Cambridge University’s Sir Shankar Balasubramanian in winning DNA sequencing team

Cambridge University’s Sir Shankar Balasubramanian in winning DNA sequencing team

Cambridge University chemists Shankar Balasubramanian and David Klenerman have been declared the winners of the 2020 Millennium Technology Prize for their development of revolutionary sequencing techniques which means DNA can now be read in super-fast times.

The prestigious global science and technology prize, awarded by Technology Academy Finland (TAF) at two-year intervals since 2004 to highlight the extensive impact of science and innovation on the wellbeing of society, is worth €1 million. Sir Shankar Balasubramanian, an India-born British professor of medicinal chemistry, and Sir David Klenerman, a British biophysical chemist, co-invented the Solexa-Illumina Next Generation DNA Sequencing (NGS), technology enabling fast, accurate, low-cost and large-scale genome sequencing – the process of determining the complete DNA sequence of an organism's make-up, which is proving crucial in humanity’s fight against the COVID-19 pandemic. The duo went on to co-found the company Solexa to make the technology more broadly available to the world.

Next Gen Sequencing

The 2020 prize marks the first time that the honour has been awarded to more than one recipient for the same innovation, celebrating the significance of collaboration.

Professor Marja Makarow, Chair of Technology Academy Finland said: “Collaboration is an essential part of ensuring positive change for the future. Next Generation Sequencing is the perfect example of what can be achieved through teamwork and individuals from different scientific backgrounds coming together to solve a problem.

“The technology pioneered by Professor Balasubramanian and Professor Klenerman has also played a key role in helping discover the coronavirus’s sequence, which in turn enabled the creation of the vaccines – itself a triumph for cross-border collaboration – and helped identify new variants of COVID-19.”

The winning work has helped the creation of multiple vaccines, now being administered worldwide, and is critical to the creation of new vaccines against new dangerous viral strains. The results will also be used to prevent future pandemics. However, the International Selection Committee – the body of experts that evaluates all nominations for the prize – pointed out that it had made its decision in February 2020, before the global spread of the COVID-19 pandemic.

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Here are some insights from Prof. Balasubramanian:

Q

Does it make a difference to you personally winning awards like the Millennium Technology Prize?

A

I think these things are always given to individuals, so you have to give it to someone, but it is a team prize. And as a scientist you appreciate there’s a piece of science and technology here that has made an impact. So, I’m pleased to see that the science has been recognised as something that's important.

Q

How would you explain what Next Generation DNA sequencing technology does in simple terms?

A

The first stage is to explain what DNA is. DNA is the blueprint or code for everything in a living system, made up of four letters: G, C, T and A. One copy of the human genome has 3.2 billion of these. The challenge is to read the sequence to decode the order of these four letters and you need to do it accurately; 3.2 billion is a lot of letters, so you need to be able to do it quickly and affordably.

What next-generation sequencing has achieved is enhancing the speed of reading DNA and reducing the cost of doing it by a very large degree – more than a million-fold.

The way it works is that it exploits fluorescence detection and massively parallelises the process.

The silicon chip has revolutionised computation and electronics by miniaturising everything so that you can do lots of things in parallel in a tiny area. The way the technology works is instead of sequencing all of the DNA in parts, you break up the DNA into lots of fragments and, in essence, you give each fragment a place on a chip on a surface, so you have millions and millions of fragments of DNA on a chip.

And then you decode them all in parallel at the same time – that's what achieves huge capacity and speed and economies of cost.

What we did is we colour-coded each of the building blocks that make up DNA so that during enzyme-mediated synthesis of a copy strand for each fragment, as a building block goes in at every site on the chip, you can produce an image after each step and see what colour has gone in each site and so you read one of the bases, one of the letters.

If you've got millions on a chip, you read millions in one step. And then you remove that colour, and you do the same thing for the next step, and the next step, and build up a series of letters through colour change.

Then, you take these individual sequences (or reads) and using computers you realign them to the reference of the human genome to find out where they came from, assemble the sequenced genome and can then you look at the differences between genomes to detect genetic variation.

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Q

What do you think will be the impact of your technology in terms of helping us to understand novel viruses like this better?

A

The sequencing is providing a natural history of how this virus evolves when it spreads through a population in real time. Beyond this there'll be valuable information tracking what happened and studying our response to certain measures like lockdowns. A retrospective analysis of that will be very insightful in terms of what would we do differently if a similar thing were to happen again.

Sequencing the genomes of people who've had Covid and trying to get an understanding of why some people were absolutely fine and others were not is in a sense another form of patient (or people) stratification. This approach could identify risk factors in specific people that may also apply to other viral infections in the future.

The infrastructure that has been set up on the fly is also handling information in real time which itself is a framework that could be quite useful for flu pandemics that happen much more frequently. Now that we've got testing capacity at scale and as we run into more routine blood tests, we could begin to routinely collect information to survey and understand what's going on via asymptomatic testing. It allows us to pick up threats very early as part of a structured monitoring system and early response system.

A big question is why some people are asymptomatic and some people end up on ventilators and I think sequencing will contribute to that understanding and it has really highlighted how little we know about the innate immune response to the virus and its encouraging research in that area. And if we can continue to do that, we can follow people and see who's likely to end up in intensive care and who’s likely to be asymptomatic. Using this information, we can try and work out how one would intervene to stop people developing a very exaggerated inflammatory response, which is partly responsible for some of the symptoms of Covid.

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