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Although first conceived in the late 1890s,mass spectrometry (MS) is a technologyborn and bred in the 20th century. Mass

spectrometers are perhaps the most fundamentaltools for understanding the nature of chemicalcomposition and have become the mainstay of ahealthy instruments industry. In the 21th century,MS has the brightest possible future as it adapts to

a biological world.At its heart, a mass spectrometer separates

ionscreated from molecules subjected to one of avariety of stresses, from simplecollisions to laser blastsaccord-ing to their mass-to-charge ratio(m/z) by passing them through amagnetic and an electrical fieldsimultaneously. The ions are eval-uated with a detector when theycollide. Evolution in the technol-ogy involved modifications toeach of these components.

At first, MS seemed an obscure

technology at best. The first massspectrometer (then called aparabola spectrograph) wasconstructed by British physicist

J. J. Thomson, the discoverer of theelectron, in 1912. But there was little significantdevelopment of the technique until World War II.

Wages of War

In the early 1940s, physicist E. O. Lawrence at theUniversity of California, Berkeley, took an MS-based separation approach to enrich fissile uranium,uranium-235, from the natural isotopic distributionof uranium. This method used a gigantic magnetic

device called a Calutron (for California and cyclo-tron) to separate ions according to their m/z; onceseparated, the ions were collected. This preparativemass spectrometer was able to purify the uranium-235 used to construct the atomic bomb.

During the war, in 1940, the prototype of thefirst commercially successful mass spectrometer wasdeveloped. It ultimately became known as theConsolidated Engineering Corp. (CEC) Model21-101, first sold in 1943 to the Atlantic RefiningCorp. in Philadelphia. (Although WestinghouseElectric sold a portable mass spectrometer designed

by John Hipple, in 1941,it was not a marketsuccess.) By 1944, aCEC 21-101 users groupformed in Pasadena,CA; the group later becamethe American Society for Mass Spectrometry.Ancillary standards and tools were seen as an

immediate necessity, and the U.S. National Bureauof Standards produced the first 15 official hydrocar-bon calibration standards for mass spectrometers.

The obvious need for compu-tational tools for MS led tothe introduction by CEC ofthe Model 30-103, an analogcomputer that could be usedto analyze mixed hydrocarbonspectra.

The Expanding Industry

Immediately after the war, signifi-cant breakthroughs occurred in

MS. In 1946, William E.Stephens of the University ofPennsylvania developed the firsttime-of-flight (TOF) mass analyz-er. The principle of TOF relies on

accelerating ions toward a detector with equivalentenergy. In such a case, the time of flight becomesa comparative function of mass, that is, smaller ionsmove faster than larger ones. In addition, Metro-politan Vickers introduced the MS 1 massspectrometer in the same year.

In 1947, CEC introduced the Consoli-dated-Nier isotope ratio mass spectrometer,and the Bureau of Standards and the Ameri-

can Petroleum Institute collaborated on alibrary of reference mass spectra. In addition,MAT (Mess und Analysen-Technik) was foundedin Bremen, Germany. In 1948, the Omegatron,the first ion cyclotron mass spectrometer, wasdeveloped, and a dual inlet with a changeovervalve was designed for rapid sample switching inhigh-precision isotope ratio MS by researchers atthe University of Minnesota. The year 1949 sawthe birth of ion cyclotron resonance.

In 1950, CEC introduced the Model 21-103mass spectrometer, which would rapidly be coupled

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SpectacularSpectrometryThe corporate-led evolution of MS

produced an irreplaceable tool.M A R K S . L E S N E Y

Top: Finnigan quadrupole MS unit,Chromatography, 2001

Center: TOF MS, Bendix ad,AnalyticalChemistry, 1969

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to heated inlet systems capable of allowing gas-liquid samples to be introduced easily. In 1953,Wolfgang Paul published the first papers onquadrupole MS and ion-trap detectors. Quadru-pole filters used a quadrupolar field to manipulatesingle ions or ranges of ions based on theirm/z,thus acting as true mass filters.

In 1956, Roland Gohlke and Fred McLafferty

first demonstrated GC/MS using a TOF mass spec-trometer (Model 12-101) developed by the BendixAviation Corp. Also in 1956, MS was first used toidentify an organic compound by bombarding thecompounds vapor, at a pressure of 105106

mmHg, with electrons having energies of 50100eV. This process broke down the molecules of thecompound to form reproducible positive, negative,and neutral fragments, making it possible to identi-fy organic impurities in a sample without anypreconcentration of the impurity.

