The phenomenon at the centre of the argument is evolutionary coherence: the persistence of organised biological function across deep time, through the continual turnover of organisms, environmental variation, and the accumulation of genetic and epigenetic change. A fish, a sea urchin, and their chordate ancestor share recognisable patterns of body-plan organisation, and the regulatory architecture that produced them in the ancestor produces them in their descendants essentially unchanged across hundreds of millions of generations. The paper analyses this coherence through four aspects — stability, transformation, connectivity, and coordination — each expressed at both the lineage and the organism scale. At the lineage level, stability appears as the pronounced stasis documented across many clades, with directional change rare; transformation appears as the structured reorganisations that punctuate that stasis, clustering around particular periods and preferentially involving shifts in developmental regulatory organisation rather than gradual accumulation of small modifications. These patterns sit awkwardly with a purely gradualist account, and the paper argues that the standard framework has accommodated them through auxiliary hypotheses — punctuated equilibria, canalisation, developmental constraint, evolvability — each introduced after the fact to shield the core from anomaly.

The molecular evidence the paper assembles is drawn entirely from mainstream biology, but read through a new lens. The first architecture is the hierarchical organisation of developmental gene regulatory networks. Deeply embedded within these networks are small numbers of transcription factors linked by recursive positive-feedback interactions, termed kernels, which stabilise core aspects of body-plan organisation. Their stability depends on all components being present together — an instance of what philosophers of biology call generative entrenchment — and alterations to them are almost invariably catastrophic. The Hox gene clusters, which specify position along the anterior-posterior body axis and are conserved across the bilateria, are the most fully characterised instance: their disruption produces homeotic transformation, a qualitative substitution of one body-region identity for another, not a graded decline. Crucially, the components above the kernel are more readily modified, so intermediate sub-circuits are the locus of major body-plan reorganisation while peripheral components account for finer-grained variation. The stasis-and-transition pattern of the fossil record is consistent with this logic: with kernels fixed, stasis reflects conservation of intermediate components and transition their modification.

The second architecture is the bow-tie organisation of physiological regulation: a wide fan-in of diverse inputs converging through a narrow, deeply conserved core of central processing, and a wide fan-out into diverse outputs. The clearest case is metabolism, where the conserved core — glycolysis, the citric acid cycle, the pentose phosphate pathway — is essentially invariant across the tree of life and traceable to the last universal common ancestor, while the pathways fanning in and out of it are extensively modified across lineages. The same architecture recurs in signal transduction, the immune system, the integrated stress response, and circadian regulation. Like a gene regulatory network kernel, the bow-tie core operates as a coupled whole, so its disruption produces loss of integrated function rather than quantitative adjustment: the metabolic dysregulation of cancer, the loss of metabolic flexibility in ageing, and the entrenched alternative regimes of chronic metabolic disease all involve disturbances at or near this conserved centre.

The remaining three architectures sit in domains traditionally read through population-genetic or molecular-genetic frameworks rather than as architectural organisation, and their inclusion is a substantive claim. The germline hosts coordinated epigenetic reprogramming, in which parental marks are largely erased and new marks established so that descendant cells inherit a regulatory configuration capable of supporting development rather than a residuum of the parental somatic state. What is conserved across generations is not the inventory of marks but the architecture and machinery of reprogramming itself. The germline also operates a dedicated surveillance system centred on the piRNA pathway, which targets active transposable elements with sequence specificity; when this pathway is compromised, elements are derepressed and germline function fails in a cascading rather than gradual manner. The paper argues that the standard arms-race framing — transposons as parasites, piRNA as host defence — accounts for the silencing machinery but not for the finding that transposable elements are pervasively regulatory, shaping chromatin organisation and generating new regulatory interactions across the genome.

That finding connects to the fourth architecture, the regulation of repetitive DNA. Such sequences constitute a substantial fraction of most eukaryotic genomes, often a majority, and were originally labelled junk DNA — a designation that placed them outside the explanatory scope of the standard framework. The selfish-DNA account later brought them back within it by proposing selection at the level of the genetic element, but subsequent research has revealed substantive regulatory function for much of this sequence, undermining both framings in their original forms. On the architectural reading, repetitive-element dynamics are channelled through regulatory organisation whose conservation across lineages is what makes their persistence intelligible: the PIWI-protein surveillance machinery is deeply conserved across animals even as the sequences it controls diverge widely — conserved control over a variable substrate. The fifth architecture, centromere identity, resolves what has been called the centromere paradox: centromeric DNA sequences are among the most rapidly evolving regions of the genome, diverging even between closely related species, yet centromere function is highly conserved. The resolution is that identity is not specified primarily by DNA sequence but maintained through epigenetic mechanisms, including the specialised histone variant CENP-A and a characteristic chromatin state propagated across cell divisions by self-templating feedback. Function is conserved because the sequence is not what specifies it — and rapid centromere evolution persists even in yeasts whose symmetrical meiosis affords no opportunity for the centromere-drive conflict usually invoked to explain it.

