Health workers slaughtered chickens at a wholesale poultry market in Hong Kong after three dead chickens tested positive for "bird flu" in 2008. New research shows the H5N1 flu virus could become easily transmissible among people if it acquired just five genetic mutations. (Kin Cheung / Associated Press) 
 
 It’s a flu virus so deadly that scientists once halted research on the disease because governments feared it might be used by terrorists to stage a biological attack. 
 
 Yet despite the fact that the H5N1 avian influenza has killed 60% of the 650 humans known to be infected since it was identified in Hong Kong 17 years ago, the “bird flu” virus has yet to evolve a means of spreading easily among people. 
 
 Now Dutch researchers have found that the virus needs only five favorable gene mutations to become transmissible through coughing or sneezing, like regular flu viruses. 
 
 World health officials have long feared that the H5N1 virus will someday evolve a knack for airborne transmission, setting off a devastating pandemic. While the new study suggests the mutations needed are relatively few, it remains unclear whether they’re likely to happen outside the laboratory. 
 
 “This certainly does not mean that H5N1 is now more likely to cause a pandemic,” said Ron Fouchier, a virologist at Erasmus University Medical Center in Rotterdam, Netherlands, and coauthor of the study published Thursday in the journal Cell. “But it does mean that we should not exclude the possibility that it might happen.” 
 
 As with many other influenza studies, the scientists used ferrets as the stand-in for humans, because their immune system responds similarly to the disease. 
 
 Prior research had established that H5N1 could become contagious in ferrets if the virus was passed through a succession of animals, essentially forcing the virus to evolve at an accelerated rate. In those experiments, Fouchier and his colleagues found that the newly contagious viruses had accumulated nine or more mutations. 
 
 In the new study, the authors set out to determine the minimum number of mutations necessary for airborne infection. 
 
 To do this, the researchers took a strain of the virus that had previously infected a human and altered its genes in the lab. Then they sprayed the altered version of the virus into a ferret’s nose and placed the animal in a specially constructed cage with a second ferret who had not been exposed to the virus. 
 
 The layout of the cages prevented direct contact between the animals, but allowed them to share airflow. When the healthy ferret developed flu symptoms — ruffled fur, loss of appetite and lack of energy — researchers knew the virus had spread through the air. 
 
 By exposing ferrets and human tissue samples to a variety of genetically altered viruses, study authors identified five key gene mutations. 
 
 Two of them improved the virus’ ability to latch onto cells in the animal’s upper respiratory tract. Once there, it could enter the cell, disgorge its genetic material and cause the cell to mass-produce copies of the virus. 
 
 “Another mutation increases the stability of the virus,” Fouchier said. “The remaining mutations enable the virus to replicate more efficiently.” 
 
 [Updated at 3:48 p.m. PDT April 10: The altered virus was much less deadly than the natural version. Only two of the ferrets in the study died, but neither death was caused by the flu. 
 
 Fouchier said he thought this was because the virus attacked cells in the upper airway instead of the lower airway and was therefore less likely to cause pneumonia.] 
 
 Virologists who were not involved in the study said the findings were important, as they provided health authorities with a means of discerning whether mutations observed in the wild are dangerous to people. 
 
 “This is important work,” said Yoshihiro Kawaoka, a virologist at the University of Wisconsin School of Veterinary Medicine. “This could contribute to surveillance of avian influenza viruses in nature.” 
 
 Richard Webby, a virologist at St. Jude Children’s Research Hospital in Memphis, said that although the study provided a valuable list of genetic traits to look for, the most important question for scientists and health officials remained unanswered. 
 
 “The biggest unknown is whether the viruses are likely to gain the critical mutations naturally,” Webby said. “If they can appear readily, then it is very worrisome. If not, then there’s still a major hurdle that these viruses have to get over to become human-transmissible.” 
 
 Fouchier, Kawaoka and other researchers touched off an international biosecurity furor in 2011 when they demonstrated that the H5N1 virus could be made transmissible among ferrets. As a result of the controversy, the U.S. National Science Advisory Board for Biosecurity asked the virologists to omit some details of their work before publishing it in the journals Science and Nature. Scientists responded by imposing a temporary moratorium on their research. 
 
 Also, because of the Dutch government’s concern that the virus could be weaponized, it successfully sued Fouchier and now requires him to apply for and receive an “export permit” before publishing his studies. 
 
 Fouchier, who obtained such a permit for the Cell study, said he did not expect it to ignite the same amount of controversy as his past work. 
 
 “Certainly, there are still some people that would prefer that this type of research be discontinued,” Fouchier said. “We will continue the debate with these people, but we have to realize that it is impossible to reach a global consensus on everything — or anything.” 
 
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 MERS: CDC confirms first U.S. case of Middle East respiratory syndrome ||||| Balinese government officials prepare to cull chickens as a precautionary measure to prevent the spread of bird flu, at a market in Denpasar, Bali, Indonesia on April 26. (Firdia Lisnawati/AP) 
 
 The journal Nature, after much debate and delay, on Wednesday published a paper in which scientists describe how they engineered a part of the deadly H5N1 “bird flu” virus to become more transmissible in mammals. 
 
 The research, led by Yoshihiro Kawaoka of the University of Wisconsin, was one of two experiments that a federal advisory panel had asked journals to hold off publishing because the papers might provide a how-to guide for terrorists or mischief-makers. The panel later dropped its objections after it became clear the engineered viruses were less virulent than had been feared. 
 
 Since it emerged in Hong Kong in 1997, H5N1 influenza has killed millions of chickens, mostly in Asia. People are rarely infected, but when that happens they are likely to die. Since 2003 there have been 602 human cases and 355 deaths. 
 
 In the lab, Kawaoka started with an H5N1 strain that had killed several people in Vietnam in 2004. He isolated the gene for “hemagglutinin,” which is most responsible for contagiousness. He put into it two mutations that allow the flu virus to attach more easily to cells in a person’s throat. 
 
 He then combined that doctored gene with the “normal” genes from the strain of H1N1 flue that caused the human flu pandemic in 2009. Two more mutations in hemagglutinin appeared during lab experiments and after ferrets — which stand in for people in flu studies — were infected with the virus. 
 
 Together, the four mutations made the engineered virus transmissible through the air, although it didn’t kill the ferrets who caught it, or even make them very sick. Whether “wild” bird flu virus containing them would be both contagious and deadly isn’t known. 
 
 However, the experiment has given scientists an idea of what mutations to look out for — which was the purpose of the research from the beginning. 
 
 One of the mutations is already widespread in H5N1 strains circulating in the Middle East. Some of those strains also carry a mutation in a different gene that makes growth in human cells easier. 
 
 “These viruses may be several steps closer to those capable of efficient transmission in humans and are of concern,” Kawaoka and his colleagues wrote in their Nature article. 
 
 A second paper, by Dutch scientist Ron A. M. Fouchier, that made a more contagious bird flu virus using other methods, is awaiting publication at the journal Science. 
 
 The National Science Advisory Board for Biosecurity, a panel of independent experts that advises the federal government, in December asked the two journals to hold off publishing the papers while researchers and governments thought about how to handle this kind of research. In late March the board looked at the experiments more closely and said it no longer opposed publication.
– The journal Nature has published a controversial paper describing how University of Wisconsin scientists created an airborne strain of H5N1—aka "bird flu"—that was transmissible in mammals. A federal panel had asked Nature not to publish the study, and a similar one from a Dutch virologist, fearing they might provide a handy DIY guide for bioterrorists, the Washington Post reports. They eventually dropped their objections, however, once they realized that the more-contagious virus was also less deadly. Researchers added two mutations to a deadly H5N1 strain, mixed in some swine flu genes, and released it on a group of ferrets. The ferrets caught the virus easily—but didn't die or even get very sick. The research was conducted to understand how the virus might mutate in nature—and indeed, scientists say the process was simple enough to occur naturally, the LA Times reports. "It's a great place to start looking for exactly what's going on," says one virologist.