Dementia Research - meet the scientists

Big data, fruit flies and the battle against brain diseases

The fruit fly lab at Cardiff’s Dementia Research Institute

When I got an invitation to the Dementia Research Institute in Cardiff I accepted with some trepidation. While I knew there was some crossover between research into Alzheimer’s and Parkinson’s I wondered how relevant much of the Institute’s work would be to my main interests. And as someone who in the words of the Movers and Shakers’ ‘We Will Survive’ anthem is impatient for a cure “if not tomorrow morning then tomorrow afternoon” I sometimes find it depressing to hear about blue sky research that may take decades to have an impact.

But instead, the sheer brilliance and dedication of the scientists I met in my morning at the institute on the Cardiff University campus left me feeling invigorated and strangely hopeful.

Professor Caleb Webber

My guide for the morning was Professor Caleb Webber who as well as doing his own research in Cardiff is the Director of Data Science for what he describes as a “distributed” organisation - the DRI has nine centres across the UK including Imperial College, UCL and King’s College in London, and the universities of Cambridge and Edinburgh. I quickly learned that the ‘dementia’ in the institute’s name was in this context a catch-all term for all neurodegenerative diseases

Professor Webber was about as far from the cliché of the uncommunicative scientist stuck in his ivory tower as you can get. He was fizzing with excitement as he outlined the balancing act between the need for fundamental research that might eventually tell us what causes diseases like Parkinson’s and something that might make a difference in healthcare in the next 10 years.

His own work looks to take advantage of the big datasets now becoming available to researchers from organisations like UK Biobank which are collecting medical information from volunteers who agree to be monitored:“When you get big data, you can start to see patterns that you would never see before.”

I talked about my frustrations with the time it took to complete clinical trials. He said data science could speed some things up by, for instance, looking back at the records of people diagnosed with Parkinson’s or Alzheimers and working out whether their lives before diagnosis were any different from those who stayed healthy.

He was particularly upbeat because, along with scientists at UCL, he had just been given the go-ahead that day to run what was effectively a trial combining two common forms of medication. One was for hypertension, the other for diabetes - one appeared to reduce Parkinson’s, the other did not.

Dr Dayne Beccano-Kelly

Now it was time to hand me on to my next scientist, Dr Dayne Beccano-Kelly. His research goes deep into the brain to examine how different cells communicate with each other, the assumption being that an internal communications breakdown is what is behind many neurodegenerative diseases.

After 20 years in cell communication he says technology advances have made it a good time to be a scientist in this field: “For the first time, we can now access human neurons and measure them in ways we haven't been able to measure them previously.” That means he can observe what happens to the electrical communications of brain cells from someone with Parkinson’s and compare it to the brain of someone who is disease-free.

This really does feel like fundamental research, very far from being relevant to the patient but Dr Beccano-Kelly sketches out two areas which he sees as promising. The fact that Deep Brain Stimulation works. suggests that isn’t just the death of dopamine cells that is the problem in Parkinson’s, it’s also a breakdown of communication between cells. The scientist suggests that as our understanding of what is going on in the brain deepens, DBS could be replaced by a tablet doing the same job.

But Dayne also sees the possibility of a bigger prize. As it becomes possible to identify people who may be pre-symptomatic but on the road to Parkinson’s, he wonders whether it might be possible to stop the disease ever really taking hold. By intervening before cells begin to die with a bespoke drug designed to stop that process from happening, the ultimate aim, he says, would be “staving off symptom onset in the first place.”

Wow, plenty to think about there. My next stop was a quick tour of the lab where I took on board two things - biomedical research still involves a lot of laborious work with pipettes and petri dishes but this is now being rapidly automated, and fruit flies are incredibly useful (more on this later).

Professor Vincent Dion

Whereas my first two interviews were with two scientists focused mainly on Parkinson’s, Professor Vincent Dion is tackling Huntington’s, a much rarer neurodegenerative disease, inherited from a parent. For families with the genetic mutation that causes Huntington’s it casts a very dark shadow over their lives, with no hope that anything can be done once someone contracts the disease. Until now, that is.

