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Illumina’s HiSeq 2000: Secrets and Buys

By Kevin Davies

January 22, 2010 | If Illumina’s new HiSeq 2000 sequencer proves even half as effective as the invisibility cloak that the San Diego firm deployed before dramatically revealing its existence last week, then it has a good shot to “redefine the trajectory of sequencing,” as Illumina CEO Jay Flatley told analysts last week at the JP Morgan Healthcare conference in San Francisco.

“It is the culmination of the vision we had when we acquired Solexa,” said Flatley. The instrument, priced at $690,000, can generate 200 Gigabases (Gb) in a single run lasting eight days (paired 100 base reads) using dual flow cells. “The output is unprecedented,” said Flatley. Whereas the HiSeq 2000 can deliver 25 Gb/day, the GA II is only just scaling up to 50 Gb for a week run. Flatley also said the HiSeq is “unmatched in cost effectiveness” and can “drive the cost of a genome under $10,000 and a transcriptome under $200.” He noted the cost of sequencing has dropped by a factor of 100 since the Solexa acquisition. One run on the HiSeq 2000 could recreate the Human Genome Project in a week. Besides human genomes, it could sequence thousands of bacterial genomes simultaneously or unravel 16 transcriptomes in a mere four days.

BGI News

The HiSeq 2000 will begin shipping in February, with China’s Beijing Genomics Institute (BGI) ordering a staggering 128 instruments. Flatley described it as the largest single order for next-gen sequencing systems to date. BGI committed to a massive investment in its sequencing platforms last December. “The discussions we’ve had over the last few months have been centered on the GA,” said Omead Ostadan, Illumina’s VP marketing. BGI’s decision to switch to the HiSeq 2000 came very soon after Illumina disclosed the instrument. “They had some flexibility in their scale-up plans to make that change,” said Ostadan.

Genome center managers were afforded previews of the HiSeq just days before Illumina announced the instrument. One staffer requesting anonymity told Bio-IT World that, “It's going to be very hard for ABI or Complete [Genomics] to counter this move with a 4-5-fold improvement anytime soon.” Some centers might have trouble freeing up millions of dollars of surplus capital for such an unanticipated upgrade.

According to a BGI spokesperson, 100 of the 128 HiSeq 2000 instruments will be deployed in at a new genome center in Hong Kong, the remaining 28 on the mainland in Shenzhen. Once fully deployed, that would give BGI the capacity to sequence about 11,000 human genomes in a full year, although its interests extend far beyond humans. BGI also stated that despite its massive sequencer investment, it was not its intention to become the largest genome center in the world. The HiSeq order simply reflects “calculation about how many projects need to be done at BGI, and that needs over 100 instruments.”

New Standard

The name “HiSeq” was chosen, Ostadan says, because “this platform is going to set a new standard for high-performance sequencing… We think this will be the first in a portfolio of products based on the core engineering architecture.” The “-2000” suffix is, Ostadan admits, somewhat arbitrary, but made sense given the platform has two flow cells, each with two surfaces.

Ostadan said Illumina was very nervous about the veil of secrecy around the HiSeq 2000’s launch, and delighted that word did not leak out in advance. One reason for such stealth was “to set the context around it -- we felt if anything leaked out, because we wouldn’t be in a position to comment as a public company, any rumors would get a life of their own.” And of course, Illumina didn’t want to tip off the competition either.

The launch of the HiSeq 2000 has no immediate impact on the established GA line. “We have no intention of abandoning the GA or relegating its status,” affirmed Ostadan. “There’s a really impressive macro-environment around [the GA] in terms of analysis tools, protocols, [and] user community.” The same week, Illumina introduced the GA IIe, which will deliver about 40% output of its cousin, priced at just $250,000.  Ostadan anticipates that the mature market for next-generation sequencing will resemble the capillary sequencing market in terms of its heterogeneity. “You’re going to have a diversity of users with different levels of output need, cost sensitivity and capital expenditure sensitivity,” he said.

Like the SOLiD platform from Life Technologies, the HiSeq 2000 introduces two flow cells, with completely independent of one another. “You can run different applications on both flow cells,” says Ostadan, such as different read lengths, stop/start times, or amount of reagents. A 30-fold human genome could in principle be run on a single flow cell for a reagent cost of $10,000. A dual flow-cell run could be used to sequence a tumor genome and the corresponding healthy control side by side. 

Aside from the dual flow cells, the increase in throughput comes from the ingenious ability to image two surfaces of the flow cell using new optics. Ostadan maintains there remains “tremendous headroom” in the sequence-by-synthesis chemistry. “There are many parameters to explore and advance,” he said.

Customer Compatibility

Illumina’s task for new customers is to minimize any deviations on the front and back end. Many advances in sample prep and analysis are completely compatible with existing workflows and architectures, said Ostadan. The new instrument offers some advances in transferring data – files sizes end up being an order of magnitude smaller in size (Gigabytes) but perfectly compatible with any users’ IT architecture around the GA IIx. Ostadan admits that if someone purchased the instrument today, some of the extended laboratory information management systems (LIMS) capabilities aren’t yet ready. But Ostadan stresses the major modifications to the plug-and-play base callers and aligners, variant detectors and visualization tools.

The HiSeq 2000 offers a simplified user interface and touch screen capability, real-time analysis and remote monitoring, which allows users to start a run, go home, and monitor all the quality metrics on their iPhone. The Genome Studio pipeline to process data and call variants is the same. But the quality tables are specific for the HiSeq 2000 base calls. The initial read length spec was set at 2x100 bases. “We don’t believe there’s any reason we can’t extend read length on the HiSeq 2000,” said Ostadan, adding that the pre-launch priority was to lock down various parameters.

Illumina is offering a trade-in program for customers who may be interested in upgrading. “We want to make sure they get some value from the investment they made,” said Ostadan. “Our intention is to make sure they have the most suitable technology in their institution.”

The drop in reagent costs for human genome sequencing to $10,000 makes it difficult for Illumina to justify a price of $48,000 for its personal genome sequencing service, which debuted last summer. Ostadan says there are no plans to reset the price in the near future, but acknowledged that the price of the sequencing service would come down. “There are number of factors that go into that [price calculation. There’s a lot other than just the reagents involved in delivering that information,” he said. “I don’t see that happening in the next couple of months.”

Calling it a “beautifully designed platform,” Ostadan thinks “the HiSeq 2000 certainly resets the bar at the high end of the market.” He cites output, ease of use, mode of interaction, and application flexibility among its key virtues. “The platform gives any user so much more freedom than any other platform. It solidifies our position in the marketplace.”

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