Ryan Kerr, Sara Jabbari, Iain G Johnston
Scientific Reports 9 1 (2019)
The ability to process information and make decisions is fundamental to life. Intelligent organisms use their brains to do this, but individual cells are also constantly making decisions, changing their behaviour in response to microscopic stimuli. Examples of this cellular decision-making abound in biology: stem cells decide which type of cell to become; some bacteria decide to become robust "persister" cells that can survive drug treatments; cells in plant seeds decide when to germinate.
Often, the "decisions" that cells make involve which genes to express. Genes contain information on how to build cellular machinery, and "expressing" a gene in a sense means turning it on so that its machinery gets built in the cell. We often see that two genes, say A and B, build proteins that switch each other's genes off. So if we have lots of A, it's very hard to produce B, and vice versa. These genes can determine the type of cell we have -- for example, cells with lots of A might be white blood cells, and cells with lots of B might be red blood cells. A blood stem cell could then become a white or a red cell depending on how the interaction between A and B plays out.
All this is reasonably common knowledge (though rather simplified!). But we got interested in how energy plays a role in these decisions. Gene expression requires energy, which in the cell is provided by a molecule called ATP. Different cells have different amounts of ATP, so the processes involved in the interaction of our genes A and B can take place at different rates. Following some ideas we laid out here, we asked, using maths, how this energy dependence might affect the decisions that cells make.
We found, in a new paper free to read in Scientific Reports, that ATP levels strongly influence the decision-making capacity of a cell. Consider the simple A-B case above. Four states are possible: no A or B (state 0), more A than B (state A), more B than A (state B), and high A and B (state AB). We found that, at low ATP, only state 0 is possible (the cell can't make any decisions). As ATP increases, states A and B become possible, and for high ATP the state AB also appears. So, the number of states a cell can choose between (for example, white, red, or stem blood cell) depends strongly on how much energy that cell has available to power these genetic interactions.
We also found that more energy stabilised the decisions that could be made (cells are noisy, so decisions can be randomly "overturned" by gene expression fluctuations), and mapped out the "landscape" of decisions that can be made as the biochemical features of the genes involved change. We're now going to the lab to explore these mathematical predictions in real cells -- particularly in bacterial persister cells -- and developing the theory further for more complicated decision-making circuits.