S. officials issued an umbrella policy for addressing such dual-purpose research, which they hope will guide future studies like Fouchier’s and Kawaoka’s and avoid the months-long delays in publishing. The U.S. Government Policy for Oversight of Life Sciences Dual Use Research of Concern lists 15 agents or toxins whose study requires additional oversight and monitoring because of their potential to cause societal harm. But the document does not detail exactly how studies with these agents should be conducted or monitored, based on the lessons learned from the Fouchier and Kawaoka papers. That will come in a more specific policy that will be open to public discussion shortly. “That policy will get down to being more granular about the kinds of things we need to pay attention to, and some principles we need to follow,” says Dr. Anthony Fauci, director of the National Institutes of Health’s National Institute of Allergy and Infectious Diseases.

In the end, the NSABB determined that both papers provided more benefit than risk, but it’s clear that such experiments will only continue to raise difficult questions about whether and how to proceed. And weighing those risk and benefits will likely not come in a single, permanent policy but in an evolving one that accommodates our changing knowledge of the threats around us and how best to contain them.

MORE: One Shot Wonder? Progress on a Universal Flu Vaccine
Alice Park is a writer at TIME. Find her on Twitter at @aliceparkny. You can also continue the discussion on TIME’s Facebook page and on Twitter at @TIME.