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Spectacular

Spectrometry
The corporate-led evolution of MS
produced an irreplaceable tool.
MARK S. LESNEY

A
lthough first conceived in the late 1890s, by John Hipple, in 1941,
mass spectrometry (MS) is a technology it was not a market
born and bred in the 20th century. Mass success.) By 1944, a
spectrometers are perhaps the most fundamental CEC 21-101 users group
tools for understanding the nature of chemical formed in Pasadena,
composition and have become the mainstay of a CA; the group later became
healthy instruments industry. In the 21th century, the American Society for Mass Spectrometry.
MS has the brightest possible future as it adapts to Ancillary standards and tools were seen as an
a biological world. immediate necessity, and the U.S. National Bureau
At its heart, a mass spectrometer separates of Standards produced the first 15 official hydrocar-
ions—created from molecules subjected to one of a bon calibration standards for mass spectrometers.
variety of stresses, from simple The obvious need for compu-
collisions to laser blasts—accord- tational tools for MS led to
ing to their mass-to-charge ratio the introduction by CEC of
(m/z) by passing them through a the Model 30-103, an analog
magnetic and an electrical field computer that could be used
simultaneously. The ions are eval- to analyze mixed hydrocarbon
uated with a detector when they spectra.
collide. Evolution in the technol-
ogy involved modifications to The Expanding Industry
each of these components. Immediately after the war, signifi-
At first, MS seemed an obscure cant breakthroughs occurred in
technology at best. The first mass MS. In 1946, William E.
spectrometer (then called a Stephens of the University of
parabola spectrograph) was Pennsylvania developed the first
constructed by British physicist time-of-flight (TOF) mass analyz-
Top: Finnigan quadrupole MS unit,
J. J. Thomson, the discoverer of the er. The principle of TOF relies on Chromatography, 2001
electron, in 1912. But there was little significant accelerating ions toward a detector with equivalent Center: TOF MS, Bendix ad, Analytical
development of the technique until World War II. energy. In such a case, the “time of flight” becomes Chemistry, 1969
a comparative function of mass, that is, smaller ions
Wages of War move faster than larger ones. In addition, Metro-
In the early 1940s, physicist E. O. Lawrence at the politan Vickers introduced the MS 1 mass
University of California, Berkeley, took an MS- spectrometer in the same year.
based separation approach to enrich fissile uranium, In 1947, CEC introduced the Consoli-
uranium-235, from the natural isotopic distribution dated-Nier isotope ratio mass spectrometer,
of uranium. This method used a gigantic magnetic and the Bureau of Standards and the Ameri-
device called a Calutron (for California and cyclo- can Petroleum Institute collaborated on a
tron) to separate ions according to their m/z; once library of reference mass spectra. In addition,
separated, the ions were collected. This preparative MAT (Mess und Analysen-Technik) was founded
mass spectrometer was able to purify the uranium- in Bremen, Germany. In 1948, the Omegatron,
235 used to construct the atomic bomb. the first ion cyclotron mass spectrometer, was
During the war, in 1940, the prototype of the developed, and a dual inlet with a changeover
first commercially successful mass spectrometer was valve was designed for rapid sample switching in
developed. It ultimately became known as the high-precision isotope ratio MS by researchers at
Consolidated Engineering Corp. (CEC) Model the University of Minnesota. The year 1949 saw
21-101, first sold in 1943 to the Atlantic Refining the birth of ion cyclotron resonance.
Corp. in Philadelphia. (Although Westinghouse In 1950, CEC introduced the Model 21-103
Electric sold a portable mass spectrometer designed mass spectrometer, which would rapidly be coupled
E NTERPRISE OF THE C HEMICAL S CIENCES 93
to heated inlet systems capable of allowing gas- the technique would not be routinely used for two
liquid samples to be introduced easily. In 1953, more decades.
Wolfgang Paul published the first papers on In 1967, PerkinElmer introduced its own mass
quadrupole MS and ion-trap detectors. Quadru- spectrometer, Model 270—the first magnetic
pole filters used a quadrupolar field to manipulate double-focusing GC/MS. By the late 1960s,
SPECTACULAR single ions or ranges of ions based on their m/z, Hewlett-Packard had entered the GC/MS
SPECTROMETRY thus acting as true mass filters. market—and would continue its involvement
In 1956, Roland Gohlke and Fred McLafferty through the 1990s. These instruments were a
first demonstrated GC/MS using a TOF mass spec- strong reflection of how the marriage of GC and
trometer (Model 12-101) developed by the Bendix MS would continue as the most powerful combi-
Aviation Corp. Also in 1956, MS was first used to nation for organic analysis.
