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Tackling Targeted Proteomics

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  • Title: Assistant Professor of Genome Sciences, University of Washington
  • Education: PhD, University of Vermont, 2001; Postdoc, Scripps Research Institute
  • Recommended by: Steven Carr, David Muddiman

Michael MacCoss' three-year-old lab is focused heavily on targeted proteomics — the result of frustration with fractionation techniques. “I had gotten some grant support to study the effect of the insulin signaling pathway in C. elegans, and how it affected protein turnover,” he recalls. “I figured we would just fractionate like crazy and monitor the turnover of all the proteins that we possibly could.” But 8 million MS/MS spectra later, “we identified no proteins in the pathway that we were interested in studying. That caused us to think a little differently about how we did it,” MacCoss adds. By using a more targeted approach using selected reaction monitoring to target specific proteins of interest, he says, “now we have methods that can, within an hour, measure all known components of the pathway.”

But the mass spec wunderkind didn't start out in proteomics; he credits his entry to the field to meeting John Yates while he was an intern working with Pat Griffin at Merck Research Laboratories. Yates was just starting his own lab at the time, and MacCoss headed back to the University of Vermont, where he did his graduate work in Dwight Matthews’ lab on a project developing “technologies for measuring amino acid metabolism using stable isotope tracers in humans.” After that project wrapped up, he realized that proteomics had grown to be the monkey on his back — so he contacted John Yates and asked to be a postdoc in his lab.

His work with Yates would shape MacCoss' early career. In fact, his own lab at the University of Washington is situated in what used to be Yates' lab there, and MacCoss contends that his work at the Yates lab is “the main reason why I was even considered” for his current position at Washington. Indeed, MacCoss says Yates has been such a supportive mentor to him that when he has questions even today, “he's still one of the first people I ask.”

At that lab, MacCoss and his crew are gearing up to make the transition from model systems — C. elegans and yeast, in particular — to human studies, thanks to the biomarker work they're just beginning. His team will use rodent studies as the stepping stone to human systems, he says.

The MacCoss lab is also knee-deep in technology development projects. In a collaboration with David Muddiman from North Carolina State University, MacCoss' team is testing technology from the Muddiman lab that “increases the number of ions that make it from the air into the vacuum system,” MacCoss says. The goal, of course, is to increase the ion transmission in mass spectrometers.

Looking ahead

MacCoss says that targeted proteomics will be the way to go, and points in particular to Leigh Anderson's work as a great example of it. As far as technology goes, he says the field needs to address the critical problem of speed before proteomics can make the impact its proponents believe is possible. “Right now, most comparisons are done just by comparing two or three samples,” he says. That needs to be upped to  tens or even hundreds of samples, but “using technologies that take a day of instrument time per sample isn't going to cut it.” MacCoss says the ideal tool would have “the peak capacity of MudPIT but could be done in about an hour.”

Publications of note

MacCoss recently published “Analysis of peptide MS/MS spectra from large-scale proteomics experiments using spectrum libraries” in Analytical Chemistry (2006 Aug 15) in which he and his colleagues demonstrate searching peptides against a library instead of a database.

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