By Julia Karow
This article has been updated to include information about Roche/IBM and Genia.
2011 will likely be remembered as the year of the desktop sequencers, as Life Technologies and Illumina launched rival systems that have been fighting for market share — a competition bound to continue in 2012.
As Life Tech's Ion Torrent and Illumina's MiSeq started to gain a foothold in the market, joining Roche's 454 GS Junior desktop sequencer, customers' appetite for high-throughput sequencing systems appeared to level off in 2011, reflected in lower-than-expected sales of both Illumina's market-leading HiSeq 2000 and Life Tech's 5500 Genetic Analysis System.
Other sequencing vendors also ran into financial troubles last year. Pacific Biosciences saw slower-than-anticipated adoption of its single-molecule real-time sequencer, prompting it to lay off almost 30 percent of its staff in late summer, while Helicos BioSciences, reduced to a crew of 10, failed to implement a diagnostic strategy for its single-molecule sequencing technology and continues to hover on the brink of bankruptcy.
In the meantime, a handful of other players — including Oxford Nanopore Technologies, GnuBio, Roche/IBM, Nabsys, NobleGen Biosciences, Stratos Genomics, Genia, Intelligent Bio-Systems, and LaserGen — are working on sequencing platforms, some of which may enter the market this year and will be based on alternative technologies.
In the sequencing services market, China's BGI established itself as a dominant force in 2011, engaging in multiple large-scale projects and establishing collaborative sequencing facilities in North America and Europe. The "sequencing factory," with its large-scale centers in Hong Kong and Shenzhen, is increasingly competing with local sequencing services across the world.
For human whole-genome sequencing services, Complete Genomics and Illumina vied for market share in 2011, driving down prices to $4,000 per genome in the process.
While vendors of sequencing platforms and services competed aggressively in the marketplace, they also continued to fight each other in the courts, with several patent infringement lawsuits ongoing involving Illumina, Life Tech, PacBio, Complete Genomics, and Helicos either as plaintiffs or defendants.
The Desktop Wars
Life Tech launched its Ion Torrent Personal Genome Machine in late 2010 and said in January 2011 that it had booked 60 orders and shipped the first systems (IS 1/11/2011).
Initially, the PGM, which costs $50,000 but also requires a Torrent Server, had a nominal output of about 10 megabases per run, using the Ion 314 chip, but its performance increased steadily over the course of the year.
During the summer, Life Tech released the Ion 316 chip, which has an output of about 100 megabases, as well as the Ion OneTouch, a $5,000 microfluidic sample prep device that streamlines the emulsion PCR process.
Later in the year, the company reduced library prep time to two hours, increased the read length to 200 base pairs (IS 10/18/2011), and released a paired-end sequencing protocol (IS 12/20/2011). As of October, the total workflow for the PGM, from DNA to sequence, took eight hours.
Life Tech originally planned to release the Ion 318 chip, which will increase the PGM's output to about 1 gigabase per run, before the end of the year, but the chip was not yet available for order on its website as of this week.
Illumina launched its MiSeq sequencer in September, following an early-access program during the summer. The $125,000 instrument, which provides integrated sample preparation, can produce 120 megabases of short reads in a total of four hours at the low end, and more than a gigabase from 150-base paired reads in 27 hours at the high end.
As of mid-October, the company had taken orders for 135 instruments and had shipped 45 MiSeq systems (IS 10/11/2011).
But even before MiSeq was launched, Illumina and Life Tech engaged in a fierce battle about which system provides faster and better data. The outbreak of a pathogenic strain of Escherichia coli in Europe last summer, for example, prompted Illumina to compare E. coli data produced internally on its MiSeq with publicly available Ion Torrent data of the outbreak strain. While the company touted the higher output per run and raw read accuracy of its MiSeq, Ion Torrent users pointed out the PGM's flexibility in experimental design and its expected future performance (IS 7/5/2011).
Later in the summer, Ion Torrent and Illumina both released analyses of each other's data, each claiming its own system provides more accurate data, while scientists posted their own data comparisons (IS 9/13/2011).
Both Life Tech and Illumina have high hopes for their desktop sequencers in the clinical market, as several labs have begun to use the MiSeq and PGM for clinical applications. Both companies plan to submit their platforms for 510(k) approval by the US Food and Drug Administration later this year.
Likewise, Roche said in October that the number of 454 GS Junior platforms in clinical and translational labs is growing, and that it expected "strong instrument placements" by year's end (IS 10/18/2011).
As desktop sequencers made a splash in 2011, sales of high-throughput sequencing systems began to level off during the year. For the third quarter, Illumina reported lower-than-expected sales of its HiSeq 2000 and reduced reagent sales, citing a "temporary" excess in sequencing capacity in the market as well as uncertainties of research funding and the overall economy (IS 10/11/2011). As a result of its overall reduced revenues, Illumina laid off 200 employees, or about 8 percent of its workforce (IS 11/1/2011).
Earlier in the year, Illumina had tripled the output of the HiSeq 2000, to about 600 gigabases per run, through new consumables, an increase in capacity that it later blamed in part for the decreased HiSeq consumables sales.
