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As GA, SOLiD, GS FLX Gain Traction, New Players Ready Their Technologies

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As 2008 comes to a close, DNA sequencing has chalked up new milestones: Vendors of second-generation systems have increased read length and throughput of their instruments, facilitated paired-end sequencing, and lowered the cost of sequencing, and users have sequenced a number of human genomes entirely on second-generation platforms.
 
At the large genome centers, second-generation sequencing moved from the testing stage into production as the centers scaled up their fleets of instruments and reduced the number of installed Sanger capillary electrophoresis sequencers (see In Sequence 10/7/2008).
 
Indeed, several new centers emerged this year that are solely equipped with multiple second-generation systems.
 
Also in 2008, a large number of smaller users, including academic core facilities, adopted second-generation sequencing, and are using the new tools for applications ranging from ChIP sequencing to RNA-seq to de novo sequencing of bacterial and resequencing of human genomes.
 
Several large-scale research projects got underway this year that depend heavily on high-throughput sequencing. Among such projects are the 1,000 Genomes Project, the 1,001 Arabidopsis Project, the International Cancer Genome Consortium, the International Human Microbiome Consortium, and the Roadmap Epigenomics Program.
 
New computational tools have also helped increase applications on second-generation sequencers, including the ability to generate de novo assemblies of bacterial genomes from short reads and calling variants in human genomes that have been resequenced with the new technologies.
 
The technologies hit a milestone this year with the publications of several human genomes resequenced entirely on second-generation platforms. However, these genomes were not assembled de novo.
 
In addition, a number of companies have been working on ancillary technologies for selecting and separating specific regions of the genome for sequencing, among them Roche NimbleGen, Agilent Technologies, Febit, and RainDance Technologies. However, researchers have yet to publish research studies in which these technologies are applied on a large scale.
 
Three vendors continue to dominate the market for second-generation sequencing systems: Illumina, Applied Biosystems (since November part of Life Technologies), and Roche’s 454 Life Sciences. Two other companies, Helicos BioSciences and Danaher Motion’s Dover, shipped sequencing systems to a small number of early-access customers this year.
 
And two new players in the sequencing market, Complete Genomics and Pacific Biosciences and, revealed their technologies this year and said they will begin to commercialize them in 2009 and 2010, respectively.
 
While PacBio plans to sell instruments that provide long reads and high throughput, Complete Genomics promises to offer a $5,000 human genome-sequencing service next year.
 
Meanwhile, a number of other academic and commercial players are working on additional sequencing technologies, most of which are still in early development.
 
Illumina
 
Illumina saw widespread adoption of its Genome Analyzer sequencer this year, both at genome centers and at smaller institutions.
 
Early in the year, the company began shipping an upgrade of its instrument, the Genome Analyzer II, which tripled to 3 gigabases the output per paired-end run and included hardware changes. In April, the San Diego-based company also started shipping paired-end modules for the GA II that enable customers to generate paired reads (see In Sequence 4/29/2008).
 
During the summer, Illumina began to look beyond the GA technology, which it acquired with its purchase of Solexa in early 2007. For instance, the company announced the acquisition of Avantome for up to $60 million. The startup firm, founded earlier in the year by pyrosequencing inventor Mostafa Ronaghi at the Stanford Genome Technology Center, has been developing technology that Illumina believes will compete with traditional Sanger sequencing, presumably by offering longer reads (see In Sequence 7/29/2008).
 
In October, Illumina said that customers had begun routinely generating 7 gigabases of data per run on a single instrument, and that in-house the company has achieved runs beyond 15 gigabases. It also started beta-testing a new chemistry that it said could allow customers to obtain reads of 100 base pairs and longer, which it hopes will enable de novo sequencing of genomes (see In Sequence 10/28/2008).
 
The following month the company published a detailed description of Solexa sequencing technology as part of a paper in which it sequenced a human genome from a HapMap individual. Two other human genomes sequenced with the platform were published the same week: the genome of an AML patient’s cancer and of a healthy Chinese individual (see In Sequence 11/11/2008).
 
