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Element Biosciences Unveils New DNA Sequencing Instrument, Chemistry

Aviti Element

NEW YORK – Element Biosciences on Monday revealed technical details about its long-awaited Aviti DNA sequencer.

In a three-hour launch event, which was webcast, the company unveiled the instrument alongside its plans to release it into the sequencing market.

The new benchtop instrument employs a riff on sequencing-by-synthesis chemistry that Element says reduces reagent usage, leading to costs of approximately $7 per Gb.

Initially, the platform can generate approximately 800 million 2 x 150 bp paired-end reads with a total data output of 240 Gb per flow cell. But the company has seen even higher performance under certain circumstances, with more than 1 billion reads per flow cell, translating to 300 Gb output and a cost of approximately $5.50 per Gb.

The firm also believes it is lowering the barrier to entry for DNA sequencing with lower instrument costs than competitors. Moreover, each Aviti instrument can run two flow cells independently, with run times around 48 hours.

Initial applications Element is targeting include RNA gene expression, single-cell RNA sequencing, whole-exome sequencing, and other targeted sequencing. The only application it suggests it won't jump into is population sequencing.

With 90 percent of bases having a raw read accuracy above Q30, Element believes it will change the conversation about sequencing accuracy. "With PCR-free [library prep], we're achieving greater than 80 percent of bases at Q40," said Cisco Garcia, Element's senior VP of engineering. "That's pretty much unprecedented."

For comparison, Illumina's NovaSeq and NextSeq platforms boast generating more than 85 percent of bases at higher than Q30 quality in 2x150 bp mode, and fellow startup Singular Genomics touts single-read accuracy of 99.6 percent to 99.9 percent and quality scores above Q30 for 75 to 90 percent of bases across all kits.

"They've got an extremely competitive platform," said Josh Hyman, director of the DNA Sequencing Facility at the University of Wisconsin-Madison Biotechnology Center. He said his lab is in the market for a mid-throughput benchtop sequencer to analyze tumor samples and human trios with faster turnaround, and Aviti's flexibility and pricing could make a difference. "If I looked at this and I looked at the NextSeq, I'd buy this," he said.

Aviti is "worth consideration for clinical and research labs," Christopher Mason, a researcher and sequencing technology expert at Weill-Cornell Medicine, said in an email. His lab sent in samples to Element for sequencing and he gave a talk on the results during the company's virtual event. "We've actually seen the Q30 rate is better than the official specification, with greater than 99 percent of the bases on almost all of our samples above Q30," he added.

Aviti will be available almost immediately, but only in the US. San Diego-based Element is accepting orders now for second quarter delivery of the $290,000 instrument and its first generation of kits.

Founded in 2018, Element has grown to 260 full-time and part-time employees and raised $267 million. For now, its headquarters are at the Alexandria GradLabs building in San Diego's La Jolla neighborhood, but it is soon moving to a 200,000-square-foot facility nearby. The firm also has a Sunnyvale, California, location that handles enzyme R&D and manufacturing.

Like many companies in the space, Element has ties to Illumina, the giant that controls most of the US sequencing market. Cofounder and CEO Molly He worked there, as did Cofounder and Chief Technology Officer Michael Previte, Cofounder and Head of Biochemistry Matt Kellinger, VP of Finance Logan Zinser, and Garcia. John Stuelpnagel, Element's board chairman, cofounded Illumina and was that company's first CEO.

But according to He, the Element origin story isn't about trying to build a new sequencer. "The concept evolved many times," He said, over long brainstorming sessions in 2018 that took place in the University of California, San Diego's biomedical library.

At first, they thought about making reagents for other platforms. "We decided that if we're making reagents for other companies, we might as well do our own system," Previte said.

After a year of tinkering with chemistry, the team finally reached the core idea upon which they built the company. The avidity-based sequencing chemistry and so-called "Avidite" compounds that enable it to leverage the concept of multivalent binding. How they came up with it depends on who you ask. "We serendipitously fell upon Avidite," He said. Kellinger said it was a mix of "stumbling" into the concept and following the data.

"We would set up reactions to generate a signal for DNA," Previte said. "You'd have to run from one room to the microscope to be able to see the signal because it was fleeting. We needed something that was persistent and controllable. We started to iterate on that."

What they all agree on is that it allowed them to build "from the ground up," He said, and "rethink how sequencing is done."

Like other SBS-inspired approaches, Avidity sequencing interrogates DNA one base at a time on polymerase colony (polony) flow cells, building up the opposite strand of a target template. But instead of having each newly incorporated base give off its own fluorescent signal, Element has taken a different approach.

The company has developed spider-like avidity complexes, featuring a taggable "body" or "core" and multiple arms, or tethers, that can be fitted with nucleotides at the end. Element declined to disclose what the core is made of or how many arms each complex has, or how many variations of it exist. But each complex provides multiple points of contact within the nested target DNA strands grown up by the polony.

"I like to think of it as Doctor Octopus," Previte said, referring to the Spiderman comic book villain Dr. Otto Octavius, whose powers are associated with long, telescoping metal appendages with claws at the end, which allow him to latch on to any available surface.

Because the complexes form several points of contact with the DNA target, the binding affinity is increased and the concentration of molecules needed to interrogate each cluster of DNA targets, in turn, is decreased.

"The affinity is orders of magnitude better than what it would be if you were trying to incorporate the base," Previte said. "You're using two orders of magnitude less reagents in labeling."

Moreover, weak interactions aren't enough to keep the complex in place. "It's gone by the time you image and all that remain are the ones with multiple toeholds," Previte said. This prevents issues with phasing and masks mismatched bases.

