Tools for assembling the cell:

Towards the era of cell structural bioinformatics

Descriptions:

Cells, the fundamental building blocks of life, exhibit an intricate multi-scale structure, from large components like organelles that recursively factor into smaller and more specialized systems, such as condensates and protein complexes. To systematically interrogate these subcellular structures across a broad range of sizes and provide insight into subcellular functions, a number of advanced technologies are emerging. Notably, these include fluorescent confocal imaging, cryo-electron tomography, and AI-guided folding algorithms, alongside biochemical approaches such as affinity purification, co-elution, crosslinking mass spectrometry, and their associated machine learning pipelines.

Recently, several groups have published whole-cell mapping strategies based on multiple distinct complementary technologies^1–7. The timely and distinct opportunity that emerges from all of this work is to assemble a key group of thought leaders in a suitable location to discuss progress, open challenges, and, most importantly, how collaborative teams can be established to marshall the various technologies towards an integrated structural map of the human cell. The ability to efficiently map cell structure will set the stage for future efforts to use these maps in pharmaceutical and clinical applications and to comprehensively define the nature of human cells across tissues, diseases, and times during development and aging. These maps will also provide an important structural scaffold for synthetic biology approaches to engineering complex cellular systems.

In this 3-hour workshop, we will convene leaders in the fields of systems biology, structural biology, cell modeling, and generative machine learning to discuss key aspects of map assembly as well as proof-of-principle interdisciplinary projects ripe to be tackled by the community.

Objectives of the workshop

● Explore the current progress made in understanding the hierarchical organizations of human subcellular components

● Learn about the cutting-edge technologies that facilitate the modeling of hierarchical cell structures

● Discuss the promises, pitfalls, and challenges of cell structural modeling, including bottom-up and top-down approaches

● Explore the interdisciplinary projects and applications of cell mapping in pharmaceutical and clinical settings

● Foster potential collaborations for driving forward cell structural biology projects for the near future

Agenda

Organizer:

Emma Lundberg, PhD

Stanford University

emmalu@stanford.edu

Trey Ideker, PhD

UC San Diego

tideker@health.ucsd.edu

Andrej Šali, PhD

UC San Francisco

sali@salilab.org

References

1. Qin, Y. et al. A multi-scale map of cell structure fusing protein images and interactions. Nature 600, 536–542 (2021).

2. Hess, H. F., Lippincott-Schwartz, J., Saalfeld, S. & Weigel, A. V. Whole-cell organelle segmentation in volume electron microscopy. Nature (2021).

3. Liu, F., Rijkers, D. T. S., Post, H. & Heck, A. J. R. Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nat. Methods 12, 1179–1184 (2015).

4. Luck, K. et al. A reference map of the human binary protein interactome. Nature 580, 402–408 (2020).

5. Johnson, K. L. et al. Revealing protein-protein interactions at the transcriptome scale by sequencing. Mol. Cell 81, 3877 (2021).

6. Salas, D., Stacey, R. G., Akinlaja, M. & Foster, L. J. Next-generation Interactomics: Considerations for the Use of Co-elution to Measure Protein Interaction Networks. Mol. Cell. Proteomics 19, 1–10 (2020).

7. Viana, M. P. et al. Integrated intracellular organization and its variations in human iPS cells. Nature 613, 345–354 (2023).