The Origin of Life and Cellular Systems: A Continuum from Prebiotic Chemistry to Biodiversity
Round 1
Reviewer 1 Report
Comments and Suggestions for Authors
This paper starts off right within the abstract with a tautological, no-new-information, circular statement of what the paper will offer:
“This study proposes that life emerged as an emergent property resulting directly from the structural and functional organization of the first living system.”
What exactly did the author just tell us?
Then he continues:
“Consequently, the origin of life can be interpreted as a spontaneous and self-organizing phenomenon inherent to the dynamic architecture of biological systems.”
These statements are a little like using a word to define that word. The author is essentially saying that the origin of life was a spontaneous self-organized event inherent to biological systems. In other words, biological systems already existed when abiogenesis occurred, so that is why life origin occurred! Life happened because of biological systems.
“Within the prebiotic environment, the convergence of multiple molecular domains facilitated the assembly of the earliest living system.” The paper does not really seem to answer the questions of “What molecular domains? How did they converge? What exactly is this “convergence of multiple molecular domains?” By what mechanisms did they cause abiogenesis?” The author seems in many places to continue to use life to explain the origin of life.
“This primordial organism.” What primordial organism”? Will the first protobiont just be presupposed, or will its derivation be explained? Will the model falsify Pasteur’s and Virchow’s First Law of Biology? How?
“referred to in this study as the 'cellular precursor of biodiversity' (PoB cells), marked the beginning of life on Earth and served as the starting point for the evolutionary processes that led to the emergence of biodiversity.” But the origin of PoB cells is just presupposed with “self-organization” and “emergence” pronouncements.
The paper fails to present some significant new explanatory insight.
Line 55: “The explanation I find most scientifically grounded is that OoL on Earth resulted from the physicochemical transformation of inanimate matter into living matter, culminating in the emergence of the first living system (the first cell).”
This is not an explanation of abiogenesis. No new model or hypothesis elucidating the means or mechanisms of how life got orchestrated are provided that would be of interest to abiogenists.
Can physicodynamics program? Can physicodynamics cybernetically process and execute formal commands? Can physicodynamics engineer the processing equipment needed to transform a representational program into computational halting?
Line 59: “all governed by the laws of nature and the principles intrinsic to living systems, which I have referred to as the “commandments of life.”
Which of the four known forces “commanded life”? Was it the strong nuclear force, or the weak nuclear force? Was it the electromagnetic force that commanded life? Was it the law of gravity?
What Law commanded the programming and the cybernetic processing of those commands?
What law of nature computed life?
Line 66: “the transition from inanimate matter to the first living organisms was a complex process, the emergence of the genetic code, the development of metabolic pathways, and energy conservation mechanisms”
Science is about “How?” questions. Exactly how did inanimate matter program the genetic code, orchestrate metabolic pathways, and figure out how to the temporarily circumvent the 2nd Law? Can the author enumerate a single naturalistic physicochemical process that circumvents the 2nd Law through sustained time into a Sustained Functional System?
Line 71: “To construct a logical, scientific, and plausible explanation for this transition from inert to living matter, we must rely on the laws of physics and chemistry,”
Exactly what laws are we talking about? Laws constrain events to occur the same way every time. Laws are compression algorithms. Laws severely limit contingency needed to steer and control. Life is all about steering toward homeostatic metabolic goals and managerial controls, not mere constraints.
The Miracle of Life Seems like a reasonable presentation to me up through “Defining Life” section.
Defining life:
Line 170: The author rightly states that any concept of life should include being “functionally organized.” But the author’s references do not include papers differentiating formal organization from mere self-ordering phenomena. The references do not address how an inanimate environment would have recognized, valued, or pursued “function.” Other references not included in the manuscript do address in what ways life is unique from nonlife. These references should be included and critiqued.
The author’s own non-model does not explain the derivation of orchestration or circuit integration, either.
Line 171: The author goes on to rightly point out, “Furthermore, it [life] should encode and process inheritable information, possess mechanisms for energy acquisition and transduction to sustain metabolic activity.”
How would physicodynamics encode information?
Shouldn’t Barbieri’s “code biology” be cited?
What is information? Is life’s information anything more than Shannon uncertainty measures or thermodynamic possibilities? Doesn’t life’s information specifically prescribe function? How did inanimacy come to do that, especially using a representational symbol system to issue those executable commands. How did physico-chemical processes acquire the ability to formally compute life? We can’t just keep saying all these abilities “emerged.” How?
Some abiogenists argue that all known life is programmed and cybernetically processed. Others argue that life is actually computed. These published contentions found within 2024 and 2025 papers address what life is. They should be included in the references and critiqued. The references are not-up to-date.
Life 179: Can the author explain how physicodynamics alone produced formal systems and formal processes? If not, the contention that life is purely physico-chemical falls flat.
Line 193: “with the appearance of the first living system, the life process arose immediately and inherently.”
It’s as though the author is pulling a rabbit out of a hat like a magician’s trick.
It’s as though he has already forgot his own entire “Miraculous” section, and now is just snapping his fingers. Life origin was “immediate and inherent” within mere physicality.
The author offers no empirical or rational support for either formal “systems” or formal “processes” being “inherent” in physicodynamics.
“From that moment onward, an inseparable relationship was established between the system—the living organism—and the process—life.”
This is like saying, “The ‘system’ (‘the living organism’) just appeared out of thin air.
The author just assumes life origin with zero explanation of “How?”
Ignored are recent papers on the reasons for the difficulty of explaining life-origin, the specific kind of information required, and the fact that efficaciouos choices are required at actual decision nodes to program, steer and control the formal processes and “systems” of which the author speaks.
What is the source out of inanimacy for the executable commands of genomics? What is the source of the machinery to execute those commands?
What is the source of the circuit integration? How did life get so formally orchestrated and computed?
How did protolife solve Turing’s halting problem when the efficacious active selections had to be made at bona fide decision nodes prior to any phenotypic productio (e.g., the choice of which nucleoside next to polymerize)? All of the 3’5’ phosphodiester bonds are the same. Functional sequencing cannot be attributed to physics and chemistry. Nucleosides were selected according to linguistic rules, not physicodynamic laws.
The only explanatory mechanism provided is the magic of “emergence.” Life just emerged spontaneously from physicodynamics. Never mind falsifying Pasteur’s and Virchow’s Frist Law of Biology. The only model presented is that Life just organized itself into existence “immediately and inherently.” This is a metaphysical presupposition, not a scientifically elucidated new model of means.
Numerous papers have been published in well-indexed peer-reviewed literature in the last couple years that the author neglects. These paper show that the concept of “self-organization” is a self-contradictory nonsense term that has no place in scientific literature. Something would have to already exist in order to organize itself into existence. The notion of “emergence” has no more substance than tautological “self-organization” does. Whatever we have no explanation for, we just claim “emerged.” Then we move happily on to “diversification.”
“Once this original system acquired the ability to divide and, consequently, to evolve, the generation of biological diversity commenced.”
This is a life-origin special issue. Nobody seems to have a problem with how diversity was achieved. Diversification is down the road aways. When it comes to abiogenesis, this paper seems uninformative. What readers are interested in within this Special Issue is the “How?” of abiogenesis. But they are not getting anything new with reference to how life got orchestrated in an inanimate environment.
Line 200: “An emergent property refers to a novel and unpredictable characteristic that arises from the ordered interactions among components within a system. Emergence can be conceptualized as the outcome of cooperative dynamics among autonomous elements, which collectively give rise to new macroscopic structures and systemic behaviors [30].”
What is the mechanism of the pipe dream of “emergence?” Are we sure it is not just a catch-all term amounting to a pipe dream? We often seem to fail to appreciate the difference between “formal organization” vs “order” and the mere self-ordering phenomena of Prigogine’s “dissipative structures” vs. “formally organized true systems.” Self-ordering (e.g., hurricanes and tornadoes) require zero active selections. Organization always requires active selections, including molecular evolution. Active programming decisions must be made prior to the existence of any organisms that could diversify and evolve. Evolution is nothing more than the differential survival and reproduction of already living organisms. What programmed and cybernetically processed these organisms? They didn’t just “spontaneously generate.” They only became fittest through algorithmic optimization. Algorithmic optimization occurs at the genomic level, prior to the existence of any phenotype that the environment could prefer. Algorithmic optimization is formal, not physical—as formal as mathematics.
