Recent technological innovations in next-generation sequencing (NGS) have users spoiled for choice. At first, new options began trickling in. But then the floodgates opened in 2022 as several new companies burst on the scene. And veteran companies contributed to the surge by introducing new instruments. Indeed, James Hadfield, PhD, senior director, epigenomics, oncology translational medicine, AstraZeneca, told GEN that 2022 was the best year for NGS since 2006.
Folding into this market expansion is the growth in the demand for sequencing, not only from directed genomic sequencing, but also from the growth of other omics technologies such as single-cell genomics and spatial transcriptomics, and of clinical applications such as liquid biopsy—all of which rely on sequencing. In addition, Charlie Johnson, PhD, director, genomics and bioinformatics, Texas A&M AgriLife Research, predicts that low-cost genotyping will continue to grow as software tools for low-coverage genotyping analysis become more broadly available—something that has limited this technology in the past.
Now it’s 2024. And it is time to look ahead to the next 12 months to predict what changes this year will bring for the genomics community. Here, we approach a group of experts and ask: What trends will emerge in the coming year? What will be the hot topic this time next year? And which companies will be left standing at the end of it?
Illumina’s next dance
Last year was rough for Illumina. The company endured headline-worthy drama in the boardroom, a CEO change, and a Federal Trade Commission order to undo the Grail acquisition.
But that all might be behind Illumina. Alex Dickinson, PhD, ex-Illumina senior vice president (and current chair of Ryght.AI) told GEN that he thinks “Illumina has got its mojo back” and “is going to be unstoppable now.” (These are particularly strong words coming from Dickinson, who can be skeptical of his former employer.) The company successfully launched the NovaSeq X and recruited Jacob Thaysen, PhD (Illumina’s newest CEO), from Agilent Technologies, which Dickinson says is “a classic life sciences tools leader.” And he thinks that Thaysen’s experience will put the focus back in the business. Dickinson sees no reason why any of the competitors would be able to “out-NGS Illumina.”
But Keith Robison, PhD, genomics expert and blogger, notes that Thaysen is largely “an unknown” who comes from a company that has a very different business model. Robison also wonders if the company will spend a large part of 2024 being consumed with divesting Grail.
That said, the big question for Robison is if any of the new short-read entrants (such as the AVITI from Element Biosciences, the G4 from Singular Genomics, and the Onso from PacBio) can go beyond a toehold? In addition to those new entrants, competition also entered the United States from overseas, as the fleet of sequencers sold around the globe by MGI was brought stateside by Complete Genomics.
Change can be scary
Changing to a new NGS instrument can be hard. Dickinson says that trust in the company is needed to make the switch. On a more practical note, users need a reagent stream that lasts indefinitely. And there is uncertainty as to how long these new companies will survive. “They all have some finite chance of going out of business,” he asserts, “because they all have incredible burn rates, and we live in an environment where funding is very scarce.”
Catharine Aquino, group leader, genomics analytics, Functional Genomics Center Zurich, ETH Zürich and the University of Zürich, explains that the challenge for the newer companies is that they will have to “provide a big added value” if they are to make a dent with Illumina. She adds, “Most of the people who are doing sequencing already have Illumina machines.”
But for Aquino, who runs a facility that has an AVITI from Element and may soon have a G4 from Singular, there are valid reasons to try something new. Cost is one. A second reason is that the newer companies anticipate releasing new technology in the future, and it is good to “have a foot in the door” when it comes to having access to early technology. Another reason for a user to try a new instrument is, quite simply, because now they can. Users might be motivated to switch if they’re disgruntled. For example, they might feel they’ve been overcharged or given inadequate support. At the end of the day, the technology in the new short-read instruments is not all that disruptive. It is still, basically, about short-read sequencing. It does not allow for new applications. At least, not yet.
Sequencers moving beyond DNA
Singular Genomics, a San Diego–based NGS startup, has been hinting at its intent to build an instrument that combines spatial and sequencing technology. The company has revealed little about its plan (other than sharing that it is working on an instrument called the PX), but perhaps 2024 will be the year that we learn more about what this combo means for the worlds of both spatial and sequencing. And Singular is not the only sequencing company that talks about sensing more than one “ome” on an instrument.
When I first visited Element’s headquarters in March 2022, the company was launching the AVITI instrument. My hosts noted that the AVITI incorporates technology, such as low-binding surface chemistry and optical imaging system, that could enable applications beyond DNA sequencing.
