LASER ANALYTICS GROUP

We design optical microscopes, sensors and analytical methods to study neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and other biomedical processes, in higher resolution than previously thought possible.

The challenge Many processes in molecular biology, and throughout medical and materials science, are only observable with the aid of new, cutting-edge technologies such as super-resolution microscopy. In particular, the advanced analysis of the mechanisms of neurodegenerative diseases is crucial if we are to find cures for them.

Our work in tackling thisWe develop super-resolution microscopes to examine diseases in much higher resolution than previously possible. We use these techniques to answer questions such as: what are the toxic proteins, such as aβ42, that lead to neurodegeneration in Alzheimer’s disease? How do these agents traffic from cell to cell? How can we inhibit the aggregation or infectivity in neurodegenerative diseases through the application of small molecule drugs?

Methodology The central them of our work is the development and application of modern laser spectroscopy and imaging methods to elucidate the details and dynamics of chemical processes. These range from basic chemical processes to the molecular mechanisms of disease. We conduct our work on live cell models.

Our work uses cutting edge techniques, including the extensive use of super-resolution microscopy and optical nanoscopy. These methods are based on the Nobel Prize winning work of Betzig, Hell and Moerner (Chemistry, 2014). Recently, we have pioneered the use of direct stochastic optical reconstruction microscopy (dSTORM) for direct optical super-resolution imaging of the protein fibrils in neuronal cells.

Our research is highly interdisciplinary in nature: we are a team of and physicists, neurobiologists, chemists, biophysicists and medics working together. Much of our work is performed within the Wellcome Trust/MRC-funded Neurodegenerative Disease consortium.

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Super resolution: left are HSV-1 viruses imaged with a conventional microscope; right with our super-resolution microscopy (dSTORM).

Fluorescent: combined lens beams induce a photoswitching fluorescent state for the dSTORM microscope.

New: we invented Ellipsoid Localisation Microscopy (right) to measure the protein layers on bacterial spores used in vaccines, compared to using conventional microscopy (left).

The group is also a member of the Cambridge Advanced Imaging Centre, and the OpenLabTools initiative. We also lead strategic initiatives such as the CamBridgeSens strategic research network to unite sensor research across the University of Cambridge, and the EPSRC Centre for Doctoral Training in Sensor Technologies.

Applications we are currently working on1. Understanding the molecular mechanisms of disease

We use a range of advanced biological and biophysical methods to probe the molecular chemistry of disease in live cells and in animal models. Currently a major focus is on the study of protein misfolding and aggregation in neuro-degeneration.

2. Developing microscopy We perform both experimental and theoretical work to optimise

the speed, resolution, and sensitivity of microscopy for applications ranging from single molecule biophysics to whole organism imaging.

3. Sensing molecules We model and generate supercontinuum radiation in optical fibres

for applications in chemical sensing using instruments that are optimised for sensitivity and speed. This provides us with advanced tools for microscope development, and is related to work that we have used to study the internal structure of viruses.

Our techniques and skills• Biophysical analysis and molecular mechanisms of

neurodegeneration• Molecular and cell biology • Microscopy development (TCSPC, tgFLIM, light sheet microscopy)• Super-resolution imaging (PALM/STORM, STED/RESOLFT, SIM/mSIM)• Image analysis software development

What is new about our work? We work at the interface of sensing and imaging technology with molecular biology. We have published our original studies on the use of super-resolution microscopy to study neurotoxic protein interactions at a molecular level. Our collaborations with internationally leading biomedical researchers at Cambridge provides unique opportunities for us to develop new instruments and apply them to current research challenges.

Current industrial partnershipsThe group is a member of several consortia within the University and beyond. Our sponsors include the Wellcome Trust, MRC, Alzheimer’s Research UK, Leverhulme, Swiss National Science Foundation and China Scholarship Council. We also have many industrial partners through the Centre for Doctoral Training in Sensor Technologies. For details of these, visit: http://cdt.sensors.cam.ac.uk/about-cambridgesens-cdt/industrial-partners.

Prof Clemens Kaminski (Head of Group), Dr Oliver Hadeler (CamBridgeSens and Sensors Centre for Doctoral Training), Dr Eric Rees (Quantitative Imaging), Dr Gabrielle Kaminski-Shierle (Biochemistry)Laser Analytics Group, Department of Chemical Engineering and Biotechnology, CambridgeWeb: www.laser.ceb.cam.ac.uk

The team

LASER ANALYTICS GROUP continued

White light: generation of supercontinuum ‘white laser light’ for spectral-imaging and time-resolved spectroscopy. Supercontinuum light enables advanced imaging at any wavelength.

All in the detail: super-resolution images (top images) reveal the shape of toxic protein fibrils not visible in conventional imaging (middle images). Fibril structure varies with its position in the cell (grey).

Fluorescent lifetime imaging of protein aggregation.

Virus close up: our techniques allow us to measure the structure of viruses.