The author fails to appreciate the meaning and essence of any formal system. A weather front is not a true formal system. No choice causation is involved. But bona fide “systems” and “processes” always have formal components and goals that physicodynamics alone is blind to.
Notice that for the author to define “emergence” required “conceptualizing” and “cooperative dynamics” and “systemic behaviors”— all formalisms that physicodynamics cannot perceive or participate in. They are engineering concepts, not forces, laws, constraints.
Line 204: “Life arises from the complex interplay among non-living molecular constituents”
Apparent in the paper is a failure to appreciate the difference between mere complexity vs. conceptual complexity. What makes complexity conceptual is choices from among real options.
A pile of spaghetti noodles is complex. But that complex pile of noodles doesn’t DO anything useful.
Things have to be steered and controlled to produce nontrivial function. But physics is blind to “usefulness” because “usefulness” is a formalism, not mere physical interactions. The “work” of physics has nothing to do with utility.
The reason we have such a terrible problem explaining and defining life is because of our starting presuppositional axiom that refuses to acknowledge the reality of steering and control toward the goal of sophisticated function. We fanatically and blindly believe that “Mass and Energy are sufficient,” thereby shooting ourselves in the foot. We preclude scientific discovery by violating Einstein’s “minimum physic.” We bring our purely metaphysical presuppositions with us TO science. The religion of physicalism will never be able to explain the science of biology.
We fail to realize that denying and excluding formalisms from science makes it impossible to understand life. At the same time, we have no problem using purely formal mathematical equations to define the laws of physicality. Every month genomic papers are published that prove that life is programmed, computational and formal. It is just secondarily instantiated into physicality like using blocks of wood to play Scrabble. There is nothing physical about spelling words in the game of Scrabble. But the letters are instantiated onto “physical symbol vehicles” in a Material Symbol System. We then make the mistake of thinking that Scrabble and life are both physical because nucleosides and blocks of wood are physical. When are we going to realize and admit that life and homeostatic metabolism are, more than anything, formal CONCEPTS! The very laws of physics are formal mathematical concepts! Reality cannot be reduced to nothing but Chance and Necessity. Reality consists of Chance, Necessity and Choice. If we try to deny this, we try to deny the reality of Engineering!
Line 210-211 The author talks about “homeostatic regulation.”
That means “control.” What is doing the controlling? Does fixed law steer and control multi-step processes toward functional success (e.g., the 13-step Krebs cycle that produces no benefit until the last step)?
Line 211: “This concept is foundational in systems biology.”
Yes. Functional controls require efficacious choices at decision nodes. Laws cannot make purposeful choices at decision nodes. So, how did physics and chemistry generate biological controls? Something is missing from our abiogenic models. The only answer is disallowed by our faulty starting metaphysical axiom.
“Homeostatic regulation” is formal. It requires Choice Causation, not mere Physicodynamic Causation. To integrate circuits and to program and process algorithms requires choices, not fixed laws or constraints. Constraints can’t steer toward “usefulness.”
Line 213: “—it's the organization and interaction that matter.”
Indeed. Do we really understand the difference between organization, which is always formal, and order which can be purely physicodynamic?
Line 220: “duality of system and process” is a duality of two formalisms. Neither, nor the combination of the two, is going to be explained by Necessity! Formalisms require the freedom of contingency, and active selection from among real options.
Line 221: “Self-organization plays a pivotal role in the emergence of life, particularly in the formation of prebiotic structures preceding the OoL [33, 34]. The spontaneous emergence of order among molecular ensembles—without external direction and beyond the explanatory power of their isolated components—has been proposed as a defining feature of life’s origin [35].”
Yes, they have. But multiple well-indexed peer-reviewed references in 2024 and 2025 have shot down these attempted explanations. These references are neglected in the author’s paper. If we have no model or falsifiable hypothesis of How? systems and processes were orchestrated, we just claim they “self-organized.” This is not science. It is blind faith.
Section 4.3 on negentropy.
Negentropy is much better understood as the loss of formal organization rather than the loss of order. Many negentropy states increase in order as they approach heat death. A chamber of cold, very slow-moving inert gas molecules is highly ordered. It’s not about order or complexity. It is about formal orchestration of homeostatic metabolism. It’s about the goal of being and staying alive. Physics doesn’t have goals.
So, the question is, “How does any “Sustained Functional System” maintain its state far from equilibrium? Irreversible nonequilibrium thermodynamics cannot achieve this. Maxwell’s demon has to choose when to open and close the trap door in the partition between chambers in order to achieve an energy differential.
No efficacious choices—No heat engine! The simplest of heat engines requires Choice Causation, not just Physicodynamic Causation (The Universal Determinism Dichotomy). Life requires formal steering and control. That’s what genomics is all about.
Schrödinger confused “order” with “organization.” They are not the same! And mere “complexity” is not the same as “conceptual complexity,” either.
Line 248 talks about digestion as though it just “emerged.”
Digestion did not just “emerge.” It was genomically prescribed, and then computed! Undeniable formalisms.
Line 251 talks about “functional coordination of these components, mediated by molecular signals.”
The author here is talking about formalisms without appreciating that he is talking about formalisms, not physical reactions. “Functional coordination mediated by signals” is not physics and chemistry. It requires active selection, steering, controls and goals. These facts thoroughly embarrass the purely physicodynamic fantasy of naturalistic “emergence.” Laws and constraints cannot produce life.
Line 255 “life would have emerged as an intrinsic property of its organization.”
Tautology. No new information. Circular.
The paper is doing a good job of reviewing some of the abiogenesis problems. But it is not providing anything helpful to readers interested in solving the abiogenesis problem. It continues to offer only circular reasoning—defining words and concepts using the word and concepts to be defined.
Line 278 Aside from already existing life, there is no “the metabolic world.”
Innumerable “reaction worlds” exist. But they are not steered and controlled toward metabolic goals. Biochemical pathways lead somewhere useful. No such inanimate “metabolic world” exists. Branscomb, Russell and others overextend inorganic reactions into finished formal systems of protolife that simply do not empirically exist. Protomembrane researchers do the same. An imaginary “metabolic world” cannot be used to explain abiogenesis. It is assuming what one is claiming to prove or explain. Spontaneous Orchestration is just believed, not scientifically explained.
Line 296 “The Priming Phase, which involves the formation of disorganized living matter.”
Can the author provide any empirical evidence of a single case of “disorganized living matter”? Anything living manifests the ultimate in formal orchestration and organization. Micoplasma genitalium puts to shame the finest mainframe computer in the world.
Line 298 “The Assembly Phase, in which these molecular worlds integrate to form the first living system.”
Can the author provide any empirical evidence of a single case of “disorganized living matter” integrating circuits and itself into a living system?
Can the author name a single nontrivial circuit that integrated itself into existence?
Line 303: “The Assembled World Hypothesis” is not a falsifiable hypothesis.
The author needs to read the published critiques of Assembly Theory.
Line 635 “The emergence of the metabolic world” is just not explained and justified. It is just pre-assumed to be spontaneous.
There does not seem to be any original new abiogenic insights in this paper. I find the proposed phrases to consist mostly of empty words rather than testable hypotheses. No real mechanisms are presented.
Many of the problems of abiogenesis are often well-described.
But no reason exists why any abiogenic researcher would want to download and read this non-model.
If the author of this paper would find and read around six to eight life-origin papers published in the last two years, he would understand why he is having such difficulty providing naturalistic mechanism for the orchestration of initial life.
Protocellular metabolomics requires steering and control toward metabolic success. There will be no escaping or dodging this reality.
The author must study and critique 2024 and 2025 abiogenic literature before attempting to explain life origin.
Much of his paper can be repackaged and salvaged in a new paper, but it will require a complete rewrite after being educated about what is happening in the field in the latest literature. The current referencing is good, but very out of date.
And if the author wants to publish a meaningful life-origin model, it will have to have a lot more content rather than just words, imagination and tautologies.
Mechanisms must be suggested addressing exactly How orchestration and the pursuit of sophisticated function was accomplished.
Author Response
Manuscript ID: life-3882493
Type of manuscript: Hypothesis
Response to Reviewer 1 (R1):
Although your comments have been predominantly critical of my work, they have nonetheless prompted a thorough reassessment of the original manuscript, resulting in substantial revisions throughout the text. That said, I respectfully disagree with several of your critiques and have therefore chosen to retain my original proposal. While I value and respect your opinion, I do not concur with the core of your assessment.
