How far is H5N1 bird flu from 1918 all over again?

Reconstruction of the deadly 1918 influenza virus has been controversial because of the risk that the reconstructed virus might escape from the laboratory or fall into the wrong hands. On the other hand, research with this virus has indeed led to some important insights (reviewed by Garcia-Sastre and Whitley). One of the first of these was that the 1918 virus was probably avian in origin. Since that review the severity of symptoms has been attributed to an overactive innate immune response (Kobasa et al. 2007, summarized by Loo and Gale, 2007), and the infectivity to mammals has been attributed to two amino acid changes in the hemagglutinin gene (Tumpey et al., 2007, summarized by Enserink, 2007). Does this mean that the H5N1 virus now infecting birds in much of the world is only two point mutations away from causing a human pandemic? This is not clear. Certainly, there are those who think that we need to be more concerned about the birds (e.g. Juan Lobroth), and Yamada et al., 2006 present evidence that changes in hemagglutinin can be observed (already) in some H5N1 viruses isolated from humans even though human-to-human transmission remains extremely rare. Even so, we have learned what to look for.