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Mass Spec Retakes Center Stage in 2023 as Next-Gen Proteomics Startups Struggle


NEW YORK – Proteomics in 2023 saw mass spectrometry reassert itself as new instrumentation and sample preparation approaches offering dramatic advances in throughput and depth of coverage.

Fresh releases like Thermo Fisher Scientific's Orbitrap Astral and Bruker's timsTOF Ultra set new benchmarks for mass spec performance. At the same time, some of the next-generation proteomics firms that have turned heads in recent years ran up against the challenging realities of bringing a new technology to market.

Debuting at the American Society for Mass Spectrometry annual meeting in June, the Orbitrap Astral and timsTOF Ultra both offered dramatic improvement over the previous state of the art, providing the ability to measure many thousands of proteins at levels of throughput necessary to conduct large-scale studies.

Bruker's Ultra was an update of an existing platform, while for Thermo Fisher the Orbitrap Astral marked the introduction of a new technology, the company's Astral (for asymmetric track lossless) analyzer. Much like a time-of-flight (TOF) analyzer, the Astral measures the travel of ions along a track within the instrument and their arrival at the surface of a detector. According to the company, it achieves significantly better ion transmission than a typical TOF instrument, with more than 80 percent of ions reaching the detector.

Both instruments are meant for a wide range of proteomic applications, but of the data presented at ASMS, perhaps the most notable was that demonstrating the performance of the Orbitrap Astral for plasma analyses.

Plasma is an easily accessible and commonly collected sample source, especially for clinical work and population studies, but it has traditionally been a challenging sample source for mass spec-based proteomics. While mass spec workflows in cell lysate commonly measure 8,000 to 12,000 proteins, similar workflows in plasma may only measure 500 to 1,000 proteins. This can be improved by using depletion to eliminate high-abundance proteins or extensive fractionation, but this comes at the expense of throughput.

At ASMS, Thermo Fisher presented data in which company researchers used Seer's recently released Proteograph XT kits on the Astral instrument to measure roughly 6,000 proteins in plasma at a throughput of around 30 samples per day. That places mass spec in the ballpark of affinity-based platforms like SomaLogic's SomaScan and Olink's Explore, which were previously the only feasible options for researchers looking to measure thousands of proteins across many hundreds to thousands of plasma samples.

To many in the field, the jump in performance came as a surprise.

"We hadn't seen this massive leap coming, to be honest," Maik Pietzner, a bioinformatician at the MRC Epidemiology Unit at the University of Cambridge School of Clinical Medicine, told GenomeWeb following the release of the new instruments. "We obviously more than welcome this development."

Pietzner, who has used SomaLogic's SomaScan and Olink's Explore in large-scale proteogenomic studies, said that for the proteogenomic experiments he and his colleagues are pursuing, they need sample cohorts of 1,000 or more, which, he noted, based on the data presented at ASMS, now seems feasible.

Jennifer Van Eyk, director of the Cedars-Sinai Precision Biomarker Laboratories, likewise expressed excitement about how the new instruments might be used for large-scale plasma studies. She noted that in experiments running 60 samples per day in undepleted plasma on the Astral, her lab has been able to measure between 2 and 2.5 times as many proteins as measured using the same workflow on Thermo Fisher's Exploris 480 instrument, and with throughput of up to 180 samples per day.

"At 180 samples [per day], all of a sudden you can start talking about running 10,000 samples, and then it becomes a population study," she said.

Single-cell proteomics advances

The new platforms have also significantly boosted the power of single-cell proteomics experiments, more than doubling the number of proteins commonly measured in such work.

"We are seeing very substantial increases in the performance of single-cell protein analysis, and the new instruments are clearly an important part of those increases," said Nikolai Slavov, associate professor of bioengineering at Northeastern University and director of the Parallel Squared Technology Institute (PTI), which focuses on single-cell proteomics research.

The Astral has been "a real game-changer," said Jesper Olsen, professor and vice director of the Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen. In November, Olsen and colleagues published a BioRxiv preprint that provided one of the first looks at the use of the Astral for single-cell work. In the study, the researchers were able to identify more than 5,000 proteins in individual HeLa cells, which they noted is more than twice the roughly 2,000 proteins per cell previous single-cell experiments have typically topped out at.

At ASMS, Karl Mechtler, head of the proteomics tech hub at Vienna's Research Institute of Molecular Pathology, presented data generated using the Ultra at a Bruker facility in which he and his colleagues were able to measure roughly 6,000 protein groups with a median coefficient of variation of 10 percent in a 250-picogram standard (approximately equivalent to the amount of protein in a single cell). Looking at actual single HeLa and K562 cells (as opposed to standards), they identified, respectively, 3,803 and 3,221 proteins using the Ultra.

Mechtler, whose lab has purchased an Ultra and is in the process of buying an Astral, said that he believes it will be difficult to keep up with advances in single-cell work without access to the newer instruments.

"I'm in discussion with other people in the single-cell field, and we all together agree that the new generation of instruments is a big step forward," he said. "If you don't have the new instruments, you cannot really do single-cell proteomics anymore. They are so much better; it is really amazing."

Affinity platforms on the move

Looking beyond mass spectrometry, the two major players in the affinity-based discovery proteomics market — Olink and SomaLogic — also saw notable developments. In November, SomaLogic launched its SomaScan 11K Platform, boosting the platform's protein content from 7,000 to 11,000 analytes. In July, Olink launched its Explore HT platform, which measures more than 5,300 proteins, up from around 3,000 and with four times the throughput of its previous platform.

