Milestone Spectroscopy When Ions Head off on their Travels: Opportunities and Challenges in Modern Mass Spectrometry
Bremen and MS — both linked by a tradition extending over many years. No surprise, then, that one of the most outstanding MS technologies in recent history has made its way in the world from there. Where will this journey take us next?
LP: Dr. Moehring, mass spectrometry enjoys a long tradition at the Thermo Fisher Scientific site in Bremen. If you think about milestones, what do you consider to be the first one?
Dr. Thomas Moehring: When I started here in 2004, we had one device, based on what is known as Fourier-transform MS technology. That was the classic FT-ICR system, with a superconducting magnet, with a high field strength, which for us was 7 tesla. This device, introduced in 2003 as the LTQ FT, was the first step towards life-science mass spectrometry by the Bremen site. It was the first time we got to grips here with applications from fields such as proteomics and metabolomics. In 2005, a further FT-MS detector was added, which I would describe as the true milestone for analyzer technology: it is known as the Orbitrap analyzer.
LP: How did the Orbitrap come about?
Dr. Moehring: The “main brain” behind the Orbitrap is Alexander Makarov, who today is Director of Global Research for Life Sciences Mass Spectrometry here in Bremen. In 1999 at the annual convention of the American Society for Mass Spectrometry (ASMS), he presented findings for the first time that were revolutionary for a device not based on FT-ICR: extremely high resolutions, and extremely good mass accuracy — two of the key features of mass spectrometry.
LP: Revolutionary data — but could it be readily adapted for day-to-day use in the laboratory?
Dr. Moehring: The problem we had to grapple with was that a customer naturally does not want to be restricted to a small mass window and a precisely-controlled numberof ions in order to be able to apply the technology in day-to-day use. In various market segments, it was more a case of the customer requirements being different: they had complex samples to analyze, with different intensities, which were pre-separated using chromatography but nevertheless still had background signals.
Development, starting from the initial results in 1999 through to the first commercially-available LTQ Orbitrap device, then took another six years. That covered the Orbitrap analyzer itself and the injection system. For example, what angle was needed for the central electrode, and what angle for the outer electrodes? The means of controlling the ions was initially derived from the LTQ FT. This concept of the hybrid with two functional mass spectrometers, where one of them (the linear ion trap) is able to collect packets of ions, amongst other things, which can then be analyzed in the second (FT-ICR or Orbitrap), was something we revisited, and it gave rise to the LTQ Orbitrap, which was presented for the first time at ASMS in San Antonio in 2005.
LP: How have the market requirements changed since then?
Dr. Moehring: Whereas proteomics labs at that time were often interested in characterizing one sample or sometimes three or four as a time series, today’s requirements are in the range of hundreds or thousands of samples. Precision medicine or cancer moonshot programs are currently major key-words in this area. Ultimately, it is about characterizing large numbers of samples, using high throughput rates.
LP: So speed is vital for that, but surely it’s not the only thing needed? What else do your customers expect?
Dr. Moehring: Because the analyses are frequently being carried out at different centers or sites, in addition to throughput they are also concerned to ensure high reproducibility and comparability between measurements. That is one of the main requirements at the moment in the hardware criteria. So it is not just about extending the key ratios for mass spectrometers, such as sensitivity, dynamic range or scan speed, but also about guaranteeing comparability in the sense of instrument-to-instrument reproducibility and robustness, etc.
If you discuss key ratios with customers at a user meeting these days, then generally you hear things like: dynamic range: Factor 10, sensitivity: Factor 10 and scan speed: Factor 10. That’s pretty well established — it’s what our customers expect of us, that we would be working on these anyway. But alongside this, device comparability has moved increasingly into the foreground, along with robustness, including for Life Science. If you look at other market segments, such as Food & Beverage — these are areas where robustness is fundamental to market success.
LP: Are markets still expanding?
Dr. Moehring: The majority of the applications were initially for uses relating to proteomics, but the technology has also found its way into other markets. At the moment, biopharma is a very attractive and strongly-growing market. This is heavily due to the fact that in the pharma area a lot of things today no longer only involve small molecule applications, since protein-based active ingredients — antibodies, peptides, hormones — are becoming much more important. In the area of biosimilars/biotherapeutics, we can draw on our work in proteomics to make technologies available to customers where we are already strong. That’s why, for example. a Q Exactive — being a benchtop FT-MS device — is also highly attractive for biopharma applications, and we see that as one of the markets that will continue to grow in future too.