By Aaron Krol
UPDATED 11/21/13: See note at bottom for more information on the GeneReader's specifications.
November 20, 2013 | CLC bio has been in the genomic analysis space long enough to see its customer base transformed by changing technology. Brothers Thomas and Bjarne Knudsen opened CLC bio’s headquarters in Aarhus, Denmark, in 2005, just shy of nine years ago: a blink of an eye in some industries, but a revolution ago in genetics. “We started when the 454 had been out a few years, and the Solexa had just been released,” says CEO Thomas Knudsen, referring to the first commercial next-generation sequencer and the precursor instrument to Illumina’s industry-leading MiSeq and HiSeq instruments, respectively. “Back in those days, the science was to sequence something, and then look at what came out of the sequencing instrument. Maybe even writing a paper on, ‘Did it work, or not?’ So that was very exploratory research.”
“Now things are moving closer and closer to the clinic,” Knudsen continues, “closer and closer to the patient, and we are following that development.” As the cost and time investments of sequencing have dropped exponentially, the applications have shifted from tentative fishing expeditions through the genome, to confident hunts for variations based on well-curated databases, and now, tentatively again, toward real clinical and diagnostic practice. CLC bio has expanded all the while, becoming the market leader in processing raw sequencing reads into the useful genetic data that powers all this research. Now the company has reached a turning point as it contemplates its industry’s clinical ambitions. On October 29, CLC bio announced its acquisition by biochemistry giant QIAGEN, and its participation in building the GeneReader genetic sequencing pipeline.
QIAGEN, as a dominant player in biological sample preparation, has had a toe in the next-generation sequencing industry for years, producing the chemistry that extracts and enriches DNA for sequencing on other companies’ instruments. In mid-2012, QIAGEN dove headlong into the storm with the acquisition of Intelligent BioSystems, a small Massachusetts company developing a next-generation sequencer of their own. Intelligent BioSystems’ technology has formed the basis of the GeneReader, a forthcoming QIAGEN sequencer that will compete with the MiSeq, Ion Proton and others for a slice of the growing NGS pie.
Like those sequencers’ manufacturers, QIAGEN would like to be the first to assemble an in-house, end-to-end sequencing pipeline, from sample preparation all the way up to sophisticated analysis of the results, completely within the QIAGEN product catalogue. While Illumina has tried to build a robust analytics environment in BaseSpace, and Ion Torrent has plugged away at the Ion Reporter informatics software, QIAGEN has been buying up leading third-party software companies, beginning with Ingenuity Systems in April and now followed by the CLC bio purchase.
Despite these unignorable signals, QIAGEN has kept the GeneReader project close to its chest, declining to make specific comments on the instrument’s read depth, specificity or cost even as a selective access program in early 2014 draws near (UPDATED*)
Not much known about the GeneReader’s technological underpinnings other than that it will use sequencing-by-synthesis, the technique pioneered by 454 Life Sciences in 2005 and now near-universal in DNA sequencing.
However, three main points of market differentiation have emerged. The first is a driving ambition to see the GeneReader adopted in the clinical space, still a largely untapped market for NGS technology (though FDA announced approval of Illumina’s MiSeqDx for clinical use today). The second is the ability to sequence up to 240 samples at once, twelve each on twenty different flow cells – if successful, a significant boon for busy hospital systems and other institutions with the potential for much higher throughput than even the most active research laboratories today.
And the third is inseparably entwined with the acquisitions of Ingenuity and CLC bio. The Ingenuity Variant Analysis, like CLC bio’s Genomics Workbench and Genomics Server, is already a staple of the industry with a large dedicated user population that relies on the Ingenuity Knowledge Base of curated genetic information to interpret their sequenced genomes. These users cannot be unilaterally herded into the whole QIAGEN pipeline, so QIAGEN is adopting a more light-handed approach than its counterparts. Both the Ingenuity and the CLC bio software will remain sequencer-agnostic, compatible with every instrument on the market, and users who don’t like the GeneReader are free to pick and choose from the pipeline at any juncture.
At a QIAGEN Analyst Day held in New York on November 18, Knudsen spoke to Bio-IT World about the sequencing ecosystem being pieced together under the QIAGEN umbrella. “There will be some customers that will buy the interpretation from Ingenuity, and they will have some other pipeline of preparing the data for interpretation [rather than CLC bio]… Some would like to have the CLC/Ingenuity software, and some would like the whole workflow.” Knudsen’s perspective provides a much-needed window into the GeneReader project, which remains an unknown in the sequencing market with both the instrument and the buffet approach to the pipeline untested. One thing Knudsen stresses is CLC bio’s remarkable independence, an experience shared by Ingenuity.
“The strategy of the CLC bio franchise is multi-dimensional,” says Knudsen. “Of course we work closely with a lot of people at QIAGEN, for example the GeneReader team, on developing software that supports the next-generation sequencing workflow… so that part is new to us. The other part on the product development side is our existing products and upcoming products, and they will more or less continue as planned.” Indeed, despite the urgent demand to assemble an integrated sequencing solution by the time the GeneReader is released next year, CLC bio has not applied the brakes to any of its unrelated projects scheduled for 2014.
