21 November 2019

Why the NGS Race is Science's Greatest Story.

By George Coe

NGS will change the world; giving us precision medicine, early cancer diagnosis and a better understanding of where we come from.

This promise has made NGS a multi-billion-dollar market, expected to be worth more than $10bn by 2025.

It’s dominated by Illumina, who are responsible for 90% of the market share. They’re now one of the world’s most attractive stocks too, with a $40+bn market cap.

It’s not always been this simple though. It’s not always been Illumina.

NGS has been on a fascinating journey, featuring numerous pioneering players all racing to get their technology to market.

A little over 20 years ago, the race began…

Like a lot of great ideas, NGS started in a British pub. To be precise, a small but pleasant pub in Cambridge called the Panton Arms.

The year is 1997. Patrons on that day included faculty members Shankar Balasubramanian, David Klenerman – both now knights of the queen - and two other postdocs, one of which was my good friend, Mark Osborne.  

It was here, that the first concept of Illumina’s NGS was discussed. Unlike a lot of pub-fuelled plans, this one didn’t go away in the morning, it blossomed into something ready to change the world.

It was a privilege to have worked on such a transformative and disruptive technology that now forms the core of the Illumina NGS portfolio."

Mark Osborne, Department of Chemistry, Sussex University

Fast forward a year to 1998, the first company committed to massively parallel sequencing was born, Solexa. This was a small UK company, supported by venture capitalists from Abingworth.

By 2000, Solexa was growing with new leadership and more backing from a larger consortium of investors.

While these were exciting times for Solexa, revolutionary ideas were also being spawned across the pond in the US.

In a hospital, waiting for his son to be treated, Jonathan Rothberg, an accomplished entrepreneur and chemical engineer, was thinking up an innovation - which later led him to being awarded National Medal of Technology and Innovation by President Obama.

Rothberg, frustrated at the lack of tools to establish why his son couldn’t breathe properly, sought to create a machine which explored health problems caused by DNA. His concept was simple, if we could put a computer onto a chip, why not a DNA Sequencer?

With his idea came the company 454 Life Sciences.

In 2003, thinking along the same lines, DNA Electronics (DNAe) also created a semiconductor chip. DNAe’s chip was a new way of detecting the protons released during DNA synthesis. However, unlike their competitors, DNAe strived to push this directly into the clinical realm.

Helicos Biosciences also came along in 2003 with a new approach. Their single molecule fluorescent sequencing was designed to reduce NGS costs. This attracted serious investment, raising more than $50m in funding.

In 2004, Pacific Biosciences introduced their long-read technology and joined the race too.

Now there were lots of players, but nothing in NGS had come to market… That all changed in 2005.

Jonathan Rothberg

Under Rothberg’s leadership, 454 went commercial with the first NGS system. If the NGS race was a triathlon, 454 had left the water first.

Solexa didn’t stay quiet for long though. In a reverse merger, they acquired failing gene expression company Lynx Therapeutics – hoping to complement each other’s management, technology and market infrastructure.

The move was a piece of economic genius. Two companies, one worth $12m and one worth £20m, quickly became a $200m NGS corporation. Their system, the Genome Analyzer, went commercial in 2006.

Solexa’s technology hit the ground running. Although 454 had gone to market quickest and their read length was longer, Solexa’s cost and speed quickly made them the choice for most customers.

It all looked like Solexa were ready to dominate this multi-billion-dollar industry.

Enter Illumina…

With a $650 million deal, Illumina acquired Solexa and became an NGS powerhouse almost overnight. Despite not having their own platform, the San Diego company’s impressive infrastructure and capital meant it could push NGS into the market and develop its systems even more.

Today’s industry leader, Illumina, were now a runner, but NGS was still making headlines elsewhere.

Understanding NGS’ potential, Rothberg wanted to showcase the full power of the technology. Harnessing the power of the cold call, he managed to convince genetic researcher Svante Pääbo that he could help with his work on the genome of the Neanderthal - doing it quicker and cheaper.

In 2006, together they showcased the power of NGS and initiated the Neanderthal Genome Project, using NGS to work out the connections between the two species.  

This exciting project was short-lived by Rothberg though.

One year on, after he’d lost voting control of 454, his company was acquired by Roche for $159m. That next morning, the man who’d first brought NGS into the world, woke up out of a job and had no further involvement in the Neanderthal Genome Project.

Still to this day, Rothberg remains the only person who knows what ‘454’ stands for.

Heading into 2008, Illumina’s dominance continued, owning most of the market.

Helicos – remember them – did take their first order for their system but could not compete. The company was forced to cut its sales forecast and trim its workforce down considerably.

Two years later, Rothberg re-emerged with his company Ion Torrent Systems, who were now ready to release their own system.  This led to a $725m acquisition by Life Technologies who were attracted by Rothberg’s new Ion Torrent system - you can’t keep that man down.

Life Technologies later went on to be acquired by Thermo Fisher for $13.bn.

By 2011, the 454 business wasn’t going how Roche had planned. To combat this, they moved to acquire Illumina in a hostile takeover worth $6.2bn. However, the offer was rebuffed and Roche opted to walk away.

Soon after, casualties started to fall as Illumina’s dominance reigned supreme.

First to go were Helicos, who filed for bankruptcy soon after they were sued by Illumina for patent infringements.

They were quickly followed by Roche’s 454 business, which was shut down in 2013.

This sad 454 news for Rothberg was sweetened by the exciting introduction of his ‘Gene Machine’. No, not his latest genomics innovation. This was his $55m luxury yacht with an on-deck lab bench. That’d put a smile on any scientist’s face.

Challengers like Oxford Nanopore have come into the fray in recent years, while new start-ups continue to explore methods to bring down the costs of NGS and simplify the process. Genapsys have announced the launch of their iPad sized system, while others including Stratos Genomics, Omniome and Quantapore are closing in on commercialisation.

The number of transistors on a microchip doubles every two years, though the cost of computers is halved. Therefore, we can expect the speed and capability of our computers to increase every couple of years, and we will pay less for them.

Moore's Law

Now we arrive in 2019, 20 years on from that revolutionary pub talk. Illumina dominate the market and claim to have the $100 dollar genome within their sight. That’s an exciting prospect to leave you with, considering that NGS is going at twice the rate of Moore’s law.

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By George Coe

George Coe works across genomics and cellular biology, partnering with companies and candidates who are at the very forefront of research today. He is fascinated by the way in which genomics is going to affect our everyday lives and the growing regulations surrounding the technology.

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