Putting proteins in focus

3D models of a HeLa cell nucleus.

3D models of a HeLa cell nucleus, generated from volume electron microscopy images by citizen scientists through the Etch a Cell project on the Zooniverse platform. Small dots illustrate how proteins may be distributed on the organelle surface using visual proteomics.

The Crick’s Electron Microscopy team has been awarded £2.7million from the Chan Zuckerberg Initiative to develop a new toolkit to help researchers understand how proteins behave within cells and improve access to imaging technologies globally. We spoke with Lucy Collinson, head of the team, to find out more.

What’s the advantage of being able to see proteins within cells?

Scientists use imaging techniques to track how proteins move and interact within cells, painting a complete picture of the interactions that underlie all cellular functions. For example, they can help us spot the differences between how proteins act in healthy and diseased tissue.

This area of science is called visual proteomics and there are a few different techniques that can be used to do this. The main two are mass spectrometry imaging, which involves gathering information about the molecular mass of different proteins at multiple points in a sample, and cryo-electron microscopy, which requires samples to be flash frozen before being examined using huge specialist microscopes. 

These are both very complicated and costly and they also have their limitations; for example, with cryo-electron microscopy, you can only image a very small volume of a cell, about one twentieth of it, so you can’t see the proteins in context.

We want to find new, simpler ways to visualise proteins within whole cells and tissues. 

How will you build your toolkit?

We want to find new, simpler ways to visualise proteins within whole cells and tissues. 
Lucy Collinson

We’ll be working with Professor Paul French at Imperial College London and Professor Ricardo Henriques at IGC and UCL to create a new toolkit for a type of visual proteomics, which combines two imaging techniques: fluorescence microscopy, which uses fluorescent markers added to the samples in order to capture particular elements, and electron microscopy, which fires beams of electrons at the sample to capture incredibly minute details. 

The combination of the two methods, which is called correlative light and electron microscopy or CLEM, requires multiple steps: labelling proteins with fluorescent markers; encasing the cells in resin; cutting this into really thin slices; imaging all the slices separately with both a light and an electron microscope and finally using computer software to merge the data. 

At the end of this process, we’re able to see proteins within the wider context of the cell — you can see exactly where they are and how they’re interacting. This provides clues as to what processes the proteins are involved in and, in the case of disease, you can see which of these processes might have been disrupted. 

What is the overall aim of this project?

Traditionally, CLEM uses microscopes that cost millions of pounds and requires very specialised expertise to operate. This means that it’s only accessible to a handful of scientists at institutes with specialist teams like our own. We want to change this and open visual proteomics up to more researchers, around the UK and across the world, who don’t have access to the advanced tools and financial resources that are currently needed to use this technique. 

We’ll ensure that our toolkit method costs a fraction of the price of traditional CLEM apparatus. It will use open source software, free to anyone who wants to use it, and will include guidance on every stage of the process, including the protocols.

How will you be testing your toolkit?

To make sure our toolkit is effective and useful for researchers, we’ll be working with Dr Sonia Gandhi, head of the Crick’s Neurodegeneration Biology Laboratory, to trial our new method in the context of Parkinson’s disease, looking at the protein interactions in neurons grown from patient cells. We’ll also be collaborating with Dr Candice Roufosse at Imperial to look at proteins in tissues that are infected with SARS-CoV-2.

Further afield, we’ll be working with Ben Loos, Associate Professor at Stellenbosch University in South Africa, who will be testing the kit in his research on degenerating neurons and brain tumours. Once it’s developed, he’ll also help in rolling the kit out across Africa. 

The electron microscopy team at the Crick already develop new hardware and software solutions for CLEM, so we are really well set up to tackle this task and share our expertise as widely as possible.  

Can people get involved in this work?

Yes! We need members of the public to help us with part of this. We need people to take part in Etch-A-Cell, an online citizen science project which asks people to look at images of cells that were produced using an electron microscope and draw lines around different parts of the cell, for example the mitochondria. The data produced will be used to help train a deep learning algorithm so that it can automatically create 3D models of cells. This will allow us to map the location of proteins within the cell. 


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