The company’s two flagship products, the CLC Genomics Workbench and CLC Genomics Server, will be rereleased with major updates in January or February, with beta releases planned for this December. Perhaps more notably, 2014 will also see the launch of a workbench specifically for cancer research, and another for drug discovery based on the molecular docking algorithms of CLC bio’s 2012 acquisition Molegro. These latter two projects are conspicuous for just how far they lie from the clinical path QIAGEN hopes to pave for the GeneReader.
QIAGEN seems to actively encourage this commercially restless approach. The existing software at CLC bio and Ingenuity will of course be essential to building an in-house sequencing solution, but QIAGEN’s executives don’t like to think of this as the guiding principle behind the recent purchases. “It’s rather short-sighted to buy a company for just the IP, or one great hit,” Dr. Tadd Lazarus, QIAGEN’s CMO, told Bio-IT World at the Analyst Day. “Ultimately companies are people, and we are incredibly impressed by the founders and leaderships of both companies.” QIAGEN seems to have little penchant for getting involved in the day-to-day activities of its new acquisitions, or tearing them away from prior plans for expansion.
Which is not to say that QIAGEN has been distracted from bringing a unified sequencing solution to market. The company’s ambition to provide the first sequencing pipeline optimized for clinical use is its major preoccupation at the moment, and for all the unanswered questions surrounding the GeneReader, the rest of that project is coming into sharp focus. In specimen preparation, QIAGEN is particularly concerned with overcoming the DNA degradation that occurs in the Formalin-fixed, Paraffin-embedded samples common in clinical settings, and with automating as much of the enrichment and library preparation procedure as possible with the QIAcube and QIAcube NGS instruments. A minimum of manual intervention, Dr. Lazarus hopes, “will be the value proposition.” On the analytical end, software applications will be made as routinized as possible, with predefined workflows for different clinical tasks that don’t require users to understand either the computing structure or even much of the genetics. A medium-term goal is to unite the CLC Genomics Workbench and the Ingenuity Variant Analysis in a single interface, with no moving between programs, although it is unclear that this feature will be ready upon initial product launch.
“What makes GeneReader unique,” says Dr. Lazarus, “is it has been designed from the ground up to be a clinical workhorse… We have and are creating for the first time, a sample-in, result-out [process] from one manufacturer with full automation and standardization of chemistries.” Yet he expresses the same casual attitude, and even sidelong pride, toward the prospect of customers drifting in and out of the pipeline as does Knudsen. “I can also envision a solution where people will use all of our front-end automation, an NGS sequencer of their choice, and port data out to our informatics solutions,” Dr. Lazarus readily concedes. “We believe in giving people choices.”
Knudsen’s team on the GeneReader project has had access to prototype instruments, but he’s not giving much away. “We are very confident that this will be a success,” is his only comment on the device itself. He does, however, provide some insight into how QIAGEN will encourage users to stay in-house. Every user who purchases a GeneReader, he revealed to Bio-IT World, will receive the CLC Genomics Workbench bundled in the package, including some unique analytical features tailored to QIAGEN’s gene panels. “This software will include an option to choose which gene panel you are running, and then completely automatically the data will be analyzed,” Knudsen says. In this way, adopters of the GeneReader are likely to be naturally channeled into the CLC bio environment, although it remains to be seen whether CLC’s current users will feel similarly inclined to pick up the GeneReader.
It looks as though integrated pipelines like the QIAGEN-CLC-Ingenuity system will become increasingly prevalent in genetic sequencing, even as the market rapidly expands. Knudsen, however, doesn’t see the linkage to QIAGEN as a bid for continued relevance in this changing industry. “If CLC bio was not acquired by QIAGEN—and I think I can say the same for Ingenuity—we would have continued our lives being successful companies,” he says. “But I think there are a lot of great opportunities in becoming part of a bigger family.” In this regard, Knudsen cited not the GeneReader project, but the much larger sales and marketing force available under QIAGEN, and shared technology access with QIAGEN’s and Ingenuity’s R&D departments. These are the resources that will help CLC bio continue to do just as the company has always done: produce superior, sequencer-agnostic bioinformatics software, and strike out in unexplored directions as it gains expertise in new areas of molecular analysis.
*Since this article's posting, QIAGEN has confirmed some more precise specifications for the GeneReader to Bio-IT World. The instrument's accuracy will be Q30 "or better," indicating one read error per 1,000 calls, and a read length of 100 base pairs will be "more than enough" to perform accurate sequencing. The machine will be an appropriate tool for whole exome sequencing, but in line with its clinical focus, it will be more specialized for targeted gene panels. A QIAGEN spokesperson added that it was "important to note that it is not the specs of the machine people should pay attention to, but more the workflow."