"Stealth mode" barely scratches the surface of Element Biosciences' secrecy over the past few years. would be more accurateGame of ThronesTermination function.
The San Diego-based company kicked things off in January 2020, when it raised more than $80 million in Series B funding. It followed that up with a $276 million Series C round 18 months later in June 2021. But it was then that Element was introduced as a silver sponsor of this year's Advances in Genome Biology and Technology (AGBT) conference -- a meeting known for launching the next conference -- Gene Sequencing Technologies (NGS) -- was a clear sign that the veil was about to lift. removed. Since the AGBT was postponed until June 2022, the element of surprise was not long in coming. Today the company started its business activities. He hosted a webinar to announce a new NGS platform, AVITI, and released details of what they've been working on since the company was founded five years ago.
I was invited to visit Element prior to the company's product launch. In the Quorum Lounge—an inviting, open-air space on the third floor with tables and chairs—one employee ate lunch and another group met for coffee. The view from the living room is spectacular - overlooking the San Diego countryside. You can't see the sea, but if you squint you can see the old Illumina headquarters in the distance.
Element was first introduced on whiteboards in the libraries of the University of California, San Diego in 2017. Element CEO Molly He, PhD says she didn't plan this. At the time, she was happy in her position as a venture partner at Foresite Capital. But Matt Kellinger, PhD, and Mike Previte, PhD, left Illumina, the NGS leader, to brainstorm ideas for a new company. Their original idea was to develop new reagents for the life sciences. They even registered the domain name for their potential startup, 4-nomics. But as the trio continued to talk and plan, the idea expanded and evolved. They decided to take on a more complex task and build a bigger system with a bigger impact.
How does Element intend to achieve this result? They are adopting a decentralized genome sequencing model in hopes of increasing access. Today, he says, the market is dominated by a centralized force that may or may not fit into a single lab. Researchers lose control of their samples when they send them for sequencing. It can take weeks to retrieve data from a central sequencing facility. They say Element's platform will lead to more freedom and flexibility. This is because in the Element model, each lab can have a sequencer.
Element's leadership team is full of experience, as many have spent their careers in genome sequencing. Yes, they are leaders, but first and foremost they are scientists. There's no doubt that Mike Previte (Chief Technology Officer) has attended enough lab meetings in his life when he's been handed a colored pen on a white board.
Co-founders Matt Kellinger (Head of Biochemistry) and Previte spent five and six years at Illumina, respectively. Molly was with Illumina for seven years and two years ago with PacBio. Francisco Garcia, PhD, SVP of Engineering, spent nearly two decades at Illumina.
With a large team of Illumina veterans at the helm, one might wonder, is Element just Illumina 2.0? They will argue no. You are building something new. The thought process for developing Element's technology was fundamentally different from the work he did at Illumina, Previte says. This is partly because Illumina's technology was so well established.
John Stuelpnagel, DVM, Chairman of the Board of Element (and co-founder of Illumina), notes that Element scientists sequence and innovate across all of their elements.
Molly He adds that Illumina is a great institution for educating many people about genomics and sequencing. But "we are actually partly responsible for the fact that the institution is so successful today." Because we contributed to the institution," he adds.
Under the hood
Element's new NGS instrument is AVITI, a large tabletop sequencer about 2.5 feet tall and about a meter wide at depth.If the overall AVITI process sounds familiar, that's because it is. A polymerase inserts nucleotides that are detected by fluorescence and measured by an optical system. But Element insists there's nothing old about the process. They claim to have innovated every step of the way, a claim backed by 15 patents.
Can the process be called Sequencing by Synthesis (SBS) - the technology used by Illumina? It's "a little gray," notes Keith Robison, PhD, a genomics expert and blogger atwww.omicsomics.blogspot.com. Because the recognition doesn't happen at the synthesis stage, one can argue that it's not SBS, he says. However, since synthesis is required, one could argue that it is.
AVITI has two flow cells that can operate independently - a user does not have to wait for one to finish before starting the other. Each flow cell has a throughput of 800 million reads. Read length is 2×150 bases. Data quality is over 90% at Q30 and over 80% at Q40 (for non-PCR libraries). Molly Says they are moving the "language" from Q30 to Q40.
Another advantage he emphasizes is the flexibility and adaptability of AVITI. A researcher does not need to do all 800 million reads. With the software, they can do 200 or 400 million reads with less turnaround time.
