Unsupervised SE(3) Disentanglement for in situ Macromolecular Morphology Identification from Cryo-Electron Tomography

Cryo-electron tomography (cryo-ET) provides direct 3D visualization of macromolecules inside the cell, enabling analysis of their in situ morphology. This morphology can be regarded as an SE(3)-invariant, denoised volumetric representation of subvolumes extracted from tomograms. Inferring morphology is therefore an inverse problem of estimating both a template morphology and its SE(3) transformation. Existing expectation-maximization based solution to this problem often misses rare but important morphologies and requires extensive manual hyperparameter tuning. Addressing this issue, we present a disentangled deep representation learning framework that separates SE(3) transformations from morphological content in the representation space. The framework includes a novel multi-choice learning module that enables this disentanglement for highly noisy cryo-ET data, and the learned morphological content is used to generate template morphologies. Experiments on simulated and real cryo-ET datasets demonstrate clear improvements over prior methods, including the discovery of previously unidentified macromolecular morphologies.