New Ultrasensitive Technique For Accurately Characterizing Biomolecules Is Developed By Cornell Chemists

August 30, 1996

ITHACA, N.Y. -- Cornell University scientists report the accurate characterization of a sample representing 1 percent of the protein in a single red blood cell using electrospray mass spectrometry -- a feat that opens the door to a wide area of basic medical exploration.

The technique allows researchers to take samples as small as a single cell and identify many of its components with unusually high confidence, something that is almost impossible with current analytical technologies, the researchers say. The technique could be used for molecular investigations about human medical disorders at the cellular level.

"We have three orders of magnitude better sensitivity than what was possible before. The biggest thing about this is that you can get a complete identification of a totally unknown molecule. Just knowing the molecular weight at our accuracy level is a big help," said Fred W. McLafferty, Cornell professor emeritus of chemistry who led the work. Their accuracy provides less than 0.01 percent error. "With this, you can also measure masses of individual pieces of a molecule for further characterization."

The researchers -- McLafferty; Gary A. Valaskovic, a postdoctoral associate in McLafferty's lab; and Neil L. Kelleher, a doctoral student -- reported their studies in the journal Science (Aug. 29, 1996). Their work was funded by the National Institutes of Health.

Previous methods of analysis at this level, such as laser detectors, are useful only if the researcher knows what to look for. "But if you start without knowing anything about what's in a single cell, you need mass spectrometry," McLafferty said. "We don't even need to know that it's a protein."

Electrospray is a method for ionizing relatively big molecules and getting them into the gas phase. The solution containing the sample is sprayed at high voltage, forming charged droplets. These droplets evaporate, leaving the sample's ionized molecules in the gas phase. These ions continue into the mass spectrometer, which is a sophisticated weighing machine.

Using a spectrometer with a 6.1 Tesla superconducting magnet, the Cornell team took a sample representing 1 percent of the protein in a single red blood cell and correctly deduced its molecular weight -- 28,780.6 daltons.

The breakthrough in sample reduction came about as a result of customizing very small quartz capillaries for electrospray. Valaskovic used laser heated fabrication, chemical etching and vaporized gold plating to produce capillary tips with a diameter of only one ten-thousandth of an inch (2.5 micrometers).

The capillary flow rate is about 1,000 times slower than is typical for electrospray, lowering sample requirements. Also, the spray diameter is reduced so that more of the sample goes into the mass spectrometer, creating greater efficiency.

"The achievement really is due to two things: slowing down the flow rate and having one of the highest performing mass spectrometers in the world for protein analysis," said Valaskovic, who received his Cornell Ph.D. last year under George H. Morrison, Cornell professor emeritus of chemistry. "We have extremely high analytical resolution, so we not only can analyze the sample, but we can tell what it is. With mass spectrometry, we can characterize and identify."

The technique may be useful for examining a host of human medical disorders, the researchers said.

"This is an excellent tool for looking at an isolated biological system at the cellular level, like a single nerve synapse," McLafferty said. "Or say your microscopic examination shows suspicious red blood cells in a sample -- do these contain new molecular components as clues to their formation? You could get a better idea of how a cell system works or how a single signal nerve functions. You can use it with RNA and DNA, as well as proteins."

Cornell University

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