Conventional light microscopes hit a hard physical limit at around 250 nanometres—too blurry to see individual proteins or the molecular machinery inside cells. This grant will install commercial super-resolution microscopes at UCL that break that barrier, achieving two to twenty times sharper images, and then push the technology further for live-cell imaging. The problem is that electron microscopes, the only alternative for high resolution, require samples to be killed, fixed, and heavily processed. They cannot track dynamic processes in living cells or easily identify specific molecules. Super-resolution imaging bridges this gap, letting researchers watch molecular events unfold in real time inside living tissue. If successful, the facility will give cell biologists, neuroscientists, and virologists a direct view of the molecular faults underlying infection and disease. This is primarily a capacity-building and technology-development programme—it does not promise a specific therapy or device. But similar fundamental imaging advances have repeatedly transformed medicine: fluorescence microscopy, for instance, made modern cell biology possible. Sharper eyes on the molecular world will almost certainly reveal mechanisms that current tools simply cannot see.
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Microscopy has been one of the principle tools for discovery-based research at the cell and molecular level, allowing insights to the organisation and dynamics of cells, as well as the faults associated with infection and disease. Over the last 25 years increasingly sophisticated microscopes, together with new experimental tools such as fluorescent protein tags, improved lasers and cameras, and developments in live cell imaging, have led to rapid advances in our understanding of cell organisation and function. Nevertheless, imaging at high resolution is limited by the properties of light to ~250 nm, meaning that information at the level of molecules and molecular complexes cannot be obtained using conventional light microscopes. Thus, high-resolution studies have been restricted to electron microscopy (EM), which can only be used on fixed and highly processed samples, and has limited capacity to identify specific molecular components. In recent years several novel optical and computational approaches have been developed to break the diffraction-limit of conventional light microscopy, with the potential to obtain molecular/structural information at significantly higher resolution (approx. 2-20 fold improvement). By combining multiple fluorescently-labelled probes, within the same sample, together with live cell imaging, these so-called super-resolution nanoscopy techniques are able to bridge the current technologies of diffraction-limited microscopy and EM to generate new detailed molecular and mechanistic insights into the cellular and molecular processes that underlie normal cell function and disease. Super-resolution imaging (SRI) instruments are now becoming commercially available allowing cellular biomedical researchers to begin to apply these exciting new technologies to a multitude of questions in cell biology, neurobiology, infectious disease and many other fields of biomedical research. Development is still at an early stage and there remain many opportunities for progress, particularly in live cell imaging, probe development, software development, analytical tools, etc. However, SRI instruments and technical developers are needed now to work in close collaboration with biomedical researchers to establish the technology and push instrument and application development. This application will link MRC-funded scientists in the Cell Biology Unit/Laboratory for Molecular Cell Biology (CBU/LMCB) and Prion Unit (MRC PU), as well as the MRC/UCL Centre in Molecular Medical Virology (MRC CMMV), with members of UCL's Faculties of Life Sciences, Medicine and Brain Sciences, the London Centre for Nanotechnology (LCN), UCL physicists and chemists, computer scientists, image-based bio-informaticians and the National Physics Laboratory Teddington (NPL), to establish and develop platforms for SRI. The facility will be centred on commercial off-the-shelf SRI instruments that will provide a benchmark against which UCL and NPL members of the programme will develop new systems and instruments optimised for biomedical research. The facility will also provide capacity-building opportunities for students and postdoctoral fellows to train/work at the interface of biology, imaging and instrument development. Together this presents a timely window of opportunity in which to build on UCL's excellent imaging facilities and world leading biomedical research community to create a cutting edge, interactive SRI research and development programme for application to biomedical research.
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