Budget cuts for the three genome centers funded under the National Human Genome Research Institute's large-scale sequencing program — the Broad Institute, the Genome Institute at Washington University, and the Human Genome Sequencing Center at Baylor College of Medicine — may have been another contributing factor (IS 12/6/2011).
Life Tech early in the year reported a delay in the manufacturing of its 5500 Genetic Analysis System, the successor to the SOLiD 4, related to the March earthquake in Japan, where the system is built by its partner Hitachi (IS 8/2/2011). But even in the third quarter, after those problems were overcome, Life Tech reported lower-than-expected sales for the 5500 (IS 11/2/2011).
At least for the moment, SOLiD and 5500 seem to have lost market share to Illumina's HiSeq, the preferred high-throughput platform of most genome centers. Even some centers who made big investments in SOLiD in 2010 appear to have turned away from the platform: for example, the German Cancer Research Center, which said in 2010 that it would open a facility with 10 SOLiD machines, currently has about half that number of SOLiDs and 5500s combined and is building out its HiSeq fleet (IS 12/7/2011). Meanwhile, the Genome Sciences Centre of the BC Cancer Agency, which purchased 10 SOLiDs in 2010 (IS 4/13/2010), no longer mentions the platform on its website and its director, Marco Marra, told In Sequence last month that he cannot comment on the instruments. The center currently has 12 HiSeq machines and plans to add more.
Roche's 454 Life Sciences launched its long-awaited GS FLX+ upgrade in the summer, enabling 1-kilobase reads, and said in the fall that the uptake has been exceeding its expectations (IS 10/18/2011). But there are early signs that the platform's best days might be over: the Department of Energy's Joint Genome Institute, for example, recently phased out its 454 machines, replacing them with Illumina and Pacific Biosciences instruments (IS 11/8/2011).
Tough Times for Single-Molecule Sequencing
Pacific Biosciences and Helicos BioSciences, both providers of single-molecule sequencing technology, faced difficult times last year, with the former trying to establish its platform in the marketplace and the latter searching for a new business model.
Following its IPO in late 2010, PacBio started the new year with 11 early-access customers and 38 orders for its $695,000 PacBio RS systems (IS 2/22/2011). In May, it shipped its first two commercial-grade instruments to customers, which generate 35 to 45 megabases of data per SMRT cell with a raw read error rate of 15 percent and an average read length of 1,500 base pairs.
But during the first half of the year, the company only booked 13 new orders for its instrument, and in September, it laid off 130 employees, or almost 30 percent of its workforce, as a result of the slow adoption rate (IS 9/20/2011).
In the third quarter, the company booked another seven orders and had a total installed base of 31 instruments (IS 11/1/20011). It delayed a chemistry upgrade, called C2, that will increase the average read length to 2,700 bases, lower the raw read error rate to 13 percent, and double the SMRT cell output to 90 megabases, until the first quarter of 2012.
As of October, customers were still experiencing problems with reliability and variability of their instruments, the company said, though one of PacBio's early-access customers, JGI, already purchased a second RS sequencer for microbial sequencing applications. Other customers, such as the Ontario Institute of Cancer Research, have been using their instrument for targeted resequencing of cancer genes (Clinical Sequencing News 8/3/2011).
Helicos BioSciences scaled back service and reagent supplies for its remaining customers in 2011 as it focused on deploying its single-molecule sequencing technology for molecular diagnostic applications. Though the company generated some revenue from sequencing service work, it was unable to partner with a CLIA lab and commercialize any MDx tests and was forced to reduce its headcount to 10 employees in the summer (IS 8/16/2011). The firm, which continues to assert its intellectual property in the courts, received a $700,000 cash advance from two of its investors last month after almost depleting its financial resources (IS 12/6/2011).
New Platforms Behind the Curtain
Several new sequencing platforms remain in development, some of which may make their debut this year. Early in 2011, Oxford Nanopore Technologies presented its GridIon platform, an electronic nanopore sensing system that will be at the core of the exonuclease DNA sequencing, strand DNA sequencing, and protein analysis systems it is developing (IS 3/15/2011).
In the spring, the company raised about $41 million from new and existing investors, including its partner Illumina, to develop the GridIon platform further, and over the summer, it expanded its labs and opened an informatics facility in Cambridge, UK. Though Oxford Nanopore has not provided a timeline for the commercial launch of its system, a representative of a genome center told In Sequence last month that he looks forward to testing the system soon.
GnuBio, based in Cambridge, Mass., also developed its droplet-based sequencing technology further towards commercialization. In the spring of 2011, the firm said that it had demonstrated proof of principle, sequencing a PCR amplicon with high fidelity (IS 4/12/2011), and during the summer, it shipped an alpha instrument to the Pharmacogenomics Centre at the Montreal Heart Institute, its first early-access user.
Last month, the company said that it has started to build beta versions of its instrument, which it plans to commercialize in the second quarter of 2012. The system will provide 1-kilobase reads, will have a list price of $50,000, and a turnaround time of two hours for targeted sequencing (IS 12/13/2011).
