editorial are models for embracing diversity The frst demonstration that RNA populations are groups of closely related sequences, proposed to behave as a quasispecies, was published 40 years ago this month, marking the beginning of a fundamental change in how we understand RNA virus dynamics, pathogenesis and response to therapy.

his month marks 40 years since attenuated or non-pathogenic virus variants of heterogeneous populations has historically the publication of a study in Cell have been shown to attenuate disease been quite uncommon in biology. However, reporting that populations of the caused by more virulent components of a more recently, the quasispecies concept has T 5,6 bacteriophage Qβ​ are not genetically quasispecies . Another consequence of this also been connected to other settings in homogeneous, but rather a collection of heterogeneity is that drug-resistance mutations which heterogeneity exists, such as mutator distinct but closely related RNA sequences can pre-exist in the population before the bacterial strains, conformational that arise as a consequence of the high error onset of antiviral treatment, which should heterogeneity and cellular heterogeneity rate during replication1. The study, led by thus be initiated early, before the quasispecies within tumours, although whether these Esteban Domingo while in the laboratory has had a chance to diversify5. Quasispecies systems behave according to the theory of of Charles Weissmann, proposed that such theory also predicts the existence of an error quasispecies remains unclear. a population structure was an example threshold beyond which an increase in As with the establishment of molecular of quasispecies, a concept that had been mutation rates would lead to extinction of viral biology a couple of decades earlier, close recently developed by biophysical chemists populations. This has been shown to occur collaboration between theoreticians and and Peter Schuster to explain in vitro upon treatment of a variety of viruses experimentalists was key for the application the error-prone self-organization and with mutagens, and is the basis of the antiviral of the quasispecies theory to RNA of macromolecules present at the approach known as lethal mutagenesis5, populations. During a small, interdisciplinary origin of life2. To mark the anniversary of which is an active area of research. In short, meeting convened by Eigen, he heard the this seminal study in viral evolution, this existing as a constantly changing cloud of unpublished results of the Weissmann issue features an interview with Esteban related but non-identical gives RNA lab and subsequent discussions led to the Domingo, in which he discusses how the viruses a plasticity that is important in the notion that Qβ​ could group came to these results, how they were complex environments encountered in a , be explained by his recent theory. That seed received, their implications and his vision during transmission to different hosts, and in fell on fertile ground, and a new field aiming for the future of the quasispecies field. response to therapy, and should be taken into to understand RNA virus heterogeneity, In the intervening 40 years, and although consideration when developing evolution and their manifold implications, exactly how the quasispecies theory can be and strategies. took off. In the era of instant communication, applied to RNA viruses has been the subject It is remarkable that Domingo’s first of ‘bubbles’ or ‘echo chambers’ in social of some debate3,4, the concept has provided experiments were carried out before the and professional networks, when often the an important framework to understand methods to reverse-transcribe, amplify and same researchers attend the same meetings the population structure and dynamics sequence nucleic acids were established, over the course of a year to discuss the of numerous RNA viruses, including when only a very partial view of the same issues, we risk failing to learn a lesson HIV, , influenza virus quasispecies could be obtained. The advent from viruses on the strengths that can be and flaviviruses5. Viral pathogenesis was of next-generation sequencing, including gained from a diverse population enabling previously thought to be unrelated to virus methods that reduce background error complementary and critical interactions. variability and evolution — indeed, RNA specifically developed for the analysis of viral Gathering discussion in small, forward- viruses where thought to be a single genetic populations, has revolutionized this field. looking meetings of intentionally disparate entity — yet quasispecies theory predicts These approaches provide an unprecedented researchers, often from entirely distinct that the population as a whole is the target of view of the composition of RNA virus disciplines, around a common topic, can selection during infection. This is important, quasispecies from human, animal and plant foster a ‘blue sky’ atmosphere and the sharing as evolution is thus affected not only by high samples. When combined with the use of unpublished data, thus catalysing the mutation rates but also by interactions between of model systems and clinical data, these emergence of new ideas and collaborations the mutants, which can be positive or negative, approaches are beginning to enable virologists that are essential for scientific advancement. and the breadth of the mutant spectrum can to link the molecular understanding of Such meetings should not be forfeit as a determine the behaviour of the population. quasispecies behaviour obtained in vitro luxury in the face of budgetary strictures. ❐ For example, viral mutants that have higher- with in vivo (intra-host) and population- fidelity polymerases (and thus populations level (inter-host) responses. The viral Published online: 27 March 2018 with reduced heterogeneity) are generally quasispecies field thus reaches middle age https://doi.org/10.1038/s41564-018-0145-3 attenuated in vivo and can have altered tissue clearly re-energized by recent technological tropism. In the case of , these effects developments, in a vibrant mood and full of References have been shown to be reversed by increasing ideas, such as using in-host viral population 1. Domingo, E. et al. Cell 13, 735–744 (1978). 2. Eigen, M. & Schuster, P. Naturwissenschafen 64, 541–565 (1977). the breadth of the mutant spectrum using dynamics as predictors of disease outcome or 3. Wilke, C. BMC Evol. Biol. 5, 44 (2005). chemical mutagenesis, evidencing positive response to therapy, or the rational design of 4. Holmes, E. C. J. Mol. Biol. 400, 271–273 (2010). interactions within the quasispecies5,6. On the safe and effective live attenuated vaccines7. 5. Domingo, E. & Schuster, P. Quasispecies: From Teory to Experimental Systems (Springer, Switzerland, 2016). other hand, mutant spectra can also suppress As noted by Eigen in the foreword to a 6. Andino, R. & Domingo, E. Virology 479–480, 46–51 (2015). 5 more fit genomes within a population, and recent book on viral quasispecies , the idea 7. Moratorio, G. et al. Nat. Microbiol. 2, 17088 (2017).

Nature Microbiology | VOL 3 | APRIL 2018 | 389 | www.nature.com/naturemicrobiology 389 © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.