A few years ago, a new NGS platform being announced at the Advances in Genome Biology and Technology (AGBT) meeting would not have been a surprise; multiple new instruments entered the NGS arena over the span of a few years. In turn, the genomics community has grown used to teams touting their “game-changing” platforms, with promises of either lower cost, longer reads, higher accuracy, more throughput (or all of the above!) But those days had settled down. Or so we thought.
This week, Roche made it feel like 2022 again. Just days before the AGBT meeting kicks off in Marco Island, FL, the company hosted a much-anticipated webinar to offer a technical introduction to their sequencing expansion technology (SBX): a coming together of two companies that Roche had previously acquired—Stratos Genomics and Genia Technologies.
Why now for the technology unveiling? “It just felt like this was the right timing based on where we were, and our comfort with where we are with the technology which we’re very excited about,” noted Mark Kokoris, vice president, head of SBX technology RS.
Kokoris, who co-founded Stratos Genomics in 2007 and served as the company’s CEO until the acquisition, invented SBX technology. The webinar was designed to be “a heavy dive in on the technical,” he told GEN, with less focus on the timeline of the instrument launch and more focus on “the technology, what we’re putting forward, and what we’re seeing.”
The technology
“Our approach to efficiently sequencing DNA is to not sequence DNA,” Kokoris told GEN, chuckling. Instead, he explained, they created and innovated a biochemical conversion process to change DNA into an expanded surrogate molecule with the idea to rescale the signal-to-noise problem. He brought the idea to his friend Bob McRuer, Stratos’ former CTO, almost 20 years ago, who loved it because it simplified measurement. Then, Kokoris had to figure out how to make the chemistry come together without a roadmap.
Nothing existed, he remembers, to explain how to build a cleavable X-NTP (one of the keys to the technology). When you see the structure of an X-NTP, Kokoris asserted, you probably think, this is crazy! “And I knew it was going to require innovation in protein engineering, molecular engineering, and developing chemistries that didn’t exist. And there was a bunch of other stuff that we didn’t realize at the time that we had to innovate.”
SBX creates a surrogate molecule called an Xpandomer (which is 50 times longer than target DNA) and encodes the DNA sequence information in large, high signal-to-noise reporters. The backbone of the Xpandomer is X-NTPs, which are linked along a target DNA template. The DNA sequence is represented in the X-NTP sequence. The four X-NTP types have a tether that is linked between the base and the alpha phosphate. In the process, the DNA template is degraded and the backbone expands, becoming an Xpandomer which is pulled through a nanopore. This is performed in millions of wells on a CMOS-based sensor.
“When we got to the other side of [building the technology] it was exactly what we had thought. We had solved that single molecule signal to noise. And now that we have transitioned that to a large, 8 million array. It’s bonkers.”
Not Roche’s first rodeo
Roche is not a newcomer to the sequencing space: the company bought Jonathan Rothberg’s 454 in 2007 for $140 million. 454 had just announced the completion of Jim Watson’s genome (in May 2007) and published in Nature the following the year. But it was evident that 454’s platform could not get the WGS price down significantly, while competition from Illumina and others was rapidly intensifying (PacBio launched at AGBT in 2008). The writing was on the wall when Nature published three back-to-back landmark NGS papers in November 2008—the first African genome, the first Asian genome, and the first cancer genome—all featuring the Illumina platform.
Roche shut down the 454 program in 2013. Meanwhile, Roche had taken a shine to Genia Technologies, the developer of a single molecule, semiconductor-based, DNA sequencing platform using nanopore technology. Roche eventually bought Genia for $350M in 2014.
A crazy idea
At this point, a new NGS technology has to offer something new or different to users to get noticed. What are the advantages of SBX? Is it read length, cost, accuracy? According to Kokoris, the cost, scale, throughput, and accuracy have all been considered. (The data from the webinar suggested that read accuracy and speed are strengths of the system.) But the one thing that was always the focus—even back when McRuer and he would meet at Starbucks on First Avenue (in Seattle) for six-hour sessions back in 2007—was flexible operation. That was at the top of mind then and “hasn’t changed one bit in 18 years,” noted Kokoris.
“We envisioned a platform that can sequence up and down the throughput spectrum with impunity,” Kokoris explained. “In other words, one system where someone could do four minutes, 40 minutes, or four hours depending on your throughput. That’s what I wanted on one system. And that is why we did single molecule.”
The technology will be released as research use only, but Kokoris noted that there are future ambitions to take it to the clinical setting. This year will be early access, with the plan to commercialize in 2026. No other details on pricing or sample prep were offered at this time.
At the end of the webinar, Kokoris thanked his team and many others. And he thanked those who believed in this when “it seemed like a crazy idea.” Although Kokoris was referring to the technology, it might also seem crazy to some to launch a new NGS technology into an already extremely crowded market. Time will tell. But the SBX announcement has succeeded in creating a buzz that the NGS community hasn’t experienced for a few years. And in the words of Peter Diamandis, MD: “The day before something is a breakthrough, it’s a crazy idea.”