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NanoString Shares First Details of New Sequencing Chemistry at AGBT


NEW YORK (GenomeWeb) – After hinting at last month's JP Morgan Healthcare Conference about a new chemistry that will expand its technology into the targeted sequencing space, NanoString has now shared a detailed description of the method in a proof of concept poster presented at this week's annual Advances in Genome Biology and Technology meeting. It's called Hyb & Seq.

Based on the company's proprietary optical barcoding technology, Hyb & Seq approaches sequencing in an enzyme and amplification-free manner, NanoString Senior Vice President of R&D Joe Beechem and CEO Brad Gray told GenomeWeb this week.

The chemistry is designed to enable a workflow that is simpler and faster than current sequencing methods, Gray said. The goal is to target customers in the clinical sequencing market for whom Nanostring's technology would offer significant reductions in complexity and time commitment, with the added capability to sequence the same types of targeted cancer panels as other currently used technologies.

By the time the company launches Hyb & Seq commercially, Gray and Beechem said, it intends the system to be capable of sequencing panels of between 100 and 1,000 genes.

As described by NanoString, the Hyb & Seq process involves four steps. First, native DNA molecules from regions of interest are captured on a flow cell. Second, a mixture of NanoString probes with fluorescent optical barcodes hybridizes to matched regions along the captured DNA molecules. These thousands of barcode probes represent all the possible permutations of a six-base stretch, Beechem explained.

In step three, the system reads the optical barcodes of probes that have hybridized in order to identify bases and their positions. According to Beechem, each of the six optical base-reading steps takes less than 10 seconds. Last, the probes are washed away. Then the cycle is repeated until the targeted regions have been read sufficiently, six bases at a time, to assemble the DNA sequence.

During this process, regions of target molecules are read repeatedly, creating overlap that help bring down the sequencing error rate, Beechem said.

In the company's POC study, Beechem and colleagues created a prototype sequencer based on a modified nCounter Sprint Profiler, an instrument that NanoString launched in mid-2015.

According to Gray, the Sprint launch was what really catalyzed the development of Hyb & Seq. "Joe had the foresight to build into the same [instrument] both the optics and the fluidics, which allows us to cycle, which we couldn't typically do on our other instruments," he said. "Almost immediately after we received the prototypes [last July], he was ripping them apart and turning them into sequencers."

Up to that point, Beechem had been leading earlier stealth-mode development of the Hyb & Seq chemistry by hand. But without an instrument to automate the process, the company couldn't produce good statistics on its sequencing accuracy or error rate.

In the new poster, Beechem and other NanoString researchers demonstrate these capabilities of the process for the first time. Using mixtures of synthetic DNA targets, including a BRAF V600E model system, the team demonstrated the chemistry's low error rate and ability to provide high consensus accuracy at low coverage.

According to the authors, the raw single pass error rate in their POC experiments was approximately 2 percent for a single target and between 2 percent and 4 percent for mixtures of 10 targets.

However, Hyb & Seq is still years from commercialization. Moving forward, Beechem said that technical development efforts will take the form of a "slow, diligent walk" in which researchers will, for example, methodically demonstrate increasing multiplexing capabilities toward the ultimate goal of sequencing cancer panels of 100- to 1,000-target genes.

Before the end of the year, he added, Nanostring hopes to be able to report on using the chemistry to sequence 100 targets.

While the group performed their initial POC experiments using a modified nCounter Sprint, the plan is to develop a separate instrument specifically for Hyb & Seq. This will include some subcomponents of the Sprint, Beechem said.

On the business side, Gray said that NanoString intends to focus its future marketing of Hyb & Seq on the clinical sequencing market, where the relative simplicity and ease of the company's approach may offer advantages over current technologies.

NanoString is also presenting new data at AGBT this week on expanded capabilities for its nCounter technology to simultaneously interrogate proteins, RNA, and now DNA. This so-called 3D biology approach is something the company has been highlighting since last year, but its data at the meeting this week will be the first to demonstrate the ability to detect SNPs in addition to RNA and proteins.

Unlike with Hyb & Seq, NanoString is already in the process of making products in this 3D biology vein commercially available. At JP Morgan, the company said it plans to release three DNA panels, three protein panels, and nine RNA panels this year.