identify an organic compound by bombarding the Also in the 1960s, the first secondary-ion MS,
compound’s vapor, at a pressure of 10–5–10–6 or SIMS, instrument was constructed under a
mmHg, with electrons having energies of 50–100 NASA contract to analyze moon rocks. In SIMS,
eV. This process broke down the molecules of the a sample surface is bombarded with a primary ion
compound to form reproducible positive, negative, beam, followed by MS of the emitted secondary
and neutral fragments, making it possible to identi- ions. The instrument was copied and marketed,
fy organic impurities in a sample without any creating an expanding demand for SIMS in the
preconcentration of the impurity. decades to follow, especially in the developing
Perhaps the key business trend of the 1960s was electronic materials industry.
that of increased competition as MS gained popu-
larity and expanded its forms and as more and That ’70s Flow
more companies began manufacturing and distrib- By the early 1970s, GC/MS was the technique of
uting the instruments. choice for monitoring illegal drug trafficking and
In 1962, the first commercial quadrupole mass use. With the development of the environmental
spectrometer was sold to movement prompted by Earth Day and the estab-
NASA by Electronics Associ- lishment of the Environmental Protection Agency
TIMELY TANAKA ates, Inc. (EAI). In a clever (EPA), the issue of pollution monitoring became
The 2002 Nobel Prize in Chemistry was given circumvention of a ban on critical. An early example of this was the use of
to three pioneers of methods for identification instrument exhibits at the DuPont’s DIMASPEC (digitized GC/MS) in 1971
and structure analyses of biological macro- 1963 annual meeting of the to detect contaminant diethylstilbestrol in beef. In
molecules. Among them was Koichi Tanaka American Society for Testing 1978, EPA accepted Finnigan’s GC/MS system as a
(Shimadzu Corp.), who was awarded the prize and Materials, Applied standard means of analyzing pollutants. Because of
for his development of MALDI—in part through Physics Corp. exhibited its this endorsement, the company came to dominate
a fortuitous mistake in his laboratory. While MAT CH4 MS unit to atten- the global market, even though units were priced
attempting to develop an optimal matrix to dees who were willing to walk in the $150,000 range. Such sales indicate the
contain a sample to be ionized by a laser blast, to a bar across the street from impact of the environmental movement in the
Tanaka mistakenly mixed glycerin instead of the conference. 1970s—an impact that continues today—on the
acetone with cobalt. According to the In 1964, Jeol produced its overall market for analytical instruments.
Shimadzu website, “Tanaka—part of a team first mass spectrometer; and Throughout the decade, MS continued to
noted for its faith in trial and error—came to throughout the 1960s, develop new incarnations. In 1974, Fourier trans-
the conclusion that even this presumably PerkinElmer became a signifi- form ion cyclotron resonance was introduced. By
wasteful mixture, like any other, might have cant force in the MS market 1977, Finnigan was offering an early line of
some potential—and might even be the ‘right in the United States, acting as LC/MS systems.
one’—and he set it on a sample plate and the the distributor of Hitachi New companies were formed to take advantage
road to becoming a miracle matrix.” units. Competition continued of new technologies. For example, Comstock was
One of Tanaka’s two co-winners was John to expand as, in 1967, the founded in Oak Ridge, TN, in 1979 by physicists
B. Fenn, who was awarded the prize for his Finnigan Co. (acquired by Robert N. Compton and John A. D. Stockdale.
development of ESI. Together with MALDI, ESI Thermo in 1990) was formed Although their initial product was an electrostatic
has helped to make MS not only a viable but an by Robert Finnigan (formerly energy analyzer, they became noted for their TOF
ideal tool for biological analysis. of EAI) to take advantage of MS line introduced in 1987, and they would
the potential he saw in continue to develop specialized TOF instruments
quadrupole GC/MS and the thereafter.
advancements computers would provide to MS
instruments. That company’s introduction of the The ’80s and ’90s
first commercial quadrupole GC/MS came just one This decade saw the development of one of the
year later. Also in 1967, MAT, which came out most powerful inorganic analysis techniques.
with the CH5 that same year, was acquired by Vari- PerkinElmer became involved in inductively
an, becoming Varian MAT. Significant to the coupled plasma (ICP)-MS when through a joint
biological future of MS, in 1968, electrospray venture with SCIEX, the company helped to
Above: Artist’s rendering of MALDI,
ionization (ESI) at atmospheric pressure was devel- develop and market the ELAN 250, the first ICP-
Modern Drug Discovery, 2003 oped by Malcolm Dole and colleagues, although MS instrument for commercial applications.
