Rules of Life — ANTAGONISTIC REGULATION
Cellular intelligence refers to information processing in single cells, i.e. genetic regulation, protein signaling and metabolic processing, all tightly integrated with each other. We study it to uncover general ‘rules of life’ with respect to the transmission of information, learning and memory, 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. Gear shifting, 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.
Negative feedback cycles can achieve similar effects by acting on the signal itself: the positive signal is counteracted by a negative input which reduces the input signal. The result is again a fast peak response followed by a downregulation to an equilibrium value. The advantage for antagonistic interactions is that the original signal is left intact, which is useful. because the same signal may act on other targets unchanged. In a feedback cycle the signal itself is consumed by the feedback interaction. The characteristic shape, fast peak response with a slower downregulation, is a hallmark of life everywhere. Such a signal may arise from antagonistic interactions as well as negative feedback.
The type of modules that can be built from antagonistic interactions and feedback together have not been explored systematically. One example relies on a positive feedback cycle by an activator, plus antagonistic interactions (activator/inhibitor) with a time delay for the inhibitor. This is known as morphogenetic patterning, often referred to as ‘Turing patterns’ (s. image), a powerful mechanism built from the rules of life.
