Integrating cellular electron microscopy with multimodal data to explore biology across space and time

Biology spans a continuum of length and time scales. Individual experimental methods see only discrete parts of this spectrum but can be combined to create a more holistic view. In this Review, we detail recent advances in volume electron microscopy (vEM) and cryo-electron tomography (cryo-ET), which together can visualize biological complexity across scales from the organization of cells in large tissues to molecular details in natural cellular environments. We also discuss emerging methodologies for integrating three-dimensional electron microscopy (3DEM) imaging with multimodal data, including fluorescence microscopy, mass spectrometry, single particle analysis, and AI-based structure prediction. This multifaceted approach fills gaps in the biological continuum, providing functional context, spatial organization, molecular identity, and natural interactions. We conclude with a perspective for incorporating diverse data into computational simulations that further bridge and extend length scales while integrating the time dimension.