94 E NTERPRISE OF THE C HEMICAL S CIENCES
In 1987, PerkinElmer SCIEX introduced the growth of biological applications. For example, in
ELAN 500, the first ICP-MS system with platinum 1992, low-level peptide analysis became possible,
cones and an inert sample introduction system. and by 1993, driven in part by the demands of the
The company went on to launch the ELAN 5000, burgeoning Human Genome Project, limited
the first turbomolecular-pumped ICP-MS instru- oligonucleotide sequencing became possible. By
ment, in 1990, and later the ELAN 6000, the first 1996, MS of viruses was being attempted. All of SPECTACULAR
ICP-MS system with a simultaneous automatic this was becoming possible as MS became ever SPECTROMETRY
extended dynamic range detection system. more linked to liquid chromatography—HPLC.
New companies were unveiled and changes For example, in 1996, Waters made its
took place in corporate structure through mergers largest acquisition up to that point by acquiring
and acquisitions. In 1980, the Bruker Daltonics Micromass of Manchester, U.K. The acquisition
Corp. formed as part of the global Bruker organiza- achieved its goal, immediately putting Waters
tion. The company’s roots were in the German in the forefront of the market for LC/MS
Bruker-Franzen Analytik GmbH and the Swiss instruments.
Spectrospin AG. These companies developed
mobile detectors and mass spectrometers for physi-
cal chemistry. In 1981, Varian MAT was acquired
by 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 of
Shimadzu Corp. of Japan in 1990. CMS produced
surface analysis instruments using quadrupole and
TOF-SIMS technology. In 1992, the company
Kore was founded by a “core” of engineers and
accountants at CMS who decided not to transfer to
Manchester, U.K., as part of a cost-cutting effort to
merge the CMS products with Kratos.
With similar intent, in 2001, Varian expanded
MALDI and More its MS technology by acquiring Bear Instruments
Because MS techniques were typically too harsh for of Santa Clara, CA, in order to increase its partici-
most biomolecules, it wasn’t until the development pation in the growing life science applications
and routine deployment of the so-called soft ioniza- market. Bear produced analytical instruments
tion techniques—ESI (which was only then achiev- based on triple-quadrupole MS/MS technology,
ing popularity) and matrix-assisted laser including triple-quadrupole GC/MS/MS and
desorption/ionization (MALDI)—that MS became LC/MS/MS systems. Quadrupole LC/MS/MS is a
a key tool in modern biology. MALDI was devel- critical technology to the pharmaceutical industry
oped in 1985 (see sidebar). In 1988, the LAMS- for assessing ADME (absorption, distribution,
50K, the first commercial MALDI-TOF MS instru- metabolism, and excretion) parameters for drug
ment, was released by Shimadzu. MALDI rapidly development. Similarly, in late 2002, Waters and
became an important biological analysis technique, Micromass merged completely, with the stated
such that by 1990, protein structure studies were intention of responding more readily to the
being performed using MALDI techniques. increasing demand for LC/MS.
Founded in 1987 in Branford, CT, Analytica
began as a spin-off from Yale University to Future of MS
commercialize ESI MS. But it wasn’t until 1989 Overall, MS is still an evolving technology. Its
that ESI was first reported to be useful for studying limits are being pushed and adapted to the latest
large biomolecules in a significant article published demands of biotechnology with innovations such
in Science (vol. 246, pp 64–71) by John B. Fenn as tandem expansions and multiple connections
and colleagues (see sidebar). to HPLC. With newer portable systems, such as
New MS companies continued to proliferate. the Inficon (formerly Leybold Inficon) Hapsite,
Bergmann Messgeraete Entwicklung KG was being devised, the classic GC/MS instrument also
founded in 1991 by Thorald Bergmann to devel- remains strong—adapting to the world of bioter-
op and produce advanced TOF mass spectrome- rorism. It seems likely that MS will remain for all
ters based on an instrument he designed as his time the stand-alone staple of modern chemical
Ph.D thesis. analysis, as well as the ultimate chromatography
detector—expanding the practical and theoreti-
Burgeoning Bio cal range of chemistry as a whole to the benefit of
If anything were to define MS in the 1990s, an unlimited set of applications, now and in the Above: GC/MS, Finnigan ad, Analytical
perhaps most notable would be the explosive future. ◆ Chemistry, 1971

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