Helmholtz Munich Establishes State-of-the-Art Cryo-Electron Microscopy Technology
Enabling Breakthroughs in High-Resolution Structural Analysis of Therapeutic Targets and their Visualization in the Native Cellular Context
Structural biology techniques such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy single-particle analysis (cryo-EM SPA) provide unique insights into the molecular mechanisms underlying biological processes and enable structure-based drug discovery for the treatment of human diseases. Here, high-resolution structures of biological molecules are obtained using isolated biomolecules purified in vitro. Until recently, it was difficult to study subcellular compartments in their native cellular environment.
Going a significant step further, a fruitful cross-departmental collaboration between the Helmholtz Pioneer Campus and the Targets and Therapeutics Center (MTTC) facilitated the implementation of a globally emerging, novel technology, called in situ cryo-electron tomography (cryo-ET) @HelmholtzMunich. Cryo-ET allows the visualization of cellular structures in their natural and functional environment at molecular resolution. This technology is at the heart of the new Helmholtz Munich Cryo-EM Platform (CEMP), which provides complete and state-of the art cryo-EM infrastructures for both in situ cryo-ET and cryo-EM SPA. The new multimillion euro instrumentation covers all workflows of advanced cryo-EM applications and can be employed to study a large variety of research topics – ranging from unraveling molecular mechanisms to the acceleration of new therapeutic approaches. Helmholtz Munich is thus one of few sites globally to leverage and offer the full spectrum of atomic resolution structural technologies, now including state-of-the-art cryo-EM and 1.2 GHz ultra highfield NMR spectroscopy (https://www.bnmrz.org/).
Prof. Michael Sattler, Head of Molecular Targets and Therapeutics Center and Director of the Institute of Structural Biology at Helmholtz Munich, comments: “We expect unprecedented insight into the biomolecular structures in their native environment in healthy and disease-linked states and thereby enabling the development of novel therapeutic approaches.”
How will the Helmholtz Munich Cryo-EM Platform be used?
The Helmholtz Munich CEMP provides unique access and expertise to cryo-EM SPA as well as cryo-ET workflows. The former enables high-resolution structural analysis of biomolecular complexes that are of the highest biomedical importance and thus enable structure-guided drug discovery on challenging targets, such as signaling receptors, membrane-associated protein complexes, and large protein-RNA complexes in gene regulation, enabling structure-based drug discovery efforts of Michael Sattler and team.
Dr. Marion Jasnin, Principal Investigator of the Cryoskeleton Lab at the Helmholtz Pioneer Campus leads the implementation of the cryo-ET workflow. She was only recently recruited from Prof. Baumeister’s lab (MPI Martinsried), one of the globally recognized pioneers of cryo-ET. Marion also accelerates her own research program that investigates actin, a small globular protein, and its associated cytoskeletal proteins in their native cellular environment to advance our understanding of cellular structure, the underlying biology and disease mechanisms, in particular tumor cell invasion.
Together, the integration of scientific expertise of cryo-EM SPA, NMR spectroscopy, X-ray crystallography, in situ cryo-ET, optical imaging and artificial intelligence (AI) at Helmholtz Munich will ultimately lead to a better understanding of cellular structures, dynamics and mechanisms across scales, from individual macromolecules to whole organisms.
Who utilizes the Helmholtz Munich Cryo-EM Platform?
Many research groups at Helmholtz Munich have already established collaborations and have access to the cryo-EM technologies at the Helmholtz Munich CEMP. A cooperation on structural biology applications is currently being established with the Technical University of Munich (TUM School of Natural Sciences, Department of Bioscience, and Center for functional Protein Assemblies (CPA)). The Helmholtz Munich CEMP, managed by Dr. Stefan Bohn, will be used to study emerging topics in biomedical research, ranging from stem cell, diabetes and environmental health to molecular targets and therapeutics. In addition, the unique expertise in AI-based computational tools for image analysis available at the Computational Health Center and Helmholtz AI at Helmholtz Munich is expected to significantly advance the application of cryo-ET technology for in-cell structural biology to understand physiological and pathological pathways and enable the development of new therapeutic concepts to treat human diseases.
About the scientists
Prof. Dr. Michael Sattler, Head of the Molecular Targets & Therapeutics Center, Director of the Institute of Structural Biology and the Bavarian NMR Center (Helmholtz Munich & TUM)
Dr. Marion Jasnin, Principal investigator of the Cryoskeleton Lab at the Helmholtz Munich Pioneer Campus
Dr. Stefan Bohn, CEMP Facility Manager and Staff Scientist at the Institute of Structural Biology at the Molecular Targets & Therapeutics Center at Helmholtz Munich
How does cryo-ET work and what can be analyzed?
During cryo-ET acquisition, 2D images of a vitrified sample are taken at different angles (typically from -60 to +60 degrees), which can then be reconstructed into a 3D volume called a tomogram. The tomogram shows not only the macromolecule of interest, but also its location and spatial arrangement within the cellular environment, from which the biological function can be inferred. Although cryo-ET provides lower (nanometer to subnanometer) resolutions than cryo-EM SPA, where single atoms can be resolved, cryo-ET has a decisive advantage in revealing spatial information. Cryo-ET already facilitates the analysis of samples such as cellular organelles, membrane structures with membrane proteins, bacteria, viruses and large molecular machineries. In addition, dynamic organelles such as cilia or other structures associated with cell mobility, signal transport or transmission have been visualized so far. Furthermore, recent progress in the field demonstrates that structural analysis of organoids, large mammalian cells, and even whole organisms such as the nematode C. elegans is feasible. The only limitation is the crystal-free freezing of the biological sample. In situ cryo-ET is a rapidly emerging technique, with many breakthroughs still to come.