An attractive aspect of AVITI is the cost. He says that having two independent flow cells is like having two independent NextSeq (Illumina's bench) for the price of one. While NextSeq costs about $335,000, AVITI is listed at $289,000.
Element supplies are also cheaper. A kit costs $1,680—three times cheaper than a NextSeq kit. In terms of cost per gigabase (Gb), NextSeq is around $20-30/Gb, but AVITI offers $5-7/Gb -- a price close to Illumina's flagship instrument, the NovaSeq.
The key to this competitive pricing is chemistry.
New tricks - Avidity Sequencing
One cannot speak of element without the wordGames. Literally.
The word, or a variation of it, is embedded in many aspects of the company. As Previte explains, greed can be represented polyvalently. More binding sites mean higher affinity and therefore fewer reagents. To achieve this, Element uses something called Avidit.
Element-owned Avidit is perhaps the newest system innovation. The composition of avidite remains unknown. Element says it could be many different things: protein, chemical compounds or synthetics.
avidit is a multipronged scaffold that carries fluorescence and recognizes DNA. Imagine an octopus with a certain number of arms (element indicates more than two and less than 10). At the end of each arm are attached nucleotides that recognize the DNA bound to the flow cell. Each avidite carries multiple copies of one type of nucleotide. In the core of avidite - the body of the octopus - are several fluorophores that are measured by an optical imaging system. Avidity occurs when a multi-nucleotide avidite binds to multiple contact points to create tighter binding. Because of this, AVITI can use nanomolar concentrations of reagent while other sequencing methods require micromolar concentrations. This results in lower costs and a stronger signal.
The strong signal and new surface chemistry result in more "contrast to noise" or CNR. CNR is essentially a signal-to-noise ratio that takes background into account. More signal and less background allow for less sophisticated (and cheaper) optics.
According to He, Element is "the first short-read technology that also offers long-read" sequencing. This was made possible by the recent acquisition of Loop Genomics, a long-read synthetic company. (Synthetic long reads combine short reads to make them longer.) These long reads -- up to about 10 kilobases -- are shorter than those offered by real 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 senior vice president of applications and scientific affairs and will continue his role as a researcher at the HudsonAlpha Institute for Biotechnology, says a 10-kb read has a huge advantage over short reads. According to Levy, increasing the size from hundreds to thousands of base pairs offers the greatest impact for the greatest number of applications. Using loop chemistry requires the addition of a library preparation kit. Additionally, users can multiplex short and long read libraries in the same flow cell.
Have it all
Scientists who sequence DNA usually have to decide which characteristics -- read length, cost, accuracy -- they want to prioritize. But he says Element's tagline is "having it all." Researchers no longer have to make compromises, he says. When asked if there were any downsides, he deftly dodged: "This is a new platform and it hasn't hardened significantly in this area."
The untold downside is that the field in question is already flooded. Element, like all other NGS entrants, must carve out a niche in a market with little room for maneuver.
Who does Element expect to have the most interest in AVITI? For now, he says, priority is given to individual and centralized academic laboratories. Element's competitive pricing allows such labs to afford an AVITI, he says. And researchers no longer need to send their samples for sequencing.
Why is Element starting now? "The product is ready," confirms Logan Zinser, Element's VP of Finance. "And I think the market is ready."
Element has touted a number of technical improvements, notes Shawn Baker, PhD, a consultant and adviser to genomics startups, including better surface chemistry and higher read quality. But right now, he says, "price really matters." They offer NovaSeq-like sample pricing in a NextSeq-like box. That's a pretty compelling price, he adds, but it's very hard to compete on price alone.
According to Zinser, Illumina took 16 years to reach its price, while Element did it in just a few years. Some would argue that Illumina could significantly lower its prices even if there was just a hint of competition. What will Element do if Illumina responds to AVITI with a bulk sale of NextSeqs?
"Because of the short reading room, it could be a chaotic race," notes Baker. "But the customers really have to come out on top."
"We anticipate and welcome a pricing backlash from competitors," said Jeff Labbadia, Element's Vice President of Operations. “Our goal is to open up the world of biology and create better access to sequencing. We want to participate in this market. But competition is good for innovation."
Time will tell if Element can revolutionize the NGS market and give Illumina real competition. The company's message is clear: their technology is not the status quo, it's better than their competitors, and they're just getting started. They built with evolution and expansion in mind. The surface chemistry and low-binding imaging system are designed to go beyond DNA.
But the company is no longer hidden. The element of surprise is gone. Now it's time to deliver.