History of sequencing by synthesis

The evolution of the next-generation sequencing technology powering Illumina instruments

History of Illumina Sequencing

What began as “blue-sky” research in the Chemistry Department of Cambridge University evolved into the revolutionary sequencing by synthesis (SBS) technology that is the foundation of Illumina sequencing instruments.

Sequencing Technology Video
Sequencing Technology Video

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In the mid-1990s, Cambridge scientists Shankar Balasubramanian, Ph.D. and David Klenerman, Ph.D. were using fluorescently labeled nucleotides to observe the motion of a polymerase at the single molecule level as it synthesized DNA immobilized to a surface.

The contributions of Cambridge scientists to the first draft of the human genome, and the University’s rich history of DNA research by Alexander Todd, James Watson, Francis Crick, and Fred Sanger, inspired Drs. Balasubramanian and Klenerman to theorize how this approach might be used to sequence DNA.

A series of creative discussions in the lab and at a local pub during the summer of 1997 sparked ideas surrounding the use of clonal arrays and massively parallel sequencing of short reads using solid phase sequencing by reversible terminators (subsequently referred to as sequencing by synthesis technology, or SBS). This became the basis of a new DNA sequencing approach.

Balasubramanian and Klenerman approached the venture capital firm Abingworth Management and obtained initial seed funding to form Solexa in 1998. Early research and development work was conducted in the Cambridge Chemistry Department until 2000, when Solexa’s corporate facilities were established at Chesterford Research Park.

In 2001, the team’s research progress attracted £12 million in Series A funding, enabling it to build its management team. Three years later, Solexa acquired molecular clustering technology from Manteia. The amplification of single DNA molecules into clusters enhanced the fidelity and accuracy of gene calling, while reducing the cost of the system optics through generation of a stronger signal.

One year later, the team sequenced the complete genome of bacteriophage phiX-174, the same genome Sanger first sequenced using his method. However, the SBS technology generated significantly more sequence data, delivering over 3 million bases from a single run.

In 2005, Solexa acquired instrumentation company Lynx Therapeutics in a reverse merger, becoming an international public company (NASDAQ) with offices in Chesterford, UK and Hayward, CA. Engineering and software production teams based in Hayward immediately went to work transforming the successful Solexa prototype into a commercial sequencing instrument.

The first Solexa sequencer, the Genome Analyzer, was launched in 2006 and gave scientists the power to sequence 1 gigabase (Gb) of data in a single run.

Solexa was acquired by Illumina in early 2007. In the intervening years, numerous microbe, plant, human, and animal genomes have been sequenced with this technology. Next-generation sequencing (NGS) data output has increased at a rate that outpaces Moore's law -- more than doubling each year.

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One Decade of Sequencing

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Through refinements and optimization, the latest generation of Illumina SBS technology-based instruments can generate multiple terabases (Tb) of data per run. With this enormous increase in the ability to generate sequencing data, researchers can move quickly from ideas to data in a matter of hours or days. We have only just begun to tap the strength of this technology... stay tuned for further developments.

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