Perhaps the key business trend of the 1960s wasthat of increased competition as MS gained popu-larity and expanded its forms and as more and

more companies began manufacturing and distrib-uting the instruments.

In 1962, the first commercial quadrupole massspectrometer was sold toNASA by Electronics Associ-ates, Inc. (EAI). In a clevercircumvention of a ban oninstrument exhibits at the1963 annual meeting of theAmerican Society for Testingand Materials, AppliedPhysics Corp. exhibited itsMAT CH4 MS unit to atten-dees who were willing to walk

to a bar across the street fromthe conference.

In 1964, Jeol produced itsfirst mass spectrometer; andthroughout the 1960s,PerkinElmer became a signifi-cant force in the MS marketin the United States, acting asthe distributor of Hitachiunits. Competition continuedto expand as, in 1967, theFinnigan Co. (acquired byThermo in 1990) was formedby Robert Finnigan (formerly

of EAI) to take advantage ofthe potential he saw in

quadrupole GC/MS and theadvancements computers would provide to MSinstruments. That companys introduction of thefirst commercial quadrupole GC/MS came just oneyear later. Also in 1967, MAT, which came outwith the CH5 that same year, was acquired by Vari-an, becoming Varian MAT. Significant to thebiological future of MS, in 1968, electrosprayionization (ESI) at atmospheric pressure was devel-oped by Malcolm Dole and colleagues, although

the technique would not be routinely used for twomore decades.

In 1967, PerkinElmer introduced its own massspectrometer, Model 270the first magneticdouble-focusing GC/MS. By the late 1960s,Hewlett-Packard had entered the GC/MSmarketand would continue its involvementthrough the 1990s. These instruments were a

strong reflection of how the marriage of GC andMS would continue as the most powerful combi-nation for organic analysis.

Also in the 1960s, the first secondary-ion MS,or SIMS, instrument was constructed under a

NASA contract to analyze moon rocks. In SIMS,a sample surface is bombarded with a primary ionbeam, followed by MS of the emitted secondaryions. The instrument was copied and marketed,creating an expanding demand for SIMS in thedecades to follow, especially in the developingelectronic materials industry.

That 70s Flow

By the early 1970s, GC/MS was the technique ofchoice for monitoring illegal drug trafficking anduse. With the development of the environmentalmovement prompted by Earth Day and the estab-lishment of the Environmental Protection Agency(EPA), the issue of pollution monitoring becamecritical. An early example of this was the use ofDuPonts DIMASPEC (digitized GC/MS) in 1971to detect contaminant diethylstilbestrol in beef. In1978, EPA accepted Finnigans GC/MS system as astandard means of analyzing pollutants. Because ofthis endorsement, the company came to dominatethe global market, even though units were pricedin the $150,000 range. Such sales indicate the

impact of the environmental movement in the1970san impact that continues todayon theoverall market for analytical instruments.

Throughout the decade, MS continued todevelop new incarnations. In 1974, Fourier trans-form ion cyclotron resonance was introduced. By1977, Finnigan was offering an early line ofLC/MS systems.

New companies were formed to take advantageof new technologies. For example, Comstock wasfounded in Oak Ridge, TN, in 1979 by physicistsRobert N. Compton and John A. D. Stockdale.Although their initial product was an electrostaticenergy analyzer, they became noted for their TOF

MS line introduced in 1987, and they wouldcontinue to develop specialized TOF instrumentsthereafter.

The 80s and 90s

This decade saw the development of one of themost powerful inorganic analysis techniques.PerkinElmer became involved in inductivelycoupled plasma (ICP)-MS when through a jointventure with SCIEX, the company helped todevelop and market the ELAN 250, the first ICP-MS instrument for commercial applications.

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TIMELY TANAKA

The 2002 Nobel Prize in Chemistry was givento three pioneers of methods for identificationand structure analyses of biological macro-molecules. Among them was Koichi Tanaka(Shimadzu Corp.), who was awarded the prizefor his development of MALDIin part througha fortuitous mistake in his laboratory. Whileattempting to develop an optimal matrix to

contain a sample to be ionized by a laser blast,Tanaka mistakenly mixed glycerin instead ofacetone with cobalt. According to theShimadzu website, Tanakapart of a teamnoted for its faith in trial and errorcame tothe conclusion that even this presumablywasteful mixture, like any other, might havesome potentialand might even be the rightoneand he set it on a sample plate and theroad to becoming a miracle matrix.

One of Tanakas two co-winners was JohnB. Fenn, who was awarded the prize for hisdevelopment of ESI. Together with MALDI, ESIhas helped to make MS not only a viable but an

ideal tool for biological analysis.

