Optical super-resolution microscopy

Academic lead: Professor Christian Soeller

Our research focus is strongly technology driven and adoption of the latest imaging methods is a major thrust to enable qualitatively new insight. A current emphasis is on non-diffraction limited optical microscopy termed 'optical super-resolution microscopy' or ‘nanoscopy’ that promises resolution down to the nanometer level with the specificity and high contrast of fluorescent labelling. These nanometer resolution optical methods are motivated by the wish to clarify the structural and functional changes underlying fundamental cell biological processes with a particular emphasis on cardio-myopathies and other muscle related conditions.

For many years it had been assumed that fluorescence imaging is of little utility in revealing the detailed distribution of proteins at the nanometer scale, a view that has greatly changed since the recent introduction of practical optical “super-resolution” methods. There are now a variety of fluorescence super-resolution approaches that can resolve nanoscale detail in biological structures. None of these methods invalidate the “diffraction limit” as first formulated by Abbe but they provide effective workarounds to overcome it. Most importantly, these super-resolution imaging techniques are “far-field” methods (as opposed to optical “near-field” methods, such as TIRF) which allow the study of samples far away from the objective and other interfaces (e.g. the coverslip) relatively deep within cells and tissues.

These new approaches allow us to obtain near-molecular scale data of biological cells and tissue. Such data is crucial to improve our understanding of basic biological and biophysical processes and will in the future enable the construction of data-driven detailed mathematical models.

In our laboratory we use and further advance super-resolution techniques that are based on localisation microscopy, i.e. single molecule imaging based approaches known under acronyms such as PALM or STORM. We have pioneered their use for the study of structures and proteins in heart muscle cells. Our interest in heart muscle cells is based on both their importance as the main force producing cell type that powers the heart as a pump but more importantly because of its interest as a prototypical biophysical system that is complex, non-linear and depends critically on nanoscale structure.

We conducted the first molecular scale resolution imaging of ryanodine receptors (RyRs) which are the intracellular calcium release channel whose regulation is critical for heart muscle activation. Several of our projects are focusing on using our advanced imaging methods to reveal the organization and dynamics of these and related proteins in cardiac myocytes with the goal to advance our biophysical understanding.

In addition, we investigate and model other excitable and non-excitable cell types using advanced fluorescence imaging, quantitative image processing and mathematical modeling. This work is conducted collaboratively with colleagues across several colleges in Exeter (including Biosciences and the Medical School) as well as a network of national and international collaborators.