Cells don't all act in a uniform fashion, as was previously thought.
"Think of cells as musicians in a jazz band," said Markus Covert, PhD, assistant professor of bioengineering and senior author of the study, which will be published online in Nature June 27. Covert's lab studies complex genetic systems. "One little trumpet starts to play, and the cells go off on their own riffs. One plays off of the other."
Up to now, most of the scientific information gathered on cell signaling has been obtained from populations of cells using bulk assays due to technological limitations on the ability to examine each individual cell. The new study, using an imaging system developed at Stanford based on microfluidics, shows that scientists have been misled by the results of the cell-population-based studies.
"While the outcome of activation may be the same, the process the cells use to achieve this outcome is very different," the study authors wrote. "Population studies have not revealed the intricate network of information one observes at the single cell level."
"This really surprised us," said study co-author Stephen Quake, PhD, a professor of bioengineering at Stanford, investigator of the Howard Hughes Medical Institute and a leader in the field of microfluidics. "It sends us back to the drawing board to figure out what is really going on in cells."
Cell signaling governs basic cellular activities and coordinates cell actions in the human body. The ability of cells to correctly respond to their environments is the basis of all development, tissue repair and immunity. A better understanding of how cells talk to each other could lead to new insights into how larger biological systems operate, and possibly lead to cures for such diseases as cancer, diabetes and autoimmune disorders, which are caused by errors in this process.
"What we see is that differences between cells matter," Covert said. "Even the nuances can play a role."
To achieve his goal of studying individual cell reactions during the cell-signaling process, Covert's lab joined forces with Quake's lab.
Quake, who is also the Lee Otterson Professor in the School of Engineering, had invented the biological equivalent of the integrated circuit — the microfluidic chip — which enables a single researcher to achieve what once would have required dozens or more. Three years ago, researchers in his lab, Rafael Gomez-Sjoberg and Annel Leyrat, developed a microfluidic chip specifically for the study of single cells. In this study, Quake and Covert put it to use to investigate inflammatory cell signaling.
"This study is a beautiful biological application of microfluidic cell culture and really illustrates the power of the technology," Quake said.
The chip is made of three layers of a silicon-based clear elastic material and contains the microscopic equivalent of test tubes, pipettes and petri dishes. Valves and gates control fluid flow. By regulating flow, the chip carries out dozens of experiments at the same time. It's essentially a lab on a chip.
"We used a microfluidics platform that could maintain and monitor cell cultures 96 at a time," Covert said. "I was doing one at a time before that. Over a one-year period, we were able to study, with unprecedented detail, how 5,000 cells responded to signals. This took us to a totally new dimension."
The scientists put mouse fibroblast cells onto the chip and let them grow in an environmental chamber, which is mounted on an inverted microscope. The entire system, which fits on a small desktop, is computerized and provides long-term monitoring of the individual cell's response to a signal by taking pictures every few minutes.
For this study, Covert, Quake and their colleagues stimulated the cells with various concentrations of a protein that typically elicits the immune system's response to infection or cancer.
"What we found is that some cells receive the signal and activate, and some don't," said Savas Tay, PhD, a postdoctoral scholar at Stanford and at the Howard Hughes Medical Institute and co-first author of the study with graduate student Jacob Hughey. In the images, the scientists could see that the cells responded in various ways, with different timing and number of oscillations, yet their primary response, in many respects, was equal.
"Previously, we used to see the cell as a messy blob of biological material, yet there is great engineering down there," said Tay. "We needed to use mathematical modeling to understand what is going on"
"The cells were doing totally different things and we've been totally missing it," Covert said.
Added Hughey, "By observing thousands of individual cells, we were able to characterize with unprecedented detail how the cells interpret varying intensities of an external stimulus."
The study was supported, in part, by a National Institutes of Health Director's Pioneer Award, a National Cancer Institute Pathway to Independence Award, the Howard Hughes Medical Institute, a Stanford graduate fellowship and a Stanford Bio-X graduate fellowship. Quake is a founder, shareholder and consultant for Fluidigm, whose technology was used in some of the experiments.
Graduate student Timothy Lee also contributed to the study.
More information about Stanford's Department of Bioengineering, which also supported the work, is available at http://bioengineering.stanford.edu/. The department is jointly operated by the School of Medicine and the School of Engineering.The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.
Tracie White | EurekAlert!
A sudden drop in outdoor temperature increases the risk of respiratory infections
11.01.2017 | University of Gothenburg
Urbanization to convert 300,000 km2 of prime croplands
27.12.2016 | Mercator Research Institute on Global Commons and Climate Change (MCC) gGmbH
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales
Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...
Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.
As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...
At TU Wien, an alternative for resource intensive formwork for the construction of concrete domes was developed. It is now used in a test dome for the Austrian Federal Railways Infrastructure (ÖBB Infrastruktur).
Concrete shells are efficient structures, but not very resource efficient. The formwork for the construction of concrete domes alone requires a high amount of...
Many pathogens use certain sugar compounds from their host to help conceal themselves against the immune system. Scientists at the University of Bonn have now, in cooperation with researchers at the University of York in the United Kingdom, analyzed the dynamics of a bacterial molecule that is involved in this process. They demonstrate that the protein grabs onto the sugar molecule with a Pac Man-like chewing motion and holds it until it can be used. Their results could help design therapeutics that could make the protein poorer at grabbing and holding and hence compromise the pathogen in the host. The study has now been published in “Biophysical Journal”.
The cells of the mouth, nose and intestinal mucosa produce large quantities of a chemical called sialic acid. Many bacteria possess a special transport system...
10.01.2017 | Event News
09.01.2017 | Event News
05.01.2017 | Event News
17.01.2017 | Earth Sciences
17.01.2017 | Materials Sciences
17.01.2017 | Architecture and Construction