In 2011, the United States government and the National Institutes of Health were alerted to manuscripts submitted by Kawaoka et al. and Fouchier et al. in Nature and Science, describing mutations in the H5N1 HA gene which allowed for the transmission of the virus in ferrets. But why all the attention and scrutiny? Well, to an influenza researcher, the authors had just published a set of mutations that could be used to create a pandemic influenza virus capable of human-to-human transmission. These studies brought the National Science Advisory Board for Biosecurity (NSABB) to action and in January 2012, the influenza research community imposed a voluntary moratorium on this line of study.

(top left) Transmission electron microscopy of two H5N1 virions at 108,000X. False colour added for illustration purposes only. Image credit: Cynthia Goldsmith and Jackie Katz, the Centers for Disease Control and Prevention.
Transmission electron microscopy of two H5N1 virions at 108,000X. False colour added for illustration purposes only. Image credit: Cynthia Goldsmith and Jackie Katz, the Centers for Disease Control and Prevention.

Historically, emergent strains of highly virulent and infectious influenza viruses have taken a severe toll on the human population. The most severe pandemic was the 1918 H1N1 “Spanish flu”, which spanned the far reaches of the globe and resulted in an estimated 50-100 million deaths – approximately 5% of the world’s population at the time. Since then, new influenza strains have continued to emerge, causing major pandemics that have included the 1957 H2N2 “Asian flu”, the 1968 H3N2 “Hong Kong flu”, and most recently, the outbreak of H1N1 “Swine flu” in 2009. A common characteristic of these pandemic-inducing flu viruses is that they contain gene segments from strains of influenza virus circulating in avian and swine populations. It is exactly this ability to undergo genetic reassortment in different animal populations that makes influenza viruses such a potent threat to human health.

Over the last decade, the highly pathogenic H5N1 avian influenza has spread across the eastern hemisphere, due in part to its presence in migratory bird populations. Already, H5N1 has been the cause of widespread epidemics in poultry, resulting in the culling of millions of birds every year. While zoonotic transmission of H5N1 is uncommon, in the rare cases where transmission from birds to humans does occur, there is a 60% mortality rate. Luckily, cases of human-to-human transmission have been limited so far. However, given the possibility of further genetic reassortment, compounded by the proximity of humans to poultry and swine in high-risk areas of the world (e.g. southern China), it is not unreasonable to predict an outbreak of H5N1 in humans in the near future.

To better prepare for pandemic outbreaks, scientists have developed a number of approaches to study the virulence and transmission of highly pathogenic influenza viruses. One such method is to reverse engineer recombinant influenza viruses composed of genes from two or more different strains. This approach – and naturally occurring genetic reassortment – is possible because the influenza virus genome is comprised of 8 distinct single-stranded negative sense RNA segments (HA, NA, PA, PB1, PB2, M, NP, NS) encoding 14 proteins including the viral RNA polymerase. By transfecting a combination of the 8 genes into cell lines to generate live recombinant viruses and then further manipulating the individual gene segments, it is possible to determine the consequences of mutagenesis on influenza virulence and transmission. Furthermore, recombinant influenza viruses are often suitable candidates for live-attenuated vaccines.

In the controversial studies by Kawaoka et al. and Fouchier et al., a recombinant influenza virus encoding the H5N1 HA gene segment was recombined with 7 genes from the 2009 H1N1 virus. Kawaoka et al. identified 4 mutations that allowed the H5N1 HA protein to recognize “human-type” receptors and infect ferrets through droplet transmission. Fouchier et al. used a recombinant H5N1 virus with a mutated HA gene to show that the virus could become an airborne pathogen transmissible in ferrets due to mutations acquired after passaging the virus through multiple ferret hosts.

But does the scientific benefit of understanding the evolution of potentially pandemic influenza viruses outweigh the risks of misuse? And should this information be made available to the community at large? On one hand, the mutations revealed in present and future studies could be maliciously exploited to produce H5N1 viruses with a higher capacity for human-to-human transmission, or a higher mortality rate upon infection. On the other hand, the insight gained from these studies also further our understanding of influenza virus transmission and helps develop and enhance current antiviral therapies. Ultimately, the NSABB voted to publish revised versions of the manuscripts and lifted the moratorium on the studies, but as many scientists are still wary of this controversial research, the ethical quandary surrounding the study of influenza viruses will continue to be an issue in the years to come.

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Ben Wang

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