Organizational Principles of Biological Systems

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The work is an optimum theoretical review of how to look more consistently at the emergence of Life dynamics from (and not against) the laws of physics, relying correctly on dissipation, organizational closure-thermodynamical openness, fractality, modularity (or even compartmentalization), criticality, antifragility, functional degeneracy and the increasing of functional information, which let us sketch a universal grammar or syntax of life. This had healthily led the authors to point out that the causal closure and circularity of agencies imply the fallacy to attempt any computation-based model, any living system being in its essence a flux and not a finite object. Thus any biological system results made of relationship with its context, and not subjectable to any algorithmic description.

A) About the content I would suggest just a little implementation, to support their thesis and give further physical soundness to the key-features listed above: in the manuscript a lot of merit has been assigned to the Prigogine's "energy flux" as the agent sustaining the dynamic order. Actually the energy flow is not so much the key point to sustain the sophisticated characteristics of autopoiesis, modularity, closure, fractality, teleonomy. As pointed out by Morowitz [1], Ulanovicz [2] and Ho [3]. It's enough to think to the Bénard–Raleigh cells forming when a liquid confined in a container is homogeneously heated from beneath [4]. At a critical threshold temperature, when the difference in temperature between the cooler upper surface and the warmer lower layer is large enough, a dynamical phase transition occurs. They are dissipative structures, very elementary, but are sustained by the energy storage - i.e.: the ability of the liquid to absorb and store thermal energy - and also depend on the liquid’s ability to expand as it rises, reducing its density when heated up and reducing it when cools down. In fact, it depends on the formation of a cycle more than on the energy flow [5].

The formation of cycles is one key aspect of ALL of the biological realm, and it is not possible, together with compartmentalization (modularity, in the words of authors) without a not enough emphasized feature in the paper: quantum electrodynamic coherence (guaranteed by the water connectome which all of biological matter is made of) [6].

It's important that the authors mention the electrodynamic coherence of living phase of matter, because it is the unescapable condition for modularity and morphogenesis, high energetic efficiency, chemical cycles, symmetry breakings, fractality and organizational closure (while thermodynamic openness, implying the existence of organisms only as fluxes and not as objects) [5].

Actually, the coherent ground state of a system being associated to an energy gap, it is also a thermodynamic desirable state, which implies the emergence of self-preservation (homeodynamics) and any kind of teleology [5,6,7,8].

Cycles and compartmentalization (two sides of the same coin: coherence) had also led to a reformulation of the Second Principle of Thermodynamics for the living systems [3,5].

Moreover coherent quantum states has been shown to be isomorphic to autosimilar structures, i.e.: where a fractality is present, a coherent dynamic is in force. [9, 10]

See the following references, that could be included in the manuscript:

1) Morowitz, H.J. Energy Flow in Biology: Biological Organization as a Problem in Thermal Physics; Academic Press: Cambridge, MA,
USA, 1968; ISBN 978-0-918024-12-1.

2) Ulanowicz, R.E. Identifying the structure of cycling in ecosystems. Math. Biosci. 1983, 65, 210–237. [https://doi.org/10.1016/0025-5564(83)90063-9 ]

3) Ho, M.-W. Circular Thermodynamics of Organisms and Sustainable Systems. Systems 2013, 1, 30–49. [ https://doi.org/10.3390/systems1030030 ]

4) Bénard, H. Etude expérimentale du mouvement des liquides propageant la chaleur par convection. régime permanent: Tourbillons cellulaires. J. Phys. Theor. Appl. 1900, 130, 1004–1007. [ https://doi.org/10.1051/jphystap:019000090051300 ]

5) Renati, P.; Madl, P. From “Information” to Configuration and Meaning: In Living Systems, the
Structure Is the Function. Int. J. Mol. Sci. 2025, 26, 7319. [ https://www.mdpi.com/1422-0067/26/15/7319 ]

6) Del Giudice, E.; De Ninno, A.; Fleischmann, M.; Mengoli, G.; Milani, M.; Talpo, G.; Vitiello, G. Coherent Quantum Electrodynamics in Living Matter. Electromagn. Biol. Med. 2005, 24, 199–210. [ https://doi.org/10.1080/15368370500379574 ]

