The Cryo-electron Microscope, or Cryo-EM, is a Titan Krios G2 model manufactured by FEI, the world leader in developing this type of microscope.
It enables us to build up a 3D image of complex proteins at incredible resolution. This kit ‘averages’ the images of say 100,000 individual molecules. By imaging an object in many orientations to computationally construct a 3D model, you then know what the molecule looks like and can see the biological mechanism of how it works.
This enables us to study complex proteins at a tenth of a millionth of a millimetre in scale. It means we can directly image single molecules using electron beams. The protein is frozen in a thin, single-molecule thick, layer of vitreous ice. Advances in camera technology allow very low noise imaging from single molecules, meaning that images are clearer and higher resolution.
Cryo-EM enables us to study complex proteins at a tenth of a millionth of a millimetre in scale
In 2 days it can collect 3000 images, previously 50 per day
One of only 100 in the world
Dramatically improves image quality and resolution of molecules
We can study molecules of a complexity it has not been possible to see before
Easy for scientists to use and high throughput relative to previous techniques
Real-time imaging readouts - at a speed of 400HZ
Automatically corrects for instability of image - multiple conflations of the protein image are created simultaneously
A scientist's perspective
Chris Phillips Associate Director, Discovery Sciences
What is the key function of this equipment?
Cryo-EM allows us to determine near atomic resolution models of complex protein molecules. You can directly image individual molecules, using a focused electron beam, and from the 2D projections obtained build a 3D object – by imaging an object in many orientations you can construct a 3D image – you then know what the molecule looks like and can understand how it functions casting light on important biological mechanisms. Images from say 60,000 individual molecules are used to computationally build a 3D model.
The signals we are detecting to generate these images are extremely low in frequency, this means that the cameras we are using must have exceptionally low ‘noise’ levels (ie background signal) or we would not be able to see the signal we are looking for above the noise.
Why did AstraZeneca invest in it?
This technology means we can accelerate the development of new chemical entities to bring potential new medicines to patients.
Who uses it?
Cryo-EM is used by the Discovery Sciences team at AstraZeneca together with several collaboration partners as part of a Cambridge area consortium of five pharma companies, the Laboratory of Molecular Biology/Medical Research Council, the University of Cambridge, and FEI (the leading microscope company) to give access to this state of the art technology.
Can scientists from outside AstraZeneca use it?
As well as our academic consortium partners the University of Cambridge and the MRC/LMB, the technology is also available to scientists in GSK, UCB, Aztecs and Heptares as well as AstraZeneca. This shared cost model allows us to access the very highest level technology in a pre-competitive manner.
How does it help AstraZeneca achieve scientific leadership?
Cryo-EM is revolutionising structural biology allowing us to resolve the structures of complex macromolecular machines for the first time. High resolution structures of our target proteins have previously only been available through crystallography but many molecules of high interest to the pharma industry, such as integral membrane protein, can’t be crystallised. Cryo-EM allows us to investigate the biological mechanisms underlying disease states and design potential new drugs based on this knowledge.
What have we achieved that we could we not have done without it?
Single molecule cryo-electron microscopy is changing the structural world. The last few years have seen technical advances that have enabled a step change in the capability of electron microscopy and there are now an impressive number of high resolution protein structures that have been determined by this technique. For the structural biologist this is transformational, as many target proteins important to drug discovery, such as integral membrane proteins or large multicomponent macromolecular machines, now become accessible for study for the first time.
This technology has already allowed a group of leading structural biologists in Cambridge to uncover ground-breaking insights into a prime therapeutic target in cancer, recently published in Science Advances.
Has this kit been used in any notable discoveries or activities in IMED/AstraZeneca?
In collaboration with the MRC Laboratory of Molecular Biology we have applied this technology to define the world’s first protein structures for human ataxia telangiectasia mutated (ATM). ATM is a key trigger protein in the DNA damage response and a prime therapeutic target in cancer.
The LMB Cambridge are world leaders in this field and many other high impact studies have come out of this institution.
Find out more here about single molecule science.
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