“Stealth mode” barely scratches the surface of Element Biosciences’s secrecy over the past few years. More accurate would be Game of Thrones finale mode.
The San Diego company’s buzz started in January 2020, when it closed a Series B financing round surpassing $80 million. It followed that by closing a $276 million Series C round 18 months later in June 2021. But when Element was listed as a silver sponsor of this year’s Advances in Genome Biology and Technology (AGBT) conference—a meeting famous for providing the launchpad of next-gen sequencing (NGS) technologies—it was a clear sign that the veil was about to be lifted. With AGBT postponed until June 2022, the Element of surprise wouldn’t wait. Today, the company opened for business. It hosted an online event to announce a new NGS platform, the AVITI, and released the details of what they have been working on since the company started five years ago.
I was invited to visit Element prior to the company’s product launch. In the Quorum Lounge—a welcoming, open-air space on the third floor with tables and chairs—one employee was eating lunch, another group was meeting over coffee. The view from the lounge is impressive—it looks out over the San Diego landscape. You can’t see the ocean, but if you squint, you can see Illumina’s old headquarters in the distance.
Element was started on white boards in the libraries at the University of California, San Diego back in 2017. Molly He, PhD, Element’s CEO, says she did not plan on it happening. At the time, she was happy in her position as a venture partner at Foresite Capital. But Matt Kellinger, PhD, and Mike Previte, PhD, were departing Illumina, the NGS market leader, and wanted to brainstorm ideas for a new company. Their original idea was to develop new reagents for life sciences. They even registered the domain name for their potential start-up—4-nomics. But as the trio kept talking and drawing, the idea expanded and evolved. They decided they wanted to take on a more complex project and make a bigger system with a greater impact.
How does Element plan to make that impact? They are adopting a decentralized genomic sequencing model with hopes to increase access. Today, He says, the market is dominated by a centralizing force that may or may not fit into an individual lab. Researchers lose control of their samples when they send them out for sequencing. It can take weeks to get data back from a core sequencing facility. Element’s platform will, they say, result in more freedom and flexibility. That’s because, in Element’s model, every lab can have a sequencer.
Element’s leadership team is bursting with experience, many having spent their careers working in genomic sequencing. Yes, they are executives, but they are scientists first. There is little doubt that Mike Previte (chief technology officer), when handed a colored marker at a white board, has been in a few lab meetings in his life.
Co-founders Matt Kellinger (head of biochemistry) and Previte spent five and six years, respectively, at Illumina. Molly He was at Illumina for seven years, and two years at PacBio before that. Francisco Garcia, PhD, SVP of Engineering, spent almost two decades at Illumina.
With a large cluster of Illumina veterans at the helm, one could ask if Element is simply Illumina 2.0? They would argue no; they are building something new. The thought process for developing Element’s technology from the ground up, notes Previte, was different from the work he did at Illumina. This is, in part, because Illumina’s technology was so well established.
John Stuelpnagel, DVM, Element’s Chairman (and a co-founder of Illumina) notes that what the scientists at Element are doing is breaking down sequencing down to all of its elements and innovating on all of those components.
Molly He adds that Illumina is a great institution to educate a lot of people about genomics and sequencing. But, “we are actually part of why the institution became so successful today. Because we contributed to the institution,” she adds.
Under the Hood
Element’s new NGS instrument is the AVITI, a large benchtop sequencer about 2.5 feet tall and deep and three feet wide. If AVITI’s overall process sounds familiar, that’s because it is. A polymerase inserts nucleotides, which are recognized using fluorescence, and measured using an optical system. But Element insists that there is nothing old about the process. They assert that they innovated at each step, a claim supported by 15 patents.
Can the process be called sequencing by synthesis (SBS)—the technology used by Illumina? It’s “a bit grey,” notes Keith Robison, PhD, genomics expert and blogger at www.omicsomics.blogspot.com. Because the detection is not in the synthesis step, he says, it could be argued it’s not SBS. But, since synthesis is required, it could be argued that it is.
The AVITI has two flow cells that can operate independently—a user doesn’t have to wait for one to finish to start the other. Each flow cell has a throughput of 800 million reads. The read length is 2×150 bases. Data quality is greater than 90% for Q30 and exceeds 80% for Q40 (for PCR-free libraries). Molly He says that they are “shifting the language” from Q30 to Q40.
Another advantage He points out is the AVITI’s flexibility and tuneability. A researcher does not have to run all 800 million reads; they can use software to run 200 or 400 million reads with a faster turnaround time.
One attractive aspect of the AVITI is cost. He says that the two, independent flow cells are like having two independent NextSeqs (Illumina’s benchtop) for the price of one. Whereas the NextSeq costs around $335,000, the AVITI is listed at $289,000.