These and other advances have enabled Illumina’s platform to become the dominant second-generation sequencer at large genome centers. As of early October, almost 90 GAs were installed at seven established genome centers in the US, Europe, and Asia, representing almost 60 percent of all second-generation sequencers installed at these centers.
 
Later that month, Illumina — which has not revealed the number of installed GAs since the end of 2007, when there were 200 — said that 30 percent of its sequencers are housed at genome centers.
 
ABI/Life Technologies
 
Applied Biosystems launched its SOLiD system in October 2007. The company, which merged with Invitrogen last month to form Life Technologies (see In Sequence 6/17/2008), started shipping version in May.
 
The upgrade, which includes new chemistry but no hardware changes, doubled the output per instrument run to 6 gigabases (see In Sequence 4/29/2008). In the summer, the company said some customers had already obtained almost 15 gigabases of data in a single run, and that ABI in-house had generated more than 20 gigabases in a run. 
 

The new technologies hit a milestone this year with the publications of several human genomes resequenced entirely on next-generation platforms.

In July, ABI said it had taken almost 100 orders for the SOLiD system (see In Sequence 7/29/2008). At large established genome centers, the platform appears to not yet have gained the same traction as Illumina’s Genome Analyzer, which was launched almost a year earlier, and against which the SOLiD directly competes.
 
As of early October ABI had placed approximately 20 SOLiD units at seven of these genome centers, representing around 15 percent of their collective second-generation instrument fleets.
 
ABI, now called Life Technologies, has said it plans to launch SOLiD 3.0 in early 2009, which will include changes in both hardware and reagents. That version will increase the read length to 50 base pairs and enable customers to generate 20 gigabases of data per run initially, the company said (see In Sequence 9/30/2008).
 
One challenge ABI may face with SOLiD is penetration of customer sites that already have Genome Analyzers installed, since these customers don’t seem to find appreciable differences between the two systems’ capabilities.
 
Notably, the Wellcome Trust Sanger Institute recently returned five SOLiD instruments that ABI had placed at the institute a year ago for a research collaboration (see In Sequence 12/16/2008). The center took this step shortly after deciding to expand its fleet of Illumina GAs by 11 instruments. The reason was not quality differences between the SOLiD and the GA, according to the institute, but the lower cost of adding GAs to its existing pipeline (see In Sequence 11/18/2008).
 
454 Life Sciences
 
Roche’s 454 Life Sciences continued this year to build on the key advantage that its sequencing platform has over the other two second-generation platforms: longer reads.
 
Its platform, which has been on the market for almost four years, has been used in a variety of published studies, among them bacterial de novo sequencing, human resequencing, transcriptome sequencing, ancient DNA analysis, and metagenomics.
 
In April, 454 and its Baylor College of Medicine collaborators published the genome of Jim Watson, the first human genome to be sequenced with a second-generation technology (see In Sequence 4/22/2008), although the researchers did not perform a de novo assembly.
 
But the company has set its eyes on the de novo assembly of eukaryotic genomes and said this fall that its customers have already used its technology to sequence Arabidopsis, Drosophila, and apple de novo.
 
In August, a research team from the Max Planck Institute in Germany published the mitochondrial genome of a Neandertal individual based on data generated by 454. By the end of this year, the company plans to complete data production for a 1-fold coverage of that genome (see In Sequence 8/12/2008).
 
The following month, 454 launched the Titanium set of reagents and consumables for its Genome Sequencer FLX, which increased the average read length to between 350 and 400 base pairs; and the throughput per run, which rose to about half a gigabase in less than a day compared with the multiple-day runs required by its two competitors (see In Sequence 9/30/2008).
 
With the increased read length, 454 said it hopes to take over additional applications from Sanger sequencing. 454 has not yet publicly announced its plans for improving the platform, but has hinted that a five-fold improvement in output per run over the next one to two years appears feasible.
 
