Dreamt up over a pint at the Panton Arms: Cambridge chemists tell astonishing story of DNA sequencing after 1m euro prize
In Cambridge, it seems, most success stories appear to begin in a pub.
It was famously in The Eagle, of course, where Francis Crick announced to lunchtime punters on February 28, 1953, that he and James Watson had "discovered the secret of life" - namely, the structure of DNA.
How appropriate then, that it was in the beer garden of the Panton Arms that University of Cambridge chemists Dr Shankar Balasubramanian and Dr David Klenerman sketched out their ideas for what was to become groundbreaking DNA sequencing technology.
Shankar’s diary denotes August 26, 1997, as the day of ‘The Solexa Idea’, in reference to the company they would go on to form within a year.
The concept was to watch DNA polymerase as it assembled the building blocks of life. By observing the enzyme copying a genome, they would, in fact, be reading it.
And they calculated that they could do so at such a speed that genome sequencing could be scalable and low-cost.
By 2006, Solexa had launched its first sequencer, and a year later it was acquired by Illumina for $600million - today, that looks like a bargain.
Solexa-Illumina next-generation sequencing is now believed to be responsible for about 90 per cent of all the DNA and RNA sequenced worldwide.
The genomic revolution - sketched out over a pint at the Panton Arms - has enabled the tracking of Covid-19 variants, the diagnosis of disease, the advent of personalised medicines, new therapies and vaccines, improved crops and more.
Little wonder, then, that Shankar and David have been awarded the highly prestigious Millennium Technology Prize - worth one million euros - by Technology Academy Finland.
“No one knew how much being able to read the building blocks of life would contribute to science and medicine,” says David. “It really hit home when I heard someone had used our technology to sequence and treat a baby born with a rare disease. I realised, wow, it’s not just a technology for scientists, it’s actually a technology that can make a difference.”
Shakar adds: “Probably the biggest surprise to me has been the broad impact of the technology in many unanticipated areas, and this is still on a rising curve.”
Speed has proved all important.
“In the 1990s, a global effort was going into sequencing one genome through the Human Genome Project, but given the goal was to understand the genetic bases of human variation and diseases, then more genomes would need to be sequenced, and ultimately at population scale,” recalls Shankar.
“We spoke to colleagues at the Sanger [Institute] involved in the Human Genome Project and asked the question ‘is this the right time for a sequencing technology like ours?’ They were tremendously enthusiastic for us to make it happen.”
David says:: “I wrote down a very simple calculation on a flight to Germany and left it in Shankar's pigeon hole. Our proposal was to anchor one strand of DNA to a surface and use DNA polymerase to build a new copy using coloured building blocks that we could measure. The key was to make this massively parallel. It was quite a trivial calculation really, but seeing the answer was the moment I thought ‘this is something’.”
Shankar adds: “Someone once asked if we were ‘sequencing jocks’ back then – we weren’t, we worked in fundamental chemistry. But one August evening in the Panton Arms, we suddenly saw the pieces of the jigsaw come together that led us to see a way of sequencing DNA that could be scalable, massively scalable.
“I remember going home that evening feeling pretty excited, as I often did after a beer summit at the Panton Arms. The acid test, of course, is how you feel about it the next day.
“We thought it would be ten thousand times faster. It’s actually ten million times faster. It has gone way beyond our expectations.”
After proof-of-concept experiments, and due diligence, the pair were supported by Cambridge Enterprise and raised some “modest” investment, with Abingworth funding two post-docs in the Department of Chemistry.
They built it up, founding Solexa, and the 2006 release of the 1G Genome Analyser “proved our initial calculations, which predicted that one day we would sequence a billion bases”.
Shankar says it is “quite remarkable” that Illumina has taken Solexa’s technology and improved on it “ten thousand fold”.
Illumina’s NovaSeq 6000 can sequence 48 human genomes - each at 30-fold depth - in two days, the equivalent of one high-quality genome an hour.
David notes: “To put this in context, the international Human Genome Project started in 1990 and completed in 2003 and cost more than a billion dollars. Of course, that was the very first genome to be sequenced, which makes it much harder to piece together.
“Today, the human genome can be sequenced in less than one day at a cost of less than $1,000. This has effectively ‘democratised’ sequencing to the point that even quite small labs can have a bench-top DNA sequencer.”
Now there is talk of a new cost milestone - sequencing the human genome for £100.
“If the cost comes down to $100 a genome, it becomes economically viable to sequence a population and it also becomes practical to sequence people regularly as part of blood-based preventative health checks,” says Shankar.
“The impact and breadth of utility of this technology has gone way beyond my imagination, and it’s still in its infancy.”
David says: “What surprised me was we literally went from a piece of paper to something that was used all over the world in just under 10 years.”
The pair were presented with the Millennium Technology Prize by the president of Finland, Sauli Niinistö, at a virtual ceremony last week.
They said: “This is the first time we’ve received an international prize that recognises our contribution to developing the technology – but it's not just for us, it's for the whole team that played a key role in the development of the technology and for all those that have inspired us on our journey.”
Previous winners of the Millennium Technology Prize:
- Sir Tim Berners-Lee (2004), for the World Wide Web;
- Professor Shuji Nakamura (2006), for the production of the first successful blue LED, the final step in creating a brilliant white LED;
- Professor Robert Langer (2008), for his work in pioneering controlled drug release where medication is released in a patient’s body over time;
- Professor Michael Grätzel (2010), for third-generation dye-sensitized solar cells, which promise electricity-generating windows and low-cost solar panels;
- Joint winners (2012): Professor Shinya Yamanaka, for ethical stem cell research; and Linus Torvalds for the Linux open-source operating system, which has become the basis of Android smartphones, tablets, digital television recorders and supercomputers the world over;
- Professor Stuart Parkin (2014), for developing increased data storage density, which has enabled a thousand-fold increase in the storage capacity of magnetic disk drives;
- Dr Frances Arnold (2016), for her work on directed evolution; and,
- Dr Tuomo Suntola (2018), for atomic layer deposition (ALD), that enables the manufacture of nanoscale thin material layers for microprocessors and digital memory devices, which has helped revolutionise smartphones.
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