“We’re about to start living in interesting times again,” declares Shawn Baker, PhD, genomics startup advisor and consultant at SanDiegOmics.com. He points out that the market for next-generation sequencing (NGS) technology has lacked excitement because Illumina has been the dominant provider for so long. But with long reads gaining prominence, and with some of Illumina’s patents beginning to expire, new opportunities are emerging that newly launched firms may be able to capitalize on. These firms will challenge Illumina, subjecting the stalwart to the strongest competition it has seen in many years.

One of the newest entrants to the field is San Diego–based Element Biosciences, a deep-pocketed five-year-old company founded, and led, by a team consisting of several former Illumina scientists. After raising approximately $400 million, the company introduced its much-anticipated sequencer, the AVITI. The online launch event, which took place last month, was an impressive three-hour presentation in which partners shared raw data illustrating AVITI’s capabilities. The presentation made a strong case that the AVITI provides highly accurate sequencing data, read-length flexibility (short or long reads), and cost efficiency. Element’s motto—“have it all”—was proudly displayed and hard
to argue with.

Drew Spaventa
Drew Spaventa
CEO, Singular Genomics

Another newcomer in the NGS space is Singular Genomics, a company that went public and launched their product last year. Like Element (and Illumina), Singular is based in San Diego. Drew Spaventa, Singular’s CEO, says that the company is “taking orders” for its benchtop platform, the G4, and is on target to start shipping instruments in the next few months. Why would someone choose a G4? Spaventa says it’s for users who prioritize flexibility and speed.

Cheaper, faster, better products citing drastic improvements over the status quo might, in other markets, equate to a sure bet. But the sequencing market is more forbidding than most. For two decades, one company has held the commanding heights against many ambitious startups.

The sequencing market’s history is familiar to John Stuelpnagel, DVM, Element’s chairman (and co-founder of Illumina). At Element’s virtual event, he noted, “The last 15 years have been littered with sequencing failures.” But this year might be different. Experts suggest that an inflection point is coming. James Hadfield, PhD, genomics consultant at Enseqlopedia, wrote that this year “is going to be a year to remember for genomics afficionados.” If so, Element and Singular face pressing questions: How will they compete with Illumina? How will they compete with each other?

Singular Genomics sequencing instruments
Founded in 2016, Singular Genomics develops sequencing instruments that incorporate the company’s proprietary sequencing-by-synthesis chemistry. The company currently employs 240 people and asserts that it is rapidly expanding. It recently launched a new sequencer, the G4, and indicates that two early-access partners, Adaptive Biosciences and Exact Sciences, have signed purchase orders.

The price is right

Element and Singular are, for the moment, going after the same customers, namely, individual and core academic laboratories. With Element’s competitive pricing, those types of laboratories can afford an AVITI, says Molly He, PhD, Element’s CEO. And researchers won’t need to send their samples out to be
sequenced anymore.

Element touts several technical improvements, notes Baker, including better surface chemistry and higher quality reads. But for now, he says, “What it most clearly boils down to is price.”

Element’s NGS instrument, the AVITI
Element’s NGS instrument, the AVITI, is a large benchtop sequencer about 2.5 feet tall, 2.5 feet deep, and 3 feet wide. The AVITI has two flow cells. Each has a throughput of 800 million reads, and each can operate independently. Element says that it has innovated at every step of the sequencing process, a claim supported by 15 patents.

Molly He says that having the AVITI, which incorporates dual flow cells, is like having two independent NextSeq instruments for the price of one. (NextSeq is Illumina’s benchtop instrument.) 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—threefold less than a NextSeq kit. In terms of cost per gigabase (Gb), the NextSeq offers around $20–30/Gb, but the AVITI offers $5–7/Gb—a cost rate approaching that of Illumina’s top-of-the-line instrument, the NovaSeq. Baker points out that Element is offering NovaSeq-like sample costs on a NextSeq-like box. That’s a pretty compelling price point, he remarks, but it’s very difficult to compete just on price.

Illumina probably has many ways that it can respond. The company has hinted at introducing improvements that would allow it to simply shift NextSeq prices to match those of its latest rivals. Further, the company could reduce NovaSeq prices.

Fast and flexible

Singular, the most expensive platform of the three, lists its G4 at $350,000. The consumable price per Gb ranges from the high single digits to the mid-30s, depending on factors like the type of kit and the number of cycles.