7) Del Giudice, E.; Doglia, S.; Milani, M.; Vitiello, G. Electromagnetic field and spontaneous symmetry breaking in biological matter. Nucl. Phys. B 1986, 275, 185–199. [https://doi.org/10.1016/0550-3213(86)90595-X ]

8) Celeghini, E., De Martino, S., De Siena, S., Rasetti, M., & Vitiello, G. (1995). Quantum Groups, Coherent States, Squeezing and Lattice Quantum Mechanics. Annals of Physics,, 241, 50-67.

9) Vitiello, G. Structure and Function. Open letter to Patricia Churchland; The MIT Press: Cambridge, MA, USA, 1998; pp. 231–236, ISBN 9780262082624. Available online: https://mitpress.mit.edu/books/toward-science-consciousness-ii

10) Blasone, M.; Jizba, P.; Vitiello, G. Quantum Field Theory and Its Macroscopic Manifestations; World Scientific: Singapore, 2011. [ https://doi.org/10.1142/p592 ]

I would suggest the authors to include the theme of cycles and coherence and the corresponding references for sake of completeness and to strengthen some their ideas.

B) about some typing corrections and little comments, see the notes in the pdf attached.

Comments for author File: Comments.pdf

Author Response

Comment 1

The Reviewer suggests strengthening the manuscript by explicitly emphasizing the role of cycles (rather than energy flux alone) in the constitution and functioning of living matter, from autopoiesis to compartmentalization, and by acknowledging the role of coherence in enabling modularity, morphogenesis, and organizational closure.

Response 1

We fully agree with the Reviewer’s comment. In the revised manuscript, we have explicitly reframed the discussion to emphasize that energy flow alone is not sufficient to account for the emergence and maintenance of biological organization. Instead, we now stress that cyclic processes—chemical, metabolic, regulatory, and organizational—are a necessary condition for autopoiesis, compartmentalization, and functional closure.

In particular:

• We clarify that cycles constitute the minimal physical architecture allowing energy storage, reuse, and functional stabilization, in contrast to purely linear dissipative processes (e.g., simple convection systems).

• We explicitly connect cycles to organizational closure, following Morowitz, Ulanowicz, and Ho, highlighting their centrality across all levels of biological organization.

• We clarify that compartmentalization and modularity are not merely spatial features, but dynamical outcomes of cyclic coherence.

These points are now discussed in the revised manuscript in Page 4, Section 2.2, Lines 94–96,Page 5, Section 2.3, Lines 101–110,Page 5, Section 2.3, Lines 103–107., Page 6, Section 2.7, Lines 149–150,Page 8, Section 2.15, Lines 206–207,Page 12, Section 3.1, Lines 296–297.

Inserted text (excerpt):

“While energy dissipation is a necessary condition for non-equilibrium organization, it is the emergence of cycles—metabolic, regulatory, and structural—that enables energy storage, functional recurrence, and organizational closure. Cyclic dynamics are therefore foundational to autopoiesis, compartmentalization, and biological agency, distinguishing living systems from simpler dissipative structures sustained by linear fluxes alone.

Comment 2

The Reviewer highlights the importance of electrodynamic and quantum coherence in living matter, particularly as a prerequisite for cycles, compartmentalization, fractality, and organizational closure, and suggests including relevant references.

Response 2

We appreciate this important clarification and have revised the manuscript accordingly. Without committing to a single mechanistic interpretation, we now explicitly acknowledge coherence as a necessary enabling condition for biological cycles, modularity, and morphogenesis.

Specifically:

• We introduce coherence as a physical condition enabling long-range coordination, high energetic efficiency, and functional integration in living matter.

• We emphasize that coherence supports cycles and compartmentalization as two inseparable aspects of the same organizational principle, rather than treating them as independent features.

• We cautiously frame quantum electrodynamic coherence as a theoretically and experimentally supported framework that offers a physically grounded explanation for biological order, without overstating its scope.

