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PNNL s Smith Brings FTICR Mass Spectrometry to Bear on Proteomics

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AT A GLANCE

Name: Richard D. Smith

Age: 52

Position: Group Leader and Chief Scientist, Pacific Northwest National Lab, Adjunct Professor of Chemistry at Washington State University

Prior Experience: Developed capillary separations and FTICR mass spectrometry for proteomics

Over his 25 years at the Pacific Northwest National Lab (PNNL), in Richland, Wash., Dick Smith has done his fair share of designing high resolution analytical instruments. Beginning in the late 1970s, Smith took mass spectrometry — and later its Fourier transform ion cyclotron resonance (FTICR) variation — and turned PNNL into the preeminent facility for applying FTICR mass spectrometry to biology, and most recently, to proteomics.

“In the last five years or so I’ve decided to spend less of my time developing technology and to focus more on its actual use,” he said with a laugh.

Smith started out as a graduate student in physical chemistry at the University of Utah, where he worked with ICR mass spectrometry (the Fourier transform part of the technology hadn’t been invented yet). As a postdoc at the Naval Research Laboratory in Washington, DC, Smith spent a year using the technique to study the combustion of fuels “of interest to the Navy,” he said. “It was a far cry from proteomics.”

In 1976 Smith took a research position at PNNL, located in the sagebrush-covered Columbia Basin of eastern Washington State, partly because it allowed him to live in a part of the country he enjoys. In addition, Smith saw the Department of Energy’s (DOE) interest in fundamental biology, and felt inspired by the challenge of applying his mass spectrometry expertise to new disciplines.

Smith’s initial work at PNNL in biological separations revolved around liquid chromatography and capillary electrophoresis (CE); later when electrospray ionization came into existence in the mid-80s he designed the first approach for integrating CE with mass spectrometry. “That opened up a lot of opportunities,” Smith said. “Number one, it was important for obtaining funding to pursue other ideas.”

Around this time, Smith also began to get involved with planning the Environmental Molecular Sciences Laboratory (EMSL), a large user facility designed to give scientists access to advanced equipment for molecular-level chemistry of interest to DOE. With about $8 million of the $200 million EMSL budget, Smith began to build the high-field FTICR mass spectrometer of his dreams. “During the creation [of the lab] I was able to get a commitment [from PNNL] to do it the way I wanted to have it done,” he said.

High-field FTICR mass spectrometry is undoubtedly expensive, but the payoff in data quality is significant, Smith said. The instrument’s ability to trap and detect ions is superior to ion trap or time-of-flight mass spectrometers, and the FTICR technology surpasses all others in terms of resolution, accuracy, and sensitivity, Smith said. But perhaps the most important advantage for proteomics is in dynamic range, which is at least an order of magnitude better than conventional mass spectrometers. “In everything you rely on mass spectrometers to do, FTICR excels,” he said. In fact, PNNL has a technology development agreement with Bruker Daltonics, which hopes to commercialize a version of the instrument within a few years.

To give his approach credibility, Smith and his team embarked on a pilot project in February 2000 to study Deinococcus radiodurans—one of the most radiation-resistant organisms known. The project aimed to demonstrate the accuracy of FTICR measurements to greatly increase the throughput and comprehensiveness of proteome measurements, and also the use of the technique for quantitative studies. “It was a nine-month crash program to see what we could do,” he said. The results, still to be published, showed that Smith’s team had identified over 60 percent of all predicted proteins, the highest level of proteome coverage for an organism that size, he said.

Smith’s current work involves studying the proteomes of several additional microorganisms of interest to DOE, and extending the approach to mammalian systems. While there are many ways to improve the technology, particularly in the area of automated sample processing and data analysis, Smith has found satisfaction in bringing a range of advanced techniques to bear on proteomics. “What’s exciting for me is seeing the individual pieces of the technology that I’ve been involved with coalescing, and being used in a coordinated fashion in doing our proteomics work.” —JSM

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