I would like to emphasize that this manuscript represents my original contribution, and I retain the right to express my ideas in the manner I consider most appropriate. The manuscript presents a conceptual narrative intended to explore plausible pathways for the emergence of the first living system and the subsequent development of biodiversity. It is important to clarify that I do not claim to describe the precise origin of life—such knowledge remains beyond the current reach of science. Rather, my objective is to propose a scientifically grounded hypothesis regarding how this process might have occurred.
If additional references are deemed necessary, I would greatly appreciate specific suggestions. The literature on prebiotic chemistry, the origin of life, and the emergence of biodiversity is vast, and it is not my intention to conduct an exhaustive review or cite every publication in the field.
The principal modifications introduced in the revised manuscript include:
- A new title that better reflects the conceptual framework of the study.
- A redesigned Figure 1 to illustrate the updated hypotheses.
- A complete rewrite of the text, from the abstract through to the conclusion.
- 27 new references to strengthen the scientific grounding of the manuscript.
- New examples that support key aspects of this work
With these considerations in mind, I now proceed to address the specific critical comments raised in the review.
Point-by-Point Reply
R1 Comments:
This paper starts off right within the abstract with a tautological, no-new-information, circular statement of what the paper will offer: “This study proposes that life emerged as an emergent property resulting directly from the structural and functional organization of the first living system.” What exactly did the author just tell us? Then he continues: “Consequently, the origin of life can be interpreted as a spontaneous and self-organizing phenomenon inherent to the dynamic architecture of biological systems.” These statements are a little like using a word to define that word. The author is essentially saying that the origin of life was a spontaneous self-organized event inherent to biological systems. In other words, biological systems already existed when abiogenesis occurred, so that is why life origin occurred! Life happened because of biological systems.
My Answer:
Firstly, I acknowledge that the original abstract required substantial improvement, which is why I have undertaken a complete revision. I also recognise that my linguistic limitations may impede the precise articulation of my ideas. Nevertheless, I believe the reviewer has attributed to me certain lines of reasoning and conclusions that I do not endorse. Biology, as a discipline, begins with the emergence of life; all phenomena preceding this event are classified as prebiotic. This, however, does not contradict a key assertion: numerous molecular processes and structural components associated with living systems likely originated prior to the formation of the first cell. For example, metabolic pathways such as glycolysis—the conversion of glucose to pyruvate—have been demonstrated to occur in the absence of enzymatic catalysis, implying a form of chemical determinism. Likewise, the assembly of ribosomes may have occurred under prebiotic conditions or within the context of the RNA world, potentially serving as a precursor to genetic systems and the establishment of the central dogma of molecular biology. I maintain that life, in its strictest sense, commenced when these prebiotic systems coalesced into the first cellular entity, thereby transitioning into bona fide biological systems.
R1 Comments:
“Within the prebiotic environment, the convergence of multiple molecular domains facilitated the assembly of the earliest living system.” The paper does not really seem to answer the questions of “What molecular domains? How did they converge? What exactly is this “convergence of multiple molecular domains?” By what mechanisms did they cause abiogenesis?” The author seems in many places to continue to use life to explain the origin of life.
My Answer:
The term molecular domains refers to the distinct “molecular worlds” (e.g., the RNA world, peptide world, supramolecular world, and metabolic world) that may have coexisted within the prebiotic milieu, as outlined in the main text. While this concept is clearly hypothetical and may ultimately be validated or refuted, it does not constitute mere speculation—it is supported by experimental evidence (see main text and cited references). The precise events that transpired over four billion years ago remain unknown to both the reviewer and myself, and it is likely that definitive knowledge will remain elusive. This field, by its very nature, requires engagement with uncertainty.
R1 Comments:
“This primordial organism.” What primordial organism”? Will the first protobiont just be
presupposed, or will its derivation be explained? Will the model falsify Pasteur’s and Virchow’s First Law of Biology? How? “referred to in this study as the 'cellular precursor of biodiversity' (PoB cells), marked the beginning of life on Earth and served as the starting point for the evolutionary processes that led to the emergence of biodiversity.” But the origin of PoB cells is just presupposed with “self-organization” and “emergence” pronouncements. The paper fails to present some significant new explanatory insight.
My Answer:
The term primordial organism refers to the earliest living system that emerged from the prebiotic environment. This conceptual framework does not contravene the first law of biology. I contend that the principles governing contemporary biological systems were not fully applicable at the onset of life. During this initial phase, a period of instability likely prevailed until one or more primitive cellular entities succeeded in achieving self-replication.
The origin of PoB cells marks the emergence of the first living systems. Whether referred to as PoB cells or by another designation, it is hypothesized that these entities arose through the self-organization of molecular components present in the prebiotic environment. Just as a jigsaw puzzle only reveals its complete image when all pieces are correctly assembled, a living system comes into existence when its constituent components are precisely organized, thereby generating the internal order required for vital processes to occur.
R1 Comments:
Line 55: “The explanation I find most scientifically grounded is that OoL on Earth resulted
from the physicochemical transformation of inanimate matter into living matter, culminating in the emergence of the first living system (the first cell).”This is not an explanation of abiogenesis. No new model or hypothesis elucidating the means or mechanisms of how life got orchestrated are provided that would be of interest to abiogenists. Can physicodynamics program? Can physicodynamics cybernetically process and execute formal commands? Can physicodynamics engineer the processing equipment needed to transform a representational program into computational halting?
My Answer:
I sincerely appreciate the reviewer’s observation, although I must admit that I found the formulation of the comment somewhat difficult to fully interpret. If my understanding is correct, the comment raises a fundamental question regarding whether physicochemical processes—referred to here as physicodynamics—are, in themselves, capable of generating systems that can formally process information, execute functional operations, or even construct the structural frameworks necessary to support representational programming.
From my perspective, the approach adopted in this work does not assume that physicochemical processes possess intentionality or teleological properties akin to those found in engineered computational systems. Rather, it posits that, under specific conditions of self-organization within the prebiotic environment, molecular structures may have emerged that were capable of replication and evolution, ultimately giving rise to systems with informational functionality.
I acknowledge that this is a profound and complex question, situated at the intersection of physics, biology, and information theory. I would be pleased to clarify or revise the relevant sections of the manuscript to prevent any potential misunderstanding. However, in the new version there have been several changes to the direction suggested by this reviewer. There is a better definition of the term physicochemical driving force and a new section on “Information and Life” has been included.
R1 Comments:
Line 59: “all governed by the laws of nature and the principles intrinsic to living systems,
which I have referred to as the “commandments of life.”Which of the four known forces “commanded life”? Was it the strong nuclear force, or the weak nuclear force? Was it the electromagnetic force that commanded life? Was it the law of gravity? What Law commanded the programming and the cybernetic processing of those commands? What law of nature computed life?
My Answer:
I regret that my limited expertise in nuclear physics may not meet the expectations of the reviewer. However, I wish to emphasize that nuclear physics offers limited explanatory power with respect to the origin of life and, more specifically, the emergence of biodiversity. It is widely accepted that living matter is composed of the same atomic constituents as non-living matter, albeit arranged in more complex and dynamic configurations. Accordingly, the fundamental laws of physics and chemistry apply equally to biological systems.
It is not uncommon for some physicists to assume that all phenomena in the universe can be explained exclusively through the lens of physics, without recourse to other disciplines. This perspective may reflect a degree of disciplinary overreach and a limited appreciation of the unique characteristics of living systems. I am firmly convinced that biology encompasses its own set of principles and laws that are indispensable for understanding the phenomenon of life. Should the reviewer wish to explore what might be considered the fundamental “commandments” of life, I refer them to reference number 6. While interpretations may differ and consensus may not be attainable, such discussions are integral to the broader scientific discourse.
R1 Comments:
Line 66: “the transition from inanimate matter to the first living organisms was a complex
process, the emergence of the genetic code, the development of metabolic pathways, and
energy conservation mechanisms” Science is about “How?” questions. Exactly how did inanimate matter program the genetic code, orchestrate metabolic pathways, and figure out how to the temporarily circumvent the 2nd Law? Can the author enumerate a single naturalistic physicochemical process that circumvents the 2nd Law through sustained time into a Sustained Functional System?