Element’s consumables are cheaper as well. A kit will be offered for $1,680—3-fold less than a NextSeq kit. In terms of cost per Gigabase (Gb), the NextSeq is around $20–30/Gb, but the AVITI offers $5–7/Gb—a price that approaches Illumina’s top-of-the-line instrument, the NovaSeq.
The key to this competitive pricing is the chemistry.
New tricks—Avidity Sequencing
You cannot talk about Element without the word avidity. Literally.
The word, or some iteration of it, is built into multiple facets of the company. As Previte explains, avidity can be illustrated by multivalency. More binding sites means tighter affinity, which means less reagents. To achieve this, Element uses something called an avidite.
An avidite, trademarked by Element, is perhaps the most novel innovation of the system. The composition of the avidite remains undisclosed. Element says that it can be many different things: protein, chemical compounds, or synthetic.
The avidite is a multi-pronged scaffold that carries fluorescence and recognizes the DNA. Think of an Octopus with a certain number of arms (Element says there are more than two and less than 10.) Attached to the end of each arm are nucleotides that recognize the DNA attached to the flowcell. Each avidite carries multiple copies of one type of nucleotide. On the core of the avidite—the body of the octopus—are multiple fluorophores that are measured by an optical imaging system. The avidity comes when one avidite, with multiple nucleotides, binds on multiple contact points to create a tighter binding. Because of this, the AVITI can use nanomolar concentrations of the reagent where other sequencing methods require micromolar concentrations. That translates to lower cost and stronger signal.
The strong signal, and a reimagined surface chemistry, result in more “contrast to noise” or CNR. CNR is, essentially, signal to noise that takes the background into account. A stronger signal, and less background, allows for less sophisticated (and cheaper) optics.
Element is, according to He, “the very first short-read technology that also offers long read” sequencing. This is made possible through the recent acquisition of Loop Genomics, a synthetic long-read company. (Synthetic long reads piece short reads together to make them longer.) These long reads—up to roughly 10 kilobases—are smaller than those offered by a true long-read technologies such as PacBio and Oxford Nanopore. However, Shawn Levy, PhD, the newest member of the Element team who signed on in February as the senior vice president, Applications and Scientific Affairs, and will continue in his role as investigator at HudsonAlpha Institute for Biotechnology, says that a 10-kb read has a massive advantage over short reads. The increase in size from hundreds to thousands of base pairs offers the greatest impact over the largest number of applications, Levy says. Applying Loop’s chemistry involves the addition of a library prep kit. Moreover, users can multiplex short- and long-read libraries on the same flow cell.
Having it all
Scientists who sequence DNA typically have to choose which attribute—read length, cost, accuracy—they want to prioritize. But He says that Element’s slogan is “Have it all.” Researchers don’t need to make compromises anymore, she says. When asked if there are any disadvantages, He neatly sidesteps: “This is a new platform and has not been significantly hardened in the field.”
The unspoken disadvantage is that the field in question is already flooded. Element, like all other NGS upstarts, has to carve out a niche in a market with little room.
Who does Element expect to be most interested in the AVITI? For now, He says the priority is individual and core academic labs. With Element’s competitive pricing, those types of labs can afford an AVITI, she says. And researchers won’t need to send their samples out to be sequenced anymore.
Why is Element launching now? “The product is ready,” asserts Logan Zinser, Element’s VP of Finance. “And I think the market is ready.”
Element touted a number of technical improvements, notes Shawn Baker, PhD, genomics startup advisor & consultant, including better surface chemistry and higher quality reads. But for now, he says, “what it most clearly boils down to is price.” They are offering NovaSeq-like sample costs on a NextSeq-like box. That’s a pretty compelling price point, he adds, but it’s very difficult to compete just on price.
Zinser says it took Illumina 16 years to get to their price point, whereas Element has achieved that in just a few years. Some would argue that Illumina could lower their prices considerably, given even a whisper of competition. What will Element do if Illumina responds to the AVITI with a blowout sale on NextSeqs?
“It could be a messy battle in the short read space,” notes Baker. “But customers really should come out ahead.”
“We expect a competitor response in pricing, and we welcome that,” says Jeff Labbadia, Element’s VP of Operations. “Our purpose is to open up the world of biology and to create more access to sequencing. We want to participate in that market. But competition is good for innovation.”
Time will tell if Element can disrupt the NGS market and provide meaningful competition for Illumina. The company’s messaging is clear: their technology is not the status quo, it is better than their competitors, and they are just getting started. They built with evolution and expansion in mind. The low-binding surface chemistry and imaging system are designed to go beyond DNA.
But the company isn’t in stealth anymore. The Element of surprise is gone. Now, it’s time to deliver.