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April 1946: First Concept of Time-of-Flight Mass Spectrometer

Calutron mass spectrometer
Part of the Calutron mass spectrometer first used for preparative MS; inset photo of J.J. Thomson.
Since its humble origins nearly 100 years ago, mass spectrometry has become a virtually ubiquitous research tool, with scores of scientific breakthroughs, including the discovery of isotopes, the exact determination of atomic weights, the characterization of elements, and characterization of molecular structure. In fact, it is arguably one of the most important types of complex instruments in many fields of science and industry for much of the 20th century, yet the technology is generally unknown among the educated public.

Mass spectrometers are crucial for astronomical studies of our solar system. They are also key to the non-invasive international monitoring of nuclear facilities, and are becoming important tools in studies of surface phenomena. Commercially, mass spectrometry has long played a significant role in materials analysis and process monitoring in the petroleum, chemical and pharmaceutical industries, and are also used in the food processing and electronics industries. It is increasingly used in toxicology, drug abuse diagnosis and pollution monitoring, as well as for biological and biomedical uses.

A mass spectrometer is usually defined as any device that operates by a process used to produce a mass spectrum, and the instruments have appeared in ever-increasing variety of designs since their inception. Among these designs is the innovation known as time-of-flight mass spectrometry (TOFMS), a technique that determines the molecular weight of a substance by accelerating ions toward a detector. The time it takes to travel from the ion source to the detector is measured, then converted to mass with high accuracy. The greater the ratio of mass to charge, the slower the ion speeds toward the detector as it is accelerated.

The first mass spectrometer - originally called a parabola spectrograph - was constructed in 1912 by J.J. Thomson, best known for his discovery of the electron in 1897. He used the mass spectrometer to uncover the first evidence for the existence of nonradioactive isotopes. His device for the determination of mass-to-charge ratios of ions was based on turn-of-the-century research on kanalstrahlen, the streams of positive ions formed from residual gases in cathode ray tubes, initially found emitted from channels cut in the cathode plate. Local magnetic and electrostatic fields deflected these positive rays depending on their mass, resulting in diverging traces on a photographic plate.

Thomson's protege, Francis Aston, designed a mass spectrometer in which ions were dispersed by mass and focused by velocity, improving resolution power by an order of magnitude over Thomson's device. Other helpful innovations followed but the innovation of TOFMS as an analytical tool took several more decades. The concept was first presented at the 1946 APS April Meeting in Cambridge, Massachusetts, by William Stephens of the University of Pennsylvania.

The first TOF instruments were designed and constructed in the late 1940s, and the Bendix Corporation in Detroit, Michigan was the first to commercialize such devices. Two staff scientists - William Wiley and I.H. McLaren - are credited with devising a time-lag focusing scheme that improved mass resolution by simultaneously correcting for the initial spatial and kinetic energy distributions of the ions. The resolution was improved further by a 1974 invention by a Russian scientist, Boris Mamyrin, called the reflectron, which corrects for the effects of the kinetic energy distribution of the ions.

The quest for ever-greater resolution continues with two recently developed techniques: electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). In ESI, first conceived in the 1960s, highly charged droplets in an electric field are evaporated and the resulting ions are drawn into a mass spectroscopic inlet. MALDI, a form of laser desorption developed in 1985 by a team of German scientists, laser-desorbs sample molecules from a solid or liquid matrix containing a highly ultraviolet-absorbing substance.

These innovations have made TOFMS and other forms of lower-cost mass spectroscopy increasingly useful for sophisticated biomedical analysis, sufficiently democratizing the technology to make it available to hundreds of researchers who lack access to sophisticated magnetic sector machines. Current applications include the sequencing and analysis of peptides and proteins, DNA sequencing, and the analysis of intact viruses, among others, providing high sensitivity, specificity, and speed at a lower cost.

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Editor: Alan Chodos
Associate Editor: Jennifer Ouellette