Several of 454’s customers are also exploring using the platform for diagnostic purposes, such as genotyping HIV strains and sequencing disease genes (see In Sequence 9/9/2008).
 
As of this fall, seven established large genome centers had installed approximately 40 454 platforms, or almost 30 percent of all total second-gen instruments at those centers.
 
Helicos BioSciences
 
Helicos BioSciences placed its Helicos Genetic Analysis with its first customer, service provider Expression Analysis, in March. A second instrument went to Stanford University in October, and Helicos said last week that it will place a system at no cost at the Broad Institute in early 2009.
 
This spring, Helicos published a proof-of-concept study for its single-molecule sequencing technology in which it sequenced the M13 virus using an early version of the technology.
 
This summer, the company acknowledged that it had experienced problems with unstable reagents that it said prevented it from obtaining additional orders for its system.
 
In September, Helicos researchers showed data on bacterial genome resequencing and digital gene expression studies at a conference (see In Sequence 9/30/2008).
 
Later that month the company said it had $12.3 million in unrestricted cash and $10.5 million in restricted cash left, and said it expected a burn rate that would leave it with less than $4.8 million in unrestricted cash by the end of the year (see In Sequence 11/11/2008).
 
Earlier this month the company replaced its CEO, and said it would lay off 30 percent of its workforce by the end of the year. Two weeks later, it said it expected to raise approximately $17.9 million in net proceeds from a private placement of stock at institutional and current investors (see Short Reads, this issue).
 
Danaher Motion – Dover
 
Dover, a unit of Danaher Motion, in collaboration with George Church’s group at Harvard Medical School, has developed a low-cost open-source sequencer, dubbed the Polonator. The company debuted the technology in February at the Advances in Genome Biology and Technology meeting in Marco Island, Fla.
 
The system is designed to use different chemistries, including Church’s short-read polony sequencing chemistry. Based on feedback from the Church lab, which received several instruments this year, Dover has made changes to the fluidic system, redesigned the flow cells, and made other improvements to the hardware, software, and protocols of the platform.
 
Other early-access Polonator users include the Broad Institute, the Max Planck Institute for Molecular Genetics in Berlin, and the University of New Mexico.
 
Dover President John Therriault told In Sequence last week that the company expects to release the Polonator broadly during the first quarter of 2009 and plans to release sequence performance data and details about reagent kits at that time.
 
Complete Genomics
 
In October, Complete Genomics, which has been working quietly in its Mountain View, Calif.-based labs for two years, revealed its short-read sequencing-by-probe-ligation technology and business strategy (see In Sequence 10/7/2008).
 
Starting in the second quarter of 2009, the company said it plans to offer human genome-sequencing services for $5,000 per genome.
 
Prior to that, in a proof-of-concept study in collaboration with its first customer and partner, the Institute for Systems Biology, Complete Genomics said it plans to sequence five human genomes from a single family.
 
Also next year, the firm wants to sequence 1,000 human genomes as pilot projects for customers, followed by 20,000 genomes in 2010.
 
However, the company has yet to publish a study in a peer-reviewed journal that shows the capabilities of its technology.
 
Complete Genomics was co-founded by Rade Drmanac, who had been developing a combinatorial probe-ligation chemistry for sequencing at his former company, Callida Genomics (see In Sequence’s sister publication, GenomeWeb Daily News, 5/30/2006).
 
Besides its current sequencing technology, Complete Genomics, in partnership with BioNanomatrix, is also working on another technology that combines DNA sequence with long-range structural information. Last year, the two companies won an $8.8 million grant from the National Institute of Standards and Technology for this long-term project (see In Sequence 10/2/2007).
 
As of this fall, Complete Genomics had raised a total of $46 million in private equity.
 
Pacific Biosciences
 
After operating quietly for a number of years, Pacific Biosciences, founded in 2004 as Nanofluidics, stepped into the open at the AGBT meeting this year when it revealed details about its single-molecule real-time sequencing technology (see In Sequence 2/12/2008).
 