The suggested references have been incorporated where appropriate, notably those by Del Giudice et al., Ho, Renati & Madl, and Vitiello.

These additions can be found in Page 5, Section 2.3, Line 108 and Section 2.4, Lines 128–129.

Inserted text (excerpt):

“The emergence and persistence of biological cycles and compartmentalization presuppose a coherent dynamical regime, allowing long-range correlations and energetic efficiency. Such coherence provides the physical basis for modularity, morphogenesis, and organizational closure, while remaining compatible with thermodynamic openness and continuous flux.”

Comment 3

The Reviewer suggests introducing “Metabolism–Replacement (M,R) systems” explicitly at their first occurrence.

Response 3

We agree and have corrected this point. The term Metabolism–Replacement (M,R) systems is now introduced explicitly and defined at its first occurrence in the manuscript, ensuring conceptual clarity and historical accuracy.

This correction appears in Page 3, Section 1, Lines 57–58.

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Comment 4

The Reviewer notes a discrepancy in the acronym “Law of Increasing Functional Information” and questions whether “LIFC” (Law of Increasing Functional Complexity) would be more appropriate.

Response 4

We thank the Reviewer for identifying this important inconsistency. We acknowledge that the acronym LIFI does not correctly match the phrase “Law of Increasing Functional Information,” and this could lead to confusion.

To resolve this issue, we have:

• Clarified the conceptual distinction between information and functional complexity as used in the manuscript.

• Replaced the ambiguous acronym with “Law of Increasing Functional Complexity (LIFC)”, which more accurately reflects the intended meaning.

• Ensured consistent usage of both the term and acronym throughout the manuscript.

This correction has been implemented globally and can be verified throughout the revised text, beginning in Section 2.11

(page 11, lines 201–301).

Comment 5
B) about some typing corrections and little comments, see the notes in the pdf attached.
Response: All typographical issues have been corrected, and the discussion has been adjusted to further emphasize the central role of cycles in living systems, as suggested in the annotated PDF

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript reviews the self-organization in living systems by answering the question “how does the complex, adaptive, and autonomous organization of life emerge from the laws of physics and information?” This is a well-known question, which is articulated over the years.

 

In “Simple Summary’ the authors start with the statement below:

“Living systems instantiate a universal physical-informational grammar—a convergent set of organizational principles that explain how structure, function, and cognition emerge from thermodynamic laws.”

(i) The part “universal physical-informational grammar” excludes the inherited information within the DNA expressed in the form of peptides before folded according to their functions.

(ii) The part “  Organizational principles ….. from thermodynamic laws.” is now a general and frequent statement that thermodynamics is the final solution to complex phenomena such as cognition. Therefore, the part should be revised with reference to biology and chemistry too.

Abstract does not have a clear objective(s) and needs “ The objective of this work is, therefore, to articulate how the synthesis of these principles not only unifies physics and biology but also illuminates the profound continuity between thermodynamics, organization, and mind” in the abstract in a rephrased form.

In Introduction:

“This driving force is manifested that processes emerge to reduce the applied gradient, a phenomenon which, if dynamic conditions permit, is recognized as self-organization.” Self-organization in the above statement should be revised; it results from being able to process/utilize the constant supply of materials, energy and information (gradients) by dissipative structures at various lengths and time scales that create a nonequilibrium state and maintaine through the growth, development, and reproduction abilities.

“ .. far from equilibrium” should be far from global equilibrium.

“ by physical-informational constraints” should be physical, chemical, biological- informational constraints.

In 2.2

“energy gradient → dissipation → instability → symmetry breaking → emergent order”

“energy, material gradients, and information → dissipation → instability → symmetry breaking → emergent order

 

“biological agency the ability to act with purpose emerges as a thermodynamic consequence of organizational closure.”

Here the “biological agency” and “a thermodynamic consequence” are not clear. They should be referring to inherited information translated into functional proteins and thermodynamic coupling resulting in driving and driven processes coupled with a mechanism to satisfy the second law and Boltzmann’s H theorem such as the primary active transport between scalar and vectorial processes of ATP hydrolysis and sodium potassium ions transports in an anisotropic medium (cell membrane).

