Better living through microscopy


A revolution in electron microscopy will help researchers understand life in molecular detail

Scientists at the University of Leeds are about to launch a game-changing move in the battle to eradicate diseases as diverse as Alzheimer’s, cancer and flu.

Thanks to a multi-million pound investment from the University and the Wellcome Trust, two of the most powerful cryo-electron microscopes in the world have been installed in the University’s Astbury BioStructure Laboratory.

The microscopes, which operate using a stream of electrons rather than light to display images, will allow researchers from across the University and around the world to view biological systems in unprecedented detail.

Neil Ranson, Professor of Structural Molecular Biology at the University’s Astbury Centre, is leading the new microscope initiative.

He said, “Cryo-electron microscopy has been around for 30 years and has been incredibly useful, but until recently the technology lacked the ability to routinely look at molecules at the level of detail needed.

We’ll be able to see the structure of molecules that cause everything from a simple sneeze to cancer.

Professor Neil Ranson

“Without that detail, we sometimes struggled to understand the structure of biological molecules and how they function, especially when they are in their normal workplace: inside our cells.

“However, the Titan Krios microscopes we have installed in Leeds are absolutely state-of-the-art, and mean that these limitations have been shattered. Researchers will now be able to image biological molecules with an incredible resolution. Crucially, we’ll also be able to see how these molecules interact with each other.”

BBC report on the benefits the new microscope technology will bring to Leeds.

In ideal circumstances this can mean atomic resolution, where scientists can see the position of every atom in a large protein or complex. This is exactly the kind of detail required to see how medicines bind to proteins, and to help researchers design new or better drugs.

Professor Ranson continued: “These microscopes are a genuine game-changer. The work we will now be able to carry out in Leeds will open up new avenues of research that we’re only just beginning to get to grips with."

The University’s two electron microscopes will enable researchers to:

  • Deliver new insight into how proteins aggregate and how this process causes neurotoxicity, which is fundamental to understanding diseases like Alzheimer’s and Parkinson’s.
  • Understand how viruses are built, and how they get into and out of our cells – key steps for infection.
  • Provide new details on how ion channels and transporters work – proteins which are vital for a huge number of diseases including many cancers and cardiovascular diseases.

“The old maxim of ‘one drug for one bug’ is outdated,” Professor Ranson said. “We need to understand and tackle ever more complex, multifactorial disorders.

“Science needs to look deeper into the cell to see the structure of biological molecules, how they change shape to do their jobs, and how they interact.

“If you know how a protein complex changes shape when it starts to carry out its function, it then becomes possible to think about how we could stop it in its tracks, or manipulate it to limit its destructive behaviour.

“Bringing the incredible resolution of our new electron microscopes together with the real time information on how proteins move made possible with the new Nuclear Magnetic Resonance (NMR) facilities is a unqiue opportunity for biomedical scientists.

“This is not just imagery and information for its own sake. This kind of detail will, for example, be able to see the structure of a virus invading a cell using cryo-EM, and be able to tell which parts of its receptor are important for that binding using NMR.

“Understanding is key to eventually manipulating these interactions, and we aim to create a revolution in biological and medical insights and inform future discovery of new medicines.”

Official opening

The microscope suite is part of the Astbury Biostructure Laboratory, which was opened in January 2017 by Dr Jeremy Farrar, Director of Wellcome.

After officially launching the new centre Dr Farrar said: “There’s no doubt that in the areas Leeds has chosen to focus on, it is world-leading. The new investment and the new people coming in from all over the world are pushing research to a new level.

“We have never been able before to look at protein structures and cells and how proteins work at this level, and this will open up areas we have not even thought about yet. These are huge opportunities for students and people early in their careers, it is linking all of that fundamental science with a real understanding of biology, physics, chemistry and computer science.”

He said Leeds was ‘right at the very frontier of science’, adding: “This is the University of Leeds being out in front and playing a world-leading role, and whether that’s in areas of infection, or cancer or diabetes and other diseases, it’s at the forefront of where science is today and where it will be tomorrow, linking science into the clinic and the hospital and that is what is so exciting.”

Benefits for students

The microscopes will allow research at the cutting edge of biology and medical discovery. Students at all levels will also pick up the excitement of this pioneering research.

Professor Ranson said: “Experience of working with this data should give Leeds’ students a real advantage when they graduate and embark on their own research careers. This is a really hot area in drug discovery, and all of the major pharmaceutical companies are now doing cryo-EM.”

Postgraduate students will be able to use the microscopes in their own research, while undergraduates will have direct access to the data created on the machines by their lecturers, whose research-informed teaching will improve their studies.

