Pioneering a low cost method for Covid-19 DNA sequencing

“When the covid pandemic started in early 2020, the COVID-19 Genomics UK Consortium (known as COG-UK) approached us to be one of the academic partners of the consortium. The government invested about £20 million into sequencing or looking for the variants and sequencing Sars-Cov-2.

At the time, the protocols used were based on a similar method from when Ebola emerged, developed by Josh Quick and Nick Loman (ARTIC Network). At the beginning of 2020, this method for DNA sequencing Covid had low throughput (up to 24 at a time) which required a lot of labour and was slow.

I had the idea to pivot the methods I’d been developing for sequencing bacteria quickly and cheaply at the Quadram Institute, over to Covid sequencing.

The DNA sequencing method for Covid-19 that I developed with Alp Aydin and Alex Trotter, called CoronaHiT (High Throughput Corona Virus Sequencing), was ten times cheaper than the alternative methods out there at the time. In 2021 we published the CoronaHiT method in Genome Medicine.

We were able to sequence 3,000 samples on a single run. In the end over 2020 to 2022 we sequenced over 87,000 samples.

In the early stages of the pandemic , it was said, if the Quadram Institute were a country we’d be the fifth largest country in the world in terms of the number of uploads to the covid database. It was an impressive amount of sequencing we were doing from the middle of Norfolk.

There was an incident where a patient had arrived from overseas and the Norfolk and Norwich University Hospital needed to know if it was the Delta variant. The sample came into the Quadram Institute building and within a couple of hours the sample was sequenced using the faster Oxford Nanopore method.

During the pandemic we were able to use both Illumina short-read sequencing technology together with Oxford nanopore long-read sequencing, so we had a two-pronged attack in terms of sequencing samples dependent upon throughput verses speed of result considerations.

Types of DNA sequencing

There are two types of DNA sequencing. Short read technologies are limited in the amount of base pairs they can sequence but give a high-quality sequence, where we be confident of the order of base pairs.

In long-read sequencing you can go much further. It’s also known as single molecule sequencing and you can get a better picture overall of the whole genome. However, due to each base pair being detected by differences in the voltage as the DNA passes through a pore, means it is less accurate than short read technologies, it has less accuracy than short read technologies. Using both short-read and long-read sequencing together can give us an overall better picture of the DNA sequence.

DNA sequencing informing public health policy

During the covid pandemic we were part of the REACT-study too, which was real-time surveillance of the variants in the UK conducted by Imperial College London.

The Quadram Institute was the only sequencing hub in the UK to be sequencing REACT samples. Our DNA sequencing had a massive impact on policymaking within the government.

We were looking at the movement of variants across the country and the effectiveness of the vaccines. This helped to form recommendations of which vaccines to use.

There was an incident where we sequenced samples from Zimbabwe. They were ready to rollout vaccines, and they had several vaccines to choose from. Because of the sequencing we were doing at the Quadram Institute we were able to recommend switching to the vaccine which was more effective at the time.

Towards the end of the pandemic, sequencing was tailing off and COG-UK was dissolved. But we remained as one of three sequencing surge sites, with Northumbria and UCL.

The other two Covid Sequencing surge sites implemented our method, CoronaHiT, due to the cost-effectiveness, the robustness of the method and the speed. It was quite a proud moment.

Ready for the next pandemic

The Quadram Institute is a national capability for the country. In the future, if there is another pandemic with a different pathogen or virus, we can use our DNA sequencing method to track it.

Our method is agnostic to the source. As long as we can generate double stranded DNA, it’s future proof for another event similar to the covid-19 pandemic.

We use the same method we developed for Covid-19 sequencing, for lots of different applications at Quadram, mainly looking at bacteria, microbiomes and bacteriophages.

A career across Norwich Research Park

It’s amazing there’s a hub of different research institutes and labs in a small area in Norwich. It’s been a privilege to work on the Norwich Research Park over the years.

The Norwich Research Park attracts people from all over the world to work at the institutes. The John Innes Centre and the Sainsbury Laboratory lead in plant and microbial science, Earlham Institute has built up expertise in bioinformatics and here at the Quadram Institute we apply fundamental science to improve human health.

I’ve been on the Norwich Research Park nearly 30 years. I graduated in Mechanical Engineering and came to Norfolk to do teacher training. I found I didn’t like teacher training very much and got a job at the Sainsbury Lab on Norwich Research Park running early DNA sequences. My engineering background helped me learn DNA sequencing technology which was new at the time.

After seven years at the Sainsbury Laboratory, I joined the John Innes Centre to work in their Genome Lab at the time. I helped run the DNA sequencing and other platforms for about seven years up until 2009.

Around that time, the Biotechnology and Biological Sciences Research Council (BBSRC) had the inception of what is now the Earlham Institute and then was called The Genome Analysis Centre (TGAC). TGAC was established in Norwich by the BBSRC in partnership with regional economic development partners – The East of England Development Agency (EEDA), Norfolk County Council, South Norfolk Council, Norwich City Council and the Greater Norwich Development Partnership.

I was the first person to generate a library and run an Illumina short read sequencer at the Earlham Institute. I ended up being there for nine years. Over those nine years, I got my hands on a lot of cutting-edge sequencing instruments and ventured into long read sequencing too.

After nine years at the Earlham Institute, I left to work in a company for a short time before returning to the Norwich Research Park to join the Quadram Institute as the new Head of Sequencing. I love working in academia and having the freedom of playing around and do your own thing.

After I started at the Quadram Institute I implemented some of the high-throughput low-cost technologies I had developed while at the Earlham Institute. Over the past five or six years, we’ve sequenced 200,000 different samples, which is quite impressive for such a small team of myself and one technician.

At the Quadram we do both short-read and long-read sequencing. We take a bacterium and “shotgun sequence” it in short fragments for high-quality short-read sequences where there is very little or no errors. Then we can do longer reads which give a more zoomed out perspective, which although they have a higher error rate, can act as a scaffold to take on the high-quality short read sequences. In the future we may not need to use short read sequencing so much, because the base reading quality of the long-read sequencing is improving due to chemistry improvements and more advanced algorithms for identifying bases.”