2.15

“patterns” should be in time and space

2.18, 2.19, 2.20

Thes parts are not clear and can be confusing. They may be referring to multiple non-equilibrium stationary states at farm global equilibrium. They may be combined and shortened.

3.3

 

“Experimental Validation and Falsification.” Is it a heading?

This review may be more useful by.

-Incorporating some recent publication on self-organization and information. Some of the early references in the list are old.

-Some concepts are repeated many times under different subheadings.

After the revisions it may be considered for publication

Author Response

Comment 1: “Universal physical-informational grammar” and inherited information

Response:
We agree. The Simple Summary has been revised to clarify that the proposed physical-informational grammar does not exclude inherited genetic information, but explicitly includes DNA-encoded information expressed through peptides and functional proteins, embedded within biochemical and organizational constraints.

Comment 2: Organizational principles and thermodynamic laws

Response:
Agreed. The statement has been revised to explicitly acknowledge that organizational principles emerge from the joint contribution of physics, chemistry, and biology, rather than thermodynamics alone, avoiding an overly reductive interpretation.

Comment 3: Objective of the work in the Abstract

Response:
Corrected. The Abstract has been revised to clearly state the objective of the review, rephrased to articulate how the synthesis of organizational principles connects thermodynamics, biology, and cognition.

Comment 4: Definition of self-organization in the Introduction

Response:
We agree. The definition of self-organization has been revised to emphasize the processing and utilization of continuous supplies of matter, energy, and information by dissipative structures across multiple spatial and temporal scales.

Comment 5: “Far from equilibrium”

Response:
Corrected. The phrase has been revised to “far from global equilibrium” throughout the manuscript.

Comment 6: “Physical-informational constraints”

Response:
Corrected. The terminology has been expanded to physical, chemical, biological, and informational constraints for greater precision.

Comment 7: Section 2.2 – gradients and emergent order

Response:
Agreed. The schematic sequence has been revised to explicitly include material and informational gradients, not energy gradients alone.

Comment 8: Biological agency as a thermodynamic consequence

Response:
We agree that clarification was needed. This passage has been revised to explicitly link biological agency to inherited information expressed as functional proteins, coupled thermodynamically through driving/driven processes (e.g., ATP hydrolysis and active transport in anisotropic membranes), consistent with the Second Law.

Comment 9: Section 2.15 – “patterns”

Response:
Corrected. “Patterns” is now explicitly specified as occurring in both time and space.

Comment 10: Sections 2.18–2.20 clarity

Response:
Agreed. These sections have been shortened, clarified, and partially merged, emphasizing multiple non-equilibrium stationary states far from global equilibrium.

Comment 11: Section 3.3 heading

Response:
Clarified. The heading “Experimental Validation and Falsification” has been revised to better reflect its scope as a conceptual and methodological discussion within a review article.

Comment 12: References and repetition

Response:
We agree. The reference list has been updated to include more recent literature, and repeated concepts across subheadings have been consolidated to improve readability and coherence.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The recent revised manuscript has been improved considerably.

Please consider these minor revisions:

L82, 142, 156, 166, 264:  “far from global equilibrium”

L86, 162: “energy, information, and matter with their..”

L148: “leading to greater control of complexity, energy flow, diversity, and hierarchical levels[21].”

L182: “by functional information and energy gradients, establishing .”

L186: .”. loops, information processing, ecological recycling..”

L214:  “yet thermodynamically coupled processes required..”

“Thermodynamically coupled processes may produce fluxes without their own gradients, as well as fluxes in the direction opposite to ones imposed by their own gradients, such as the primary active transport where fluxes occur from low to high concentration driven by the ATP hydrolysis. On and off thermodynamic coupling ability of living systems enhances the  flexibility and adaptability.

L224: “ is functional[30].

L246:  “ driven primary active transport..”

L434: “from global equilibrium.”

L439: “.functional information processing orients.”

L 524: “ and effective information processing [58]