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Pacific Biosciences Hopes Circulomics Tech Will Help Standardize HiFi Sequencing Yield

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NEW YORK – Pacific Biosciences' acquisition of sample preparation firm Circulomics, announced on Tuesday, could help researchers get more consistent yield from HiFi sequencing, according to company officials, as well as set the stage for sequencing more samples with long reads, at a faster pace.

PacBio's HiFi sequencing, a process that computationally combines circular reads into high-quality sequences with median accuracy higher than 99.9 percent, has taken off over the last year, but it is still not without quirks.

Customers can see a wide range in the amount of HiFi data coming off a sequencer, PacBio Chief Operating Officer Mark Van Oene said. Some get 30 to 35 gigabases output, but others can, on occaision, get less than 10 gigabases, he said, with the difference often due to the quality of the DNA input. Output can also depend on the source of DNA as well as the sequencing application. "We're trying to help standardize more of that upfront extraction, so the field sees more consistent results." He later added, that for whole-genome sequencing PacBio seeks to "narrow the range of variability, so the output is consistently greater than 30 gigabases."

Circulomics' Nanobind technology, which uses magnetic disks to extract high molecular weight DNA needed for a variety of long-read genomic technologies that compete with each other, offers a chance at more consistency, PacBio officials believe. Moreover, during a conference call following the release of the firm's second quarter financial results on Tuesday they said that Nanobind has already been shown to work with ThermoFisher Scientific's KingFisher robots, giving them reason to believe it will help scale long-read sequencing to the throughput required by clinical applications.

Van Oene noted that the firm would explore using Circulomics' technology at multiple steps in its workflow, including library preparation and library quality control. "Over time, we'll be able to incorporate it into more broadly kitted solutions," he said, for now, PacBio will continue to offer Nanobind kits as they exist.

High molecular weight DNA is important for HiFi sequencing yields, because it "helps the shearing to be more concise in size range," according to Molly Zeller, lab manager at the University of Wisconsin-Madison Biotechnology Center DNA sequencing facility, a PacBio certified service provider. "We have found that the shearing is the most important part of HiFi library preparation, as it lends to a more homogeneous mixture with fragment lengths in a size range that is perfect for HiFi sequencing," she said in an email. Her core lab uses Circulomics for some DNA extractions, but only for certain sample types, namely human cells and blood, or mammalian blood or tissue. "It is clean and of good quality, but we can still see variation [in HiFi yield] between organisms," she said, such as mice, horses, dogs, rats, and pigs.

Van Oene and PacBio CEO Christian Henry stressed that they would have Circulomics continue to support DNA extraction for other platforms, including Oxford Nanopore Technologies' long-read sequencing. Earlier this year, Oxford Nanopore launched a kit for ultra-long reads that depends on Circulomics' extraction. Also, Bionano Genomics had previously collaborated with Circulomics on DNA extraction. 

"We're going to continue to support Oxford Nanopore and Bionano using Circulomics' tech," Van Oene said. "We'll continue to honor all those arrangements and enable higher-quality analysis of long fragments of DNA."

Severing the links between Circulomics and other platforms was "not something we've contemplated, and I don't believe that would be appropriate for how we're trying to drive science into the community," Van Oene said. "It was not a consideration."

Henry told investors that he "was on the phone with competitors [Tuesday] morning reassuring them to that effect, that we will support everyone in the market."

Founded in 2012 as a Johns Hopkins University spinout, Baltimore-based Circulomics first started working in the micro RNA analysis market before switching focus to sample preparation around 2017.

The company had nine employees and 700 customers, including the National Institutes of Health Center for Alzheimer's and Related Dementias, PacBio officials said. However, Circulomics' revenues are small and won't materially contribute to PacBio's revenues in 2021.

Van Oene said PacBio has been looking to improve the front end of the workflow and was open to either partnering with another company or to an acquisition. It was already familiar with Circulomics and its founder, Kelvin Liu, which made the deal fast and relatively seamless, he said. Overall, it took about two to three months to close. PacBio has not disclosed financial details of the deal.

The acquisition was not predicated on the potential for PacBio's commercial team to help grow sales of Circulomics' kits, though Van Oene said he expected the firm's "broader commercial channel and marketing engine" to help in that regard.

"But what you really need to think about is how this impacts our sequencing workflow and allows us to make the upfront extraction and sample preparation [and] library prep easier so that customers can scale faster using the single-molecule real-time sequencing technology," Henry said.  "The real benefit here is to our base business … This is going to be especially important as we think about launching new platforms, as we've talked about, that can sequence many, many more samples per year than our current platforms can."

Improving sample prep may also help lower costs: "Making sample prep easier gives you more yield through the sequencer. More yield means lower cost per base, so, therefore, lower cost overall," Henry said.

PacBio officials downplayed the potential for the Circulomics acquisition to help with its other recent acquisition, short-read sequencing technology developer Omniome. "High-quality DNA is always a better starting input. You could fragment or shear DNA into better fragment sizes for short read, but the focus, initially, is to make sure that we're optimizing the long reads and focused on the Sequel platform with this team."

Henry noted that PacBio has completed its regulatory filings for the Omniome deal and is on track to close the deal in the third quarter. He said that PacBio also remains on the hunt for ways to improve the back end of its workflow.

"The informatics and data science side are going to be very, very important to us, particularly as we get to scale with the next generation of systems and with our collaboration with Invitae, for example," he said. "It's clearly on our radar, but it's one step at a time here."

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