Magnetic attraction of AstraZeneca to MRC Laboratory of Molecular Biology

AZ has moved some of its equipment into world-renowned lab while its new global R&D centre is built nearby

You know what it’s like when you move offices: you have to clear your desk, empty your drawers, move the filing, transfer the nuclear magnetic resonance laboratory…

Well, that was the challenge at least for Maria Flocco, who leads AstraZeneca’s structure, biophysics and fragment-based lead generation (SB&FBLG) team.

They decided it was beneficial to make the move from Alderley Park, near Macclesfield, before the firm’s new £500million R&D centre and global HQ on Cambridge Biomedical Campus was completed.

But they had more than a pot plant and a stapler to box up – and it’s not easy finding a home for nuclear magnetic resonance (NMR) equipment.

It is used by the pharmaceutical industry primarily to study molecular interactions and can also be used to determine the three-dimensional structure of drug targets.

Maria says: “There was no space in any of the local AstraZeneca sites to host the nuclear magnetic resonance lab, so we had to look for a host site outside AstraZeneca.

“We considered all the options and decided to talk to Sir Hugh Pelham, director of the Medical Research Council Laboratory of Molecular Biology, which is also based on the Cambridge Biomedical Campus. Sir Hugh was receptive to the proposal.”

Two scientists from AstraZeneca – Kevin Embrey and Alex Milbradt – are now sited at the MRC LMB.

“Everyone knows the quality of the science at the LMB,” Maria tell the Cambridge Independent. “We have research collaborations with them and it’s fantastic to discuss ideas and learn from them. We also hope to contribute a different angle, because we have a very clear purpose to what we do.”

The NMR technique uses the magnetic properties of certain atomic nuclei to provide detailed information about the structure and dynamics of molecules.

This aids the drug discovery process, which typically starts with the search for a molecule that can interact with a protein and modulate its activity.

“To arrive at a drug, you go through iterative optimisation,” explains Maria. “In a programme you may synthesise a thousand or two thousand molecules.

“We use NMR as a tool to look at the interactions between the small molecules that we generate and the target protein. It’s an in vitro system and you can study those interactions at the atomic level of detail. You can determine the strength of the interaction and structures.

“The other use is screening very small collections of tiny molecules called fragments. These have the ability to probe very efficiently the chemical space.

“Being so small, these fragments are very weak at binding and very difficult to detect using the usual biochemical methods, so NMR is the ideal tool because it’s extremely sensitive.”

The platform supports most of AstraZeneca’s portfolio – including the key therapy areas of oncology, cardiovascular and metabolic diseases and respiratory diseases.

The move of the team and its equipment to the MRC LMB represents the latest collaboration between the two organisations.

Since 2014, they have worked on the ‘Blue Skies’ scheme, which offers investment and support to collaborative, innovative, early-stage research projects.

Proposals for Blue Skies are jointly assessed by AstraZeneca and the MRC LMB, which look to support ground-breaking projects that develop understanding of the biology of disease.

The close working between the firm and the research lab has also extended to the use of equipment.

As the Cambridge Independent has reported, the MRC LMB is home to a cryo-electron microscopy facility that is jointly owned by a consortium of locally-based scientific organisations, including AstraZeneca, and the firm’s scientists have worked side-by-side with those from the lab.

And, of course, it’s no coincidence that AstraZeneca’s state-of-the-art new site is next door to the MRC LMB, for it was the proximity to Cambridge’s research community that attracted the company to set up home here.

“It’s a fantastic eco-system,” says Maria. “The MRC LMB is a world-class research laboratory, where many of the game-changing techniques that greatly contributed to the understanding of biology at the molecular level were pioneered, including DNA sequencing, methods used to determine the three-dimensional structure of proteins and the development of monoclonal antibodies.

“The possibility of having an AstraZeneca team embedded ino the MRC LMB’s MRS facility is a great opportunity to expose our scientists to the great science ongoing at the LMB and further strengthen our existing relationship.

“The relocation of much of AstraZeneca’s research to Cambridge provides us with n opportunity to be next door to and engage with the top research institutions in the UK. These interactions strengthen our own science and our drive to excellence.”

AstraZeneca’s new buildings are due to be weather tight imminently, while its energy and data centre is now complete. In a phased process, the firm’s science groups will begin moving to the site by the end of 2018. In the meantime, the benefits of moving to Cambridge are clearly already being felt by the company.

Studying how molecules behave at an atomic level

If you should ever visit David Neuhaus at the MRC Laboratory of Molecular Biology, remember to leave your wallet outside.

