David Henshall. Image: © FutureNeuro/Jane Henderson/alex_aldo/Stock.adobe.com
‘I trust our brains’: How leading epilepsy researcher Prof David Henshall finds harmony with microRNAs.
With 150,000 scientific articles and counting, the field of microRNA research has been quick to develop in the 30 years since this mighty molecule was discovered.
And that landmark discovery was made, not in humans, but in a tiny roundworm, C elegans. It would be another seven years before two studies confirmed that microRNAs were present in plants and most exciting, in the human genome.
“I love the fact that these [microRNAs] were found by people looking at worms and then they were found in humans.
“And actually, the one in the worm was also in humans which means that we’ve basically been using these things for 600m years,” Prof David Henshall tells SiliconRepublic.com.
Henshall is a professor in the Department of Physiology and Medical Physics at RSCI University of Medicine and Health Sciences and director of FutureNeuro, the Research Ireland Centre for Neurological Conditions.
He’s been studying microRNAs for about 15 years and has just published a book about them, Fine-Tuning Life: A Guide to MicroRNAs, Your Genome’s Master Regulators.
Henshall describes microRNAs as “our genome’s master controller, making sure that the right amount of protein is made at the right time and in the right place for each cell in the body”.
They are akin to the conductor of an orchestra who “fine-tunes to perfection what would otherwise be a-bit-hard-to-listen-to noise”, Henshall explains in the book.
“If you could listen to the journey from gene to protein, I’d hazard a guess that it would begin with a cacophony of noise. Vast assemblies of enzymes joining together, jostling for space on DNA, generating copy upon copy of mRNA. These are spewed out to be read and translated into proteins.
“But this is skewed towards overproduction, the molecular equivalent of everyone playing their instruments as loudly as possible. The molecular noise needs to quieten down.
“This is what microRNAs do. They reduce, they sharpen and they shape the protein landscape, until the sound from the whole molecular orchestra is perfect.”
In Fine-Tuning Life, Henshall traces the history and development of microRNA research, offering insights on key studies and pointing to future research directions.
“I love the discovery story,” says Henshall, explaining what drew him to writing the book. “I just saw there was a book in it.”
Epilepsy overture
It’s clear from talking to Henshall that his work means a lot to him. The focus of his research for 20 years has been epilepsy.
Epilepsy is a neurological condition characterised by repeated seizures that affects 45,000 people in Ireland and about 50m people worldwide. About a third of sufferers have a drug-resistant form of the condition, meaning conventional drugs don’t stop the seizures.
Henshall started out looking at stroke. His PhD at the University of Edinburgh looked at developing drugs to protect the brain when someone has a stroke.
During postdoctoral work at the University of Pittsburgh, the team he was working with were interested in hibernating animals. If you take a snapshot of the brain of a hibernating animal, it looks dead, but then they wake up and are back to normal.
“The thinking at the time was that if we could figure out how the brain can switch itself off and then recover, and we could mimic that somehow with a drug or a gene therapy or something, we would have the cure for stroke,” Henshall explains.
The head of his group said they had plenty of people looking at stroke, and he should look at epilepsy. As an eager young researcher, he jumped at his boss’ suggestion and has never looked back.
In trying to answer the question of how to protect the brain from seizures, this is where microRNAs come in.
“The short answer was that genes switch themselves off, metabolic pathways switch themselves off. It sounds pretty obvious in a way, right?
“But how they switch off and switch back on again is the interesting bit,” Henshall says.
MicroRNAs dial up and down gene activity so maybe Henshall could identify microRNAs that dial down genes associated with seizure activity. After learning from cancer researchers who were already looking at microRNAs (“cancer is almost always a few years ahead of everyone else”), Henshall and his team set about investigating the role of microRNAs in epilepsy in their new lab at RCSI.
“One of the first things we did was to try and detect as many of these microRNA genes as we could in the brain, find out which were on and off. And then look at what happens when a seizure occurs. That was when we found some microRNAs that were going up in the brain.
“That gives us a druggable target, you know, if you’ve got something that’s increased, can you block that increase and see if that does something?”
This led to the discovery of microRNAs that can be targets for epilepsy and “that linked with everything I was interested in”, Henshall says.
Research crescendo
Fast forward a few years and Henshall and his team have identified ways to target microRNAs that have dramatically reduced seizure activity in several trials in animals. However, he stresses the many challenges of moving to human trials.
“Any time you play with a new gene, there’s this great fear that you jump to humans and there’s just something that you didn’t know, didn’t see coming. And it could be catastrophic.”
