NEW YORK (360Dx) – With the introduction of high-profile new platforms from companies like Thermo Fisher Scientific and Sciex, 2017 was something of a watershed for clinical mass spectrometry.
2018 was somewhat lower key but significant all the same as vendors worked to translate the dramatic announcements of the prior year into actual instruments and sales.
Most notably, Thermo Fisher received the CE-IVD mark for its Cascadion SM Clinical Analyzer and launched sales of the instrument in Europe. A fully automated and closed system, the Cascadion is the closest that mass spectrometry has come to approximating a traditional clinical analyzer, which could potentially open up the technology to a wide range of clinical users.
Thermo Fisher has beta-tested the instrument at Berkshire and Surrey Pathology Services, Frimley Park Hospital in the UK. Sally Benton, a consultant biochemist at that facility, said that based on her experience with the system, she could envision a place for it both in labs with mass spec expertise as well as in mass spec-naïve labs.
She suggested that in the case of expert labs, the instrument could handle routine assays like Vitamin D, which would let clinicians to use their traditional mass specs for more esoteric testing and assay development.
In the case of a non-expert lab like the Frimley Park facility, Benton said the Cascadion does appear straightforward enough for technicians with no mass spec experience to operate it with relatively little training, which makes it a feasible option for mass spec-naïve labs interested in adding mass spec testing.
"It's as easy to run as a chemistry analyzer," Benton said. "It's all been remarkably straightforward."
Sciex this year released an automated sample prep workstation and automated Vitamin D test for use with its Topaz clinical mass spec system, which the company launched in 2017. According to the company, the new releases allow for "completely unattended sample preparation," which further streamlines and simplifies the platform.
Even with the new sample prep module, the Topaz doesn't provide end-to-end automation of the Cascadion, retaining more of the form of a conventional mass spec. Additionally, unlike the Cascadion, which is a fully closed system, the Topaz allows for users to develop their own tests on the instrument.
How this trade-off between simplicity and flexibility will play out in the market remains to be seen. Both instruments are new to the market (the Cascadion is not yet available in the US) and neither vendor has released sales numbers for the platforms.
Several clinical mass spec users suggested, though, that trends were moving in the direction of the Cascadion.
James Ritchie, professor of pathology and laboratory medicine at Emory University and director of the core laboratory at Emory Crawford Long Hospital, said the Cascadion "would be a total break" with existing clinical mass spec technology, and one that would likely draw users who had previously avoided mass spec. Ritchie was an early access user of the Topaz system.
Victoria Zhang, director of the clinical mass spectrometry and toxicology lab at the University of Rochester Medical Center and founding chair of the American Association for Clinical Chemistry's Mass Spectrometry and Separation Sciences division, said that she expected that open systems like the Topaz and closed ones like the Cascadion would coexist in the near term but that the market would shift over time toward higher levels of automation and ultimately toward closed systems.
Roche is also working on a turnkey clinical mass spec system in collaboration with Hitachi, but the company reported little about that effort over the last year.
While Thermo Fisher, Sciex, and Roche set out to tackle the challenges of clinical mass spec by packaging traditional LC-MS/MS instruments in more streamlined offerings, other researchers and vendors are looking to similarly simplify mass spec, but through the use of several relatively novel technologies that eliminate the need for LC separation upfront of mass spec analysis.
LC separation reduces the complexity of the sample as it enters the instrument, eliminating noise and improving the sensitivity of mass spec experiments. However, the approach can be time-consuming, which lowers throughput. Additionally, some LC devices — particularly nanoLC systems used for experiments like plasma proteomics — can be somewhat finicky and require expertise to operate and troubleshoot.
This has led some to explore whether direct ionization approaches, which skip upfront LC, could provide the simplicity and throughput desired by clinicians while maintain necessary levels of analytical performance.