Creating a data tsunami

The direct electron detecting cameras fitted to the Titan Krios microscopes will produce an avalanche of data: around four terabytes of information per day each. The University has just installed 2.6 petabytes of computer storage to accommodate this unprecedented volume of data.

One megabyte

is the equivalent of

  • 4x 200 page books

One gigabyte

is the equivalent of

  • 4,473 books (200 pages)
  • 1x 650MB CD

One terabyte

Approximately six hours data from each microscope is the equivalent of

  • 4,581,298 books
  • 1,613 CD's

One petabyte

is the equivalent of

  • 4,691,249,611 books
  • 1,651,910 CD's

Astbury Centre

The Astbury Centre for Structural Molecular Biology at the University of Leeds is named after biophysicist WT Astbury who originally identified the two major recurring patterns of protein structure and took the first X-ray fibre diffraction pictures of DNA in 1938. WT Asbury worked at Leeds from 1928-1961 and is widely credited with the definition of the field of molecular biology.

Professor Sheena Radford FMedSci, FRS, the Director of the Astbury Centre for Structural Molecular Biology which includes the Astbury BioStructure Laboratory, said:

“The investment in the two Titan Krios microscopes, together with enhancements in our ability to interrogate proteins using nuclear magnetic resonance techniques has ensured that the long history of the University of Leeds in leading structural biology research internationally will continue apace.

There is enormous demand in the field for access to these microscopes, and we anticipate that they will be highly sought-after by the scientific community

Professor Sheena Radford FMedSci, FRS

“There is enormous demand in the field for access to these microscopes, and we anticipate that they will be highly sought-after by the scientific community. We want to grow our research, and a brilliant way to do that is build new collaborations with scientists from academia and industry across the world.”

At Leeds, the two microscopes will become an essential part of the work of the Astbury Centre. They will be installed in a multi-million pound renovation of a former television studio in the grade II* listed Roger Stevens building.

They will be used alongside a recently acquired 950MHz nuclear magnetic resonance (NMR) magnet to allow unrivalled insight into the structure and behaviour of biological molcules.

Factfile

  • Two Titan Krios G2, 300kV electron microscopes
  • Approximately £3.5m each
  • Built by FEI in Eindhoven, Netherlands.
  • One is fitted with an FEI Falcon3 camera
  • One is fitted with an FEI Falcon3 camera and a Gatan energy-filtered K2 Summit camera and a Volta-potential phase plate
  • Both optimised for 24/7 automatic operation
  • Each produces 3-5 terabytes of raw data per day

Viewpoint

Dr Rebecca Thompson completed her PhD at Leeds in 2015, and is now the University’s Cryo-electron Microscopy Support Scientist. She is one of a small number of staff who will have direct access to the inner workings of these delicate machines.

“These microscopes will enable us to do cutting-edge research, with all the positive knock-on effects for early career researchers that comes with it. This is a rapidly growing technique so having these facilities at Leeds means PhD students and post-doctoral researchers can take advantage of the data produced on campus, and that’s very valuable.

We can now look inside a cell, watching biology in situ doing its job in its normal environment, which is a very crowded and busy place. That is the pinnacle, you cannot get better than that.

Dr Rebecca Thompson

“There is research we can do using these microscopes which is just not possible on other equipment. There will be very few places in the world where you can do this science.

The wavelength of electrons is much shorter than that of light, meaning that an electron microscope can operate at much higher magnification, and resolve much finer details.

Together with the fact that the electrons go straight through the sample being studied scientists can work out the 3D structure of molecules which is impossible with a light microscope.

The “Cryo” in cryo-EM means imaging biological samples that have been snap-frozen in liquid nitrogen at temperatures of minus-196C. This traps and protects the molecules in a very natural environment – essentially a slice of solid water - ideal for studying biological systems.

“The difference in resolution is the equivalent of someone with extensive blurred vision looking at an optician’s chart to read the letters, then wearing a pair of top-of-the-range glasses and seeing the shape of the dot of the letter i in crystal-clear detail.”

Researchers across the UK already have some access to cryo-electron microscopes through Diamond Light Source, the Crick Institute and the Laboratory of Medical Biology at Cambridge, all of which are primarily research institutions.

Leeds is the first university to have these microscopes available to its own postgraduate students.

There are fewer than 10 of these microscopes in the UK, and the decision to create the Astbury BioStructure Laboratory to host two of the most advanced means Leeds students and academics will benefit significantly from having the equipment on campus.

Dr Thompson continued, “Leeds is going to go from strength to strength in this field, we have experts across structural, chemical and cell biology and light microscopy and we have these brilliant microscopes. The most amazing thing is combining this together: that’s not something you can do in very many places at all.”

Learn about the Astbury BioStructure Laboratory