PacBio this spring acquired intellectual property on sequencing-by-synthesis technology from Li-Cor Biosciences, which had also been developing a single-molecule sequencing technology (see In Sequence 6/3/2008)
 
In September, PacBio said it plans to start shipping its first instruments to customers in the second half of 2010, following an early-access program that is slated to begin next year [see In Sequence 9/30/2008).
 
The first commercial instrument will deliver reads that are similar in length to traditional Sanger-sequencing systems, while PacBio has yet to specify the throughput.
 
In October, the company showed sequencing data for the genome of bacteriophage φX174 and said it plans to present data from additional, more complex sequencing projects at AGBT in February (see In Sequence 10/14/2008).
 
The following month, PacBio published a proof-of-concept study with a detailed description of the technology, in which it showed that it can sequence short stretches of DNA (see In Sequence 12/2/2008).
 
The company raised $120 million in private equity this year, bringing its total fundraising to $193 million.
 
VisiGen Biotechnologies
 
VisiGen Biotechnologies, like PacBio developing a single-molecule real-time sequencing technology, was acquired by Invitrogen for $20 million this fall (see In Sequence 10/28/2008).
 
Invitrogen — which has since merged with Applied Biosystems to form Life Technologies — said that the company’s intellectual property enhances its own portfolio, and that VisiGen’s technology complements its own efforts in developing a third-generation sequencing technology.
 
The life-science giant first mentioned this internal program earlier this year (see In Sequence 6/17/2008).
 
VisiGen has yet to publish a proof-of-concept study of its technology, which measures interactions between a labeled DNA polymerase and labeled nucleotides using fluorescence resonance energy transfer (see In Sequence 5/8/2007).
 
Oxford Nanopore Technologies
 
Oxford Nanopore Technologies has been working on establishing itself as the dominant commercial player in nanopore-based DNA sequencing this year.
 
The company, which changed its name from Oxford NanoLabs this summer, was co-founded by Hagan Bayley, a professor at the University of Oxford who has developed protein nanopore technology, and is currently working on a sequencing technology that couples an exonuclease with a protein nanopore.
 
This summer, the company licensed intellectual property from Harvard University that covers both biological and solid-state nanopore technology and complements its own portfolio (see In Sequence 8/12/2008).
 
Oxford Nanopore is also collaborating on a nanopore project with a number of European research groups as part of a consortium to develop new DNA-analysis technologies that began this summer and is funded with €12 million ($16.6 million) by the European Union (see In Sequence 12/9/2008).
 
The company has not yet provided a timeline for when it expects to begin selling its first sequencing platform.
 
As of this spring, it had raised approximately £18 million ($26.8 million) in funding from non-VC institutional and private investors (see In Sequence 4/8/2008).
 
Other Players
 
Other commercial players in the DNA sequencing technology sector are also at early stages in their development, or have kept a low profile this year.
 
Among them is Intelligent Bio-Systems, which said more than a year ago that it was going to commercialize a high-throughput clinical sequencer this year that is based on a sequencing chemistry developed by Jing Ju at Columbia University.
 
IBS President and CEO Steve Gordon told In Sequence last week that the company is currently “completing initial trials” with a prototype system and plans to start testing a commercial prototype “at one or two large laboratories” in the first quarter of 2009. He said that the current prototype produces sequence data “at similar read lengths and quality levels as some of the other commercial systems.”
 
Other nascent players include Sequenom, which licensed nanopore technology last year that was developed by Amit Meller, a professor at Boston University; NABsys, which is working on hybridization-assisted nanopore sequencing; ZS Genetics and Halcyon Molecular, which are both working on electron-microscopy-based sequencing; Genome Corp., which said a year ago that it was planning to establish a sequencing “factory” based on Sanger electrophoresis sequencing); Genizon BioSciences, which has been developing a shotgun sequencing-by-hybridization resequencing technology that it is seeking to commercialize; and Lightspeed Genomics.

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