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Using a new technology that allows scientists to monitor how individual cells react in a complex system of cell signaling, researchers at Stanford University have discovered a large spectrum of differences between cells than ever before noticed.

The Cells Do Not Act in The Same Way

All the cells do not act in the same way as was previously thought. "The cells are like musicians in a jazz band," said dr. Markus Covert, assistant professor of biotechnology and the lead author of a study that was recently published in the journal Nature. His laboratory research studies complex genetic systems. "One little trumpet starts to play, and the cells begin to play by their own rhythm, each different from the others."
So far, most of the scientific information about cell signaling was obtained from populations of cells in large clusters due to the technological limitations of the testing of each individual cell. The new study, which used a recording system developed at Stanford University based on mikrofluidics, shows that scientists are misled by the research based on studies of cell populations.

"Although the results of activation may be the same, process that cells use to achieve this outcome is very different," says the study's author. "Population studies didn’t reveal an intricate network of information that is shown in the single cell level. "It was really surprising," said study co-author Dr.. Stephen Quake, a professor of bioengineering at Stanford, a researcher at the Howard Hughes Medical Institute and a leading expert in the field mikrofluidics. "This brings us back to the beginning to understand what's really going on in the cells."

Communication Between The Cells

Cellular signaling controls basic cellular activities and coordinates the activities of the cells in the human body. The ability of cells to properly respond to their environment is the base of development, tissue repair and immunity. A better understanding of how cells communicate with each other could lead to new insights about how biological systems work, and could possibly lead to discovering cures for diseases such as cancer, diabetes and autoimmune disorders that are caused by errors in the process. "What we see is that the differences between cells are important," said Covert. "Even the nuances can play a big role."

The Microfluidic Chip

To achieve the study of reactions of individual cells during the process of cell signaling, Covert’s Laboratory has teamed with Quake’s laboratory. Quake invented the biological equivalent of the integrated circuit - microfluidic chip - which allows the individual researcher to accomplish tasks that once required a dozen scientists work. Three years ago, Rafael Gomez-Sjöberg and Annelle Leyrat, researchers in his lab have developed a microfluidic chip specifically for the study of individual cells. In this study, Quake and Covert used this chip to explore the signaling of inflammatory cells. "This work is a beautiful biological application of microfluidic cell culture and it really illustrates the power of technology," says Quake.

The chip is made of three layers of silicon on the basis of pure elastic material and contains the microscopic equivalent of test tubes, pipettes and Petri dishes. Gate and valves control the flow of fluids. By controlling the flow, the chip performs ten experiments at the same time. This is actually a lab on a chip. "We used a microfluidics platform that could maintain and monitor the 96 cell cultures at the same time," said Covert. "Before that I was doing one at a time. More than a year we were able to study in detail how 5 000 cells responded to stimuli. It took us into a whole new dimension. "

The scientists put mouse fibroblast cells onto the chip and let them grow in the chamber, which is set to inverted microscope. The whole system is computerized and provides long-term response follow-up to the signal in individual cells, making the image every few minutes. For this research Covert, Quake and his colleagues stimulated the cells with different concentrations of proteins that normally causeimmune system response to infection or cancer.

"We found that some cells receive signals and are activated, and some aren’t," said Dr. Savas Tay, a postdoctoral scholar at Stanford University and the Howard Hughes Medical Institute and the first co-author of the study with graduate student Jacob Hugheyjem. The pictures show the scientists could see that the cells respond in different ways, at different times and the number of oscillations, although their primary response was in many ways the same. "Earlier we were accustomed to look at the cell as if it is a chaotic assemblage of biological material, although there is a great engineering," said Tay. "We had to use mathematical modeling to understand what is happening."

"The cells have performed completely different operations, and we did not notice that," said Covert. Hughey added: "Looking at thousands of individual cells, we were able to characterize in detail how cells interpret different intensities of external stimuli."