Set up last December in the Department of Chemistry, the Cambridge-Elan Centre is a joint enterprise between the University and pharmaceutical firm Elan. Dedicated to research into innovative therapies for Alzheimer’s and Parkinson’s diseases, it is a prime example of the value of basic science, interdisciplinary research – and the odd lucky break

“One has to accept that collective efforts are essential in order to make significant contributions to very complex problems. Cambridge attracts bright people but it also takes openness to do collaborative research. We are extremely lucky because our group shares this aptitude”

Professor Michele Vendruscolo

Every 3.2 seconds, someone in the UK is diagnosed with dementia, and one in three people alive today aged over 65 will die with a form of dementia. More than 820,000 Britons have dementia, a number set to increase as we live longer.

According to Professor Chris Dobson who, together with colleagues Professor Michele Vendruscolo and Dr Tuomas Knowles, has established the centre: “Neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases arguably represent the greatest challenges to the social fabric and healthcare systems of much of the modern world.”

Yet despite the huge personal, social and economic impact of these diseases – they cost the UK economy more than £23 billion a year – just 2.5 per cent of the government’s medical research budget is spent on dementia, compared with 25 per cent on cancer, whose costs are about half of those of dementia. According to the Alzheimer’s Research Trust combined government and charitable investment in dementia research is 12-times lower than spending on cancer research. “£590 million is spent on cancer research each year, while just £50 million is invested in dementia research,” the charity says.

Explaining this disparity is difficult but, says Professor Dobson, taboo and the age groups hardest hit by these diseases may play a role. “It could simply be that dementias were originally considered as part of the normal ageing process, and so were not considered to be as important to understand as diseases that hit the young,” he says.

“Moreover, there is still a reluctance to talk about them openly because relatives and friends naturally find the symptoms enormously upsetting”.

Although as yet there is no cure, Dobson, Vendruscolo and Knowles are helping build up a detailed picture of the molecular basis of these diseases – a knowledge that they hope can be exploited to develop therapeutic interventions through the collaboration with Elan.

Only in the past 20 years or so have researchers realised that aberrant protein behaviour plays a central role in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Creutzfeldt-Jakob, Motor Neurone and Huntington’s diseases – as well as other seemingly unrelated conditions. “One of the most important findings has been that many neurodegenerative diseases seem to have very similar underlying molecular origins,” Professor Dobson explains. “Perhaps more remarkable is that the same processes are also responsible for a variety of non-neurological disorders with quite different symptoms, such as type-2 diabetes.”

What unites this seemly disparate group of diseases is a phenomenon known as protein folding, something that Professor Dobson had been studying for years before it was linked with disease. Constantly produced and degraded in our cells, proteins, which are molecules involved in essentially all biochemical processes in living organisms, begin their existence as long chains, but must then fold individually into specific three-dimensional shapes to function correctly.

“It was a very exciting intellectual problem to understand the process of protein folding,” says Dobson. “So for 20 years, until the mid-90s, that was what most of our research was on – this basic understanding of proteins and how they fold.”

Then, while working on a protein called lysozyme – which Dobson admits is “not in itself the most exciting biological molecule in the world” – a chance conversation transformed this basic research into something highly relevant to human disease.

“One day we were contacted by a medical colleague who told us that he had come across a very small number of patients who had enormous quantities of lysozyme deposited in their bodies,” he says.

“We then found out that rare genetic mutations in these patients stopped lysozyme from folding properly and caused it to aggregate into intractable deposits. Astonishingly, these looked just the same as the ‘amyloid’ deposits that are found in the brains of people suffering from Alzheimer’s disease.”

Armed with the experience gained from the lysozyme studies, Dobson then set about investigating the proteins involved in the much more common neurodegenerative diseases. “What seems to happen is that perfectly normal proteins, which are soluble and functional, start to clump together when they misfold and eventually end up in these amyloid structures, the most famous of which are plaques in Alzheimer's and Lewy bodies in Parkinson’s,” he explains. “And the crucial issue is that during the course of the clumping together, you first get much smaller particles that we now know are very toxic.”

Proteins constantly misfold and aggregate in our cells, but do so at a rate that the body’s defence mechanisms can normally cope with. “It’s a widespread phenomenon but we have quality control mechanisms that degrade the aggregates,” explains Professor Vendruscolo. These mechanisms function amazingly well when we are young but, says Vendruscolo: “With age, they become impaired and are less effective in maintaining proteins in their soluble functional states, so they go on aggregating and eventually start killing neurones or other types of cells.”

Dobson, Vendruscolo and Knowles believe that if they can design small molecules to give our bodies’ natural defence mechanisms a helping hand, they might be able to prevent, or slow down, the aggregation process. But to discover where along the protein misfolding pathway they might be able to intervene, they needed to develop new tools to study the process at a molecular level.

“The question of what’s going on and how we might be able to interfere with the process wasn’t really amenable to traditional biochemical methods,” Dr Knowles explains. This is partly because working at very small scales is key to studying one of the most crucial events – how the misfolding process begins.

According to Knowles: “It’s called nucleation, and probing it in the lab is very difficult because typically in a test tube you would have 1020 molecules and might only see one of these events, so we’ve had to find ways of making measurements in very small systems.”

Using his background in solid state physics and nanotechnology, he turned to techniques more commonly found in the semiconductor industry than in a lab studying human disease.

“We developed microchips to make very small compartments – the size of a living cell – of protein solution in a carrier fluid,” he says. “Physical methods like this are becoming increasingly important to problems in biology where it is essential to have a quantitative understanding of what’s happening.”

Coupled with Dobson’s discoveries and Vendruscolo’s work on a technique call nuclear magnetic resonance spectroscopy, which has allowed Dr Knowles to record ‘movies’ of how proteins move and change shape en route to aggregating, the trio’s progress is a persuasive advertisement for interdisciplinary research.

“Research into neurodegenerative diseases must include tools from maths, physics and chemistry, through to molecular and cell biology and medicine. None of these components can be neglected, and I consider myself a component in this big picture. We each bring our own experience and ideas,” says Vendruscolo.

As well as contributing different skills, interdisciplinary researchers also need to leave something behind – their egos. “One has to accept that collective efforts are essential in order to make significant contributions to very complex problems,” he explains.

“Cambridge attracts bright people, but it also takes openness to do collaborative research. We are extremely lucky because our group shares this aptitude.”

Knowles agrees. “That’s why this set-up has been so successful, because it’s brought together people with very diverse backgrounds and has harnessed their energy in a way that’s really pushed things forwards. There aren’t that many environments where this happens, but it’s something that Chris Dobson has spent many years and a lot of effort creating.”

Their eventual aim is to come up with small molecules that could help prevent proteins misfolding. “Our dream drug would be preventive or risk-reducing in the same way that statins reduce the risk of heart disease,” says Dobson. And as a result of what they’ve achieved so far, the group are in upbeat mood.

“We’re very excited about where we are because we have a set of fundamental concepts and powerful technical tools to follow them up,” explains Vendruscolo. “And because we have this collaboration with Elan, a pharmaceutical company that can then take our results further, we think we have an extremely good arrangement now for making a contribution.”
 


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