Perhaps most notably from a commercial perspective, Waters this year continued to build its direct ionization mass spec portfolio with the purchase of Prosolia's desorption electrospray ionization (DESI) technology. DESI uses a stream of ionized solvent droplets shot at an angle toward the sample of interest. These droplets extract ions from the sample, which are then directed into the mass spec for analysis.
Waters is also continuing to develop the rapid evaporative ionization mass spectrometry (REIMS) technology that it acquired in 2014 and which, like DESI, is a direct ionization approach requiring no upfront sample prep or separations.
While both are research-focused technologies at the moment, Waters aims to ultimately move them into the clinic, said Jose Castro-Perez, the company's director of health sciences.
Other researchers and companies are using MALDI mass spec, which similarly does not require LC separation, to streamline mass spec approaches for clinical use.
Mass spec firm MRM Proteomics announced this year a collaboration with the Canadian research network Exactis Innovation to develop MALDI-based protein assays for guiding therapy in breast and colorectal cancer patients.
Isoformix, a diagnostics startup led by Dobrin Nedelkov, formerly a group leader at the ASU Biodesign Institute and CEO of clinical proteomics firm Intrinsic Bioprobes, is looking to further simplify mass spec-based protein assays by eliminating both LC separation and protein digestion, which is another major source of complexity for mass spec protein measurements.
Isoformix plans to use MALDI mass spec to look at disease-linked forms of intact proteins, enriching target proteins with antibodies prior to MALDI-MS analysis. The company launched a large cohort clinical study this year looking into an indication that Nedelkov declined to disclose.
So far as clinical proteomics is concerned, MALDI technology underpins what is by far that field's greatest success story — the broad uptake of Bruker's MALDI Biotyper and BioMérieux's Vitek MS instruments for microbial identification in clinical microbiology.
MALDI is at this point a fairly mature technology within clinical microbiology, but the space did see some advances over the last year, particularly in terms of testing for antibiotic resistance, which is widely viewed as the next frontier for MALDI clinical microbiology platforms.
In April, Bruker introduced its Bologna workflow, which combines microbial identification from positive blood cultures with testing for antibiotic resistance to cephalosporin and carbapenem antibiotics.
The year also saw the demise of a pair of clinical mass spec pioneers, as proteomic diagnostic firms Integrated Diagnostics and Applied Proteomics both went out of business.
In July, Biodesix acquired Seattle-based Indi and its mass spec-based XL2 assay, which measures two plasma proteins to help physicians assess the likelihood that an indeterminate lung nodule detected via imaging is malignant. When the initial version of the XL2 test, called Xpresys Lung, launched in 2013, it was the first multiplexed protein assay on a LC-MS/MS system to come to market and, as such, something of a clinical mass spec landmark. The test never gained traction in the marketplace, however, with only around 2,000 sold over the course of three years.
That led Indi to develop a second-generation version of the test, the XL2 assay, which also used LC-MS/MS. The test received a positive coverage decision from Medicare contractor Noridian last year, but Indi exhausted its funding in the course of obtaining this coverage, leading to the decision to sell to Biodesix.
In January, startup DiscernDx purchased the assets of Applied Proteomics for $1.85 million. Backed by venture firm Khosla Ventures and led by Bruce Wilcox, Applied's former head scientist and leader of research and development, the new company plans to use Applied's mass spec technology for undisclosed clinical applications.
Launched in 2007 by David Agus, director of the University of Southern California's Center for Applied Molecular Medicine, and Danny Hillis, chairman and cofounder of technology firm Applied Minds, Applied built an LC-MS/MS discovery and validation platform that it used to develop its lead product, SimpliPro Colon, a proteomic test for colon cancer that it launched in 2015.
The test was never a commercial success, but, as Khosla principal and DiscernDx board member Alex Morgan described it, in the process of developing it, the company created "a very robust [mass spec proteomics] pipeline, both in hardware and software."
"One of the challenges [to mass spec proteomics] has been in a lot of these operational efficiencies and consistency and getting robust data both out of your physical system and your informatics pipeline," he said. "Those are important [challenges] that the company did a very good job at solving."