For David’s nuclear magnetic resonance (NMR) instruments feature magnets so powerful that they will wipe your credit card if you get too close.

And you’ll need a serious credit card if you want to buy one: the largest on the market will set you back a seven-figure sum.

It’s enough to set your heart racing – but if you’ve got a pacemaker, steer clear.

“The requirement for housing these instrument is quite severe because the magnets are very strong,” David tells the Cambridge Independent. “You need not to have people wheeling large iron objects around…”

The laboratory has five of these in its MRS building for studying large molecules and two smaller instruments for its chemists to use.

David was brought in by the Medical Research Council in 1988 to establish the LMB’s nuclear magnetic resonance lab and has seen the magnets available get bigger and more expensive every few years.

“The biggest system we have is an 800MHz instrument – they are named by the frequency at which protons resonate,” he says.

“The magnetic field comes from a superconducting solenoid. These magnets have currents of 100 or 200 amps swirling around inside continuously against zero resistance because they are at liquid helium temperature or in some cases lower, at two degrees Kelvin.

“They stay magnets even when the electrical power to the building is off.”

The point of this massive magnetic power is to generate signals from molecules that enable researchers to study them and their interactions.

“The idea is you look for a signal from the nuclei – usually hydrogen – that have to have a particular property called spin, which makes them behave like tiny bar magnets,” explains David.

“The signal comes from the fact that when you put the material into a very strong magnetic field, those magnets want to align with the field. They only have two energy states – with the field or against it. Then it becomes like a normal form of spectroscopy: you are looking for transitions between those two energy levels – high and low.

“The magnet has to be extremely stable. When you put your sample in it, you excite the signal by giving pulses of radio waves at exactly the right frequency. You then measure the signal as it decays away.

“There are more sophisticated experiments that we do all the time where you measure not just the signals but how they interact with one another – which atoms are close together in space and which atoms are close together through the bonding network of the molecule you are looking at.”

Unlike other methods of determining the structure of molecules like X-ray crystallography or cryo-electron microscopy (cryo-EM), which are used elsewhere at the LMB, this technique doesn’t directly generate an image.

“You are working with a spectrum and in principle each chemically distinct atom gives you a separate signal at a different point in the spectrum,” says David.

“Looking at interactions, you can build up an assignment, so you know which signal comes from which atom – for big molecules that’s actually the hard part. When you know that, then experiments that tell you about close distances can be used to get you the structure.”

One advantage of NMR is that it works in solution, similar to the environment these molecules would be in naturally.

“Another advantage is flexibility,” explains David. “For crystallography or cryo-EM, flexibility is the big enemy. If parts of the molecule move around, it’s often a problem. But that doesn’t affect NMR in the same way at all. In fact in certain experiments, you can measure where the flexibility is.

“With drug discovery, flexibility can be a big part of the way a particular protein works.”

NMR is also particularly good for looking at interactions between molecules.

“That’s one of its great strengths and it’s particularly good at looking at interactions that are quite weak,” says David. “For crystallography and cryo-EM you have to prepare a sample of the complex – that is, both molecules bound together in a consistent structural state.

“NMR is quite good at looking at cases where the interaction is too weak for a complex to be a species you can isolate in its own right.”

The technology can be used to understand better how molecules within the body interact, which can lead to drug development.

“AstraZeneca will look at drugs interacting with molecules from the body, particularly proteins. We are interested in both small molecules, which can be drugs or natural small molecules like hormones or small peptides, interacting with proteins. We are also interested in proteins interacting with DNA and RNA,” says David, who added that housing AstraZeneca’s instruments was a natural fit for the lab.

One project within David’s research group in the lab, supported by Blue Skies funding, concerns a protein called PARP – poly (ADP-ribose) polymerase.

“That’s a molecule that detects DNA damage – in particular where the DNA has a break in one of the two strands,” says David.

“When it detects the damage, it makes this polymer, which acts as a signal that basically says ‘Here is damage, please come and repair it’.”

Stopping this repair process using drugs called PARP inhibitors is useful in cancer therapy.

“The reason why inhibiting the DNA repair is a good idea is that it turns out, for quite a few types of cancer, the thing that distinguishes the cells as being tumourgenic is that they are already deficient in a different DNA repair pathway.

“So if you then knock the PARP-dependent DNA pathway as well, those cells die. This idea is called synthetic lethality.”

In other words, a drug can be used to kill tumour cells by stopping them from being repaired by the body’s natural processes.

With even bigger magnets in the pipeline, NMR is likely to remain a useful tool in the armoury of scientists trying to understand such biological processes for some time to come.