 Lung diseases are the third leading cause of death worldwide. To understand the processes that lead to disease, scientists are actively mapping the numerous types of cells that reside in the lungs. The problem? The lungs are incredibly complex. While bulk sampling techniques and traditional profiling methods have been useful for surveying major cell populations, they can't quite reach the smallest regions deep within the lungs or report on cells' location. In a new study, researchers led by the Tata Lab at Duke University revealed the discovery of new types of cells in the lungs, their location, and their function. Their findings were made possible by combining spatial transcriptomics, single cell RNA sequencing, and computational predictions of cell fate. Together, these techniques shed light on how healthy cells in alveolar structures respond and change after lung injury caused by pollutants and viruses such as SARS-CoV-2, the virus that causes COVID-19. When applied to human lung tissue, spatial transcriptomics produced physical maps of the cells that reside in the proximal and distal airways. Data gathered by single cell RNA sequencing enabled the team to cluster cells according to their molecular machinery. While many types of cells were found to be well known, some appeared to be entirely new. Among these were cells labeled terminal and respiratory bronchial secretory cells, or TRBSCs, and TRB-specific alveolar cells type 0 or AT0 cells. Using multiple computational algorithms for predicting cell fate, the team placed TRBSCs and AT0s in context with other alveolar cells in the lungs. They observed a strong trajectory originating from AT2 cells and transitioning toward AT1s or TRBSCs through AT0s. To validate their computational predictions, the team used their recently developed mini-lung model, a common type of model known as an organoid. Using organoids, the team found that removal of a key growth factor called epidermal growth factor changed lung stem cells into AT0 cells and later TRBSCs. These organoids were found to organize into 3D cysts, resembling structures found in human lung disease. Interestingly, the newly identified cells and tissue structures are completely absent in mouse lungs, a model system commonly used to study lung diseases. But when the team looked at tissue from monkeys, a close relative of humans, they found similar changes after lung damage. This role in repair was confirmed in tissue from humans with lung injury, where AT0s were found to occur in distal gas-exchanging air sacs. Furthermore, in fibrotic tissue, AT0s and TRBSCs localized in regions of varying injury severity, AT0s in mildly fibrotic regions, and TRBSCs in severely fibrotic areas, resembling classical histological descriptions of bronchialized regions. More work is needed to determine the genetic machinery that controls how human AT0s differentiate into AT1s and TRBSCs. As genome editing tools and large animal models become more available, scientists will be able to continue their exploration of the lungs with unprecedented resolution.