By Aaron Krol
Corrected 12/4/13: The original text of this article erroneously gave Sean Scott's title as Senior Vice President for Global Sales and Operations. The article has been revised to reflect his actual title, Senior Vice President for Corporate Development.
November 27, 2013 | Last week, this author ran a story on CLC bio’s future as a member of the QIAGEN corporate family and a key player in the forthcoming GeneReader sequencing pipeline. CLC bio is one of a pair of bioinformatics companies acquired by QIAGEN this year in the run-up to the GeneReader’s planned 2014 release. The other company, Ingenuity Systems – which is now trading under the name QIAGEN Redwood City – provides tertiary analysis of genomic data: the interpretive annotation of genetic variation that allows researchers to make sense of genes’ behavior on the cellular and organism-wide scales.
Like CLC bio, Ingenuity will have significant freedom to pursue independent projects under QIAGEN, and although its software will be a crucial component of the GeneReader pipeline, all Ingenuity products will remain sequencer-agnostic moving forward. Yet unlike CLC bio, which is developing direct integration of CLC Genomics Workbench with the GeneReader instrument, Ingenuity will also maintain tight partnerships with competing genetic sequencing companies. Ingenuity Variant Analysis, a standard-setting interpretive platform for genomic research, is already fully incorporated into Life Technology’s Ion Reporter user interface. This puts Ingenuity in the unique position of providing the dedicated tertiary analysis tools for two separate sequencing pipelines: the GeneReader pathway at QIAGEN, and the Ion PGM and Ion Proton pathway at Life.
Ingenuity is also excited by the prospect of partnering with third-party companies performing alignment and assembly of raw genetic data, like DNAnexus, Real Time Genomics, or Seven Bridges Genomics. “We’re going after a very big problem,” says Sean Scott, Ingenuity’s Senior Vice President for Corporate Development, “and customers quite frankly need open solutions, and they want options… While we’ll have potentially very elegant integrations with CLC’s primary and secondary analysis capabilities, that’s not going to mean that we’re not going to continue to partner with the other companies and open source tools that are doing the upstream analysis.”
Two broad principles seem to govern QIAGEN’s laissez faire attitude to their subsidiary’s external partnerships. One is simply that Ingenuity is a secure and profitable company in its own right, with a diverse and well-established user base who are accustomed to fitting Ingenuity’s software into any sequencing pipelines they’ve cobbled together in the age of pick-and-choose genomic analysis. “We’ve had roughly 90,000-some samples analyzed and interpreted through the Variant Analysis platform to date,” says Scott, “and the sample volume continues to grow exponentially there. Probably 85-90% of those samples were generated off of Illumina instruments.” The remaining 10-15% represents instruments from Life Technologies, 454, and other sequencing players. If integrating Variant Analysis into these pipelines costs QIAGEN a GeneReader sale here and there, this is nothing next to the cost of forcing researchers to abandon their licensing deals with Ingenuity. Besides, QIAGEN executives have expressed a philosophical distaste for forcing a thriving company like Ingenuity into a narrow role at its new corporate home. “It’s rather short-sighted to buy a company for just the IP, or one great hit,” said QIAGEN CMO Tadd Lazarus to Bio-IT World. “Ultimately companies are people, and we are incredibly impressed by the [Ingenuity leadership team].”
The second reason to be relaxed about Ingenuity software’s ubiquity in the sequencing world, however, is that instruments like the Ion Proton may not prove to be competitors for the GeneReader at all. Current sequencing devices have been aimed squarely at the research market, which has so far dominated sequencing applications. But as the medical relevance of specific genetic information is validated, and the FDA grows more open to genetic diagnostics, the industry is undergoing a seismic shift toward clinical use. Just over a week ago, Illumina’s MiSeq Dx received FDA approval for use in clinical tests for cystic fibrosis, making it the first next-generation sequencer to enter the diagnostics market. The breaking down of this barrier may in time be seen as a second revolution in genomics, after the move from Sanger sequencing to NGS technology in the mid-2000s.