The CRISPR gene editing technology is a revolutionary tool for biomedical research and Professor Dion is using it to take on Huntington’s. He describes it as a pair of molecular scissors which allows him to snip the DNA, targeting the protein that is causing damage to the cells. “It does this really, really efficiently. It's very good at what it does,” he says.

But here’s the problem: “The thing with Huntington’s is that it's a special mutation. It's a stutter, a DNA sequence that repeats itself over and over.” He asked me if I remembered CDs getting stuck and endlessly repeating a note - of course I did. “So this is basically what happens to DNA.” But the scale of the problem was immense with billions of brain cells affected and needing a snip.

Back in 2016 the Professor and his team had shown that they could mend cells in a dish in the lab, and then moved on to working with mice. But getting CRISPR into the human brain is a huge challenge.

“CRISPR is big. It's a big protein, and so you can't just put it in the bloodstream and hope that it's going to do its thing. You have to really make sure it gets inside the cells. And the way you do that is you first put it into a virus.” It is a similar approach to that used with some of the Covid vaccines. But this will involve a neurosurgeon, meaning that the procedure would be very expensive. “But it would be a one off ,” he says, “because once you've corrected the mutation, then you've corrected the mutation.”

It suddenly strikes me that I am hearing about extraordinary, world-leading science, taking place here in Cardiff, which could transform the lives of people at risk from this horrible disease. Nothing “blue sky” about this research, even though it started with Professor Dion just exploring whether CRISPR would work with “stuttering” DNA rather than looking for a cure for Huntington’s.

Even so, not everyone is impressed. “I get asked on a regular basis by other scientific colleagues why bother with a rare disease?” He says if you don’t have that rare disease it’s a fair question - but things look a little different if you do.

At the end of our conversation I ask this Canadian scientist born in Quebec, and with previous jobs in the United States and Switzerland, what he thought about living in Cardiff. He was very enthusiastic, both about the location - “you're not far away from the beach, you're not far away from the mountains” - and the warm welcome he and his Turkish wife had received in what is quite a diverse city.

Vindication then for the decision by David Cameron’s government to create this institute and spread its work across the UK, attracting world-class scientists to work here.

Dr Gaynor Smith

By contrast, when Dr Gaynor Smith accepted a job at the Dementia Research Institute she was coming home. Born in the Welsh valleys town of Merthyr Tydfil, Gaynor did her undergraduate degree and PhD at Cardiff University, then set off for the United States to continue her research at Harvard Medical School, then at universities in Massachusetts and Oregon.

In the American labs she had been involved in cell replacement and gene therapy and now she is focused on mitochondria, the power units of cells which seem to fail in a number of neurodegenerative diseases. And one important tool in her investigations is that swarm of fruit flies downstairs in the lab.

One aspect of her research involves giving a fly a genetic mutation that causes Parkinson’s: “We look at it in a tube and compare it to one that doesn't have the gene mutation and they can't climb up the tube, whereas the “control” [fly] is buzzing and climbing around.”

I struggled to understand why an insect with as simple a physiology as a fruit fly could be useful in researching what goes on inside the infinitely more complex human body. But Dr Smith explained that accessing the genome of the fly - or drosophila to give it its Latin name - allowed researchers to go on fishing expeditions that might help uncover new clues about the genetic causes of conditions like Parkinson’s: “By using the fly and being able to manipulate almost every gene in the Drosophila genome, we might find something completely unexpected.”

Now this did feel like pure science, a very long way from delivering anything which might have tangible results for people living with neurodegenerative diseases. But Gaynor Smith said that was not necessarily the case:

“It's a data driven approach - this gene, we weren't expecting it to be linked to Parkinson's, but it turns out if you manipulate this molecule, it makes things better.”

She said that kind of information could then be fed to Cardiff’s Medical Discovery Institute, a separate team of medical chemists far closer to the clinical world. But Professor Smith had a very simple explanation for why it is vital that, in the battle against Parkinson’s and similar diseases of the brain, we continue to invest in science like hers:

“We just need to understand what goes wrong before we can think about treating it.”

Four scientists, then, each with a mission to deepen our understanding of some of the most destructive diseases to afflict millions and the people who care for them. At a time when science is under fire from all manner of cranks, conspiracy theorists and populist politicians, how refreshing to meet people just getting on with pushing back its frontiers.