A next-generation sequencing (NGS) novice planning to buy a sequencing instrument might expect to hear a used-car-style sales pitch:
“You want short reads? Sure, we’ve got that. Long reads? Yup, that’s an easy add-on. And do I have a price for you! … You bought one just last year? No worries! We have a special discount. Also, we offer steep discounts on reagents. You want to see the instrument? Step right over here. … Isn’t it sleek? Too big? It’s no bigger than a refrigerator! What—you don’t like the color? But black is so in right now. You want accuracy? Do I have a graph to show you! Step into my office. …”
Today, researchers who sequence DNA have choices that they have not had before. The NGS industry has, in one year, grown from a few players to a crowded field. For the past decade, most of the sequencing around the world has been done on instruments made by Illumina, the San Diego-based company that has dominated the market. Others, like Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT), have earned their place on the podium. Still others have tried to enter the game, but never made it past the first round.
But 2022 may change that, with the emergence of new entrants to the industry and new products launched by the veteran companies. James Hadfield, PhD, senior director, epigenomics, oncology translational medicine, AstraZeneca, told GEN that 2022 was the best year for NGS since 2006.
What does this tectonic shift in the field mean? Shawn Baker, PhD, genomics consultant, tells GEN it means that “customers are going to have to get used to making hard choices again, and the vendors are going to have to remember what it takes to fight for sales.”
Blooms of companies in the spring
It was rumored, a few years back, that Molly He, PhD, an Illumina veteran, would launch a new NGS company. In March 2022, the rumors were solidified when He’s new company, Element Biosciences, revealed its benchtop AVITI platform, touting its high accuracy, an option for synthetic long reads, and a low price point.
Another San Diego–based company, Singular Genomics, launched a new benchtop instrument. It is called the G4. According to Singular, it offers flexibility (with four independent flow cells) and very fast run times.
Both mid-throughput instruments (the AVITI and G4) go toe-to-toe with Illumina’s NextSeq instrument.
Then, as the genomics community was packing its bags for the Advances in Genome Biology and Technology (AGBT) conference in Orlando, FL, last June, Ultima Genomics surprised everyone with the launch of its high-throughput UG-100—poised to compete with Illumina’s NovaSeq. Everything about the UG-100 is grandiose: the box, the throughput, the price tag, and the claims surrounding it.
Catharine Aquino, group leader of genomics analytics at the Functional Genomics Center Zurich, ETH Zurich, and the University of Zurich, tells GEN that she will consider buying a UG-100. Moreover, one goal of her sequencing center is to provide the latest technologies to the center’s users. The center consistently runs two NovaSeqs and is interested in exploring cheaper technologies. The cheaper the sequencing, the larger the projects the center can handle.
But Aquino is also wary of new technologies. For example, although Ultima has revealed its target price per genome, the company has been vague about its instrument’s price and actual specifications. In addition, at AGBT, the company only presented data that had been generated internally or in collaboration with the Broad Institute—not customer-generated data. Some of the data made available have drawn criticism from the laboratory of Lior Pachter, PhD, professor of computational biology at the California Institute of Technology. And Aquino has heard little information about the sequencing infrastructure—library prep, the automation necessary to feed the machine, and the support Ultima will provide.
With any new technology, “everything has to work, and everything has to be optimized, out of the box,” she says. New NGS technology may be cool, but if only a few laboratories can make it work, or if it needs a lot of support, it won’t take off. She emphasizes that, in her experience, Illumina’s engineering and support teams are near-perfect.
Timing is also important. Aquino says that her team aims to hit a sweet spot when adopting new technologies. “We cannot be super late, but we also cannot be super early—because [we need] something that already works,” she remarks. “We would rather be a little early than very late.”
Overall, Aquino is excited by the movement in the NGS space. The field has been enlivened by having the choices of new companies such as Ultima, Element, and Singular. The time is right for the “speciation of NGS technologies,” Aquino says.
After a relatively quiet summer, the veteran companies responded in the fall. Last September, Illumina hosted its inaugural Illumina Genomics Forum, during which CEO Francis deSouza squeezed in announcements of new platform advances between talks by Bill Gates and tennis legend Chris Evert and an interview with former President Barack Obama.
In and among the splashy headliners, Illumina revealed the NovaSeq X series of sequencing instruments, which includes a pair of new instruments—the NovaSeq X and NovaSeq X Plus—designed to cement Illumina’s position as the NGS leader.
The new platform may share the same name as an older platform, but Charlie Johnson, PhD, director of genomics and bioinformatics services at Texas A&M AgriLife Research, says that nearly everything else is different. Indeed, he asserts that about the only thing the new instrument shares with older instruments is the Illumina logo.
The NovaSeq X uses a new chemistry, XLEAP-SBS. Johnson says that while XLEAP-SBS is still sequencing-by-synthesis (SBS) (the fundamental chemistry developed by Solexa—the British company acquired by Illumina in 2007), it features a new polymerase, blockers, linkers, and dyes. Illumina also emphasized sustainability in its reagents and shipping program.
Despite the company’s announcement being timely, the major advancements won’t really be available until late 2023 or even 2024. For example, XLEAP-SBS won’t be available on the NextSeq until the P4 flowcell comes out in 2024. Although Illumina has declared that the cost per gigabase will be $2 (a 59% reduction in cost per gigabase relative to the current NovaSeq 6000 S4), that goal won’t be reached until the 25B (25 billion clusters) flowcell launches in the “second half” of 2023.
The timing of when these new platforms hit the market may be an important factor in how the competition shakes out, Baker notes. For example, the Ultima UG-100, an instrument which offers $1/Gb, may launch before Illumina’s new products. If that happens, customers may jump on it, including customers who might have chosen the Illumina platforms instead, had they been available.
