Localization of Macromolecules in Crowded Cellular Cryo-electron Tomograms from Extremely Sparse Labels

MotivationLocalizing macromolecules in crowded cellular cryo-electron tomograms (cryo-ET) is crucial for determining their in situ structures. Traditional template matching-based approaches for this task suffer from template-specific biases and have low throughput. Given these problems, learning-based solutions are necessary. However, the paucity of annotated data for training poses substantial challenges for such learning-based methods. Moreover, preparing extensively annotated cellular cryo-ET tomograms for training macromolecule localization methods is extremely time-consuming and burdensome due to the large volume and low signal-to-noise ratio of the tomograms. ResultsIn this work, we developed TomoPicker, an annotation-efficient macromolecule localization method for cryo-ET tomograms. To achieve such annotation-efficiency, TomoPicker regards macromolecule localization as a voxel classification problem and solves it with two different positive-unlabeled learning approaches. We evaluated TomoPicker on two experimental cryo-electron tomography (cryo-ET) datasets of crowded eukaryotic cells and one experimental dataset of relatively less crowded prokaryotic cell. We observed that, with only 10 annotated macromolecule locations, TomoPicker with positive unlabeled learning achieved a performance comparable to that of state-of-the-art supervised methods trained with several hundred annotations. In other words, TomoPicker achieved plausible segmentation with up to 98% less data compared to supervised learning-based methods. Furthermore, it demonstrated substantial improvements over existing learning-based macromolecule localization methods under sparse annotation scenarios. CodeThe code to train and use TomoPicker is available on https://github.com/DuranRafid/TomoPicker.