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Roche Sparks Interest, Speculation About New Nanopore Sequencer With Upcoming Webinar

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NEW YORK – Roche is seemingly preparing to launch its nanopore sequencing platform, as the company recently announced a webinar in late February to showcase its so-called Sequencing by Expansion (SBX) technology.

The online event, which will be held shortly before this year's Advances in Genome Biology and Technology annual meeting, has already generated buzz and speculation in the genomics community. However, with little information publicly available, researchers are reluctant to pass judgment on the technology yet.

"It is certainly piquing everyone's interest," said Christopher Mason, a genomics expert and professor at Weill Cornell Medicine. "I think it will be the talk of the town over the next month."

Roche declined to comment on the technology before the webinar. On the event's registration webpage, the company said it will showcase how SBX will allow for "flexible system operation across a range of throughput scales" as well as "methods to accelerate data analysis and movement of data with real-time compute."

It also teased a few technical details, including that SBX is a single-molecule nanopore sequencing technology that can read over 500 Mb per second using a highly parallel 8 million sensor array. The technology can also generate over 15 billion reads in four hours for "highly accurate" whole-genome sequencing, according to the firm.

Additionally, Roche claimed that SBX enables "high-throughput, large-scale" RNA and single-cell RNA sequencing applications "with longer reads than a traditional short-read platform."

"It looks like they are gearing it up for throughput," setting it up against firms like Illumina, "but we don't know yet," Mason said. Assuming the platform does have high throughput, it could open up new applications for rapid diagnostics as well as population-scale studies, and longer reads "would be very appealing," he added.

Originally developed by Stratos Genomics, which Roche acquired in 2020, the SBX chemistry works by enzymatically converting a DNA molecule into a larger surrogate, dubbed Xpandomer. Four distinct novel nucleotides called X-NTPs, or High Signal-to-Noise Reporters — one for each DNA base — are used during the Xpandomer synthesis.

The Xpandomer, which is more than 50 times longer than the original DNA fragment, then passes through a biological nanopore, creating distinct electrical signals for each X-NTP that are translated back into the original nucleic acid sequence.

By employing a signal amplification strategy, Roche’s SBX is trying to address the limitations of both traditional sequencing-by-synthesis and nanopore sequencing, allowing more time for bases to pass through the nanopore for increased accuracy while boosting read length, Vijay Kumar of investment bank Evercore ISI wrote in an analyst report last week.

At Roche's investor meeting last May, company officials said there were two key elements to the firm's nanopore sequencing technology: a semiconductor chip, which Roche obtained through its acquisition of Genia in 2014, and SBX, from its Stratos acquisition, though it is unclear what improvements Roche has made to both technologies.

The company also noted at that time that it had been developing end-to-end workflows for the SBX sequencing platform, with clinical and pharmaceutical markets in mind.

"It could be exciting, but without detailed information, I'm mostly curious," said Xiaoling Xuei, a sequencing consultant and retired technical director of Indiana University School of Medicine's Center for Medical Genomics.

According to Xuei, one of the very first questions she asks when evaluating a new sequencing technology is its accuracy, which is still unknown for SBX. She said the technology does not eliminate the polymerization steps, which could be a source of error. Another question Xuei has for SBX is how long the read length can be.

Meanwhile, some other genomics experts have gleaned clues from the scant metrics Roche has put out so far. Eric Chow, a core lab director at the University of California, San Francisco, calculated that 500 Mb per second over four hours translates to 7.2 Tb of sequence data. With 15 billion reads in four hours, this suggests a read length of almost 500 bp, he said in an email.

With a reasonable work shift, and depending on how long it takes to prep the system for another run, a customer might be able to do two or three runs per day, Chow speculated, yielding 30 billion to 45 billion reads.

While Chow considers these prospects "exciting," he is also waiting to find out more specs including cost, robustness, input material requirements, and turnaround time.

Chow also wondered about the error profile of Roche's sequencer, especially how library prep can contribute to error. "It's clear that part of the library prep converts a DNA template into an expandomer with heavily modified nucleotides that are much larger than the ones used in current platforms," Chow noted. "This could be a source of inaccuracy."

It remains unclear when Roche will actually make the SBX technology available to customers, as the company noted on the event webpage that SBX "is under development and not yet commercially available."

Notably, this is not Roche's first attempt to develop a next-gen sequencing system, as the company has had a long and checkered past with acquisitions and partnerships in the space. In 2017, for example, Roche terminated a collaboration with Pacific Biosciences to develop a diagnostic sequencing platform. Before that, the company attempted, and failed, to take over Illumina in a hostile bid in 2012. Its acquisition of 454 Life Sciences in 2007 led to the discontinuation of the technology several years later.

"Roche doesn’t have the best track record with NGS technology," Brewster Kingham, director of the DNA Sequencing and Genotyping Center at the University of Delaware, wrote in an email. The company "came up with some innovative names for the technology: Xpandomer, X-NTPs — I hope the technology itself is equally innovative."

Still, Kingham said the little information Roche has made publicly available is "interesting," and he is "very intrigued and excited to learn more." Like others, he is also waiting to learn more specs about the technology before making any moves. "The chemistry is unconventional and unique, so my interest is piqued, but my checkbook is closed until I learn a lot more," he said.