One experiment showed that genetic robustness improved evolvability of phage 6 populations when heat shock was used as an adaptive challenge. 15 Phage 6 is typically cultured at 25°C, and exposure to 45°C heat shock for as little as 5 min leads to ϳ20% survival ͑%S͒ in populations of the virus. Robust and brittle clones of the virus from the aforementioned MOI experiment 14 were used to found lineages passaged for 50 generations of experimental evolution with periodic ͑every fifth generation͒ exposure to 45°C heat shock. At the end of the study, we measured mean %S at 45°C measured for each founding clone and its derived end point population to estimate ⌬%S, the change in percent survival after heat-shock selection. The results showed that the lineages founded by robust genotypes were more evolvable ͑greater ⌬%S͒, indicating that robustness promoted evolvability in phage 6, under the test conditions. The explanation was that robust genotypes of phage 6 may have proteins that better tolerate mutations while maintaining proper folding especially at moderate temperatures, 16 similar to suggestions from in vitro studies where less-sensitive ͑relatively robust͒ proteins seem more likely to maintain their function in a new environment where innovation is needed. 11 That is, despite equivalent sensitivity to 45°C heat shock in the robust and brittle founding strains, the robust viruses may have proteins that tend to be capable of undergoing mutations while maintaining their proper folding when 45°C constitutes a selective environment. 15 Whether this exact relationship extends to other novel environments has yet to be explored. But the fact that a positive relationship exists at all is essential for tests of existing theory, 8 and begs the question of whether the observed relationship between genetic robustness and evolvability extends to evolution of human pathogens, as implicated in recent claims of evolved increases in genetic robustness in HIV. 38 Antiviral therapy consisting of chemical mutagenesis that induces an insurmountable mutational load seems promising for treatment of RNA virus infections. [39] [40] [41] But such measures may select for RNA viruses to evolve altered polymerases with improved replication fidelity that reduces genomic mutation rates. 42 Alternatively, viruses may be selected to evolve mechanisms of genetic robustness where high mutation rates are preserved but phenotypic effects of the mutagen are buffered. This outcome is perhaps unlikely given the empirical data thus far. 43 However, further data involving a variety of different viruses are warranted, and the results from experimental evolution studies caution that robustness may be positively related to evolvability and to competitive superiority in RNA viruses. 15 A second experiment centered closely on the potential link between robustness and pathogen evolvability on novel hosts. Environmental robustness of a virus may be defined in terms of its host generalization ͑host range, the number of host types it can productively infect͒. 44 Theory predicts that evolved generalization may be particularly useful if organ-isms tend to encounter environments that change unexpectedly. 45 That is, generalists may be favored by selection because they are better predisposed to survive and give rise to successful progeny in the face of variable environments, relative to specialists that possess a narrow niche. This idea may explain why pathogens with a pre-existing broad host range seem better able to emerge on novel hosts, relative to specialized pathogens. [46] [47] [48] To test this idea directly, we used populations of VSV that evolved differences in host use because of prior selection in constant versus variable host environments. 49, 50 The formal prediction was that VSV populations experiencing direct selection for host range would have higher mean growth and less variance in mean growth on a collection of challenge hosts, compared to VSV populations that were either relatively specialized or indirectly selected for host range. 51 When challenged to grow on four novel hosts in vitro, the viruses that had been selected for generalism exhibited higher or equivalent host growth, lower among-population variance in host growth, and lower variance in population growth across hosts. Thus, these three predictions relating to the hypothesis were generally supported because direct selection for host breadth more often allowed successful emergence. The results suggested that determination of current niche breadth should be further investigated as a potentially useful indicator in predicting pathogen emergence. 51, 52 Because these many recent empirical breakthroughs in the study of robustness have involved microbes, one might predict that infectious disease is the primary biomedical realm where these robustness results might have an immediate, practical impact. Below we describe three examples of biomedically important human disease systems where robustness theory appears highly relevant.