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Looking at life in molecular detail

The University of Leeds played a key role in the birth of structural biology as a scientific discipline. Now, a £17 million investment in some of the best nuclear magnetic resonance and electron microscopy facilities in the world is ensuring that Leeds stays ahead of the field.


To a bystander, the tarpaulin-covered load on the lorry edging its way through central Leeds on a misty morning in late September would have seemed unremarkable enough. A new machine for a factory production line, perhaps?

For Dr Anastasia Zhuravleva, however, it represented nothing less than a revolution.

“We are at a time now in structural biology when we are starting to be able to see things, and understand things, that a few years ago were completely out of our reach,” said Dr Zhuravleva, a lecturer in Molecular and Cellular Biology in the University’s Astbury Centre for Structural Molecular Biology. “And that is largely down to equipment like this.”

The 950 MHz Bruker nuclear magnetic resonance (NMR) magnet painstakingly unloaded into a specially designed facility in the University’s Astbury Biostructure Laboratory on September 29 is one of the most powerful in the world and, when fully installed, will be the most advanced equipment of its type in the UK.

“For the first time we are seeing the real life of proteins; not just a few relatively simple molecules, but complex proteins—the key molecules that make cells and disease work,” Dr Anastasia Zhuravleva

It joins the Astbury Centre’s newly upgraded 600 and 750 MHz NMR machines and will soon be followed by two state-of-the-art FEI 300 kilovolt cryo-electron microscopes (EM) to add to existing 120kV and 200kV systems.

The flurry of esoteric equipment names has a simple meaning for researchers in the Astbury Centre: an unprecedented ability to glimpse the processes of life in atomic detail.

“For the first time we are seeing the real life of proteins; not just a few relatively simple molecules, but complex proteins—the key molecules that make cells and disease work,” Dr Zhuravleva said. “And we are seeing them not only as a few snapshots, but as dynamic systems. This will transform our scientific understanding and will also allow us to tackle diseases in new ways.”

How does NMR work ?

To bring the new 950 MHz magnet up to power, researchers will first start cooling down with liquid nitrogen at close to -200 degrees centigrade and then continue with even colder liquid helium.

The whole process, taking several days, will bring the temperature in the instrument’s core close to absolute zero (to about -270 degrees centigrade), bringing atomic movement almost to a halt.

Professor Alex Breeze, Professor of Biological NMR, who is overseeing the installation of the 950 MHz magnet, said: “At the centre of the vessel, we have a coil of superconducting wire. Once we are down to near absolute zero, we will be able to start to trickle current into it very slowly and, eventually, ramp that up to well over 200 amps. Because the wire becomes superconducting at those very low temperatures, we can take the power supply away and the current will continue to circulate, essentially, forever because there is no electrical resistance. That current will create the extremely strong magnetic field that is at the heart of an ultra-sensitive NMR system.”

It is a delicate process. If the wire moves even minutely, generating a tiny amount of heat, the researchers can expect a “quench”: thousands of litres of expensive liquid helium bursting into the atmosphere in an instant. (“Enough gas to fill 480,000 children’s balloons suddenly flying straight out into space,” Research Fellow Dr Gary Thompson said). But, if everything goes to plan, Leeds researchers will have privileged access to one of the most advanced NMR magnets in the world. It will be fully operational in just a few months.

“Essentially, NMR is a close cousin of the MRI scanners in hospitals but, instead of looking at organs, we are looking at individual atoms and molecules, and we’re even starting to be able to do that inside living cells. We are searching for signals—‘resonances’ —from the nuclei of those atoms when they are in our magnetic field,” explains Professor Breeze.

“Each type of nucleus is a bit like an individual radio transmitter broadcasting a particular station: a hydrogen nucleus might ‘sound like’ Radio 1 and a carbon atom might ‘sound like’ Radio 4, providing different types of information. We are able to ‘listen to’ these resonances and build up a dynamic picture of the position of each atom and how it is interacting with other atoms.”

The more powerful the magnet, the closer researchers can zoom into the structure and motions of complex biological molecules. Add to that other advanced features of Leeds’ new magnet, and you have a transformation in the capabilities of the Astbury Centre.

Dr Zhuravleva said: “As well as cooling down the core, this system is also cooling the electronics that record the signal to extremely low temperatures to reduce noise. Overall, we are looking at improvements by a factor of 10 compared with our previous capability.”

Professor Sheena Radford, Astbury Professor of Biophysics and Director of the Astbury Centre, said: “For us, this is the first step on the way, but it is a very big step. We are investing in the very best equipment because it will allow us to bring the most talented people to Leeds and allow the people we have to do the best science.”

New insights

For the researchers at the Astbury Centre, the new 950MHz NMR instrument will be transformative.

Dr Edwin Chen arrived at Leeds from Harvard Medical School this year to take up a University Academic Fellowship. His research focuses on understanding how a mutated version of a protein called calreticulin causes myeloproliferative neoplasms, an important type of adult leukaemia.

#Dr Edwin Chen, University Academic Fellow in Molecular Mechanisms of Cancer Biology

“This is a protein that has never before been implicated in cancer, so might indicate a novel cancer-causing paradigm,” said Dr Chen. “Nobody knows how it is causing the disease, nobody even knows how this whole class of proteins could be causing cancer. Our hope is that we can use this new NMR equipment to try to understand how the new mutant protein works.”

“The facilities and culture at the University of Leeds are geared towards that central challenge: trying to grasp the basic biology that is causing these diseases” Dr Edwin Chen

Calreticulin is difficult to study because its disordered structure makes it impossible to analyse using traditional X-ray crystallography techniques, which pack proteins in crystals. That makes NMR’s ability to look at disordered and dynamic systems, and monitor how different proteins interact uniquely valuable.

