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Next-Generation Platforms Sprout in ’07, Prep for Competition to Heat Up Next Year

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It has been an eventful year for new DNA sequencing technologies and their developers.
 
The first half of 2007 was marked by several sequencing vendors repositioning themselves in the market, including two acquisitions and one initial public offering.
 
Several new platforms reached the market in 2007 and started to be rapidly adopted by customers. Other sequencing technologies are still being developed and may roll out next year, while the National Institutes of Health continued to fund promising long-term technologies aiming to hit the $1,000 genome mark.
 
Already, the new technologies have proven themselves in a variety of applications, including human whole-genome sequencing. Next year and beyond, researchers will use them in a number of large-scale research projects.
 
Vendors Reshuffle
 
The first half of the year saw several next-gen sequencing technologies change hands. In early February, Illumina completed its $615 million acquisition of Solexa, which brought together Solexa’s reversible-terminator-based sequencing-by-synthesis technology and Illumina’s BeadArray microarray and VeraCode digital microbead technologies (see In Sequence 1/2/2007).
 
Later that month, Helicos BioSciences filed for an initial public offering on the Nasdaq exchange. Initially, the company aimed to raise $68 million in net proceeds (see In Sequence 5/15/2007), but when its stock began trading in late May it wound up netting around $43.2 million.
 
The following month, in March, Roche announced that it would purchase its partner 454 Life Sciences from CuraGen for $154.9 million (see In Sequence 4/3/2007). Since 2005, Roche had marketed 454’s Genome Sequencer under a distribution agreement and had funded research activities at 454.
 
The acquisition, under which 454 stockholders eventually received $152 million, closed in late May, making 454 a subsidiary of Roche Applied Science, a business area of Roche Diagnostics.
 
To Market, to Market
 
Early in the year, Roche and 454, based in Bradford, Conn., launched the Genome Sequencer FLX, the successor to the Genome Sequencer 20, which had been on the market since the spring of 2005. The new model, which costs around $500,000, delivers reads between 200 and 300 bases in length and 100 megabases of data per run. According to users, a single run on the instrument costs around $10,000, translating to $100,000 per gigabase of data. By the end of 2006, 454 had an installed base of more than 60 instruments but 454 and Roche have since stopped providing information on placements.
 
In January, on the opposite coast, San Diego-based Illumina fully commercialized Solexa’s Genome Analyzer following an early-access phase that began in mid-2006 that sent 13 sequencers to 10 early-access customers.
 
According to the most recent specifications, the instrument delivers 1.3 gigabases of data per run with 35-base-pair reads, and twice that amount from paired-end libraries. As of mid-2007, the system listed for around $430,000 and the cost per gigabase of data was around $3,000.
 
The platform was rapidly adopted by customers. By late July, Illumina had received 95 orders for the instrument, more than half from customers outside the “core genome centers,” and increased its manufacturing and sales capacities to meet the demand.
 
The Broad Institute alone installed 16 units, and another, unnamed customer received 20 instruments. At the time, Illumina CEO Jay Flatley said the company’s sequencing business was “performing beyond our expectations, and holds great promise.” By late August, eight months after absorbing Solexa, Illumina had shipped 100 sequencers and said it plans to have an installed base of more than 200 instruments by the end of the year.
 
In June, up the coast in Foster City, Applied Biosystems shipped its first early-access SOLiD sequencers, and shortly afterwards, moved up to October 2007 the date for its full commercial launch (see In Sequence 10/30/2007), which was originally planned for early 2008.
 
At the end of October, the company was optimistic about the prospect of its new platform, but did not provide any numbers of orders or shipments. “We are pleased with the early order rates and diversity of more sophisticated sequencing customers, including genome centers, core academic labs, and commercial service labs from various parts of the world, placing orders for SOLiD,” ABI executive vice president Mark Stevenson said during a conference call.
 
According to ABI’s specification sheet, the SOLiD platform generates up to 3 gigabases of data per run with 35-base single reads, and up to 4 gigabases of data per run from 25-base paired-end reads. The entire system lists for $600,000, and as of mid-2007 the company said a gigabase of data would cost approximately $3,000 in reagents.
 
Other next-gen sequencing platforms are nearing commercialization. George Church’s group at Harvard Medical School, for example, has been developing a low-cost alternative to 454’s, Illumina’s, and ABI’s platforms designed to power Church’s Personal Genome Project.
 
The instrument, nicknamed the “Polonator,” will use open-source software and will be capable of supporting different sequencing biochemistries, among them Church’s polony sequencing-by-ligation chemistry.
 
The Church team recently hooked up with Danaher Motion’s Dover business, which plans to ship the first production units to customers by the end of the year (see In Sequence 12/4/2007). Though the exact specifications of the instrument are still being determined, it is expected to produce 10 gigabases of sequence data per run with 28-base reads and an initial running cost of $3,000 per gigabase. The system will cost approximately $150,000.
 
Helicos BioSciences has also been preparing to launch its single-molecule sequencing technology. At the end of October, Steve Lombardi, the company’s chief operating officer, said the company plans to ship the first HeliScope systems to initial customers “by the end of this year or soon thereafter.”
 
Helicos has yet to release key specifications of the instrument, including the amount of data per run, the average read length, and the reagent cost per base. The list price for the instrument is $1.35 million.
 
Another player that is preparing its market debut next year is Intelligent Biosystems, which licensed a sequencing-by-synthesis chemistry from Jing Ju’s lab at Columbia University. As of October, the company planned to launch its Pinpoint Sequencer, which targets both the research and the clinical sequencing market, some time in 2008 (see In Sequence 10/23/2007).
 
