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!
The importance of biodiversity in forests could increase due to climate change
17.11.2017 | Deutsches Zentrum für integrative Biodiversitätsforschung (iDiv) Halle-Jena-Leipzig
Win-win strategies for climate and food security
02.10.2017 | International Institute for Applied Systems Analysis (IIASA)
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses