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Thermo Fisher Releases New Tribrid Mass Spec as TOFs Cut Into Orbitraps' Dominance


NEW YORK – As it brings its newest Orbitrap mass spectrometer to market, Thermo Fisher Scientific faces mounting competition from other vendors' time-of-flight instruments.

At the International Mass Spectrometry Conference in Maastricht, Netherlands, last month, Thermo Fisher launched the Orbitrap Ascend Tribrid, a high-end instrument aimed at proteomic and biopharma applications.

The release comes at a time when new time-of-flight (TOF) instrumentation — Bruker's timsTOF line, in particular — is offering a stiff challenge to Thermo Fisher's Orbitrap technology, which has dominated proteomics research for much of the last decade.

The Ascend boasts a variety of features including a new ion funnel optimized to improve coverage of protein post-translational modifications, a new architecture with two separate collision cells to improve assay flexibility and cycle times, and Orbitrap scan speeds of up to 45 Hz.

Josh Coon, a professor of chemistry and biomolecular chemistry at the University of Wisconsin-Madison, said that in early-access work with the instrument, his team observed 20 percent to 30 percent gains in the number of phosphopeptides they were able to identify compared to their work with previous Tribrid instruments.

Coon said that to his mind, the addition of a second collision cell was the most significant advance in the new system, noting that this feature would improve the speed of the instrument and allow researchers to analyze more of the ions introduced into the machine.

Traditionally, the collision cell has been something of a chokepoint for mass spec runs, he said, especially when using slower fragmentation methods like electron transfer dissociation.

With two collision cells, researchers can inject ions into both at once, which Coon said should improve the instrument's duty cycle.

The dual collision cell architecture offers a boost in sensitivity, as well, said Jim Yano, senior director of product management at Thermo Fisher.

"You can actually accumulate ions [in a collision cell] while you are doing an analysis in the Orbitrap or the ion trap, so you get an enhancement in sensitivity," he said. "And that's been a key for our collaborators, the ability to trap those ions and increase sensitivity for low-level proteins."

The instrument could also offer improvements for top-down proteomics research, said Neil Kelleher, director of the Chemistry of Life Processes Institute at Northwestern University.

He said that in his early-access work with the system, he had been able to double the number of scans per top-down experiment compared to previous Tribrid systems.

Those additional scans should allow researchers to improve their characterization of the proteoforms they are looking at and to characterize more proteoforms per experiment, he said.

Thermo Fisher is also targeting areas outside proteomics with the new release, perhaps most prominently biopharma, where it expects the instrument's extended mass range option, enabling analysis of molecules up to 16,000 m/z, will prove useful.

Within proteomics, though, it appears unlikely the new platform will blunt the ongoing revival of TOF instrumentation, a development of recent years driven by a number of factors including the launch of new, more advanced systems, improved informatics, and the growing popularity of data-independent acquisition workflows.

The Ascend launch "isn't altering any of my purchasing plans," said Ben Orsburn, a proteomics researcher in the department of pharmacology and molecular sciences at Johns Hopkins University.

Orsburn, who was formerly a senior field applications scientist in proteomics for Thermo Fisher, said that the high speed of current TOF technology made it hard for him to go back to the slower Orbitrap-based instruments.

Bruker's timsTOF HT, the company's top-of-the-line instrument, has a top speed of 150 Hz, and Sciex's ZenoTOF 7600 systems offers speeds of up to 133 Hz. That compares to 45 Hz for the Ascend's Orbitrap analyzer.

TOFs have long offered higher scan speeds than Orbitrap-based instruments, but these scans were of poorer quality, and Orbitrap proponents have typically argued that fewer, higher quality scans produced better proteomics data than a larger number of lower quality scans.

If purchasing patterns are any indication, most researchers agreed, as Orbitraps came to dominate bottom-up proteomics research in the decade following Thermo Fisher's commercial introduction of the technology in 2005.

When Sciex (then AB Sciex) launched its TripleTOF 5600+ instrument featuring the Swath DIA technique in 2012, the system and the method seemed a strong alternative to Orbitraps, but Thermo Fisher responded with the release of several DIA approaches tailored to its instruments, including its Q Exactive, which it had launched in 2011 with the goal of targeting the QTOF market, and Orbitrap technology continued to be a clear favorite among proteomics researchers.

That trend began to shift, however, with Bruker's introduction in 2016 of its timsTOF mass spec, which couples trapped ion mobility spectrometry (TIMS) to a high-end QTOF system. The combination of TIMS with mass spectrometry was new to proteomics and enabled a variety of new workflows, such as the Parallel Accumulation-Serial Fragmentation (PASEF) that combines collection of ions via TIMS with rapid quadrupole switching on a QTOF instrument to enable the fragmentation of multiple simultaneously eluting precursor ions.

The following year, Bruker introduced an updated version of the instrument, the timsTOF Pro. In June of this year, it introduced the most recent edition of the system, the timsTOF HT. It has also released a version aimed specifically at small sample size and single-cell applications called the timsTOF SCP. The platform appears to be popular: In August, Bruker President and CEO Frank Laukien said the company has placed more than 500 timsTOF instruments since its launch and that it was generating more than $125 million in annual revenues.

Beyond the sales figures, a notable measure of the timsTOF's success and impact on proteomics is the method and technology development being done on the platform by top proteomics researchers like Matthias Mann, head of the department of proteomics and signal transduction at the Max Planck Institute of Biochemistry, and John Yates III, professor of molecular medicine and neurobiology at the Scripps Research Institute.

Orsburn suggested that the growing interest in TOFs extended beyond just the timsTOF, citing Sciex's ZenoTOF 7600 system as a platform that was also drawing attention from researchers.

He said the rise of DIA and the large amount of investment in informatics tools for DIA-based analyses are key factors driving this phenomenon, suggesting that these developments may have shifted thinking around the trade-offs between scan speed and quality.

"The informatics for DIA are really good and really advanced," he said. "Everyone is at some level using machine learning or deep learning that is digging through the spectra and making sense of it. [The TOF spectra] wasn't actually crap before; we just weren't smart enough to look at it."

Orsburn said that while Johns Hopkins' proteomics core facility has long been dominated by Orbitraps, it is currently trying out a timsTOF and a ZenoTOF.

"For the first time in a while, we actually have this competition where everybody I know is sending out samples to demo at least two instruments if not three instruments," he said.

Brett Phinney, director of the proteomics core facility at the University of California, Davis, said he hadn't had a TOF in almost 20 years before buying a timsTOF in 2019.

He said his lab first looked into the timsTOF for PTM work, thinking the instrument's speed could be useful in this regard.

"I think we were looking at ubiquitination at the time, and the data just blew away the Orbitrap we were looking at," Phinney said. "And we were like, 'Well, we have three Orbitraps, let's look at one of these.' That's why we went with it."

He said his lab currently uses the timsTOF mainly for DIA experiments but also frequently uses a Thermo Scientific Orbitrap Exploris 480 for DIA work, as well as an Orbitrap Fusion Lumos Tribrid, a predecessor of the new Ascend instrument.

Phinney said his lab typically uses the timsTOF for experiments run with shorter liquid chromatography gradients and the Orbitrap instruments for experiments requiring longer LC gradients. This, he said, is largely due to the availability of better long-gradient LC options for the Orbitraps.

In fact, Phinney said, with mass spec instrumentation having a moment of parity, the quality of the upfront LC systems available for these instruments is a key distinguishing factor.

With regard to LC, Thermo Fisher "has much better options than Bruker does right now," he said, noting that the former's mass specs are more easily compatible with a wider and newer range of devices.

"The mass specs are all really good, but the LC you put in front of them makes a huge difference." Phinney said. "Some people will say, 'Yeah, the timsTOF is really outperforming the 480, or the 480 is really outperforming the timsTOF,' but unless you keep the LC constant, you can't really make that comparison. I thought the same thing, and then I swapped LCs, and my results were completely different."