SubCell: Proteome-aware vision foundation models for microscopy capture single-cell biology

Cell morphology and subcellular protein organization provide important insights into cellular function and behavior. These cellular features can be studied using large-scale fluorescence microscopy, and machine learning has become a powerful tool to interpret the resulting images for biological insights. Here, we introduce SubCell, a deep learning model for fluorescence microscopy designed to accurately capture cellular morphology, protein localization, cellular organization, and biological function beyond what humans can readily perceive. SubCell was trained on the proteome-wide image collection from the Human Protein Atlas with a novel proteome-aware learning objective. SubCell outperforms state-of-the-art methods across a variety of tasks relevant to single-cell biology and generalizes to other fluorescence microscopy datasets without any fine-tuning. Additionally, we construct the first proteome-wide hierarchical map of proteome organization that is directly learned from image data. This vision-based multiscale cell map defines cellular subsystems down to protein complex resolution, reveals proteins with similar functions, and distinguishes dynamic and stable behaviors within cellular compartments. Finally, combining SubCell with a protein sequence model enables a rich multimodal approach to capture gene function better than either vision-only or sequence-only models alone. In conclusion, SubCell creates deep, image-driven representations of cellular architecture that are applicable across diverse biological contexts and datasets.