"We're about to live in interesting times again," said Shawn Baker, PhD, a genomics startup consultant and consultant at SanDiegOmics.com. He points out that the market for next-generation sequencing (NGS) technology lacks excitement because Illumina has been the dominant supplier for so long. However, as long reads become more important and some of Illumina's patents begin to expire, new opportunities are emerging that startups may be able to capitalize on. These companies will challenge Illumina and expose the company to its toughest competition in many years.
One of the newest entrants to the field is San Diego-based Element Biosciences, a financially strong five-year-old company founded and run by a team of several former Illumina scientists. After raising around $400 million, the company unveiled its long-awaited AVITI sequencer. The online launch event, held last month, was an impressive three-hour presentation in which partners shared raw data illustrating AVITI's capabilities. The presentation made it clear that AVITI offers high-accuracy sequence data, flexibility in read length (short or long reads), and cost-effectiveness. Element's motto - "have it all" - was displayed proudly and fiercely
Another newcomer to the NGS space is Singular Genomics, a company that went public last year and launched its product. Like Element (and Illumina), Singular is based in San Diego. Drew Spaventa, CEO of Singular, says the company is taking "orders" for the G4 desktop platform and is scheduled to begin shipping instruments within the next few months. Why would anyone choose a G4? Spaventa says it's intended for users who prefer flexibility and speed.
Cheaper, faster and better products with drastic improvements over the status quo could be assured in other markets. But the sequence market is more prohibitive than most. For two decades, one company was able to assert itself against many ambitious startups.
The history of the sequencing market is familiar to John Stuelpnagel, DVM, President of Element (and co-founder of Illumina). At Element's virtual event, he remarked, "The last 15 years have been full of sequencing errors." But this year could be different. Experts speculate that a turning point is imminent. James Hadfield, PhD, a genomics consultant at Enseqlopedia, wrote that this year will be "a year to remember for genomics enthusiasts." If so, Element and Singular face pressing questions: How will they compete with Illumina? How will they compete with each other?
The price is right
Element and Singular currently target the same customers, namely individual and academic core labs. Element's competitive pricing allows such labs to afford an AVITI, said Molly He, PhD, CEO of Element. And researchers don't have to send their samples there
it is no longer in order.
According to Baker, the Element features several technical improvements, including better surface chemistry and higher readout quality. But right now, he says, "it's all about price."
Molly He says that having the AVITI, which has two flow cells, is like having two independent NextSeq instruments for the price of one. (NextSeq is Illumina's benchtop unit.) While NextSeq costs about $335,000, AVITI is listed at $289,000.
Element supplies are also cheaper. A kit costs $1,680—three times less than a NextSeq kit. In terms of cost per gigabase (Gb), NextSeq costs approximately $20-30/Gb, while AVITI costs $5-7/Gb—a cost ratio close to that of Illumina's flagship instrument, the NovaSeq. Baker points out that Element offers a NovaSeq-like pricing sample in a NextSeq-like box. It's a pretty compelling price, he notes, but it's very hard to compete on price alone.
Illumina likely has many ways to respond to this. The company has said it will introduce improvements that will allow it to easily adjust NextSeq's pricing to match that of its newer competitors. Additionally, the company could lower NovaSeq prices.
Fast and flexible
Singular, the most expensive of the three platforms, lists their G4 at $350,000. The cost of consumables per GB ranges from the high single digits to the mid-30s, depending on factors such as kit type and cycle count.
Where customers will save, Singular says, is in accuracy. The company's platform is fast, with the longest cycle taking about 19 hours (which Spaventa says could be even faster). For others, cycles usually last about 48 hours.
How did Singular speed up the process so much? Spaventa says the company starts with the chemistry, but ultimately builds on the system as a whole. He adds that rapid sequencing by synthesis (SBS) requires rapid integration, imaging and degradation. "You also need fast throughput and image processing on the backend," he notes. From the beginning, Singular has been convinced that speed is one of the most important things to evolve. "We didn't know if we could increase cycle times as quickly as we did," he adds.
Other advantages besides speed are that the G4 has a data output rate (about 21 Gbit/hour) that is twice that of the competition. According to Spaventa, the G4's profile applies to customers in the mid-performance segment to the lower end of the high-performance segment. And the G4 has four flow cells that offer flexibility.
The Element also offers flow cell flexibility, unlike the G4. AVITI's dual independent flow cells not only look like two separate machines, but also allow the user to have a "tunable display". This means a user can aim for maximum performance throughout - around 48 hours - or manage the runtime and choose to receive less data more quickly.
Spaventa claims that other companies compete on cost and that Singular "competes on performance." Spaveda, a former basketball player, says he "loves to compete." He expects there will be more than one winner, adding that competition is good for the end market and customers will benefit.
"Neither Singular nor Element appears to be an Illumina killer," notes Baker. "But it could be a chaotic battle in the short reading space."
The long and the short of it
With increasing market demand for long-read technology, it's no surprise that short-read companies (old and new) are looking for ways to integrate longer-read technologies into their platforms. The easiest way to do this is to offer somethingsyntheticLong reads - Technology that combines short reads to make them longer.
According to He, Element is "the first short-read technology that also offers long-read sequencing." The addition of long-read capabilities was made possible last February when Element acquired Loop Genomics.
The synthetic long reads offered by Element are up to 10 kb in size - smaller than the "real" long reads offered by companies such as Pacific Biosciences and Oxford
nanopore technologies. However, Shawn Levy, PhD, the newest member of the Element team, who was hired 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 read processes. Increasing the size from hundreds to thousands of base pairs offers the greatest impact for the greatest number of applications, Levy claims. Implementing loop chemistry is straightforward and requires the addition of a library preparation kit. Additionally, users can multiplex short and long read libraries in the same flow cell.
Illumina announced its plan to include long-read technology, which J.P. The Morgan Health Care Conference last January introduced the Infinity technology platform. The move, Baker says, is Illumina's attempt to retain customers who may be drawn away by the long-standing offerings of Element and Singular. Essentially, according to Baker, Illumina is saying, "Stay here!"
Spaventa claims that Singular's bread and butter is its core sequencing kits. The company offers an application kit called XR-seq that enables targeted medium-length reads in the 500–3,000 base range. These reads are not used for mapping, but for more targeted approaches such as heavy and light chain sequencing, phage display libraries, 16S RNA and full-length isoforms.
A relative veteran of the NGS space, Pacific Biosciences is known for its longer, high-quality reads. It has proven technology. But it needs to find the right applications. It recently acquired short-reading company Omniome. Baker believes this could open the door to the clinical space.
The problem, according to Baker, is that Omniome hasn't spent much time building the platform. While platform chemistry may be solid, selling an instrument isn't enough. As a result, Pacific Biosciences must now build a platform for this chemistry, which is not a traditional strength of the company. Like Element, Pacific Biosciences recently hired a number of former Illumina executives. It will be interesting to see what happens next.
One thing that Singular and Element have in common is their commitment to stable, proactive goals. Singular talked about entering spatial genomics and single cell biology. Element says it built its platform with evolution and expansion in mind. The platform's low-binding chemistry and surface imaging system is designed to go beyond DNA.
What is certain, says Baker, is that there will be "a lot of pain." Illumina needs to start competing. Singular and Element are fighting to overtake the market leader. The only group that won't be hurt is the consumers. You will finally have a choice.