Singular’s NGS instrument, the G4
Singular’s NGS instrument, the G4, is a large benchtop sequencer about 2.7 feet tall, 2 feet deep, and just over 3 feet wide. Singular aims to deliver accurate and flexible paired-read sequencing through the instrument’s sequencing-by-synthesis chemistry (with novel nucleotides and enzymes) and four independent lanes per flow cell.

Where customers will save, Singular says, is on time. The company’s platform is fast, with the longest cycle running around 19 hours (which Spaventa thinks could get even faster). For others, cycles typically take roughly 48 hours.

How did Singular speed up the process so much? Spaventa says that the company starts with the chemistry, but ultimately relies on the system as a whole. Fast sequencing by synthesis (SBS), he adds, requires fast incorporation, fast imaging, and fast cleavage. “You also need fast fluidics and imaging processing on the back end,” he notes. From the beginning, Singular has held that speed is one of the most important things that needed to evolve. “We didn’t know if we were going to be able to push the cycle times as fast as we have,” he adds.

Other advantages, besides speed, are that the G4 has a data output rate (about 21 Gb/hour) twice that offered by competitors. Spaventa says that the profile of the G4 applies to customers in the mid-throughput to the lower end of the high-throughput segment. And the G4 has four flow cells, offering flexibility.

Element offers flow-cell flexibility as well, in a different way from the G4. The AVITI’s dual independent flow cells are not just like having two separate machines—they also allow the user a “tunable readout.” This means that a user can go for maximum throughput in the full amount of time—roughly 48 hours—or manage the run time, opting to get less data, faster.

Spaventa asserts that other companies are competing on cost, and that Singular is “competing on performance.” Spaventa, a former college basketball athlete, says that he “loves competition.” He expects that there will be more than one winner, adding that competition is good for the end market and that the customers will be the ones to benefit.

“Neither Singular nor Element seems like an Illumina killer,” notes Baker. “But it could be a messy battle in the short-read space.”

The long and short of it

With a market increasingly asking for long-read technology, it comes as no surprise that short-read companies (old and new) are looking for ways to incorporate longer reads into their platforms. The easiest way to do that is by offering synthetic long reads—technology that pieces short reads together to make them longer.

Element is, according to He, the “first short-read technology that also offers long-read sequencing.” Adding long-read capabilities became possible last February, when Element acquired Loop Genomics.

The synthetic long reads offered by Element are as large as 10 kb or so—smaller than the “true” 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 signed on in February as senior vice president, applications and scientific affairs, and who will continue in his role as investigator at the 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 maintains. Applying Loop’s chemistry is straightforward, involving the addition of a library preparation kit. Moreover, users can multiplex short- and long-read libraries on the same flow cell.

Illumina announced its plan to include long-read technology at the J.P. Morgan Health Care Conference last January, when it introduced the Infinity technology platform. This move, notes Baker, is Illumina’s attempt to retain customers who may be lured by Element and Singular’s long-read offerings. According to Baker, Illumina is essentially saying, “Just stay here!”

Spaventa maintains that Singular’s bread and butter is the core sequencing kits. The company offers an application kit called the XR-seq that is for targeted, medium-length reads in the range of 500–3,000 bases. These reads are not for mapping, but for more targeted approaches such as heavy-chain and light-chain sequencing, phage display libraries, 16S RNA, and complete isoforms.

Pacific Biosciences, a relative veteran in the NGS space, is known for its high-quality longer reads. It has a tried-and-true technology. But it needs to find the right applications. It recently acquired the short-read company, Omniome. This may, Baker believes, allow for a move into the clinical space.

The issue, Baker cautions, is that Omniome did not spend much time building the platform. So, although the platform’s chemistry may be solid, it is not enough to sell an instrument. So, Pacific Biosciences now needs to make a platform for this chemistry, which is not a traditional strength of the company. Like Element, Pacific Biosciences has recently recruited a number of ex-Illumina executives. It will be interesting to see what comes next.

One commonality between Singular and Element is their commitment to robust, forward-looking goals. Singular has talked about moving into spatial genomics and single-cell biology. Element says that it has built its platform with evolution and expansion in mind. The platform’s low-binding surface chemistry and imaging system are designed to go beyond DNA.

What is certain, says Baker, is that there is going to be “a lot of pain.” Illumina is going to have to start competing. Singular and Element have their work cut out to displace the market leader. The one group that will not experience pain consists of consumers. They will finally have choices.