Dr Chen added: “The new NMR capabilities will be important not just for this project but across a whole range of investigations. The current situation in my area, cancer research, is that we now know of hundreds of different mutations in lots of different cancers, but there has been a massive lag in our understanding of what these mutant proteins are doing biologically. The facilities and culture at the University of Leeds are geared towards that central challenge: trying to grasp the basic biology that is causing these diseases.”

Dr Darren Tomlinson, another University Academic Fellow, sees similar benefits for his research into designing artificial molecules to target and neutralise cancer-causing proteins.

He said: “My research focuses on looking at the molecular processes that cause cancer and how we can modulate these using a new technology we have developed at Leeds—the Adhiron©. These are small artificial proteins that have the ability to bind to other proteins. We have created a library of billions of these molecules. When we identify molecules that are binding to and inhibiting cancer-causing proteins, we need to understand how they are working at a molecular level so that, hopefully, we can develop new drugs.

Dr Darren Tomlinson, University Academic Fellow

“The new NMR and EM facilities in the Astbury Biostructure Laboratory offer us the ability to look at these processes in unprecedented detail and that could be the difference between knowing and not knowing how a particular molecule is binding to a cancer protein and, therefore, being able to understand how we can use it.”

Dr Zhuravleva, who moved to Leeds two years ago from the University of Massachusetts at Amherst, is researching chaperone proteins—an important class of “quality control” molecules which ensure that other proteins in the body fold up correctly so that they can do their jobs.

“This configuration, or folding process, is what goes wrong in conditions like diabetes or neurodegenerative diseases such as Alzheimer’s and Parkinson’s,” she said. “The proteins start misfolding and aggregates of the proteins start to build up, which cause disease.

“The chaperone proteins could prevent these aggregations or be used to pull aggregates apart, but the problem is they operate in very complex networks. Using traditional techniques, we might be able to solve the structure for a particular protein, but we need to know how it interacts with other proteins to understand how health and disease result from protein folding and misfolding events.

“The new 950 MHz NMR offers us the ability to use samples at concentrations very close to those in the body. Previously, we were having to use highly concentrated samples—but you can’t understand how a system works if you have to change its constituent parts. It is a bit like trying to understand how a football match works with 110 players on each side. Now, in many samples, we can aspire to look at our equivalent of 22 players on the pitch.”

A bigger story

The investment in the Astbury Centre for Structural Molecular Biology is the latest chapter in a proud history of structural biology at the University of Leeds. Indeed, the discipline has its roots at the University, with the development of X-ray crystallography by Nobel Laureates William and Lawrence Bragg in Leeds in 1912-13.

The technique allowed scientists to investigate the structure of crystalline materials at an atomic level for the first time and won William Henry Bragg, Cavendish Professor of Physics at the University of Leeds, and his son William Lawrence Bragg, a researcher in Cambridge, the Nobel Prize for Physics in 1915.

By the 1920s, scientists were starting to peer into the structures of biological structures and the Leeds professor William Astbury, after whom the Astbury Centre for Structural Molecular Biology is named, played a leading role in the development of the science. Recruited to Leeds in 1928 to investigate the molecular nature of wool, he demonstrated that the techniques of physics could revolutionise biology. His early studies of the structure of DNA formed part of the basis of Watson and Crick’s later work. The Nobel prize winner Max Perutz described Astbury’s laboratory at Leeds as the “X-ray Vatican.”

That reputation has grown in the modern era into comprehensive strength across structural biological techniques, including electron microscopy, NMR, X-ray spectroscopy, the most advanced light microscopy and mass spectrometry methods. The Astbury Centre today is a key strategic priority for the University.

Professor Breeze, who joined Leeds last year from a position as Principal Scientist in Structural Biophysics at AstraZeneca, said the investment had underlined to him how strong a priority it is.

“Six months ago, I was part of a small team in Astbury who got together to think about how we could take the centre to the next level,” he said. “We asked ourselves, ‘What is it that we need to do to transform our capabilities?’ and we came up with a plan to invest in two key technologies: NMR and EM. We took these plans to the University’s leadership and it has been amazing to witness the speed of response. We first sat down in April. Here we are in October installing the first of the major items of kit that make up a £17 million investment.”

For Dr Zhuravleva, that institutional support across structural biology disciplines translates into a rich research environment.

Dr Anastasia Zhuravleva, Lecturer in Molecular and Cellular Biology

“The power of Leeds and the Astbury Centre is that we have strength in many structural techniques, all located in one place. This adds to our great strengths in chemistry, physics, cell biology and other methods and is not a very common situation. Usually you have a very good NMR facility or a very good cryo-EM facility or a very good X-ray facility, but if you want to tackle the most challenging problems in structural biology, you need to be able to combine these techniques at the most advanced level,” said Dr Zhuravleva.

“Of course, we have always had access to the national centres such as the NMR facilities at The Francis Crick Institute in London and the Diamond Synchrotron at Harwell. These are excellent resources but, in reality, you often need time to develop the most difficult and exciting approaches, and trying to do that in an external centre can be very hard. At Leeds, we now have in-house access to best facilities in structural biology and we also have the leading researchers down the corridor. You don’t need to travel to Europe or the USA to find your collaborators—you can talk to them over lunch”.

Professor Radford added: “These are exciting times for us as researchers, but I think they are also exciting for wider society. The bottom line is that the more we can understand the fundamentals of the biology of our bodies, the more opportunity there is to understand clever ways of intervening and changing lives.”

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