From these five cases the paper develops a systems model with three defining features. The first is an operating envelope: a bounded region of system states within which coherence is sustained and ordered transformation accommodated, at both lineage and organism scales. The envelope is not static; its dimensions are shaped by the state of the architecture itself, which may be narrowed by developmental stage, chronic stress, age, or loss of surveillance, rendering a compromised system more susceptible to transitions out of coherent function. The second feature is the dynamics at the boundary, which differ qualitatively from dynamics within the envelope. Three kinds of transition matter most: transient displacement, where the architecture returns once perturbation passes, the familiar pattern of physiological recovery; ordered reorganisation, where the organisation itself is modified in a way that preserves coherence at a higher level — developmental stage transitions, immune maturation, and the extensive reorganisations of evolutionary transitions — with new architecture arising not imported from outside the system but produced through the transformation of existing architecture; and maladaptive reorganisation, where the architecture crosses into a regime in which prior coherence is lost. Which outcome obtains appears to depend on the integrity of the regulatory systems through which change proceeds.

The third feature, entrenchment, is the model’s most medically charged commitment. Not all maladaptive transitions are self-limiting: in some cases the regulatory feedbacks that normally stabilise coherent function come instead to stabilise the dysregulated state, so that return becomes difficult or effectively impossible even when the initiating perturbation has passed. Oncogenic transformation, in which feedbacks that normally sustain differentiated identity come to sustain a self-reinforcing proliferative state, is one instance; certain autoimmune conditions, in which processes that normally maintain tolerance come to maintain chronic inflammatory activation, provide another. The same integrative and stabilising properties that make the architecture robust under normal conditions — feedback, redundancy, coordinated regulation — are what allow dysregulated states, once entered, to become self-sustaining. Stability and pathology are therefore not opposites in organisational terms but alternative expressions of the same regulatory capacities under different conditions. Health and entrenched disease, on this account, are alternative regimes of one architecture rather than opposing states.

Propagation across generations completes the model, and it is here that the germline enters most directly. What is transmitted is not a fixed inventory of regulatory states but the architecture and the conditions of its execution, through epigenetic reprogramming machinery, piRNA-mediated surveillance, the regulatory organisation of meiosis, and the maintenance of centromere identity. The hypothesis commits to four claims: that the architecture operates as an integrated level across cells, tissues, organisms, and generations; that the germline is the principal conduit of its propagation; that the same features sustaining coherence also underlie its characteristic modes of failure; and that its disruption at the organism level underlies the convergent signatures of systemic disease — loss of hierarchical regulatory constraint, inappropriate activation of embryonic regulatory states in cancer, and entrenchment of dysregulated regimes through repurposed feedback. The convergence of diseases with unrelated proximate causes on shared signatures, the paper argues, is intelligible only through the evolutionary depth of the architecture that has failed.

The paper is careful about what the hypothesis does not claim. It posits no new force or substance, no vital principle animating living matter; the architecture is the conserved higher-order organisation realised by established molecular processes, and those processes are its molecular signatures, the observable sites at which it can be seen at work. It does not displace selection, which operates on the variation the architecture makes available at a different level; the two are treated as complementary. It takes no position on the levels-of-selection question and provides no mechanisms for particular diseases — it is a framework within which such mechanisms might be situated. Its intrinsic nature is left open, in an epistemic position the paper compares to dark matter in physics, defined by the motions it must account for. What keeps the posit within science, the author argues, is explanatory parsimony — one architecture in place of several separately introduced auxiliary hypotheses — and discipline by evidence: the framework commits to discriminating predictions, including catastrophic rather than graded failure at architecturally central components, concentration of lineage transitions at mid-hierarchical levels, intergenerational erosion under partial germline compromise, and convergence of distinct pathologies on shared architectural signatures. Were the organisational core shown to be independently derived across lineages rather than transmitted through them, the hypothesis would fail. Part II of the series develops those predictions and their implications for disease, ageing, intergenerational health, and therapeutic logic.

Subject of Research: Coherence, transformation, and breakdown in living systems: part I — the common higher-order regulatory architecture (CHORA) hypothesis

Article Title: Coherence, transformation, and breakdown in living systems: part I — the common higher-order regulatory architecture (CHORA) hypothesis

Article References: Nicolaides, A. (2026). Coherence, transformation, and breakdown in living systems: part I — the common higher-order regulatory architecture (CHORA) hypothesis. Frontiers in Systems Biology, 6, Article 1910966. https://doi.org/10.3389/fsysb.2026.1910966

Image Credits: AI Generated

DOI: 10.3389/fsysb.2026.1910966

Keywords: Coherence, transformation, breakdown, living, systems, part, common, higher-order, regulatory, architecture, CHORA, hypothesis