Antagonistic regulation for cellular intelligence

Cellular intelligence refers to information processing in single cells, i.e. genetic regulation, protein signaling and metabolic processing, all tightly integrated with each other. The goal is to uncover general ‘rules of life’ wrt e.g. the transmission of information, homeostatic and multistable regulation, learning and memory (habituation, sensitization etc.). These principles extend from unicellular organisms like bacteria to specialized cells, which are parts of a multicellular organism.

A prominent example is the ubiquitous role of feedback cycles in cellular information processing. These are often nested, or connected to a central hub, as a set of negative feedback cycles, sometimes interspersed with positive feedback cycles as well. Starting from Norbert Wiener’s work on cybernetics, we have gained a deeper understanding of this regulatory motif, and the complex modules that can be built from a multitude of these cycles by modeling as well as mathematical analysis.

Another motif that is similar in significance and ubiquity is antagonistic interaction. A prototypical antagonistic interaction consists of a signal, two pathways, one negative, one positive, and a target. The signal connects to the target by both pathways. No further parts are required.

On the face of it, this interaction seems redundant. When you connect a signal to a target by a positive and a negative connection, the amount of change is a sum of both connections, and for this, one connection should be sufficient. But this motif is actually very widespread and powerful, and there are two main aspects to this:

A. Gearshifting, scale-invariance or digitalization of input: for an input signal that can occur at different strengths, the antagonistic transmission allows to shift the signal to a lower level/gear with a limited bandwidth compared to the input range. This can also be described as scale-invariance or standardization of the input, or in the extreme case, digitalization of an analog input signal.

B. Fast onset-slow offset response curves: in this case the double transmission lines are used with a time delay. The positive interaction is fast, the negative interaction is slow. Therefore there is a fast peak response with a slower relaxation time– useful in many biological contexts, where fast reaction times are crucial.

There is a connection to negative feedback cycles which can achieve similar effects by acting on the signal itself: the positive signal is counteracted by a negative input which reduces the input signal. With antagonistic interactions the original signal is left intact, so it may act on different targets unchanged.

Modules that can be built from both antagonistic interactions and feedback have not been explored in detail. However, one example is morphogenetic patterning, often referred to as ‘Turing patterns’, which relies on a positive feedback cycle by an activator, plus antagonistic interactions (activator/inhibitor) with a time delay for the inhibitor.