On a similar note, “customers have over a year to ask themselves, ‘Why buy a NextSeq with “future promises” when I can buy Element’s AVITI for less money and a fraction of the sample cost today?’”
Just one month after hobnobbing with the former president at Illumina’s conference, the genomics community was hit by PacBio’s splash at the American Society of Human Genetics (ASHG) conference in Los Angeles. The company’s CEO, Christian Henry, told GEN that PacBio used the occasion to mark the “biggest jump forward in the company’s history.”
PacBio announced the launch of two new instruments, one of which is a short-read instrument called “Onso.” It adds a new dimension to the company’s current long-read offerings. (Anticipation for this news started in 2021, when PacBio acquired the company Omniome and its short-read technology—sequencing by binding.)
Why would a customer buy the Onso over Element’s AVITI, Singular’s G40, or Illumina’s NextSeq? Traditionally, PacBio’s customers have wanted two things: high accuracy and longer reads. And they are willing to pay for them. But the Onso may change that perception. Not only does the platform sit at a very competitive price point, but more accurate sequencing means less sequencing—which is cost effective.
“The Onso’s performance looks outstanding,” Johnson notes. He adds that he is eager to see more data to confirm this impression. That said, he wonders why PacBio would want to take on Illumina in the short-read market.
PacBio addressed this point on its investor day, which was held last November in New York City. The company stated, “Customers tend to gravitate one way or another [long read or short read], but they want both.” Johnson believes that some laboratories also may prefer using only one brand of sequencer, rather than using PacBio for long reads and Illumina for short reads.
In addition to the Onso, PacBio launched a new long-read platform, Revio, which will replace the company’s workhorse—the Sequel IIe. Although the Revio uses the same high-accuracy Hi-Fi chemistry, which allows for direct methylation and structural variation detection, the company says that the Revio is 15 times more powerful than the current Sequel IIe system. The new platform moves PacBio into population-scale genomics at under a $1,000 genome.
The day after the PacBio launch, Aquino told GEN, “We immediately got a lot of inquiries from our user community about when we are getting the Revio.” The announced Revio specs allow researchers to pursue projects that used to be out of reach because they were too costly or demanded too much throughput. “Now, we can get Hi-Fi reads similar to the current Illumina Novaseq price point, so I can see more projects going for 30X Hi-Fi,” Aquino relates. “There is more information to be gathered in the reads they will receive.”
How easily facilities can utilize Revio will depend on their previous experience with long reads. Preparing libraries to feed the Revio may be challenging for inexperienced users. “There will be a learning curve,” Aquino predicts.
The Revio sounds like “a great leap forward” in terms of sequencing cost and capacity, and it ties in well with PacBio’s proven long-read technology, Johnson suggests. Although 1,300 human genomes per year illustrates an improvement in PacBio’s throughput, the new Illumina NovaSeq X is designed to process 20,000 human genomes per year. Johnson states that when the cost of the machine is factored in, it becomes apparent that “Illumina is still a much less expensive way to genotype human genomes at clinical scale.”
From distant shores
Beyond the United States, other NGS companies are hoping to grab more of the market share. The new PromethION 2 Solo (P2 Solo) from ONT “looks interesting” to Johnson. A benchtop, nanopore sequencer, the P2 Solo offers direct methylation detection, chromatin confirmation capture with Pore-C, direct RNA sequencing, and read lengths from short (20 bases) to ultralong (>4 million bases). One reason Johnson is interested is the cost—a mere $10,000.
Then there is MGI, the China-based sequencing company that has, until now, deployed its systems in a relatively concentrated fashion (mostly in China and mostly in multiunit sites). Last year, MGI settled all the outstanding litigation that it had in the United States regarding Illumina. As a result, MGI started selling its CoolMPS platform in 2022 and plans to begin selling other products in early 2023.
MGI is interesting, Baker points out, because it, like Illumina, has a broad portfolio of sequencers from very low to very high throughput. MGI isn’t going after a specific segment or a niche that Illumina missed—MGI wants it all.
Baker raises two major open questions. First, in the current political environment, how many American customers are willing to purchase from a company whose parent company (BGI) has ties to the Chinese government? Second, how well set up is MGI to support a truly global launch of its platforms?
Aquino recalls that some users sought MGI instruments even in countries where the instruments raised patent issues. What might happen, she asks, when these issues are resolved? The question may not strike everyone as being decisive. Hadfield doubts that MGI/BGI will move past the geopolitical hurdles to secure real market share in the United States.
Hadfield maintains that there are enough customers to support many of the new sequencing options. Medical sequencing will continue to grow steadily—maybe exponentially. And nonmedical sequencing has many users crying out for cheaper whole genome sequencing.
When you add in pharma ambition, Hadfield says, we could enter an era where the sequencing in clinical trials is, by default, whole genome sequencing. He suggests that researchers may not bother with whole exome sequencing at $800 if 300× whole genome sequencing at $1,000 is available.
The new options in sequencing include not just new technologies, but also new companies. Historically, in the sequencing field, startups have battled for customers and market share. In addition, many promising NGS technologies have burst into the light, only to disappear into the night.
The new wave of NGS companies is not stopping at the big announcements in 2022. PacBio says that it is developing an ultra-high-throughput instrument that “will make Revio look like mid-throughput.” And Aquino credits Illumina for innovating more than it needed to, given its dominance in the market.
The figures, the numbers, the chemistries, the semiconductors—everything about these new technologies is exciting. But they’re only good if they work. As Aquino says, “If an instrument promises more throughput, and it doesn’t work, it’s not very helpful.”