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PNNL s Smith Dreams of Catching Low-abundance Proteins

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For most of the past quarter-century that Richard Smith has been working at the DOE’s Pacific Northwest National Laboratory where he’s now a chief scientist, he’s been applying mass spectrometry to biological research. He got into mass spec early on because “I saw it having a lot of potential,” he says, “[though it] didn’t really make a significant contribution to biological research until maybe eight or 10 years ago.”

Now, after 25 years, Smith is right in the thick of things. “Its role has really exploded over the last few years,” he adds. “At least for the foreseeable future, it is the key technology in proteomics.”

And that’s exactly where Smith, 52, is making an impact of his own. His lab of about 35 people works in various aspects of proteomics, and the group’s most recent accomplishment is the development of DREAMS — Dynamic Range Enhancement Applied to Mass Spectrometry — a method that increases the dynamic range of a mass spec reading by one or two orders of magnitude and enables scientists to see many more low-abundance proteins, Smith says.

It’s a matter of resizing the spectrum, he explains. Even his lab’s high-grade mass spec has an upper limit of measuring 10 million ions, making it much more likely to see the high-abundance proteins and stop measuring before finding the lower-abundance ones.

So Smith’s technique is to run a normal mass spec, then perform various manipulations such as radio frequency excitations to eliminate the high-abundance proteins before running the mass spec again. The instrument will still measure 10 million ions, but this time it’s much more likely to find low-abundance proteins. In fact, Smith says, “an initial demonstration roughly doubled the number of proteins where we can make quantitative measurements.”

DREAMS takes advantage of much of the work that’s been done in Smith’s lab over the last 10 years: improved techniques for separation, sensitivity, and range; tweaked instruments for mass spec; and an ion funnel, which gets ions more efficiently into the mass spec.

Smith’s lab has a cooperative agreement with Bruker Daltonics, which may be one way to disseminate the new technology. Because PNNL is a DOE lab, there may also be the possibility of releasing the technology to the user community.

Most of his work has been in the proteomics of microorganisms, Smith points out. He and his colleagues are just now applying their technologies to mammalian problems. Early indications show that the concepts will work there too, but, Smith is quick to add, “that still remains to be proven.”

— Meredith Salisbury

 

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