How the DNA strand is built up after each base is registered is somewhat unclear. According to patents issued to Element, the DNA strand could be built up after each base is registered in two ways. The avidity complex could be cleaved to leave the nucleotide; however, Element said it will dissociate the complex from the target strand and then incorporate a single base. But either way, the stepping is done without color and doesn't leave scars.

In general, Element feels its approach allows it to maximize the signal-to-noise ratio, or as Previte likes to frame it, "contrast-to-noise." Furthermore, company officials believe there are many opportunities to further refine the system, from its polymerase enzymes to the fluorescent tags. For example, the core could feature multiple labels. "The sky's the limit," Previte said.

Aviti's final output is FASTQ files and Element says it has built the instrument to fit into existing lab workflows. In recent weeks, the company announced multiple partnerships with upstream sample-prep or downstream data analysis companies. Element has even developed a transition kit, to take sequencing libraries prepped for Illumina's instruments and convert them to run on Aviti.

The conversion kit, which Element calls its "Adept" workflow, "made the Illumina libraries run right away; no issues," Mason said.

"We're fully compatible with all the standard data analysis tools," Garcia said. "We do not constrain our users to use a particular cloud or software package. We offer direct connections to a variety of clouds and customer cloud accounts. We want to make it as flexible and as easy as possible for customers."

So far, Aviti boxes have made their way into several labs outside Element. One went to Shawn Levy's lab at the Hudson Alpha Institute for Biotechnology. Earlier this year, Levy joined the company as senior VP of applications and scientific affairs. Element has also placed beta instruments in labs at Stanford University and the Broad Institute, Levy said.

Mason said he's happy with the data he has received so far. "The GC coverage was actually spot-on, and exactly as expected for our WGS and other samples," he said. The transition-to-transversion ratio was "also as expected, around 2.0 to 2.1," he added. In addition, "we saw very low rates of duplicated reads," he said, around 6 to 9 percent.

Levy noted that his lab saw a "mild, but very consistent" improvement in sensitivity to indel variants compared to other platforms. "Indel variants maintained higher precision compared to Illumina at similar depths," he said.

In addition to the seven sequencing applications the firm plans to have app notes for at launch, it is working with its new acquisition, Loop Genomics, to offer longer-read capabilities. The company offers products for applications such as immune repertoire sequencing, microbiome 16S ribosomal RNA sequencing, and RNA isoform sequencing.

Loop Cofounder Tuval Ben-Yehezkel noted that while Loop is a fully owned Element subsidiary, it will continue to service customers who use Illumina sequencing.

Element hopes researchers will find new ways to use its sequencer. "It's such a savvy field. Scientists will open up possibilities that we didn't intend for or didn't see," Kellinger said.

The launch makes Element the second company out of the gate in the dash to take market share in short-read sequencing from Illumina. It follows its San Diego neighbor, Singular Genomics, which launched its G4 sequencer in December, and will soon be followed by several companies, including PacBio with its Omniome short-read sequencer, Genapsys, and Ultima Genomics, a company that has stayed under the radar but is expected to reveal itself in the coming months.

Like Singular, Element is touting its flexibility and cost. With the independently run flow cells, "you're talking about two independent NextSeqs," said Zinser, Element's VP of finance, for approximately $289,000. Element plans to sell its reagent kits, including a flow cell, for $1,680 each.

For comparison, the NextSeq 2000 list price is approximately $335,000, and consumables for 2x 150 bp paired-end sequencing, including the P3 flow cell, list for about $6,150 per kit. The P3 offers 360 Gb total output with 2.4 billion reads in paired-end mode and approximately 48-hour turnaround time.

Singular's G4 with the F2 flow cell generates approximately 150 million reads with 50 Gb output. The larger F3 flow cell, due out by the end of the year, will provide up to 330 million reads and up to 100 Gb output. List pricing for Singular's sequencing kits will range from about $16 to $45 per Gb, and each G4 can run four flow cells independently.

"The specs are kind of similar to the [Illumina] NextSeq P2" flow cell, said Anoja Perera, director of sequencing and discovery genomics at the Stowers Institute for Medical Research. "One really nice feature is the ability to run two flow cells at the same time. It will save loading time and technician involvement."

"This flexibility reminds us of when random-access was introduced to molecular diagnostics and caused a major shift in customer demand for this functionality," Barclays analyst Luke Sergott wrote in a note to investors.

But aside from flexibility, she didn't think there was enough separation from Illumina's benchtop sequencer performance to really consider switching wholesale. "We all have established workflows. It's just really hard to switch," she said.

Element officials said they're targeting research customers, especially academic and core labs, but declined to say how many boxes they're ready to ship at launch.

"We'd rather only have 20 boxes out in the field where customer experience is exceptionally good, rather than flooding the market and having some user experiences that are underwhelming," Zinser said. To entice customers, the company is offering an extra year of warranty for any instruments purchased by June 30.

"I don't think there's pressure for us to get big and take over the genomics space. We're focused on scientific excellence and really leading with that," Zinser said. "Some folks are interested in higher data quality, while some are more interested in getting access to the sequencer themselves, rather than outsourcing to a core lab. If we can address what the customer wants in the short term, we've arrived."

But in the long term, Element has ambitions to become a global company. It is in the hunt for a chief commercial officer to take the company into Europe and Asia after the US launch. And its technical ambitions are perhaps even greater.

"This doesn't really stop at being a DNA sequencer," He said. "So that's a teaser."