A new microscope in London will use a beam of ions to shave frozen cells and tissues into slices thinner than a virus, making the molecular machinery inside them visible for the first time. Most biological samples thicker than 200 nanometres—about one five-hundredth the width of a human hair—are opaque to the electron beams needed for high-resolution imaging. This has kept the majority of protein complexes and molecular machines inside cells hidden from direct view. The cryo-FIB-SEM instrument solves that by milling frozen samples into electron-transparent lamellae, allowing researchers to image structures where they naturally sit, rather than after being extracted and purified. The instrument will serve 50 project co-leads across six research themes, from cell signalling and genome integrity to host-pathogen interactions and healthy ageing. Because the technique works on any macromolecular complex—not just the largest or most abundant—it opens fundamental biological processes to direct observation. This is primarily curiosity-driven fundamental science. Similar investments in cryo-electron microscopy over the past decade have transformed structural biology, revealing the atomic architecture of everything from ribosomes to viral spikes, and this equipment extends that capability into the native cellular environment.
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The structural analysis of macromolecular complexes in situ, i.e. in the near-native cellular context, can yield unprecedented mechanistic insights into fundamental biological processes and is one of the most important frontiers in both structural and cell biology1. We present an application led by the Institute of Cancer Research (ICR), Imperial (ICL), Queen Mary University London (QMUL) and King’s College London (KCL) for instrumentation to generate electron-transparent cell and tissue samples for cryogenic electron tomography (cryo-ET), using cryogenic focused ion beam milling coupled with scanning electron microscopy (cryo-FIB-SEM)1. This equipment will open a critical bottleneck and meet the current and growing unmet demand for access in London where there is a large critical mass of bioscience researchers to realise the full potential of this technology for transformational scientific impact, training and exchange. This will complete the full provision of an accessible in situ structural biology pipeline. Cryo-ET has enabled the reconstruction of macromolecular assemblies within cellular context, recently advancing to resolutions comparable to in vitro single-particle cryo-EM in favourable cases2. Fluorescent and electron-dense molecular tagging methods enable specific proteins and nucleic acids to be tracked within cells and tissues, making it possible to study any macromolecular complex and rare events for electron imaging, not only the largest and most abundant targets. However, samples thicker than 200 nm are rarely electron transparent let alone amenable to high-resolution imaging by cryo-ET. Requirements for identifiable targets and super-thin samples have kept the majority of molecular machineries inaccessible in situ studies. Now the maturing ability to prepare electron-transparent sections anywhere in cells, tissues, and even small organisms by cryo-FIB-SEM has opened vast potential for new discoveries across cellular biology1. Cryo-FIB-SEM uses a narrow ion probe to mill thin lamellae left in plane or lifted out to specialised supports, an approach that has been refined in reliability and throughput3. The unique power of targeted cryo-ET lies in its ability to image structures of high and often insufficiently understood complexity, rendering these targets unsuitable for in vitro reconstitution and analysis by single-particle cryo-EM. Moreover, the cryo-FIB-SEM enables the combination, on a single sample, of cryo-fluorescence, serial block-face SEM4, and cryo-ET of thinned sections deep within cells or tissues, providing multimodal cellular context absent from in vitro studies. The cryo-FIB-SEM instrument will be installed at the ICR, co-located with a comprehensive setup for all stages of a state-of-the-art workflow, providing high impact at excellent value for money. The new instrument will be managed and supported by dedicated Research Technical Professionals who will train, support and collaborate with researchers across the pipeline. This partnership of ICR, ICL, QMUL and KCL builds on our successfully implemented London Consortium for Electron Microscopy (LonCEM), through which we have been collaborating since 2017 and operating a high-end cryo-electron microscope since 2019. The new cryo-FIB-SEM instrument will offer sustainable access to a game-changing technology, vital opportunities for scientific exchange, collaborative synergies across related research areas, and training. Research enabled by this equipment spans a wide range of fundamental discovery science with relevance to health and biotechnology over six research themes, run by a total of 50 Project Co-Leads: Cell Signalling; Eukaryotic Molecular Machines; Genome Integrity; Gene Expression; Healthy Ageing, Amyloids and Protein Misfolding; Microbiology, Host-Pathogen Interactions and Microbial Engineering. We aim to establish this as a major UK centre for in situ structural biology.
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