Senior author Professor Marco Fritzsche leads the Biophysical Immunology Laboratory – a joint venture between the Rosalind Franklin Institute and Oxford’s Kennedy Institute...
If an astronomer wants to look at a particular space object, they often make use of a panoply of instruments both in space and on the ground that interrogate its properties in different ways. The resulting data are then brought together and aligned, or ‘correlated’, to offer a far deeper understanding of the object than would be possible from one instrument alone.
Similar advantages of correlated imaging have been proposed for the life sciences. Today, stitching together data from optical and electron microscopes is common. However, linking a wider suite of instrumentation providing different data for the same structural or biochemical problem remains undeveloped.
The Correlated Imaging theme will address the primary challenges in amalgamating data from a host of different established and new imaging techniques in the life sciences, so that researchers can build a picture of their target from the centimetre scale, which could be a tumour, all the way down to the picometre scale, which could be the individual atoms within a molecular structure.
New electron optical, X-ray and focused-ion beam instruments will be built. New sample environments will be devised for multi-instrument imaging of identical samples. And new software incorporating the latest advances in big data, artificial intelligence and machine learning will be employed to integrate different data streams across all instruments and length scales.
However, innovations in correlated imaging will not be limited to improving the breadth of instruments and spatial resolution available to researchers. A key driver for the theme is also to correlate data over a wider time scale.
Central to this will be the creation of the UK’s first pulsed cryo-electron microscope. Helping alleviate the problem of radiation damage, which currently limits resolution in cryo-electron microscopy, the new instrument will also be able to record images at a million frames per second at close to atomic resolution – a step-change in performance compared to current thousand frames per second instruments. This capability will reveal previously hidden rapid dynamic events in structural biology, including how proteins change under the influence of different drug actions, or how membranes fold and unfold in different biological systems.
With clear technological outputs in mind, the Correlated Imaging theme has not only developed an instrument roadmap that plots development over the next five years, but has also secured industrial partners JEOL and Nikon. As the world’s leading electron and optical microscope manufacturers, respectively, their role will be to build the instruments that will be designed and specified by the theme’s team members.
Those team members include experts working in the life sciences, instrument physics, computer science, mathematics and many more, largely based at the Harwell Hub but also within the Institute’s university Spokes. Furthermore, collaboration and cross-pollination with the Institute’s other themes is highly likely, and in the case of the Structural Biology theme essential, where close partnership will instigate a two-pronged approach to the challenges in understanding biomolecular structure: Structural Biology advancing existing technologies and Correlated Imaging focused on new and disruptive instrument development.
Professor Angus Kirkland
Science Director, Correlated ImagingView profile
Professor Angus Kirkland
Science Director, Correlated Imaging
Angus Kirkland completed his MA and PhD at the University of Cambridge using high resolution electron microscopy to study the structures of colloidal metals. Following a post-doctoral Fellowship Angus was elected to the Ramsay Memorial Trust Research Fellowship and subsequently […]
Dr Judy Kim
Deputy Theme Director, Correlated ImagingView profile
Deputy Theme Leader
Dr Judy Kim
Deputy Theme Director, Correlated Imaging
Judy Kim is the Deputy Director of Correlative Imaging at the Rosalind Franklin Institute, Departmental Lecturer in the Department of Materials at the University of Oxford, and a Principal Staff Scientist at the electron Physical Sciences Imaging Centre of Diamond […]
Biophotonic Correlative Optical Platform (BioCOP)
Quantitative correlative imaging of biological processes has now become mission critical in the biomedical sciences. In the recent years, state-of-the-art research has repeatedly demonstrated that the understanding of living systems demands technology with the capabilities to monitor dynamic processes over multiple length- and time-scales; dissecting the functioning of living cells within their tissue microenvironment and the context of human health and disease.
Our recent work on cryo-EM ptychography (cryo-EP) demonstrated the application potential of the technique in characterising biological structure with dose-efficiency, signal-to-noise ratio, and large field-of-view. To further realise the potential of the technique, we are developing a new workflow of cryo-EM ptychographic tomography (cryo-EPT) and cryo-EM ptychographic subtomogram averaging and classification (cryoEPSTAC).
The Franklin is developing a chromatically corrected column fitted with a new Cc corrector design in conjunction with Cs (spherical) aberration correction. This instrument will also be fitted with high speed electrostatic shutters, fast direct electron detectors and a robotic autoloader. This technology will enable structural studies of thicker biological samples.
Novel liquid cells to study biological processes in situ. To fully understand biological structure and function it is necessary to study molecules in their native state. This requires imaging in liquid environments that mimic those found in-vivo. The Franklin together with University of Manchester and Kings College London are developing new liquid cell technologies for EM with biological specimens in mind.
Time Resolved Ptychography
The Franklin is developing a new double aberration corrected column (named Ruska), which will open up new imaging modes not available in conventional cryo-EM instruments. This instrument will enable structural studies of smaller molecules in native environments. By using faster direct-electron detectors and information that can be mined from full 4D data sets, we plan to explore new directions in cryo and liquid cell microscopy.
Ultra-high Speed Imaging
The team aims to deliver high speed imaging capability on the microsecond time-scale to explore the dynamical response of biological materials. A picture is worth a 1000 words, but a high-speed video is worth 1000’s of times more. By capturing dynamic events as they unfold in video, we will enable scientists with the method to analyse processes that are currently painstakingly frozen into samples step-by-step. The Harwell Hub’s electron source has been designed by the JEOL R&D team and will enable the needed electron flux for faster imaging in conjunction with direct electron detectors.