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Microscope hackers

Today we announced funding for the Next Generation Optical Microscopy Initiative, a £25.5m investment from three research councils for scientists to create or house technology that pushes the boundaries of microscopy. They’ll be using the techniques to peer more closely at cells and the processes that bring about disease. Here we take a look at just one of the 17 projects, which aims to combine electron and light microscopy to image living cells in minute detail.

(Copyright: University of York)

(Copyright: University of York)

It might not look very pretty, but this grey image represents a step towards something of a holy grail for researchers. It’s an image of proteins within a cell taken with a combination of an electron and light microscope, a technique that scientists at the University of York and the Cancer Research UK (CR-UK) London Research Institute are about to take one step further and use on living cells.

Normal light microscopy uses simple lenses and visible light to magnify samples, while more advanced fluorescence microscopy uses particular wavelengths of light to excite fluorescent dyes in the sample. For example, researchers might tag a particular type of protein with a green dye so they can see where it is in the cell. But the resolution of light microscopy is limited, so researchers see proteins as clumps rather than individuals. Resolution is the shortest distance between two points that a microscope can see as distinct objects and depends on — and is therefore limited by — the wavelength of light.

Electron microscopy, on the other hand, can achieve a higher resolution than light microscopy because it uses electrons rather than light to examine the sample, and electrons have a wavelength around 10,000 times smaller than visible light. While this means it can produce stunningly high magnification images, it requires that samples are treated by freezing or dehydration, for example, and the samples must be imaged in a vacuum so that air doesn’t scatter the electrons — impossible conditions for looking at living cells.

Now Peter O’Toole and his colleagues are going to combine electron and light microscopy to get the best out of both techniques and look at cells in a more natural environment. The microscope, a modified off-the-shelf instrument, will use electrons rather than light to excite new types of coloured dyes that are able to fluoresce. This means Peter and his colleagues can identify proteins in different states effectively colouring in images like the grey one above.

Crucially, the imaging doesn’t need to take place in a vacuum as the sample can be placed in a special petri dish with a window that can allow electrons through, meaning that researchers can watch cellular processes in live action and can prepare their samples in the usual way.

“We’re going to make it very easy to use,” says Peter. “We want any biologist to be able to walk up to this system and use it — the only minor difference is that they have to grow the cells in a specific type of petri dish!”

Meanwhile, Lucy Collinson at the CR-UK London Research Institute will be going in the opposite direction and placing a light microscope within the electron microscope itself. These two different approaches will complement each other and use many of the same dyes.

The techniques will be used in research in a range of disease areas, from neuroscience to cancer, to provide unprecedented detail on proteins, the cell structures they’re associated with, and how their behaviour changes when scientists intervene.

The system will be the first of its kind in Europe and Peter is sure it’ll prove popular. Here’s hoping they’ll be a few more researchers with these not particularly pretty images hanging on their walls in the near future.

Katherine Nightingale

The project is led by the University of York and the Cancer Research UK (CR-UK) London Research Institute. It has been funded by £1m from the Next Generation Optical Microscopy Initiative (funded by the MRC, the Biotechnology and Biological Sciences Research Council and the Engineering and Physical Sciences Research Council) with additional funding from the University of York, CR-UK and commercial collaborators.

 

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