Such an approach can give researchers an alternative way to look at the inner workings of a complicated biological system-such as a pathway in a cell-and allow them to study systems in their natural state.
The MIT researchers focused on a pathway in yeast that controls cells' response to a specific change in the environment. The resulting model is "the simplest model you can ever reduce these systems to," said Alexander van Oudenaarden, W.M. Keck Career Development Professor in Biomedical Engineering and Associate Professor of Physics and senior author of a paper describing the work in the Jan. 25 issue of Science.
Quantitative modeling of a biological pathway normally involves intense computer simulations to crunch all available data on the dozens of relevant reactions in the pathway, producing a detailed interaction map.
"These simulations are difficult to perform and interpret because many model parameters are not or cannot be experimentally measured. Moreover, because there are so many interconnected components in the network, it is difficult to make reliable predictions," said van Oudenaarden.
Alternatively, a complex system can be treated as a "black box," where you don't know what's happening inside but can figure it out by analyzing the system's response to periodic inputs. This approach is widely used in the engineering disciplines but has rarely been applied to analyze biological pathways. The technique is very general and could be used to study any cellular pathway with measurable inputs and outputs, van Oudenaarden said.
"You don't want to open the box, but you want to shake it a little," he said. "Comparing the response when you shake it fast to when you shake it slowly reveals important information about which chemical reactions in the pathway dominate the response."
In the new study, the "black box" is a pathway involving at least 50 reactions. The pathway is activated when yeast cells are exposed to a change in the osmotic pressure of their environment, for example, when salt is added to their growth media.
The researchers controlled the inputs (bursts of salt) and measured output (activity of Hog1 kinase, an enzyme with a pivotal role in the yeast salt-stress response).
They exposed the cells to salt bursts of varying frequency, then compared those inputs with the resulting Hog1 activity.
Using that data and standard methods from systems engineering, they came up with two differential equations that describe the three major feedback loops in the pathway: one that takes action almost immediately and is independent of the kinase Hog1, and two feedbacks (one fast and one slow) that are controlled by Hog1.
The fast feedbacks prevent the yeast cell from shriveling up as water rushes out of the cell into the saltier environment. That is accomplished by increasing the cellular concentration of glycerol, a byproduct of many cell reactions. The presence of glycerol inside the cell balances the extra salt outside the cell so water is no longer under osmotic pressure to leave the cell.
In the short term, glycerol concentration is immediately increased by blocking the steady stream of glycerol that normally exits the cell. In the long-term feedback loop, Hog1 goes to the nucleus and activates a pathway that induces transcription of genes that produce enzymes that synthesize more glycerol. This process takes at least 15 minutes.
During the salt shocks, the short-term response kicks in right away, but the cells also initiate the longer-term responses.
Other authors of the paper are Jerome Mettetal, a recent MIT PhD recipient; Dale Muzzey, a graduate student in biophysics at Harvard; and Carlos Gomez-Uribe, a graduate student in the Harvard-MIT Division of Health Sciences and Technology.
The research was funded by the National Science Foundation and the National Institutes of Health.
Elizabeth A. Thomson | MIT News Office
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences