The lab is my happy place: What I've learnt from a decade of long-read sequencing

The excitement of sequencing is usually placed on the result - the discovery, the genome, the data. But for Naomi, it's the process itself that fascinates her most:

"I find making processes work extremely satisfying. The lab is my happy place. My main focus and passion is making things work better, cheaper and faster. I suppose I was more inspired by people who were in technical roles - they have a wealth of knowledge and experience,” she says.

Naomi started at the Earlham Institute as a research technician hired to wash sequencers. A decade on, she has helped build the Institute's technical expertise in long-read sequencing from the ground up.

"Most of my job is adjusting the methodology based on what's physically possible. A library, in our world, is a collection of DNA fragments: you take an organism, fragment its DNA, add barcoded sequencing ends, and using bioinformatics, piece those fragments back together. We can’t yet sequence every chromosome from beginning to end in one go - it's like a puzzle with pieces too big to read as a whole, and we can't staple DNA back together once it has been degraded,” she explains. 

“So, most of library prep is about taking what little material you have, whether it's a single insect or a precious sample that's been sitting in a freezer, and preparing it in a way that lets you sequence as much of it as possible, for as long as possible."

Traditional short read sequencing methods fragment the DNA and RNA into much smaller pieces, which makes it much harder to reassemble. However, long-read sequencing fragments the DNA and RNA into longer sections which means scientists can piece it together much more easily and uncover greater depth of information.

Long-read sequencing is a skill set that Naomi learnt by doing. When Naomi first started, the throughput simply wasn't there. She describes loading sequencers three times a week, running library preparation in between, and waiting up to 14 days to see results. Today, that same process can take just 36 hours. As a result, preparing libraries for sequencing takes longer than the sequencing itself. Naomi has had to adapt quickly to this new challenge - working out new ways to prepare samples for sequencing to keep pace. 

"I have seen the technology change and grow - there is a huge difference in the scale of the projects, which organisms are possible to sequence, and there have been significant improvements in the QC. We have been able to measure things we have never measured before,” Naomi says.

Naomi thrives on a challenge - using creativity and problem-solving to work out how to sequence notoriously difficult genomes, such as those of protists. Euglena is one such organism, teeming with bacteria and other contaminants, isolating and collecting a clean DNA sample is hugely complex. This isn't just technically demanding; it also requires real ingenuity to keep the process as cost-effective as possible.

"Cost is always going to be a drawback. Human sequencing has money behind it, but for a lot of the organisms we work on, there's very little budget, and there isn't always an established way of doing things for that species. So, part of the job is creativity and problem-solving - finding solutions, thinking about improvements, fixing things as you go. It's weird, awkward, and wonderful all at once: trying to solve something that's never been done before," she adds.

Furthermore, Naomi’s expertise in long-read sequencing has been integral to unlocking previously undecoded parts of the human genome. Her technical skill set has enabled the discovery of thousands of previously unannotated transcripts with significant impact. Alternative splicing - a key driver of transcript diversity - can profoundly impact gene function, and its dysregulation is frequently linked to diseases such as cancer and neurological disorders. 

Naomi is an expert in her field, with a skill set built over years of experience at the frontier of bioscience. Even so, she must advocate strongly for herself in the absence of a traditional academic career. 

One of the challenges of life as a research technical specialist is the absence of formal milestones: without the steady rhythm of publications, it becomes essential to be able to vouch for yourself and the value you bring to research.

"You have to be quite resilient - it fails many times before it works. We plan projects really carefully so we don't have to do it twice; often you can only do it once. Sometimes, we're talking tens of thousands of pounds, so failure isn't something you can afford to be casual about, and it takes a lot of mental focus to concentrate at that level for that long,” Naomi says.

“If you're a curious person who likes to ask questions and figure things out, even if you're not academically minded, there are so many technical roles out there for you. It just takes wanting to know more and always wanting to be learning."

If you visit the Earlham Institute, you might not find Naomi at her desk - but you'll know exactly where she is: in her happy place in the lab, untangling the sequencing challenges that underpin some of the most exciting discoveries in science.