A single microRNA gene can affect multiple genes, and one fear is that it could control a slightly different set of genes in humans. Another issue is that gene therapies are so targeted, which makes them effective, but this mechanism also makes them very long-lasting so if something unwanted was to happen, it might not be possible to reverse.
There’s no simple answer to managing this unpredictability besides rigorous, ongoing testing.
Epilepsy is quite common in dogs, and similar to people, about a third of canine sufferers have a drug-resistant form of the condition. Henshall is working with a vet to test microRNA-targeting medicines.
“It’s remarkably upsetting to see a dog have a seizure,” Henshall says. “Epilepsy in dogs is quite a serious problem and, at the same time, a potential way to test [treatments].”
Their research hasn’t been published yet but, so far, the treatments seem to be effective across a broad range of seizure types, Henshall says. “So that’s really exciting.”
Having seen the results in animals, Henshall is feeling confident about moving to human trials. “I trust our brain; I think it’s going to be able to handle a little off-target activity and can kind of compensate in other ways.”
The team hopes to move to human trials soon and they also have a few other microRNA treatments in the pipeline.
Neurologists’ ensemble
As well as developing treatments for drug-resistant epilepsy, Henshall hopes to develop precision medicines that work better for other forms of the condition. He likens current treatments to throwing a bucket of water on a match. “You put the match out right but your floor’s wet.” The idea is that targeted medicines could work better and have less side effects.
The area of precision medicine is one in which FutureNeuro is very interested.
“Personalised medicine is the future,” Henshall says, “and I think it’s also a bit the present.”
He expects that within a few years, everyone who gets an epilepsy diagnosis will get genetic testing as standard. At the moment, people get a diagnosis without necessarily finding out the exact causes of their form of the disease and finding the right treatment is a matter of trial and error.
“It’s still got a long way to go, but we’re beginning to align different types of anti-seizure medicine to different genetic backgrounds,” Henshall says.
Neurological medicine is incredibly complex and that’s one of the benefits of a centre such as FutureNeuro, which brings together experts in various fields to work on solving these issues.
“You’ve got complex brain conditions, you’ve got difficulties diagnosing, difficulties treating difficulties forecasting what’s happening in the future.
“And the centre was set up to basically bring together all the people that we have in Ireland that are working on this problem, to work together and to shape people’s focus towards real-world problems.”
From left: Kevin Mitchell with David Henshall at his book launch last month. Image: FutureNeuro
Henshall has been involved in the centre since its inception in 2017. It has recently entered a second phase with more funding and an expanded remit.
Part of the expanded remit is more of a focus on mental health and a more holistic approach to thinking about and treating neurological conditions. As Henshall explains, for example, when a person has epilepsy, they don’t necessarily just have epilepsy, they might have depression, developmental delay or other co-morbidities that are causing as many issues as the primary condition.
One way to tackle this is to design experiments which consider these other aspects. For example, in the canine epilepsy research, the dogs are tested regularly with games to understand if the medications are affecting their cognitive function and overall wellbeing.
The work of the conductor
Henshall describes it as a privilege to lead the centre. He’s keen to stress that the centre’s success is based on the collective actions of everyone involved, including the researchers and operations team headed up by centre manager Bridget Doyle.
But leading a busy research centre must impact his ability to get hands on with research?
“For sure, being centre director impacts my lab enormously,” he says. “I have so much less time than I would like to supervise.”
He hopes this downside is balanced out by the talented team he can bring together at FutureNeuro. I suggest he’s a bit like a microRNA himself in conducting all of this research activity. He likes the reuse. “I’ll make a note of that one,” he laughs.
And on top of all that conducting, he found time to write a book.
Henshall always loved English and history at school and could easily have gone down the humanities root in college, he says, but he had never really planned to write a book until a few things converged to spur him on.
His friend and colleague Prof Kevin Mitchell, a neurobiologist at Trinity College Dublin, wrote a book and Henshall was really impressed. At the book launch, he thought, “this is brilliant … maybe I should think of doing something like that”. Around this time, he was approached about writing a book and it all fell into place from there.
Unfortunately, though, there’s no clever answer, he says, to balancing all the facets of his day job and writing a book at the same time. He just had to find the time. He would get up in the early hours at weekends and force himself to make time during the week as he got closer to his deadline.
“But it’s funny, isn’t it? Because you do find ways to incorporate things that mean a lot to you.
“And I would say it was painful to find the time to do it, but it was a joy to write. I absolutely loved it.”
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