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Progress takes time but we’re building momentum

Research

4 March 2024

Time is the key to so many discoveries in science, technology, engineering and maths, so it makes a fitting theme for this year’s British Science Week (8th-17th March). We hear from Renata, a bioinformatician who’s recently joined our new Precision Diagnostics project, about how time is playing a key part in both the diagnosis of mitochondrial diseases and the evolution of the technology involved.

Thanks to her degree in biology, Renata’s always been aware of the existence of mito. Then 15 years ago, when she was working on systems to enable researchers to do their job faster, she encountered several leading mitochondrial researchers. The more she learnt about mitochondrial disease, the more curious she became.

She continued in the field of bioinformatics, taking various research positions at different universities and most recently working on another rare condition, motor neurone disease. But mito always had a hold over her, and when she saw the Lily job advertised and recognised some of the names involved, she knew it was meant to be.

“It was a real blast from the past!” she laughs. “I hadn’t heard of The Lily Foundation until I came across this opportunity, but it felt very personal and welcoming. That was a big plus. Although it was difficult to read the story about how the charity came about – Lily would’ve been the same age as my daughter. It really felt like something I wanted to be a part of.”

The time it takes to get a rare disease diagnosis

Renata understands first-hand the anguish of living with unanswered questions. “I actually have a rare disorder myself – Ehlers-Danlos syndrome,” she reveals. “I waited around five years for a diagnosis, and that wasn’t even a genetic diagnosis. I was lucky it turned out to be something relatively benign, but I have two children who have it as well. I remember the agony of waiting and waiting, being sent from one doctor to another and then another. It’s unimaginable to have to live like that for years.”

And that’s a real driving force for her in her new role. “If I could change one thing,” she says, “I’d change that. It doesn’t have to take that long, and when we start analysing patient data, that’s where we can make the biggest impact. I’ll be proud if I can say that, thanks to me, someone’s waiting time isn’t going to be 12 years.”

Our project aims to improve diagnostic rates for complex cases of mito when patients fail to get a confirmed diagnosis via the NHS. Renata’s role is to leave no stone unturned in her search for tools and techniques to make that process faster and better, and already she’s identified some that are better than standard pipelines for mitochondrial disease.

“We plan to use very new sequencing techniques that no one’s using routinely today to diagnose mito,” Renata explains. “For example, it’s faster and cheaper to sequence only exomes today, but that doesn’t examine the whole genome. Thanks to Lily, the first thing we can do is whole genome sequencing.”

“That’s so much better than what we have currently,” she continues, “but what’s really cutting edge is to use long read sequencing, and that resolves the areas where short read sequencing fails. And then there’s RNA sequencing. That’s about looking into the expression of genes – not just whether they exist in the human genome but whether they’re actively being made.”

Even though genome sequencing has been around for years, it’s still an imperfect process. “I’m dealing with very large text files,” Renata explains. “They’re too large to just double click and look at, so special tools have to be used, and I as a programmer know how to ask them to give me the information I need.”

“One of the biggest challenges is how quickly these programs are running, and the key is to make the output useful. Each one of us has so many genetic variations and most aren’t important anyway, but I try to figure out what’s important and how dangerous any variants might be. I’m guided by previous knowledge of what the genes are that could play a role in mitochondrial diseases.”

Because without knowing which gene is responsible, it’s impossible to think about potential treatments. Renata has high hopes for the RNA sequencing and believes this will tell us more about whether the protein is functioning and give the best possible avenues for treatment if it’s not.

The advance of technology over the years

It’s fair to say that gene sequencing technology has evolved over time. “When I did a postdoc 15 years ago,” she recalls, “we used microarrays. They’re these little glass slides on which you print 30,000 different sequences of genes and check for their expression. Today they’re obsolete, as we can sequence RNA instead!”

And the hope is that as the technology advances, costs become more affordable too. “Long read sequencing is still pretty costly on a whole genome,” continues Renata, “but with short read sequencing some machines can read for as little as $100 these days. When you consider that the first human genome took almost 15 years and several billions of dollars to assemble, that’s pretty incredible.”

And as the technology has developed, it’s become more reliable. Changes are happening quickly, making results more accurate, but that brings challenges too. “We have to constantly update the algorithms when they alter something,” she explains, “but it’s for good reason. And I don’t expect to have 10,000 patients, so it remains manageable.”

Despite Renata’s experience in rare diseases, she quickly realised that mito is a very different scale of rare. “For motor neurone disease, I had a data set of around 11,000 people. With mito, I’ll never have that many patients, and almost everyone has a different mutation. There’s not enough data to use really sophisticated techniques like machine learning.”

To overcome the complexities of mito, Renata believes we need more collaborative projects worldwide. “It’s very difficult to use big data methods on small data sets,” she explains. “It’s hard to deal with because everyone’s so different and has different symptoms.”

And teamwork on a smaller scale is key to Renata making a success of her role. “The best part of this project is that it’s so collaborative with the clinicians. I work closely with them, and listen to what they want, then write programs that can pull out information that’s going to help them.”

”I’m extremely grateful to be given the chance to work on the project and really hope to do my best,” she continues proudly. “I only started in November but already it feels like I’ve been doing this for longer.”

It seems time is flying by for Renata on this project. But for patients awaiting a diagnosis, that wait can feel like an eternity. As well as speeding up that process, our hope is that Lily Precision Diagnostics will add to our wider understanding of mitochondrial diseases and bring us closer to eventual treatments and a cure.

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