Read length and data per run have yet to be determined, but as of October the company planned to sell the instrument for under $300,000, while consumables will run less than $1,500 per gigabase.
 
What’s On Tap?
 
Other sequencing tech developers that have not yet announced their plans might also make their debut in 2008. Among them is Pacific BioSciences, formerly Nanofluidics, which has been working on a sequencing platform that is based on zero-mode waveguide technology developed by Watt Webb and Harold Craighead at Cornell University. Earlier this year, the company inadvertently disclosed some of its venture capital investors but has not yet confirmed the size of their investment or talked about its business plans.
 

“Nobody is hitting any roadblocks, as far as we can tell, so the science seems to be moving forward” for nanopore technologies.

Another player is Complete Genomics, which was co-founded by sequencing-by-hybridization-veteran Rade Dramanac. The company plans to commercialize a new sequencing chemistry it has been developing and said it will reveal more details in early 2008.
 
This fall, Complete Genomics won an $8.8 million joint grant with BioNanomatrix from the National Institute of Standard and Technology’s Advanced Technology Program to combine their two platforms into a low-cost sequencer, a long-term project (see In Sequence 10/2/2007).
 
Meanwhile, the National Human Genome Research Institute has continued to fund what it hopes will become the next crop of next-generation sequencing technologies. This summer, the agency announced $15 million in new research grants under its Advanced Sequencing Technology program to develop lower-cost technologies.
 
So far, the program’s track record has been impressive: 454’s, ABI’s and Helicos’ technologies were all at one point funded through the program, which since 2004 has given out $83 million in total grants.
 
One novel approach pursued by several NHGRI grant recipients is nanopore sequencing, though the technology has not been able to read an unknown DNA sequence base by base yet.
 
But researchers are still optimistic that this will be possible someday. “Nobody is hitting any roadblocks, as far as we can tell, so the science seems to be moving forward,” NHGRI program director Jeff Schloss said this summer about the concept of nanopore sequencing.
 
At least one DNA-analysis tool provider is betting on the nanopore approach: Sequenom said in September that it had exclusively licensed a nanopore array technology that is coupled to an optical readout (see In Sequence 10/2/2007). That technology is being developed by Amit Meller and colleagues at Boston University.
 
Applications
 
By and large, though users of the new technologies have been happy with the research opportunities the new sequencers provide, a consistent complaint has been the difficulty to effectively manage and analyze the large amounts of sequence data they yield.
 
Nevertheless, the new platforms have already proven themselves in a variety of applications, ranging from de novo genome sequencing to targeted re-sequencing, transcription analysis, small RNA studies, ChIP-sequencing, and metagenomics.
 
454’s platform, which has been on the market the longest, has demonstrated the widest range of applications so far. In November, the company said that 100 peer-reviewed studies using its system in a variety of areas had been published, many in high-profile scientific journals.
 
One study that has not yet published, but which the company has talked a lot about, is the sequence of Jim Watson’s genome (see In Sequence 6/5/2007). The project, which cost less than $1 million, used the company’s GS FLX to perform a 6X coverage with 250-base reads, and revealed a large number of new potential SNPs and indels.
 
Watson’s was not the only human genome to be analyzed by next-generation sequencing this year. In the fall, scientists from three Chinese research institutes said that they had used Illumina’s Genome Analyzer to sequence the genome of an undisclosed Chinese individual (see In Sequence 9/25/2007).
 
The project represents the start of a larger endeavor that will involve sequencing more individuals’ genomes, though the team has not yet decided what technologies it will use for that phase.
 
ABI’s SOLiD system is also being used for whole-genome human sequencing: Researchers at the J. Craig Venter Institute, who published the analysis of Craig Venter’s genome based on Sanger technology this summer, are using the SOLiD platform to generate an additional 12X coverage of the sequence (see In Sequence 10/16/2007).
 
Next year, the scientists plan to evaluate a number of next-gen sequencing technologies for a project that aims to sequence between 10 and 50 individuals.
 
Human whole-genome sequencing is not confined to academic research. This fall, Cambridge, Mass.-based startup Knome began offering commercial human genome sequencing and analysis services using an undisclosed next-generation technology (see In Sequence 10/30/2007).
 
Next-gen sequencing will also be used in a variety of other large-scale academic projects next year and beyond. For example, more than 60 percent of the grants, totaling $80 million, that were awarded this fall under the Encyclopedia of DNA Elements, or ENCODE, project involve the three currently available next-gen sequencing platforms (see In Sequence 11/27/2007).
 
For instance, they will be used to characterize DNA-binding proteins by chromatin immunoprecipitation followed by sequencing, or ChIP-sequencing. Earlier this year, three research groups published results of studies that used Illumina’s Genome Analyzer for ChIP sequencing, the first peer-reviewed studies involving the platform (see In Sequence 6/12/2007).
 
Other projects in which next-gen sequencing will likely play a role are the NIH Roadmap Epigenomics Program and Human Microbiome Project, which will make their first awards next year. Already, researchers are testing the new technologies for large-scale DNA-methylation analyses, such as bisulfite sequencing, and have used them for whole-genome microbial sequencing.
 
Targeted re-sequencing studies represent another area in which next-gen technologies seem promising. Several research groups published new methods this year that enabled them to capture and enrich large numbers of regions from the genome in parallel and prepare them for sequencing (see In Sequence 5/22/2007, 9/25/2007, 10/16/2007, 11/6/2007).
 
Combined with new bar-coding approaches (see In Sequence 2/20/2007), these methods will increase the usefulness of the high-throughput sequencing platforms for sequencing studies that involve lots of DNA stretches in many samples, such as exon-sequencing projects.

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