Oxford Nanopore Technologies (ONT) is actively talking about offering protein sequencing using its nanopores. At last year’s London Calling, ONT’s annual conference, Clive Brown, the company’s CTO, said that ONT has a “very active program working on protein sequencing.”
A few months ago, at the annual meeting of the American Society of Human Genetics, I sat down with Gordon Sanghera, PhD, ONT’s CEO, and he explained to me that ONT’s technology could be applied to protein sequencing—provided ONT changed the nanopore and the motor. “It sounds trivial,” he remarked. But the devil is in the details. As Brown noted in a talk last year, proteins are more difficult to get through a pore because they are folded, may lack charge, and may be heavily modified. The proteins still cannot translocate at speed.
“We can read, and we can move,” Sanghera said. “But we can’t do speed and read yet.” Although he admitted that ONT’s technology is not ready for prime time, he insisted that it is “very close.”
These are trying times, Aquino notes, and capital expenditure budgets are very tight. And these instruments—whether they’re spatial, single-cell, or sequencing instruments—cost a lot of money. It may be very appealing to customers to be able to get more than one omics readout from an instrument. In addition, users would save the costs associated with setting up a new technology, paying for an annual service contract, etc.
Long reads in 2024
What will 2024 bring for long reads? Both ONT and PacBio recently told GEN that they were excited about moving into the clinic. But the degree to which they can enter that market remains to be seen.
Johnson believes that the long-read market will expand in 2024. One of the reasons, he asserts, is that people are starting to realize the benefit of individualized telomere-to-telomere (T2T) type references.
Aquino has a Sequel IIe in her facility and anticipates that the PromethION 24 (P24) from ONT will arrive early this year—which she is excited about. She is interested in PacBio’ new Revio, but because her facility bought the NovaSeqX last year, there wasn’t enough room in the budget for a Revio as well. The facility may acquire one next year, she says, but it will see how much the other Revios in Switzerland are being used. If the other Revios are not at 100% capacity, her facility cannot justify getting its own.
But Dickinson is skeptical. He once thought that the market would separate into long reads for clinical work and short reads for other applications. But he no longer believes that, particularly as emerging applications like liquid biopsy only need short reads. He points to PacBio’s decision to move into short reads when the company developed the high-accuracy, short-read Onso instrument. To him, this is an implicit admission that the size of the long-read market is limited.
A comparison of real data
Last December, a group of researchers (including Aquino) uploaded a preprint onto bioRxiv that provided the first head-to-head comparison of the new short-read sequencers. The paper, entitled “The impact of PCR duplication on RNA-seq data generated using NovaSeq 6000, NovaSeq X, AVITI and G4 sequencers” focused on detailing what happens to library complexity after conversion.
If a researcher is working with RNA and wants to use a sequencer made by a company other than Illumina, the library has to be converted first. Because libraries are typically made with Illumina adaptors, the library has to be converted to adaptors that could be used on Element’s AVITI, Singular’s G4, etc. One concern is that the conversion could add complexity to the samples. However, the findings suggest that although conversion does result in added duplicates, it doesn’t change the complexity of the samples. Overall, one or two more genes were represented in the data, but there were no significant changes in the overall results.
What a difference a year makes
One question that may be answered this year is: How far can any NGS startup go before being bought? The world of NGS is no stranger to acquisitions. The field, as it exists today, has been shaped by many acquisitions: in the mid-2000s, Illumina bought Solexa, and Roche bought 454. In 2008, Agencourt Personal Genomics (SOLiD sequencing) was acquired by Applied Biosystems, which then merged with Invitrogen to form Life Technologies. Life Technologies bought Ion Torrent in 2010, and Thermo Fisher Scientific bought Life Technologies in 2013. Also, in 2014, Roche bought Genia (a nanopore company). In 2018, Illumina made a failed attempt to buy PacBio. The two companies called off the deal after the Federal Trade Commission filed a complaint.
A more recent example of the urge to merge is the acquisition of Omniome (for its sequencing by binding chemistry) and Apton (for its instrument) by PacBio. PacBio’ plan is to put Omniome’s chemistry into Apton’s box and bring the whole thing to market.
The omics race that kicked off in 2022 seems to be turning into an ultramarathon, with all the contenders still hydrating and sucking down gel packs. How many will be left by the end of 2024? Aquino said that it depends on how much investment capital the new companies have saved. Most of the companies are not making money yet on instruments or reagents, and it is a tough market to break into. Johnson added that “some of the short-read companies will not be around by the end of 2024.” And, when Dickinson was asked if he thought everyone will still be standing a year from today, he quickly answered, “No. No, I don’t.”