QIAGEN, which already has an immense clinical presence thanks to its diverse catalogue of molecular diagnostics kits, is skipping lightly over the research market and leaping straight into clinical settings. “What makes GeneReader unique,” says Lazarus, “is it has been designed from the ground up to be a clinical workhorse.” The GeneReader will be optimized for targeted gene panels, rather than comprehensive but time-consuming whole exome sequencing, and its system of rotating flow cells is designed to allow sequencing of up to 240 samples at a time. Entering a huge and largely untapped commercial space, the GeneReader may not need to draw Ingenuity users away from their current instruments to find customers.
Clearing a Path to the Clinic
In fact, QIAGEN’s acquisition of Ingenuity was well-tuned to the latter company’s own eagerness to see next-generation sequencing enter clinical use. Even before the FDA’s cooperation seemed certain or sequencers were being tuned to the pace of real-time diagnostics, Ingenuity was preparing to release a new software platform dedicated to clinical interpretation of genetic data. “The opportunity for NGS in molecular diagnostics is not going to be realized until someone, whether it be Ingenuity or someone else, can help identify how to automate that test interpretation and workflow so that people can develop new tests, launch those tests, [and] run more cases,” says Scott. Development of a clinical analysis platform made the corporate attachment to QIAGEN a natural fit. Peer Schatz, QIAGEN’s CEO, “presented us with a very compelling and comprehensive vision,” says Scott, “and he saw early on that interpretation from a molecular diagnostics perspective was truly the rate-limiting factor for adoption of new technologies and instruments in the lab. He saw what we were doing in terms of building out the clinical platform as fitting very nicely into his vision.”
That vision is closer than ever to becoming a reality. This month, at the annual meeting of the Association for Molecular Pathology in Phoenix, AZ, Ingenuity announced an early access program for its still-unnamed clinical platform, inviting molecular laboratories to try out the program and give feedback in advance of a wider beta release in the early months of 2014. A large scientific advisory board, including major players in patient sequencing like Dr. Heidi Rehm of the Center for Personalized Genetic Medicine at Partners Healthcare and Dr. Eric Schadt of Mt. Sinai’s Institute for Genomics and Multiscale Biology, will also be involved in the final stages of pre-release development. With a full commercial release tentatively scheduled for March or April, the platform is well-timed to coincide with the GeneReader’s arrival in the laboratory.
While the clinical platform relies on the same deeply curated Knowledge Base of genetic data that powers the Variant Analysis platform, its creation involved a whole new standard of curation to comport with the strict demands of clinical reporting. “We’ve changed the nature of our curators and our training process,” says Scott, “so that we have complemented our existing curation workforce with additional PhD/MD-type curators… We’ve defined the type of clinical evidence that is required to support evidence-based classifications of variants.”
True to form, Ingenuity intends its clinical platform to be easily integrated into any existing laboratory workflow, from sequencer up to reporting of results. In addition to a genetic variant call file, the platform also uses test indication metadata and patient information in making its interpretations, leveraging the additional depth of information that is routinely available in a clinical setting. The results can also be integrated into whatever reporting mechanism a lab is already using, whether internally developed or provided by a third-party company.
The business model for this platform has also been customized to fit a typical molecular laboratory’s needs. Laboratories will be able to use the software on a fee-per-test basis, in keeping with their case-by-case workflows.
The clinical platform will be rolled out one test indication at a time, to ensure that any results used in patient care are thoroughly validated. Scott also stresses that, at least at first, this platform will not be used as a stand-alone diagnostic tool, but as a supplementary product that allows more tailored analysis of a given clinical presentation. He uses the example of interpreting a tumor’s genetic profile, to demonstrate how the Ingenuity Knowledge Base can inform clinical care. “If you think about a somatic cancer test indication, really what someone’s trying to do is identify if there’s a clinically relevant somatic variant in a gene, in this patient, that’s causing this phenotype that’s been presented and can be treated with this drug indication… And they also want to know, based upon this diagnosis and this patient’s genetic profile and these potential drug indications, are there clinical trials accepting patients?”
On that note, Scott also hints at where Ingenuity may take its Knowledge Base next. “The other interesting opportunity where I think you’ll see more adoption and more benefit from NGS,” he says, “is with large pharma, clinical trials and drug development.”