All the world’s a phage

A renewed interest in bacteriophages has emerged from the explosive discovery of the complex pan-immune bacterial defense system and a revival of the therapeutic potential of phages in the age of widespread antimicrobial resistance to antibiotics. However, the road ahead is daunting because of the huge genetic diversity of phages and the vast numbers of genes of unknown function. A fully integrated approach that includes curiosity-driven exploration of phage biology, the development of integrated and inclusive research-education programs based on phage discovery and genomics (SEA-PHAGES), and the advancement of phage therapeutics provides a holistic structure for advancing the field. The phages of mycobacteria illustrate this model and a large mycobacteriophage collection reveals the enormous diversity of phages infecting a single bacterial strain and illuminates the evolutionary mechanisms giving rise to genomes with mosaic architectures. A set of 2,600 fully sequenced and annotated mycobacteriophage genomes and the development of tools for engineering them with desirable properties enable phage therapies for treating <i><i>Mycobacterium</i></i> infections for which antibiotics frequently fail. Technological advances in synthetic genomics and structural biology promise to rapidly advance this field and powerfully stimulate developments in all aspects of bacteriophage investigation and application. Here I describe what we have learned from the study of mycobacteriophages and how a holistic approach-integrating curiosity-driven research, inclusive education, and medicine-can serve as a model for advancing microbiology broadly.