These launches indicate that while the year's mass spec releases have made that technology competitive with Olink and SomaLogic for large-scale plasma proteome experiments, affinity-based approaches are also continuing to advance.

In fact, one mass spec company — Thermo Fisher — is looking to move into the affinity platform business. The firm announced in October plans to acquire Olink for $26 per share, or roughly $3.1 billion.

SomaLogic is similarly involved in a planned merger with Standard BioTools, with the two firms in October announcing a deal under which SomaLogic shareholders would receive 1.11 shares of Standard BioTools common stock for each share of SomaLogic common stock owned.

Both deals have run into complications in recent days, however. At the end of December, Olink disclosed that UK regulators will be investigating the planned acquisition to determine whether it will result in reduced competition.

Also in December, SomaLogic Cofounder and former CEO Larry Gold and current Chief Technology Officer Jason Cleveland filed a class action lawsuit against the company's board alleging that it has neglected its fiduciary duty in negotiating the deal and that Eli Casdin, a major investor and board member for both SomaLogic and Standard BioTools, has a conflict of interest.

Both Olink and SomaLogic are also involved in lawsuits with startups in the proteomic space, in both cases over allegations of patent infringement.

In November, Olink filed suit in the US District Court for the District of Delaware alleging that proteomics firm Alamar Biosciences' NULISA (NUcleic acid-Linked Immuno-Sandwich Assay) technology infringes on a patent covering aspects of its proximity ligation assay (PLA) immunoassay technology.

Alamar, however, disputes Olink's claims that the patent covers methods used in its NULISA system, with Yuling Luo, the company's founder, chairman, and CEO, asserting that the patent does not cover PLA and that all of Olink's patents that do cover PLA have lapsed, thereby placing the technology in the public domain.

SomaLogic, meanwhile, is engaged in a patent dispute with Nautilus Biotechnology in which Nautilus filed a complaint in US District Court for the Northern District of California asking for declaratory judgment of noninfringement on a patent SomaLogic has licensed covering DNA origami technology. According to Nautilus, SomaLogic informed the company that DNA origami technology used in its proteome analysis platform may infringe on its patent and has demanded that the company cease production and distribution of the platform.

Proteomics startups struggle

In general, 2023 was a challenging year for recently launched proteomics. Two years ago, next-generation proteomics companies like Seer, Nautilus, and Quantum-Si garnered significant buzz (and hundreds of millions of dollars in investments) for their novel approaches to analyzing the proteome. More recently, though, these firms have faced both a more difficult macroeconomic environment and the challenges inherent in bringing a new technology to market.

Quantum-Si launched sales of its Platinum protein analysis system at the beginning of the year. As of the end of Q3, the company had booked less than $1 million in sales of the instrument and had revamped its instrument software after receiving customer feedback about capability gaps. The company, which laid off roughly 12 percent of its workforce in January 2023, also decided to discontinue the development of its Carbon sample preparation system after realizing that it did not provide researchers with the flexibility needed to run a wide range of sample types and experiments.

During a call following release of Quantum-Si's Q3 2023 financial results, President and CEO Jeff Hawkins said it planned to operate in a "controlled commercial launch" mode until early 2024, after which it expects to transition to a "full commercial launch."

Nautilus, too, was forced to scale back its ambitions in 2023, announcing in August that its initial release, planned for launch in mid-2024, would not hit the targets it originally provided for minimal sample input required by the system and number of proteins it is able to quantify.

Explaining the decision, Nautilus CEO Sujal Patel said that as the company "weighed the work in front of us to get our first product out the door and balanced that with our time-to-market goal, it became clear that we needed to evaluate what part of our product specifications needed to be in our first product, and what could wait until version 1.5 or version 2 follow-on."

Patel declined to provide specifics on where the platform currently stands in terms of breadth of protein coverage and what breadth of coverage it would launch with but said that as the company hits around 2,000 proteins measured on its platform, "we will start putting [the] technology into the hands of some [key opinion leaders]."

Seer, likewise, underperformed in 2023, cutting its full-year revenue guidance by roughly a third in the middle of the year due to poor macroeconomic conditions and slower-than-expected uptake of its Proteograph Product Suite.

Seer's technology, which uses nanoparticles to enrich plasma samples for proteomic analysis, was an integral part of the plasma proteomic workflows Thermo Fisher demonstrated on the Orbitrap Astral at ASMS, but the company has nonetheless struggled to place instruments at the pace it once anticipated.

Seer is also likely to face competition from recently developed, less-expensive enrichment methods. For instance, at ASMS, proteomics sample prep firm PreOmics launched its ENRICH-ist Kits for enrichment of plasma and serum proteins. The kits use non-functionalized paramagnetic microbeads to enrich low-abundance proteins and, according to the company, boost protein detection by 50 percent to 100 percent compared to undepleted, unenriched plasma.

Additionally, researchers at the University of Washington have developed a plasma protein enrichment approach using magnetic microparticles from ReSyn Biosciences to improve depth of coverage by binding membrane-bound vesicles in plasma and analyzing the associated proteins.

According to Michael MacCoss, professor of genome sciences at UW and, with his UW colleague Christine Wu, developer of the enrichment approach, his lab is able with the method to consistently quantify around 4,800 proteins in plasma using a 30-minute LC gradient on an Orbitrap Astral, allowing for throughput of around 40 samples per day. They are able to measure between 5,000 and 6,000 proteins using a one-hour LC gradient.