The bioinformatics of the 'flu

What was the most lethal epidemic of infectious disease in modern times? AIDS perhaps? You might think so, but you would be wrong. Between the beginning of the epidemic and the end of 2007, AIDS killed people 25 million; the influenza epidemic of 1918 killed 40 million. This vast figure is also about double the number who died in the First World War, which ended the same year. Furthermore, a high proportion of those deaths were of healthy individuals in the prime of life. Yet most of the time we think of influenza as little more than a very nasty nuisance...

However, there has recently been a renewed interest in past influenza epidemics as a result of the result of the virulent strain of influenza currently sweeping through populations of wild and domestic birds worldwide. The influenza virus is endemic in birds, and strains tend to spread periodically from them to mammalian hosts: pigs as well as humans. Mapping genetic changes in the influenza virus, and how these affect its spread, is an important research area. Richard Goldstein of the National Institute for Medical Research, based in Mill Hill, London, gave a fascinating Monday seminar on this topic yesterday, looking into the past to see how genetic changes could have led to the lethal 1918 epidemic.

Influenza viruses contain two proteins on their spherical surfaces: a neuraminidase and a hemagglutinin. These proteins come in various forms: 16 different hemagglutinins are known, and 9 different neuraminidases. Any influenza virus can be characterised by these variants - for example, the most common type of influenza currently afflicting humans is H3N2, and the feared bird flu H5N1. Recent flu epidemics appear to have been caused by reassortment events, where the genomes of different viral subtypes combine to form an entirely new one that will not be recognised by human immune systems. An epidemic in 1957, for instance, coincided with a shift from influenza H1N1 (which had been circulating since 1918) to H2N2.

Influenza virus hemagglutinin and neuraminidase are both mainly-beta proteins, and their structures are described further on this page of PPS section 5.

So, what happened in, or before, 1918 to cause the epidemic of H1N1 flu? Molecular geneticists, such as Goldstein, study this by reconstructing phylogenetic trees showing the evolutionary distance between viral isolates taken in different places at different times. Yet most of these calculations can only show evolutionary distance, not the direction of change - in the jargon of phylogeny, they produce unrooted, rather than rooted, trees (there is no known "top"). The research was at rather an impasse until postdoc Mario dos Reis (a Birkbeck Ph.D.) noticed that the GC content of viruses infecting humans, but not of those infecting birds, decreased over time. This enabled the group to add an evolutionary "clock" to the phylogenetic tree for each of the influenza virus' 11 genes. This showed that some of the genes had entered the human population at different times, indicating that the variant that caused the 1918 flu had arisen from several recombination events. Interestingly, only one gene (neither H nor N) could have made the jump in 1918; most viral proteins were present in the human population in their 1918 forms well before that year. M1, like some other proteins, appears to have made the shift in 1899.

So, what did happen in 1918? There do appear to have been changes to the H gene then. But it may also be possible that the world population was so debilitated, and susceptible, after four years of war that a variant that had already been around for a few years was, unusually, able to cause such an epidemic...