Above: Artists rendering of MALDI,Modern Drug Discovery, 2003

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In 1987, PerkinElmer SCIEX introduced theELAN 500, the first ICP-MS system with platinumcones and an inert sample introduction system.The company went on to launch the ELAN 5000,the first turbomolecular-pumped ICP-MS instru-ment, in 1990, and later the ELAN 6000, the firstICP-MS system with a simultaneous automaticextended dynamic range detection system.

New companies were unveiled and changestook place in corporate structure through mergersand acquisitions. In 1980, the Bruker DaltonicsCorp. formed as part of the global Bruker organiza-tion. The companys roots were in the GermanBruker-Franzen Analytik GmbH and the SwissSpectrospin AG. These companies developedmobile detectors and mass spectrometers for physi-cal chemistry. In 1981, Varian MAT was acquiredby Finnigan, becoming Finnigan MAT.

In 1982, Cambridge Mass Spectrometry (CMS)was spun off from Cambridge Consultants Ltd.(CCL, a division of Arthur D. Little). In 1987,CMS became a wholly owned subsidiary of Kratos

Analytical, which came under the control ofShimadzu Corp. of Japan in 1990. CMS producedsurface analysis instruments using quadrupole andTOF-SIMS technology. In 1992, the companyKore was founded by a core of engineers andaccountants at CMS who decided not to transfer toManchester, U.K., as part of a cost-cutting effort tomerge the CMS products with Kratos.

MALDI and More

Because MS techniques were typically too harsh formost biomolecules, it wasnt until the developmentand routine deployment of the so-called soft ioniza-tion techniquesESI (which was only then achiev-

ing popularity) and matrix-assisted laserdesorption/ionization (MALDI)that MS becamea key tool in modern biology. MALDI was devel-oped in 1985 (see sidebar). In 1988, the LAMS-50K, the first commercial MALDI-TOF MS instru-ment, was released by Shimadzu. MALDI rapidlybecame an important biological analysis technique,such that by 1990, protein structure studies werebeing performed using MALDI techniques.

Founded in 1987 in Branford, CT, Analyticabegan as a spin-off from Yale University tocommercialize ESI MS. But it wasnt until 1989that ESI was first reported to be useful for studyinglarge biomolecules in a significant article published

in Science (vol. 246, pp 6471) by John B. Fennand colleagues (see sidebar).

New MS companies continued to proliferate.Bergmann Messgeraete Entwicklung KG wasfounded in 1991 by Thorald Bergmann to devel-op and produce advanced TOF mass spectrome-ters based on an instrument he designed as hisPh.D thesis.

Burgeoning Bio

If anything were to define MS in the 1990s,perhaps most notable would be the explosive

growth of biological applications. For example, in1992, low-level peptide analysis became possible,and by 1993, driven in part by the demands of theburgeoning Human Genome Project, limitedoligonucleotide sequencing became possible. By1996, MS of viruses was being attempted. All ofthis was becoming possible as MS became evermore linked to liquid chromatographyHPLC.

For example, in 1996, Waters made itslargest acquisition up to that point by acquiringMicromass of Manchester, U.K. The acquisitionachieved its goal, immediately putting Watersin the forefront of the market for LC/MSinstruments.

With similar intent, in 2001, Varian expandedits MS technology by acquiring Bear Instrumentsof Santa Clara, CA, in order to increase its partici-pation in the growing life science applicationsmarket. Bear produced analytical instrumentsbased on triple-quadrupole MS/MS technology,

including triple-quadrupole GC/MS/MS andLC/MS/MS systems. Quadrupole LC/MS/MS is acritical technology to the pharmaceutical industryfor assessing ADME (absorption, distribution,metabolism, and excretion) parameters for drugdevelopment. Similarly, in late 2002, Waters andMicromass merged completely, with the statedintention of responding more readily to theincreasing demand for LC/MS.

Future of MS

Overall, MS is still an evolving technology. Itslimits are being pushed and adapted to the latestdemands of biotechnology with innovations such

as tandem expansions and multiple connectionsto HPLC. With newer portable systems, such asthe Inficon (formerly Leybold Inficon) Hapsite,being devised, the classic GC/MS instrument alsoremains strongadapting to the world of bioter-rorism. It seems likely that MS will remain for alltime the stand-alone staple of modern chemicalanalysis, as well as the ultimate chromatographydetectorexpanding the practical and theoreti-cal range of chemistry as a whole to the benefit ofan unlimited set of applications, now and in thefuture.

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Above: GC/MS, Finnigan ad,AnalyticalChemistry, 1971