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Capturing and profiling rare cells

by Joshua Timmons, Biology, 2017

Northeastern University researchers have extensively profiled the proteins of rare cells in blood, a feat that was previously impossible. By successfully isolating and characterizing rare cells that make up just 0.001 percent or less of the total cells present in blood, Northeastern’s Barry Karger, Alexander Ivanov, and Shashi Murthy have built a foundation for proteomics-based personalized medicine.

Protein profiling of disease is notoriously difficult. Requiring millions of cells, and yielding insufficient data, existing methods are inefficient and unsuitable for most clinical applications where the sample amount is typically limited. With metastatic cancer, patients need to undergo extensive tumor biopsies for clinicians to understand the biology of their disease. In their paper–titled Proteomic Profiling of Rare Cells in Whole Blood–published in Molecular and Cellular Proteomics, Northeastern researchers demonstrated proof-of-concept for a less invasive technology.

“Our advance was in how you get the cells and then how you process them,” said Karger, the James L. Waters Chair in Analytical Chemistry at Northeastern and founding director of the Barnett Institute of Chemical and Biological Analysis.

“Conventional techniques typically require hundreds of thousands or millions of cells. Here we’re able to analyze less than a thousand.” Their team was able to identify and quantify over 4,000 proteins from as little as 100 cells out of 1000 cells isolated from whole blood.

Their giant leap forward was the product of innovation at each step of a complex process, where individual cells are singled out from millions and then thoroughly characterized by liquid chromatography-mass spectrometry, a tool that is used for protein identification and quantitation. “We needed advances in isolation techniques, sample preparation, separation, mass spectrometer instrumentation, and data analysis,” as Research Associate Professor Ivanov explained it, “we needed the whole integrated analytical platform.” The attention to detail paid off as their integrated approach was 5 to 10 fold better than any existing technique.

Looking forward, the researchers expect to see their integrated approach reach both the clinical and academic laboratories. The ability to capture and characterize rare circulating tumor cells, specific stem cells or other target cell subpopulations in physiological fluids and microbiopsies represents a method for understanding patient disease. “If we can identify the cells, we know if the person is going into remission and how the drug is working,” said Karger. In academic settings the platform could facilitate deeper comprehension of fundamental biology. Perhaps, one day, at the level of single cells. According to Ivanov, “single cell proteomics is possible, and it can be based on this platform.”

The platform is already being explored at the Broad Institute in the field of immunology. There is also interest from industry, with several companies considering licensing and implementing the specific parts of the technology platform. Yet, having already advanced cell profiling to an unmatched depth, the researchers are continuing to push forward, identifying more proteins with fewer cells.

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