Most patients with the genetic disease cystic fibrosis (CF) succumb to chronic airway infection caused by the bacterium Pseudomonas aeruginosa. CF lung disease follows a characteristic pattern. Early in life, patients suffer from transient airway infections with P. aeruginosa that resemble bronchitis. Genetic fingerprinting studies show that these infections are distinct events; infection develops and is subsequently cleared, and the next bout is caused by a new strain acquired from the environment (1). Unfortunately, this stage is temporary as the airways of nearly all patients become permanently colonized by P. aeruginosa. From this point forward, the same bacterial lineage can persist continuously in the lungs for years or even decades and cannot be eradicated by any known therapy (2).

Much research in CF has focused on how chronic infection affects the patient because inflammation from infecting bacteria causes persistent respiratory symptoms and an inexorable decline in lung function. However, the onset of chronic infection is also transformative for the bacteria because an environmental P. aeruginosa strain (that may have been living in, say, a water pipe) must adjust to the alien conditions of the lung and live long-term within the host. Hope for developing new treatments rests in part on understanding how bacteria adapt to the airway and resist host defenses and antibiotics. The innovative work by Smith et al. in this issue of PNAS (3) explores this question by using a powerful tool: whole-genome sequencing. Smith et al.(3) sequenced the genome of a P. aeruginosa strain early in a CF infection and the descendent of that strain, still present in the patient’s lungs, 7.5 years later. Sixty-eight mutations were found in the late isolate. Most were single-base pair changes, and many were predicted to result in a change or loss of protein function. To construct a timeline of the strain’s evolution, Smith et al. genotyped strains collected at intermediate times. They also investigated whether the identified mutations were common in CF by genotyping paired (early and late) P. aeruginosa isolates from 29 other patients and found some genes that were mutated in most CF patients.