Sol Fernández Arancibia is a fellow in the Information Processing in Cells and Tissues research group and has just published a paper in the journal Physical Review E describing how a cell makes the decision to initiate (or not) a programmed death process.

Apoptosis or programmed cell death is a mechanism of organized and irreversible cell death: it is a process by which cells self-destruct without triggering inflammatory reactions in their environment.

Sol Fernández Arancibia is part of a team at the Institute that is made up of physicists and physicists who conduct theoretical research and work with questions that come from biology. Under the direction of Luis Morelli, they study how cells and tissues process the information they receive to make decisions and organize collective behaviors. They then make theoretical descriptions of these biological dynamics. Sol has been investigating the mechanism of apoptosis since the beginning of his PhD and this publication is the result of all these years of work. 

When a cell decides to die

Apoptosis is considered a natural physiological death, a mechanism for eliminating unwanted or damaged cells that also plays a protective role against possible diseases. “During apoptosis, processes within the cell are activated, the DNA is degraded and the contents are “packaged”, which are then absorbed by other cells”, explains the fellow. This is a process that exists, for example, during the development stage to mold tissues or to maintain cellular balance in the adult organism.

At the same time, there are a lot of diseases that are related to a malfunction of apoptosis, this happens “when cells proliferate or continue to reproduce when they should not because their DNA is damaged, as in cancer and autoimmune diseases”, exemplifies Sol.

“What we are interested in studying is precisely how the cell controls this mechanism, because the cell constantly receives information on how the environment is and how it is doing internally, and it has to decide whether or not to trigger apoptosis”. What the team did in the published work, then, was to model how the cell processes this information: they described how, at the cellular level, a specific response is produced upon receiving certain intrinsic or extrinsic information.

Cell fate maps. Panels A and B show the concentration of active effector caspase for different stimuli and features of the signaling network. Yellow color indicates a higher value for caspase concentration. Panel C shows a cell fate map: gray indicates the region of bistability, where there are two possible cell fates: death or survival.

The signaling network

The signaling network functions “as a cascade of molecular events that leads to a controlled degradation of the cell, and this process is mediated by specific enzymes called caspases”, says Fernández Arancibia. In the paper they propose an effective description of this network centered on the caspase-3 protein as a readout of cell fate.

There are two types of caspases: initiators – the first to be activated upon receiving a stimulus – which in turn activate effector caspases – those that degrade structural parts of the cell, such as DNA. “In the work we interpreted that apoptosis happens if enough effector caspases accumulate. We made a model of what this signaling network is like and what we use as a guide to interpret a result is precisely the concentration of effector caspase”. 

In the model they worked to account for the decisions made by the cell according to the information received, “because it is not that this process has to be initiated at any minimum stimulus, it has to have the possibility of not doing so as well”, says Sol; and there are different control mechanisms to prevent this from being activated by any stimulus. What they proposed, then, is a differential equation that describes how the concentration of caspase – in its active form – changes over time.

“Our description provides different predictions and offers a framework for studying how this signaling network processes different stimuli to make a cell fate decision”, Sol explains. With this information, they assembled a series of cell fate maps that indicate what happens to the system according to the stimuli received. 

In this sense, they identified a bistability region as an intermediate space in which mathematically the cell has two possibilities: to die or to survive: “We wanted to be able to reflect this possibility because if the only possible destiny were death, the model would not be representative of reality, because it is true that sometimes there will be spurious stimuli, noises, which do not necessarily have to initiate apoptosis”, she concludes.

If you want to read the complete paper click here.