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A Brief History of Mass Spectrometry

Marek Smoluch1 and Jerzy Silberring1,2

1 Department of Biochemistry and Neurobiology, Faculty of Materials Science and Ceramics, AGH University of Science and Technology, Kraków, Poland

2 Centre of Polymer and Carbon Materials, Polish Academy of Sciences, Zabrze, Poland

Mass spectrometry (MS) is almost 120 years old, but despite its age, it is still an extremely attractive technique. Let us compare here its birth and development to the fate of the title character of the novel The Curious Case of Benjamin Button by F.S. Fitzgerald. The main character becomes younger and younger over time. This is somehow similar to MS, still showing new faces and possibilities.

The origin of development of this technique is considered to be 1897, when the British physicist J.J. Thomson conducted research on tubular radiation and, at that time, he experimentally confirmed the existence of an electron by estimating its m/z value. This resulted in the construction, in 1912, of a device called the parabola spectrograph for spectra measurements of O2, N2, CO, and CO2. F.W. Aston, Thomson's assistant, applied this technique for studying isotopic compositions and, in 1919, presented another construction called a mass spectrograph. From this time, there was a significant increase in the awareness of the equipment, which can quickly determine isotopic composition of the elements. The breakthrough in MS dates back to the Second World War. In 1939, the Manhattan Project management asked A. Nier for help to solve an important issue: which uranium isotope is responsible for the fission reaction and how to gather the necessary material for further work. The answer to this question was crucial to enable a possibility to construct the atomic bomb. Nier had a machine built by E. Lawrence, which was based on a magnetic analyzer, a technique that was not efficient in separation of isotopes for military purposes. Around the same time, MS was used in petrochemical industry to evaluate the components of crude oil. This branch of industry had a lot of money, which was always driving the advancement of technology. The first spectrometers offered relatively small measuring capacities, the m/z range was about 70, and the spectrum recording time was about 20?minutes. During this period, the instruments were complicated, and only the chosen were able to manage those "black boxes." With the development of computers driven by the very complex operating systems (e.g. UNIX), they became increasingly incomprehensible to scientists. The basis for further and rapid development became commercialization of the production. The apparatus no longer had to be built on its own, but it could simply be purchased.

Postwar applications of MS were focused on the analysis of the low molecular weight compounds due to the lack of ionization techniques suitable for the studies of higher molecular masses, predominantly peptides and proteins. The primary source of ions was electron ionization (EI). However, it is worth mentioning here that gas chromatography-mass spectrometry (GC-MS) systems were also utilized to analyze amino acids and peptides.

The breakthrough came in 1981 when Michael Barber from Manchester developed the fast atom bombardment (FAB). For the first time, scientists could analyze biological compounds (including peptides and lipids) in solutions and not only in the gas phase. An additional advantage of this technique was the spontaneous fragmentation leading to assignment of the amino acid sequence. The problem was the presence of glycerol, effectively contaminating the ion source that had to be thoroughly cleaned at least once a week, and in the case of a source connected to the liquid chromatography (LC) (continuous-flow FAB), cleaning routine had to be carried out daily. In parallel, the analysts had at their disposal the thermospray ionization, the protoplast of the electrospray method, but the source was operated under high vacuum.

Another breakthrough in the development of ionization techniques was made in the mid-1980s of the previous century by the introduction of electrospray technique (J. B. Fenn with the team, 1984) and matrix-assisted laser desorption/ionization (MALDI) in 1985, with the name given by the creators of the source (M. Karas and F. Hillenkamp). It was further developed by K. Tanaka, who applied it to the analysis of higher molecular compounds and obtained the Nobel Prize for his achievements, together with J.B. Fenn (for electrospray ionization [ESI]) and K. Wüthrich (for NMR). ESI and MALDI are complementary techniques, and their main advantage is the ability to analyze compounds in a very wide range of masses. ESI was the first method operating at atmospheric pressure, enabling direct coupling of separation techniques and introduction of the sample in solution.

Initially, quadrupole or sector analyzers were used, and ion traps were introduced in 1983. Ion traps were unwillingly accepted by the world of scientists, because of the very low resolution, which then reached the value of only 50-100! The promising designs included the time-of-flight (TOF) analyzers most commonly linked to the MALDI source. The initial TOF constructions were also characterized by a low resolution on the order of 50; however, the rapid development of electronics and introduction of delayed extraction and ion reflectron have already made it possible to reach a resolution of 10-15?000 by the end of the 1980s. Interestingly, the TOF was the first to be used in conjunction with the gas chromatograph in the 1950s of the twentieth century. Much later TOF was replaced with quadrupoles and traps. The problem was the lack of sufficiently fast detectors capable of counting the rapidly passing ions. It is also worth mentioning the systems for controlling the spectrometers and methods of mass spectra acquisition. Initially the photographic plates were applied, later thermosensitive paper printouts, and next computer systems controlled by software incomprehensible for the ordinary users. Anyone who controlled mass spectrometer with the PDP-11 or used UNIX commands knows exactly what we are talking about.

In the mid-1980s of the twentieth century, alongside the powerful machines weighing several hundred kilograms, miniaturization of the equipment began. One of the first constructions was the MALDI-TOF spectrometer, which could be placed on a laboratory bench (benchtop). This machine was designed by Vestec and led by Marvin Vestal, a genius in this field.

In parallel with the development of the construction, MS applications have been published in various fields of science and technology. One of the pioneers was Fred McLafferty, who described the gas-phase rearrangements, named after him. McLafferty, along with F. Turecek, has made a history as authors of a book describing the fragmentation pathways that are the basis of every MS operator. A great contribution should be attributed to Howard Morris for his work on the analysis of peptides and methods of their sequencing and identification. This is one of the few authors whose works were written in a way understandable even for the layman. The basis of nomenclature for the resulting peptide fragments is owed to Klaus Biemann and Peter Roepstorff. The latter, along with his assistant M. Mann, showed that protein digestion with a proteolytic enzyme results in the unique fragments for a given protein, which was the basis for identifying proteins using knowledge of the masses of several peptides (peptide mapping). Mann, together with his coworker M. Wilm, later became famous for introducing the nanospray, a technique commonly used in modern analytics.

It is impossible to list here all who contributed to the development of both the technique itself and the applications. The pioneers of the 1980s and even the early 1990s had to intensely convince potential users of advantages of MS over high performance liquid chromatography (HPLC). Many researchers deeply believed that MS would not solve their problems and, in addition, was much more expensive and more complex than the previously used methods, such as HPLC.1

Major Events in the History of Mass Spectrometry