Roche and IBM continued to work on their single-molecule sequencer in 2011, which will use IBM's "DNA transistor" technology to slow down the molecule. In the fall, Roche licensed readout technology developed at the Biodesign Institute at Arizona State University and at Columbia University that is based on recognition tunneling, and plans to incorporate it into its new platform (IS 10/11/2011).
Other companies that have been developing alternative sequencing technologies include Providence, RI-based Nabsys, which raised $10 million last summer to develop its semiconductor-based single-molecule sequencing-by-hybridization system (IS 9/20/2011); Concord, Mass.-based NobleGen Biosciences, which is working on nanopore sequencing of converted DNA with optical detection (IS 6/14/2011); Seattle-based Stratos Genomics, which raised $2.1 million last summer to develop its nanopore-based sequencing-by-expansion technology (IS 6/14/2011); Mountain View, Calif.-based Genia, which is developing a biological nanopore-based technology and recently closed a Series A round with a "publicly held global biotech company" (IS 10/25/2011); Waltham, Mass.-based Intelligent Bio-Systems, which launched a sequencing-by-synthesis sequencer called Max-Seq this year in collaboration with Dover and Azco BioTech (IS 8/9/2011), and which plans to commercialize a low-cost SBS sequencer (IS 3/29/2011) based on its reversible terminator chemistry; and Houston-based LaserGen, which raised $5 million last summer to develop an SBS sequencer that uses its "Lightning Terminator" chemistry (IS 8/30/2011).
BGI's Global Expansion
China's BGI — formerly known as the Beijing Genomics Institute — continued to expand around the world in 2011, establishing itself further as a provider of large-scale sequencing services. At least some local service providers have started to feel threatened by BGI's competition (IS 11/29/2011).
BGI also emerged as a collaborator in numerous international sequencing projects, such as the Earth Microbiome Project, the 1,000 Plant and Animal Genome Project, the Genomes 10K project, the International Cancer Genome Consortium, the LUCAMP consortium, the Netherlands Genome Project, the African Orphan Crops consortium, and Autism Speaks.
The institute also partnered on research projects with a number of academic institutions in the US, Europe, and Australia last year, as well as with pharmaceutical companies, including GlaxoSmithKline, Pfizer, and Merck.
In the US, BGI and the Children's Hospital of Philadelphia opened a joint genome center in the fall, called BGI@CHOP (CSN 11/9/2011). In addition, BGI plans to open a sequencing facility in partnership with the University of California, Davis, called BGI@UC Davis (IS 11/1/2011), in Sacramento next year.
In the meantime, BGI Europe has been working toward the opening of a new sequencing facility in Copenhagen, Denmark (IS 7/5/2011). Last summer, BGI also signed an agreement with the Hungarian government to establish BGI Central Europe in Budapest, though no details about that new center are available yet.
Complete Genomics vs. Illumina Genome Network
Complete Genomics and Illumina, through its Illumina Genome Network, continued to compete for human whole-genome sequencing service contracts in 2011, leading to a further erosion of prices for human genome sequencing. A recently published comparison of the two platforms by a group at Stanford University concluded that both provide high-quality data, but that each misses a large number of true variants (IS 12/20/2011).
Complete, which went public in 2010, landed a number of large-scale contracts last year, including 615 samples from the Institute for Systems Biology, more than 1,000 samples from the National Cancer Institute, and 1,500 samples from the Inova Translational Medicine Institute. As of early November, it had received orders for 6,100 human genomes in 2011 (IS 11/8/2011), and as of last month, it expected to deliver 3,200 genomes in the entire year, fewer than originally planned because of a temporary sample prep problem (IS 12/20/2011).
In addition to paid sequencing contracts, the company is also contributing 1,000 genomes to the Wellderly Study of the Scripps Science Translational Medicine Institute as well as 500 genomes to the 1000 Genomes Project for free.
As of August, Complete had reduced its prices to $4,000 per genome for orders of more than 50, with additional discounts for very large orders (IS 8/9/2011). In the fall, it also introduced a cancer genome sequencing service, at $12,000 for a tumor/normal pair and $18,000 for a tumor/normal/metastasis trio (CSN 10/12/2011).
By the middle of 2012, the company plans to install a new generation of sequencing instruments that will increase the current throughput of one genome per day and instrument to six and eventually 10 genomes per day (IS 11/8/2011).
To increase its cash, late last month, Complete filed to raise up to $100 million in a public offering.
Illumina, meantime, said last spring that its IGN had received orders for more than 1,000 human samples, which are sequenced by the company as well as its partners. Illumina also lowered its price for human whole-genome sequencing to $4,000 per sample for projects with at least 50 samples (GenomeWeb Daily News 5/9/2011). During the second quarter, it took orders for at least 1,750 additional genomes, from Cancer Research UK and Knome, and during the third quarter, it added orders for another 950 samples, from Stanford University and an undisclosed biotechnology company.
The University of Washington's Department of Genome Sciences and the British Columbia Cancer Agency's Genome Sciences Centre joined IGN as additional partners.
Have topics you'd like to see covered in In Sequence? Contact the editor at jkarow [at] genomeweb [.] com.