Biological Regulation and Integration

This article examines biological regulation in the life sciences, focusing on how functional integration links signalling, metabolism, and regulatory mechanisms in living systems.

Introduction: what do we usually mean by biological regulation?

Regulation is a central concept in biology and medicine. It refers to the fact that physiological processes (from the cellular level to entire organs) are not chaotic, but finely controlled.

Consider metabolism, for example. The activity of enzymes in biochemical reactions is tightly regulated: enzymes catalyze reactions at specific rates depending on cellular conditions, such as the availability of substrates or regulatory signals. Similarly, the pumping activity of the heart is regulated by the nervous system, hormones, and mechanical feedback, ensuring that the amount of blood circulated matches the needs of the organism.

At its most fundamental level, regulation enables organisms to cope with both internal and external variations. Internally, processes such as physical exercise require adjustments in energy use and circulation. Externally, changes in environmental conditions (such as high temperatures) trigger responses like sweating. In this sense, regulation is essential for maintaining the stability of living systems.

Regulation in biological organisations

Over the past few decades, the most influential and widespread way to define biological regulation has originated from the cybernetic tradition in the life sciences (Wiener 1948; Ashby 1956). Within this framework, biological regulation is often associated with feedback loops, which are circuits where an output is fed back into its input, either opposing it (negative feedback) or enhancing it (positive feedback).

However, this view has been criticised by philosophers such as Bich and colleagues (2016; 2020). They argue that feedback mechanisms not only control certain processes but are also directly controlled by them. For example, a thermostat regulates the system's temperature while simultaneously being influenced by it. By contrast, some regulatory mechanisms act without being directly determined by the processes they regulate. For instance, enzyme phosphorylation can modulate the rate of a metabolic reaction without being directly governed by the reaction’s products.

This perspective suggests a broader view of biological regulation, one that includes both feedback and non-feedback mechanisms and emphasises the complex networks of interactions that characterise living systems.

Bich and colleagues (2016) propose five criteria to define biological regulation: (1) regulatory components must be produced by the system itself; (2) they must be at least partially decoupled from core processes such as metabolism or gene expression; (3) they must be activated by specific signals; (4) they must play a functional role within the system; (5) and they must enable the organism to cope with perturbations and adapt to changing conditions.

Two forms of regulation: gene expression and enzyme phosphorylation

In cells, regulation takes several forms, but two of the most important are gene expression and protein modification.

Gene expression refers to the control of transcription and translation, the processes by which genetic information is used to produce proteins. By regulating which proteins are produced, when, and in what quantity, cells can adapt to changing physiological demands. This is crucial because proteins carry out most biological functions, from metabolism and movement to signalling and cell division. In this sense, controlling gene expression is one of the main ways cells control their own activity.

A second major form of regulation occurs after proteins are produced. One common mechanism is phosphorylation, the addition of a phosphate group to a protein such as an enzyme. This modification can change the protein’s activity, for example, by activating it, inhibiting it, or altering the rate of the reaction it catalyses. Through such rapid and reversible changes, cells can fine-tune their internal processes in real time.

Interdependence between the constitutive regime, regulatory subsystem, and signalling subsystem

In the blog article “What does it mean to be biologically autonomous?”, I introduced two key dimensions of constitutive autonomy: metabolism and gene expression. This raises an important question: how are these constitutive processes regulated?

The answer lies in signalling.

In biological systems, a signal is a molecule that carries information from one part of a system to another. Signals can operate within a cell (intracellular signalling) or between cells and their environment (extracellular signalling). For regulation to occur, signals must convey information to constitutive processes, indicating when and how they should be modulated. In this sense, signalling connects regulatory mechanisms with constitutive processes, forming an integrated functional system (see figure below).

[Figure taken from Militello 2025, p. 61]

Signalling (and more specifically signal transduction systems) plays a crucial organisational role in this integration. These systems act as an interface between constitutive processes and regulatory mechanisms. They do so through four key properties. First, they can detect a wide range of molecules (such as metabolites), amplify these signals, and translate them into regulatory responses. Second, they are highly specific, ensuring that only particular signals trigger specific responses. Third, they integrate multiple signalling pathways, allowing different inputs to be coordinated. Finally, they provide temporal coordination, ensuring that regulatory responses occur at the right time.

This organisation reveals a biological architecture in which control is both hierarchical and heterarchical. On the one hand, regulatory mechanisms constrain processes such as metabolism. On the other hand, these systems are not simply controlled in a one-way manner: they interact without being entirely determined by one another. For example, metabolic processes generate molecules that can act as signals, while signalling pathways modulate gene expression and enzyme activity.

The integration of signalling, regulation, and constitutive processes has important consequences for the cell. It allows the organism to detect changes in both its internal and external environment and to respond accordingly. Signals can trigger gene expression or enzyme modification, thereby adjusting protein activity and reshaping metabolic processes. In this way, signalling enables the cell to switch between different functional states depending on its needs.

More fundamentally, signalling shows that the regulation of the internal state of the cell depends on information from the external environment. By enabling this flow of information, signal transduction systems play a central role in the self-maintenance and autonomy of living systems.

Conclusion

Biological regulation is more than a simple feedback loop, as suggested by the cybernetic tradition. Regulatory mechanisms do not merely react to the processes they control: they can constrain constitutive processes (such as metabolism or gene expression) without being directly determined by them. At the same time, constitutive processes influence regulation indirectly, by shaping the production of signals that provide input to regulatory systems.

This interplay between constitutive processes, regulatory mechanisms, and signalling systems forms a first and fundamental level of functional integration within the cell. Without this basic organisation, more complex forms of biological organisation would not be possible.

This becomes particularly clear when we look at evolution. Consider the transition from prokaryotic to eukaryotic cells (often referred to as eukaryogenesis). As cells became more complex, these three subsystems had to evolve together, incorporating new layers of organisation. However, increasing the complexity of signalling systems comes at a cost: cells must maintain signal accuracy, avoid unwanted cross-talk, and preserve the reliability of information flow. This evolutionary transition therefore required the emergence of more specific and robust mechanisms of signal recognition and processing.

Ultimately, the tight integration between constitutive, regulatory, and signalling subsystems provides the foundation for biological complexity. It enables not only the addition of new structures and functions, but also increasingly sophisticated forms of functional integration. In this sense, the autonomy of living systems rests on a dynamic architecture in which control, information, and organisation are inseparably linked.

For more details see Chapter 3 of the Book Functional Integration: A Theoretical Enquiry into the Biological Unit of the Individual.

This article is part of a series on functional integration and biological individuality.