PME Associate Professor Savas Tay recently published a paper in eLife, detailing his research concerning how digital signals allow control of single-cell activation probability and population heterogeneity.
Cells have communication systems called signaling pathways that enable them to detect and respond to changes in their surrounding environment. For example, in humans and other animals, a signaling pathway called NF-κB signaling is part of the immune system and regulates the inflammation that is caused by damage to cells, or by an invading microbe. Several signal molecules, including a protein called TNF—which is released by cells during an immune response—activate NF-κB signaling. However, the levels of TNF in the environment around a cell may fluctuate randomly even when there is no immune response. Therefore, the NF-κB pathway needs to be able to tell the difference between this "noise" and a large increase in TNF associated with an immune response.
To get around this problem, many signaling pathways are activated in a switch-like manner so that only a strong signal that exceeds a particular threshold will lead to a response. These so-called "digital" responses help cells to filter out noise caused by random fluctuations in the amount of a signal molecule. NF-κB signaling responds to TNF in a digital manner, but it is not clear how information about the length of the signal can influence the degree to which NF-κB signaling is activated.
Kellogg et al. used a combination of mathematical modeling and microscopy techniques to study the activation of NF-κB signaling in mouse cells. The study shows that a molecule called LPS—which is produced by microbes known as bacteria—can also switch on the signaling pathway in a digital manner, but in a different way to TNF. In a population of cells, the fraction that activates NF-κB signaling in response to LPS or another signal is determined by the level of the signal (also known as its "concentration") multiplied by the signal's duration. This is known as the signal's "area."
On the other hand, the way that these cells respond to the activation of NF-κB signaling depends on the nature of the activity produced by the signal pathway. For example, a short but strong burst of LPS signal leads to rapid and uniform responses in the cells. A weaker but longer-lasting signaling activity leads to slower, more varied responses in cells.
These findings reveal that such switch-like, digital responses do more than just filter out noisy signals. They can also integrate information about the timing and intensity of the signal to independently control different aspects of cell responses. The next challenge will be to extend this understanding to more complex scenarios, such as when signals contain several types of molecules at the same time.