My Answer:
I appreciate the reviewer’s engagement with the manuscript and the thought-provoking nature of the comment. I must admit that I find it somewhat difficult to fully interpret the intent behind the question. If definitive, empirically verifiable knowledge regarding the origin of life were available, such a discovery would undoubtedly represent a major scientific breakthrough—perhaps even worthy of a Nobel Prize.
The aim of this work is not to provide a comprehensive or final explanation of how life originated, but rather to propose a plausible hypothesis grounded in current scientific understanding. The manuscript does not claim that inanimate matter “programmed” the genetic code or “orchestrated” metabolic pathways in a purposeful or teleological manner. Instead, it suggests that, under certain prebiotic conditions, self-organizing molecular systems may have emerged that were capable of replication and evolution, eventually giving rise to biological complexity.
Regarding the second law of thermodynamics, it is important to clarify that living systems do not circumvent this law. Rather, they maintain internal order by exporting entropy to their surroundings, resulting in a net increase in entropy consistent with thermodynamic principles. This is a well-established concept in the study of open systems far from equilibrium.
As for the reviewer’s request to enumerate a naturalistic physicochemical process that leads to a sustained functional system, I must respectfully acknowledge that I am not aware of a single process that fully meets this criterion in isolation. However, I would welcome any insights or references the reviewer might offer to further illuminate this important question.
R1 Comments:
Line 71: “To construct a logical, scientific, and plausible explanation for this transition from
inert to living matter, we must rely on the laws of physics and chemistry,” Exactly what laws are we talking about? Laws constrain events to occur the same way every time. Laws are compression algorithms. Laws severely limit contingency needed to steer and control. Life is all about steering toward homeostatic metabolic goals and managerial controls, not mere constraints.
My Answer:
Any scientific explanation for the emergence of life from non-living matter must be grounded in established physical and chemical principles—such as thermodynamics, kinetics, molecular interactions, and conservation laws. These laws govern the behaviour, interactions, and organization of atoms and molecules under various conditions. Moreover, they are universal and predictive, thereby constraining the possible configurations and dynamics of matter. Physical laws are deterministic and repetitive; they describe what must occur under specific conditions.
In contrast, life is dynamic and goal-directed—it encompasses regulation, adaptation, and purposeful behaviour (e.g., maintaining homeostasis, responding to environmental stimuli, and evolving). Living systems actively steer themselves toward survival and reproduction through mechanisms involving contingency, feedback, and control—features that are not readily captured by static physical laws.
Life exhibits emergent properties—such as self-organization, information processing, and adaptive behaviour—that transcend simple physical constraints. Thus, while physics and chemistry are necessary to understand life, they are not sufficient. A comprehensive explanation also requires biological principles (e.g., natural selection, genetic inheritance) and concepts from information theory (e.g., genetic coding, molecular signalling).
These reflections are incorporated into the revised version of the manuscript.
R1 Comments:
Line 170: The author rightly states that any concept of life should include being “functionally organized.” But the author’s references do not include papers differentiating formal organization from mere self-ordering phenomena. The references do not address how an inanimate environment would have recognized, valued, or pursued “function.” Other references not included in the manuscript do address in what ways life is unique from nonlife. These references should be included and critiqued. The author’s own non-model does not explain the derivation of orchestration or circuit integration, either.
My Answer:
I would be pleased to include and discuss any references the reviewer considers relevant, provided they are made available and deemed appropriate within the scope of this work. As is well known, the literature in this field—and indeed in virtually any scientific domain—is vast, encompassing thousands of publications that address its many facets. A comprehensive review of all existing works is beyond the scope of this study, which is not intended to serve as an exhaustive or up-to-date survey of the topic. Consequently, despite best efforts, the omission of certain key references may occur unintentionally. Additionally, I would like to clarify that the manuscript does not attempt to explain the aspects the reviewer suggests are missing, simply because it was not the intention of the study to do so.
R1 Comments:
Line 171: The author goes on to rightly point out, “Furthermore, it [life] should encode and process inheritable information, possess mechanisms for energy acquisition and transduction to sustain metabolic activity.”
How would physicodynamics encode information? Shouldn’t Barbieri’s “code biology” be cited? What is information? Is life’s information anything more than Shannon uncertainty measures or thermodynamic possibilities? Doesn’t life’s information specifically prescribe function? How did inanimacy come to do that, especially using a representational symbol system to issue those executable commands. How did physico-chemical processes acquire the ability to formally compute life? We can’t just keep saying all these abilities “emerged.” How? Some abiogenists argue that all known life is programmed and cybernetically processed. Others argue that life is actually computed. These published contentions found within 2024 and 2025 papers address what life is. They should be included in the references and critiqued. The references are not-up to-date.
My Answer:
As previously noted, the scientific literature encompasses hundreds, if not thousands, of references on virtually every topic. Moreover, I do not claim to be an expert or a professional researcher in this field. Rather, I approach this work as a learner—one who seeks understanding and contributes ideas for scientific comparison and the advancement of knowledge. Therefore, if the reviewer believes that specific references should be included to support or contextualize the points discussed, I would be grateful if they could be shared for consideration. In any case, I have incorporated three new references into the revised manuscript (Gatenby et al., 2025; Barbieri, 2024; Bartlett et al., 2025), and I welcome further suggestions for additional articles that could enrich the discussion.
The reviewer has raised a series of profound and interconnected questions regarding the nature of life, the role of information, and the adequacy of physical laws in explaining biological phenomena. The encoding and processing of inheritable information refers to the genetic system (DNA/RNA), which stores the instructions necessary for the construction and maintenance of living organisms. Energy acquisition and transduction pertains to metabolism—how organisms capture energy (e.g., from sunlight or chemical gradients) and convert it into usable forms to sustain life. These are functional hallmarks of living systems, not merely structural features.
Physicodynamics refers to the laws and dynamics governing physical systems (e.g., thermodynamics, kinetics, quantum mechanics). While these laws dictate molecular interactions, they do not inherently encode functional information. Recent work (Gatenby et al., 2025) suggests that information dynamics in early life may have emerged from environmental cycles (e.g., day/night rhythms), which imposed selective pressures on molecular systems.
Traditional definitions of information, such as Shannon entropy, treat it as statistical uncertainty. In biological systems, however, information is functional—it evolves, prescribes actions (e.g., gene expression), is differentially expressed across space (e.g., cell-specific expression) and time (e.g., during development), and is encoded symbolically (e.g., codons representing amino acids). Thus, biological information is not merely a thermodynamic possibility; it is instructional and executable, akin to software in computational systems. These reflections have been incorporated into the revised manuscript under a new section titled Information and Life (Section 3.1).
R1 Comments:
Life 179: Can the author explain how physicodynamics alone produced formal systems and formal processes? If not, the contention that life is purely physico-chemical falls flat.
My Answer:
I must respectfully note that I am unable to identify where in the manuscript the reviewer’s interpretation originates. In any case, I would like to clarify the intended meaning, which I believe is unambiguous: the matter that constitutes living organisms behaves in accordance with the laws of physics and chemistry. That said, the behaviour of living systems involves more than just physical and chemical interactions—it also responds to biological principles, which govern processes such as regulation, adaptation, reproduction, and evolution. Thus, while the laws of physics and chemistry are universally applicable, they are not sufficient on their own to fully explain the complexity and functionality of living systems. Biology introduces additional layers of organization and causality that are essential for understanding life as a dynamic and evolving phenomenon.
R1 Comments:
- Line 193: “with the appearance of the first living system, the life process arose immediately and inherently.” It’s as though the author is pulling a rabbit out of a hat like a magician’s trick. It’s as though he has already forgot his own entire “Miraculous” section, and now is just snapping his fingers. Life origin was “immediate and inherent” within mere physicality. The author offers no empirical or rational support for either formal “systems” or formal “processes” being “inherent” in physicodynamics.
- “From that moment onward, an inseparable relationship was established between the system—the living organism—and the process—life.” This is like saying, “The ‘system’ (‘the living organism’) just appeared out of thin air. The author just assumes life origin with zero explanation of “How?”
- Ignored are recent papers on the reasons for the difficulty of explaining life-origin, the specific kind of information required, and the fact that efficaciouos choices are required at actual decision nodes to program, steer and control the formal processes and “systems” of which the author speaks. What is the source out of inanimacy for the executable commands of genomics? What is the source of the machinery to execute those commands? What is the source of the circuit integration? How did life get so formally orchestrated and computed?
- How did protolife solve Turing’s halting problem when the efficacious active selections had to be made at bona fide decision nodes prior to any phenotypic productio (e.g., the choice of which nucleoside next to polymerize)? All of the 3’5’ phosphodiester bonds are the same. Functional sequencing cannot be attributed to physics and chemistry. Nucleosides were selected according to linguistic rules, not physicodynamic laws.
- The only explanatory mechanism provided is the magic of “emergence.” Life just emerged spontaneously from physicodynamics. Never mind falsifying Pasteur’s and Virchow’s Frist Law of Biology. The only model presented is that Life just organized itself into existence “immediately and inherently.” This is a metaphysical presupposition, not a scientifically elucidated new model of means.
- Numerous papers have been published in well-indexed peer-reviewed literature in the last couple years that the author neglects. These papers show that the concept of “self-organization” is a self-contradictory nonsense term that has no place in scientific literature. Something would have to already exist in order to organize itself into existence. The notion of “emergence” has no more substance than tautological “self-organization” does. Whatever we have no explanation for, we just claim “emerged.” Then we move happily on to “diversification.”
“Once this original system acquired the ability to divide and, consequently, to evolve, the generation of biological diversity commenced.” This is a life-origin special issue. Nobody seems to have a problem with how diversity was achieved. Diversification is down the road aways. When it comes to abiogenesis, this paper seems uninformative. What readers are interested in within this Special Issue is the “How?” of abiogenesis. But they are not getting anything new with reference to how life got orchestrated in an inanimate environment.
My Answer:
- It is possible that I have not communicated my position with sufficient clarity, or alternatively, that the reviewer is unwilling to engage with the perspective presented and has instead chosen to interpret it as unsubstantiated fabrication. I believe such an accusation warrants a more respectful and constructive approach.
That said, in response to the reviewer’s initial comment, I must acknowledge that I am unable to provide definitive empirical evidence for all of the assertions made—just as the reviewer cannot conclusively claim that these statements are purely imaginative or unfounded. The origin of life remains one of the most complex and unresolved questions in science, and any hypothesis in this domain necessarily operates within a framework of uncertainty.
Nonetheless, the revised version of the manuscript now includes two real examples that illustrate how molecules can self-organize to perform complex biological functions: (1) the process of translation, and (2) the in vitro packaging of lambda phage. These examples serve to demonstrate that molecular systems can organize themselves into functional assemblies under appropriate conditions.
The central idea conveyed is that the emergence of life can be conceptualized as an immediate and intrinsic outcome of physicality itself—implying that, given suitable environmental and molecular conditions, life may arise spontaneously as a fundamental property of matter. This view aligns with a growing body of literature exploring the principles of self-organization and emergence in prebiotic chemistry.
Regardless, the phrasing of the sentence highlighted by the reviewer has been revised in the updated version of the manuscript to improve clarity and avoid misinterpretation.
- The reviewer’s interpretation appears to be a misreading of my argument and suggests a lack of understanding regarding the concept ofsystem–process duality. This duality is not contingent upon any specific hypothesis about the origin of life; rather, it is a foundational principle that applies universally once a living system is established.
The concept reflects the inseparable relationship between the structural substrate (the system) and the dynamic, functional aspect (the process). In biological systems, structure and function are co-dependent: the system provides the framework within which processes occur, and the processes, in turn, define the system’s behaviour and identity. This duality remains valid irrespective of how life initially emerged and is widely recognized in systems biology and theoretical biology.
The manuscript has been revised to clarify this point and to ensure that the concept is not misinterpreted as being tied to a specific origin-of-life scenario.
- I find it challenging to engage with a language that diverges significantly from biological discourse. Moreover, as the author, it is my responsibility to select the topics I consider most relevant and to organize them in a manner that best conveys my scientific perspective. Just as you, in your own writing, would choose the structure and emphasis that most effectively express your ideas, I have done the same in this work.
- The reviewer's claim that nucleosides were selected according to linguistic rules rather than physical-dynamic laws is speculative and grounded in a non-reductionist, semiotic perspective on the origin of life. While such a view may conceptualize life and its emergence in terms more analogous to computational systems than to biological organisms, I do not share this interpretation. I maintain that living systems differ fundamentally from computers and are more appropriately explained through the framework of natural selection and physicochemical forces than through linguistic or symbolic rule-based models.
- The emergence of life is not a matter of magic, as the reviewer suggests. While the underlying mechanisms are not yet fully understood, the concept of emergence is supported by a substantial body of scientific literature. Numerous studies propose that life is an emergent property arising from complex interactions among non-living components. You are, of course, entitled to a different interpretation; however, it is inappropriate to dismiss alternative perspectives or discredit those who support them.
The reviewer’s remark—'Never mind falsifying Pasteur’s and Virchow’s First Law of Biology'—appears to misunderstand the historical and conceptual context of these foundational principles. Louis Pasteur’s dictum 'Omne vivum ex vivo' ('All life comes from life') and Rudolf Virchow’s 'Omnis cellula e cellula' ('All cells come from pre-existing cells') were formulated in opposition to the idea of spontaneous generation within already living systems. These principles apply to the continuity of life once it exists, not to the origin of life itself.
To suggest that life could not have emerged from non-living matter is to imply either a supernatural cause or an unexplained metaphysical mechanism—positions that fall outside the scope of empirical science. Those of us who support the hypothesis that life arose through a natural, evolutionary process from inanimate matter do not contradict Pasteur or Virchow, because their laws presuppose the existence of cells and living systems.
Ironically, it is the reviewer’s own invocation of symbolic selection, decision nodes, or linguistic rules in abiogenesis that more directly challenges these classical biological principles, by introducing abstract, possibly non-physical mechanisms into the origin of life. While such models may be philosophically stimulating, they require rigorous justification if they are to be considered within the framework of empirical biology.
- As previously noted, there exists an extensive body of scientific literature relevant to this work. Naturally, it is the responsibility of the authors to select the most appropriate references based on the scope and focus of the study. Consequently, there is undoubtedly literature that I have not cited—either because I was unaware of it or because I did not consider it directly pertinent to the objectives of this manuscript. I repeat for the umpteenth time: if the reviewer believes that specific, important publications have been omitted, I would appreciate it if they could be identified explicitly. I will then evaluate their relevance and consider including them where appropriate. However, I would like to emphasize that this paper is not intended as a comprehensive review, but rather as an original contribution. As such, the selection of references reflects the author’s judgment and the specific aims of the work.
I respectfully disagree with R1’s assertion that 'the concept of self-organization is a self-contradictory nonsense term that has no place in scientific literature.' The claim that 'something would have to already exist to organize itself into existence' reflects a misunderstanding of how self-organization is defined and used in the scientific context. Self-organization refers to the spontaneous emergence of ordered structures or patterns from initially disordered systems, driven by internal interactions and boundary conditions, without the need for external control. This concept is well-established in fields such as thermodynamics, systems biology, and complexity science. Furthermore, it is important to clarify that self-organization and emergence are related but distinct concepts. Emergence refers to the appearance of novel properties or behaviours at higher levels of organization that are not reducible to the properties of individual components. Self-organization, on the other hand, describes the process by which such structures or patterns arise. Conflating the two leads to conceptual confusion. Therefore, dismissing self-organization as unscientific overlooks a substantial body of empirical and theoretical work that supports its relevance in understanding complex systems, including the origin of life.
R1 should know that this manuscript was written at the request of the journal. If the editor ultimately considers that it does not contribute meaningfully to the field or that it addresses topics deemed outside the scope of Life, I will, of course, respect that decision. In that case, I will seek publication in another journal. This is part of the academic process we all accept.
I understand that this reviewer may not find the work valuable or aligned with his/her perspective. They are entitled to that opinion, but I respectfully disagree. I stand by the relevance and originality of the contribution of this work.
R1 Comments:
Line 200: “An emergent property refers to a novel and unpredictable characteristic that arises from the ordered interactions among components within a system. Emergence can be conceptualized as the outcome of cooperative dynamics among autonomous elements, which collectively give rise to new macroscopic structures and systemic behaviors [30].”
What is the mechanism of the pipe dream of “emergence?” Are we sure it is not just a catch-all term amounting to a pipe dream? We often seem to fail to appreciate the difference between “formal organization” vs “order” and the mere self-ordering phenomena of Prigogine’s “dissipative structures” vs. “formally organized true systems.” Self-ordering (e.g., hurricanes and tornadoes) require zero active selections. Organization always requires active selections, including molecular evolution. Active programming decisions must be made prior to the existence of any organisms that could diversify and evolve. Evolution is nothing more than the differential survival and reproduction of already living organisms. What programmed and cybernetically processed these organisms? They didn’t just “spontaneously generate.” They only became fittest through algorithmic optimization. Algorithmic optimization occurs at the genomic level, prior to the existence of any phenotype that the environment could prefer. Algorithmic optimization is formal, not physical—as formal as mathematics. The author fails to appreciate the meaning and essence of any formal system. A weather front is not a true formal system. No choice causation is involved. But bona fide “systems” and “processes” always have formal components and goals that physicodynamics alone is blind to. Notice that for the author to define “emergence” required “conceptualizing” and “cooperative dynamics” and “systemic behaviors”— all formalisms that physicodynamics cannot perceive or participate in. They are engineering concepts, not forces, laws, constraints.
My Answer:
I must acknowledge that I am not entirely certain of the reviewer’s intended meaning. It is evident that the reviewer’s knowledge in this domain surpasses my own. As for wisdom, I am not in a position to judge—though it is often said that true wisdom is marked by humility and the discernment to distinguish what truly matters from what does not.
R1 Comments:
Line 204: “Life arises from the complex interplay among non-living molecular constituents”
Apparent in the paper is a failure to appreciate the difference between mere complexity vs. conceptual complexity. What makes complexity conceptual is choices from among real options. A pile of spaghetti noodles is complex. But that complex pile of noodles doesn’t DO anything useful.
Things have to be steered and controlled to produce nontrivial function. But physics is blind to “usefulness” because “usefulness” is a formalism, not mere physical interactions. The “work” of physics has nothing to do with utility.
The reason we have such a terrible problem explaining and defining life is because of our starting presuppositional axiom that refuses to acknowledge the reality of steering and control toward the goal of sophisticated function. We fanatically and blindly believe that “Mass and Energy are sufficient,” thereby shooting ourselves in the foot. We preclude scientific discovery by violating Einstein’s “minimum physic.” We bring our purely metaphysical presuppositions with us TO science. The religion of physicalism will never be able to explain the science of biology.
We fail to realize that denying and excluding formalisms from science makes it impossible to understand life. At the same time, we have no problem using purely formal mathematical equations to define the laws of physicality. Every month genomic papers are published that prove that life is programmed, computational and formal. It is just secondarily instantiated into physicality like using blocks of wood to play Scrabble. There is nothing physical about spelling words in the game of Scrabble. But the letters are instantiated onto “physical symbol vehicles” in a Material Symbol System. We then make the mistake of thinking that Scrabble and life are both physical because nucleosides and blocks of wood are physical. When are we going to realize and admit that life and homeostatic metabolism are, more than anything, formal CONCEPTS! The very laws of physics are formal mathematical concepts! Reality cannot be reduced to nothing but Chance and Necessity. Reality consists of Chance, Necessity and Choice. If we try to deny this, we try to deny the reality of Engineering!
My Answer:
Once again, I find myself confronted with a lengthy digression that I struggle to fully grasp. The language used is highly abstract and, for me, feels distant from the tangible molecular reality—closer to philosophical speculation than to biological science.
Regarding the reviewer’s analogy with spaghetti, I must respectfully disagree. I do not consider a pile of spaghetti to be complex, quite the opposite. However, even if one were to accept the reviewer’s characterization, I would argue that it nonetheless serves a clear and beneficial function: it nourishes us and does so with pleasure.
As a final reflection on this point, I would like to emphasize that while I believe life must be explained through physics and chemistry, I also hold that these alone are insufficient. Additional principles are needed—what I have referred to as 'the commandments of life,' which I published in 2020 and have cited in the manuscript.
R1 Comments:
Line 210-211 The author talks about “homeostatic regulation.” That means “control.” What is doing the controlling? Does fixed law steer and control multi-step processes toward functional success (e.g., the 13-step Krebs cycle that produces no benefit until the last step)?
Line 211: “This concept is foundational in systems biology”Yes. Functional controls require efficacious choices at decision nodes. Laws cannot make purposeful choices at decision nodes. So, how did physics and chemistry generate biological controls? Something is missing from our abiogenic models. The only answer is disallowed by our faulty starting metaphysical axiom.“Homeostatic regulation” is formal. It requires Choice Causation, not mere Physicodynamic Causation. To integrate circuits and to program and process algorithms requires choices, not fixed laws or constraints. Constraints can’t steer toward “usefulness.”
My Answer:
This reviewer should know that "homeostatic regulation" is a well-established and widely used term in biology. It refers to the processes by which living organisms maintain internal stability (such as temperature, pH, glucose levels, etc.) despite changes in the external environment. This concept is central to physiology, molecular biology, and systems biology, and is foundational in understanding how organisms survive and adapt. It's not only common in academic literature but also in textbooks and clinical contexts.
The reviewer states that the Krebs cycle consists of 13 steps and provides no benefit until the final reaction. I suggest that a review of basic biochemistry may be helpful. The Krebs cycle comprises 8 well-established enzymatic reactions, not 13. Moreover, it yields multiple biologically valuable products well before the final step catalysed by malate dehydrogenase. These include NADH, FADHâ‚‚, GTP (or ATP), and key metabolic intermediates. These intermediates serve as precursors for the biosynthesis of purines, pyrimidines, amino acids, porphyrins, and heme groups, among others. In fact, the cycle’s role in energy production and biosynthetic integration is one of the reasons it is considered central to cellular metabolism. Interestingly, I had the opportunity to explain this very topic in class today, which further reinforces its foundational importance in biology.
In 1937, Hans Krebs submitted his groundbreaking paper on the citric acid cycle (now known as the Krebs cycle) to Nature. The journal rejected it, reportedly due to a backlog of submissions, not because of any flaw in the science. At the time, Nature did not recognize the significance of the work, which later became one of the most important discoveries in biochemistry. Krebs went on to publish the paper elsewhere, and in 1953, he was awarded the Nobel Prize in Physiology or Medicine for this discovery. Years later, Nature acknowledged the rejection as a major editorial mistake. This episode is often cited as a reminder that scientific breakthroughs are not always immediately recognized, and that editorial decisions, while necessary, can sometimes overlook transformative work.
As I have previously stated several times, physics and chemistry alone are insufficient to fully explain many biological processes, whether at the molecular, cellular, or ecological level. Nor can computer science or philosophical reflection, on their own, provide comprehensive explanations. These disciplines undoubtedly contribute valuable insights, but it is biology itself—through its own principles and emerging laws—that is, or will be, capable of explaining biological phenomena in their full complexity.
The following text written by R1: “Homeostatic regulation” is formal. It requires Choice Causation, not mere Physicodynamic Causation. To integrate circuits and to program and process algorithms requires choices, not fixed laws or constraints. Constraints can’t steer toward “usefulness.”, exceeds my knowledge and understanding. This reviewer is using philosophical language to describe biological processes. Terms like “choice causation” and “usefulness” are not standard scientific vocabulary, which makes the argument harder to follow. As a molecular biologist this kind of speculative reasoning makes me feel disconnected from the empirical reality I work with. I find it difficult to engage with critiques that rely on non-standard or philosophical language, because they don’t connect with the molecular and biochemical reality you study and teach.
R1 Comments:
Line 220: “duality of system and process” is a duality of two formalisms. Neither, nor the
combination of the two, is going to be explained by Necessity! Formalisms require the
freedom of contingency, and active selection from among real options.
My Answer:
I do not understand what the reviewer is saying.
R1 Comments:
Line 221: “Self-organization plays a pivotal role in the emergence of life, particularly in the
formation of prebiotic structures preceding the OoL [33, 34]. The spontaneous emergence
of order among molecular ensembles—without external direction and beyond the
explanatory power of their isolated components—has been proposed as a defining feature
of life’s origin [35].”Yes, they have. But multiple well-indexed peer-reviewed references in 2024 and 2025 have shot down these attempted explanations. These references are
neglected in the author’s paper. If we have no model or falsifiable hypothesis of
How? systems and processes were orchestrated, we just claim they “self- organized.” This is not science. It is blind faith.
My Answer:
Some individuals appear to hold the conviction that they possess definitive knowledge, and from this perceived intellectual superiority, they tend to disregard or invalidate the perspectives and beliefs of others. In relation to the origin of life, it must be emphasized that no one—absolutely no one—can claim to know with certainty what transpired or how it occurred. Furthermore, it is highly probable that such knowledge will remain beyond our reach indefinitely. Having established this general reflection, I would appreciate clarification regarding the purportedly robust sources that challenge the plausibility of self-organizing processes. It is important to note that empirical observations can be made independently of any pre-existing theoretical framework. In fact, theoretical models are often constructed based on experimental data. Conversely, theories may also generate predictions that must be rigorously validated through experimentation. Regardless of the extent of philosophical discourse, computational modelling, or other forms of abstract reasoning, such approaches do not inherently confer greater epistemic authority.
R1 Comments:
Section 4.3 on negentropy.
Negentropy is much better understood as the loss of formal organization rather than
the loss of order. Many negentropy states increase in order as they approach heat
death. A chamber of cold, very slow-moving inert gas molecules is highly ordered.
It’s not about order or complexity. It is about formal orchestration of homeostatic
metabolism. It’s about the goal of being and staying alive. Physics doesn’t have
goals. So, the question is, “How does any “Sustained Functional System” maintain its state
far from equilibrium? Irreversible nonequilibrium thermodynamics cannot achieve this. Maxwell’s demon has to choose when to open and close the trap door in the
partition between chambers in order to achieve an energy differential.
No efficacious choices—No heat engine! The simplest of heat engines requires
Choice Causation, not just Physicodynamic Causation (The Universal Determinism
Dichotomy). Life requires formal steering and control. That’s what genomics is all
about. Schrödinger confused “order” with “organization.” They are not the same! And mere
“complexity” is not the same as “conceptual complexity,” either.
My Answer:
Negentropy, short for negative entropy, is a concept used in thermodynamics, information theory, and systems biology to describe the degree of order or organization in a system. It represents the opposite of entropy, which is a measure of disorder, randomness, or energy dispersal. In living systems, it is often associated with the capacity to sustain organized, functional states far from thermodynamic equilibrium.
All of the reviewer’s arguments, in addition to being repetitive, exceed my current level of comprehension. I must acknowledge that my understanding of physics is limited. Nevertheless, I make a consistent effort to inform myself thoroughly before engaging in discussion or producing written work on any given topic.
R1 Comments:
Line 248 talks about digestion as though it just “emerged.” Digestion did not just “emerge.” It was genomically prescribed, and then computed! Undeniable formalisms.
My Answer:
I think this reviewer does not understand the same thing by “emergency” as I do. I also contest the assertion that digestion is genetically determined. There are no genes that directly encode the physiological process of digestion itself. Rather, genes encode the molecular components—such as enzymes and transport proteins—that participate in and facilitate digestive functions. In this sense, genetic information specifies the structural and functional elements of the system, but not the emergent physiological process that occurs upon the ingestion of food. Analogously, while genes contribute to the construction and regulation of the living system, they do not encode "life" as a holistic phenomenon.
R1 Comments:
Line 251 talks about “functional coordination of these components, mediated by
molecular signals.”
The author here is talking about formalisms without appreciating that he is talking
about formalisms, not physical reactions. “Functional coordination mediated by
signals” is not physics and chemistry. It requires active selection, steering, controls
and goals. These facts thoroughly embarrass the purely physicodynamic fantasy of
naturalistic “emergence.” Laws and constraints cannot produce life.
My Answer:
I must express that I do not fully understand the reviewer’s critique, nor the intended message conveyed through what appears to be a somewhat condescending tone. In the paragraph referenced, I merely stated that molecular signals—such as hormones—are essential for the coordinated functioning of multicellular organisms. My conceptual framework for interpreting biological phenomena differs significantly from that of the reviewer. Moreover, I am uncertain whether the reviewer has direct experience working in a laboratory setting with molecular and cellular systems, which may influence the perspective presented.
R1 Comments:
Line 255 “life would have emerged as an intrinsic property of its organization.”
Tautology. No new information. Circular.
The paper is doing a good job of reviewing some of the abiogenesis problems. But it
is not providing anything helpful to readers interested in solving the abiogenesis
problem. It continues to offer only circular reasoning—defining words and concepts
using the word and concepts to be defined.
My Answer:
This critique appears to reiterate previous points, and I do not intend to repeat myself in my response. In the paragraph cited by the reviewer, I am not introducing new information, as claimed, but rather offering a line of reasoning to further clarify my position—namely, that life should be understood as an emergent property. My intention was to reinforce this conceptual framework, not to present novel empirical data.
R1 Comments:
Line 278 Aside from already existing life, there is no “the metabolic world.” Innumerable “reaction worlds” exist. But they are not steered and controlled toward metabolic goals. Biochemical pathways lead somewhere useful. No such inanimate “metabolic world” exists. Branscomb, Russell and others overextend inorganic reactions into finished formal systems of protolife that simply do not empirically exist. Protomembrane researchers do the same. An imaginary “metabolic world” cannot be used to explain abiogenesis. It is assuming what oneis claiming to prove or explain. Spontaneous Orchestration is just believed, not scientifically explained.
My Answer:
Once again, it appears that the reviewer either does not understand or is unwilling to engage with the core arguments presented in my work. Moreover, the tone of the critique reflects a level of arrogance that is incompatible with the principles of scientific dialogue and mutual respect. Regardless of the intensity of one’s convictions, no individual holds absolute truth—particularly when addressing phenomena that occurred approximately four billion years ago. Scientific inquiry in such domains must remain open to interpretation, grounded in evidence, and cognizant of its inherent epistemological limitations.
The term “metabolic world” refers to the hypothetical existence of metabolic pathways—such as glycolysis—within the prebiotic environment. It is a conceptual label intended to reflect a plausible scenario supported by experimental evidence. Specifically, studies have demonstrated that, under conditions simulating the prebiotic Earth and in the absence of enzymatic catalysis, several metabolic reactions identical or analogous to those found in contemporary biological systems can occur spontaneously. The collective occurrence of these reactions is what I refer to as the metabolic world. This nomenclature is employed in analogy to the widely accepted term “RNA world”. Therefore, the reviewer’s dismissive critique appears to overlook the empirical basis and conceptual intent behind this terminology. The criticism lacks substantive justification, particularly given the experimental data supporting the plausibility of prebiotic metabolic networks.
Expressions such as “Spontaneous orchestration is just believed, not scientific explained,” which the reviewer seems to favour, are unnecessary, devoid of substantive content, and inappropriate in the context of constructive scientific critique. Such remarks contribute little to the advancement of understanding and detract from the respectful tone expected in scholarly discourse.
R1 Comment:
Line 296 “The Priming Phase, which involves the formation of disorganized living matter.”
Can the author provide any empirical evidence of a single case of “disorganized living matter”? Anything living manifests the ultimate in formal orchestration and organization. Micoplasma genitalium puts to shame the finest mainframe computer in the world.
My Answer:
Yes, I do. For instance, when the integrity of the cell membrane is compromised—resulting in its structural disorganization—the intracellular components are released into the surrounding medium. This constitutes disorganized biological matter. In the context of the prebiotic soup, as proposed herein, molecular interactions occurred over an indeterminate period and under unknown environmental conditions. These interactions led to the synthesis of organic compounds, like amino acids and proteins, or nucleotides and nucleic acids. Over time, these biomolecules became increasingly concentrated, ultimately giving rise to what is referred to as 'disorganized living matter.' The term 'living matter' is employed to denote the presence of organic molecules that are structurally identical to those found in extant biological systems. If such a scenario did indeed occur, it remains uncertain. The precise events that transpired in the enigmatic environment where life first emerged are still unknown to science.
Mycoplasma genitalium is frequently cited in discussions concerning the origin of life and minimal genome research due to its possession of one of the smallest known genomes among self-replicating organisms. It is often utilized as a model system to investigate the minimal genetic and cellular requirements for life. However, within the context of this discussion, the relevance of your comment regarding M. genitalium is unclear to me.
R1 Comments:
Line 298 “The Assembly Phase, in which these molecular worlds integrate to form the first living system.”
Can the author provide any empirical evidence of a single case of “disorganized living matter” integrating circuits and itself into a living system?
Can the author name a single nontrivial circuit that integrated itself into existence?
My Answer:
I have an answer to the first question. I don't have an answer to the second question because I don't understand it.
A cell-free extract represents a form of disorganized living matter, yet it retains the biochemical machinery necessary to perform complex tasks such as protein synthesis. This phenomenon underscores the functional potential of biological components outside the context of intact cellular structures. If required, I can provide bibliographic references to support this assertion. Furthermore, it is conceivable that analogous processes may have occurred within the prebiotic environment, contributing to the emergence of primitive biochemical systems. Noteworthy, the concept of using cell-free systems to simulate early life processes is increasingly explored in origin-of-life research.
R1 Comments:
Line 303: “The Assembled World Hypothesis” is not a falsifiable hypothesis.
The author needs to read the published critiques of Assembly Theory.
My Answer:
The Assembly Theory tries to explain how complex objects—such as molecules, biological systems, or even technological artifacts—can emerge through processes of selection and historical construction. It aims to unify concepts from physics, chemistry, and biology by introducing a new way to quantify complexity and evolution. Both assembly theory and my modest proposal provide a framework for understanding how life could arise from inert matter, following the increasing complexity of molecular assemblies. However, my proposal is something different and much less ambitious than that of Sara Walker and Lee Cronin.
R1 Comments:
Line 635 “The emergence of the metabolic world” is just not explained and justified. It is just pre-assumed to be spontaneous.
There does not seem to be any original new abiogenic insights in this paper. I find the proposed phrases to consist mostly of empty words rather than testable hypotheses. No real mechanisms are presented.
Many of the problems of abiogenesis are often well-described.
But no reason exists why any abiogenic researcher would want to download and read this non-model. If the author of this paper would find and read around six to eight life-origin papers published in the last two years, he would understand why he is having such difficulty providing naturalistic mechanism for the orchestration of initial life.
Protocellular metabolomics requires steering and control toward metabolic success. There will be no escaping or dodging this reality.
The author must study and critique 2024 and 2025 abiogenic literature before attempting to explain life origin.
My Answer:
To be concise: if you believe that my work does not offer any novel contributions, you are free to reject it. Naturally, I disagree with this assessment, as I am convinced that it presents original ideas and reflections concerning the origin of life and the biodiversity of our planet. This manuscript is not intended as a comprehensive review and therefore does not aim to exhaustively cover the existing literature on the topic. As I have previously stated, if you consider any specific work to be particularly relevant and believe it should be addressed, I would be grateful if you could indicate which one.
I would kindly suggest that you refer to the title of this work to understand its scope. It should be evident that I do not claim to solve the profound mystery of the origin of life—although I would certainly wish to—but rather aim to contribute a modest insight to the vast and still largely unexplored landscape of scientific knowledge. This work represents a small grain of sand on the immense beach of inquiry, filled with countless hidden places yet to be discovered.
Reviewer 2 Report
Comments and Suggestions for AuthorsThere are long discussion on where and how the initial life emerged, known as the origin of life (OoL). Even after the emergence of life, how the biodiversity exploded remained unknown. The article by Dr. Gómez-Márquez summarized current studies of the OoL and the emergence of biodiversity, the former as the Assembled World Hypothesis (AWH), and the latter as Environmental and Living Worlds. The story from the emergence to divergence of life was easy to read and follow, and would be suitable to overview the science to students, postdocs, and early-carrier researchers. However, I have several concerns in publication of the content in the form of Hypothesis.
Major comments
- General: Hypothesis article needs "a novel interpretation of recent data or findings". I am not sure of your original interpretation. It seems for me that the proposed hypothesis, for example the AWH in Fig 1, is not beyond the gathering of well-known "worlds" hypothesis. The article may be rather a review around the OoL though reference is not comprehensive enough.
- General: The introduction may be redundant. For example, the paragraph starting from L125 seems to be similar to that from L78.
- Ch. 2: Ch. 2 is a bit complex for readers which evolutional stage (OoL, post-OoL, evolution) the target of each paragraph is. This would be because the "life" is undefined in the beginning of the paragraph and the word OoL might habe been used in both the assembly of cells from the prebiotic soup and the cell division of LUCA.
- Ch. 4.3: What kind of energy input is considered? It can be either P-O bond energy (ATP), elecrochemical potential in hydrothermal vent, photon from the Sun, thunder, volcanic heat, non-ATP molecules synthesized as a consequence of these activities, etc.
- Ch.6: What kind of prebiotic soup do you consider? The topics to be consideres are the chirality of molecules, whether L-enriched or racemic and the possible chiral-enrichment reactions such as Soai asymmetric autocatalysis, and the mechanism of molecular accumulation. Life is an aqueous assembly of molecules, and the cellular components are, except for (phospho)lipids, water-soluble, and easily dissipates in an aqueous environment. These topics may have been included in the word "PDF", and if so, it is advised to explain the possible PDF.
- Fig. 1: Isn't there any PDF between prebiotic soup and each world, and between each world and organized living matter?
- 6.1.2.1: Ordinary cells in current nature are composed of phospho- or glycolipids. L546 states the existence of fatty acids, which may self-assemble into micelles or vesicles (Geisberger et al. Sci. Rep. 2023, 15227). This may contradict with your hypothesis that the cellular components are similar in PoB cells and current cells. How do you think the membrane in prebiotic world made of?
- L650: Hydrothermal system is of interest not only because of the metal ion abundance but also because of the electrochemical activity that potentially drives electrochemical reactions (Nakamura et al. Angew. Chem. Int. Ed. 2010, 7692, Kitadai et al. Sci. Adv. 2019, eaav7848).
- Figure 2: Where are LUCA kand LECA? It seems that they are the same as PoB cells.
Minor comments
L97 Her, ... : Is it a typo of Here,?
L341 and 1213: The definition of PDF is different each other.
L798: Wings are for "directional" flight, otherwise dandelion fluff can be an alternative.
Figure 3: Figure caption is not a caption any more. Some of the contents would be better displayed in the main text.
L1006: An recent example that shows the primitive inter-cellular interaction in archaea (Imachi et al. Nature 2020, 519)
L1037: What is TACK?
Abbreviation: LECA and GMO is missing, though only used once each in L904 and L1129. LECA appears in the title of the reference 119 so it may be worth noting, while GMO may not need to be abbreviated.
Reference: It seems that the reference style is not comprehensive; some lacks issue number and DOI.
Author Response
Manuscript ID: life-3882493
Type of manuscript: Hypothesis
Response to Reviewer 2 (R2):
General Comment:
I sincerely thank you for your insightful comments and constructive criticism. They have been instrumental in guiding a comprehensive revision of the manuscript, prompting me to reassess several core ideas and ultimately produce a substantially new version of the work.
The principal modifications introduced in the revised manuscript include:
- A new title that better reflects the conceptual framework of the study.
- A redesigned Figure 1 to illustrate the updated hypotheses.
- A complete rewrite of the text, from the abstract through to the conclusion.
- The addition of 27 new references to strengthen the scientific grounding of the discussion.
- Inclusion of new examples that support key aspects of the prebiotic soup hypothesis, particularly those concerning self-organization and the interactions among the proposed molecular worlds.
I wish to emphasize that this manuscript represents my original work, and I retain the right to articulate my ideas in the manner I consider most appropriate. The manuscript presents a conceptual narrative aimed at exploring plausible pathways for the emergence of the first living system and the subsequent development of biodiversity. My objective is to propose a scientifically informed and original hypothesis regarding how these processes might have occurred. Finally, if additional references are considered necessary, I would greatly appreciate specific suggestions.
With these considerations in mind, I now proceed to address the specific critical comments raised in the review.
Major Comments:
R2 Comment:
General: Hypothesis article needs "a novel interpretation of recent data or findings". I am not sure of your original interpretation. It seems for me that the proposed hypothesis, for example the AWH in Fig 1, is not beyond the gathering of well-known "worlds" hypothesis. The article may be rather a review around the OoL though reference is not comprehensive enough.
My Answer:
I have thoroughly re-examined the relevant literature and have not identified any existing theories or hypotheses that directly correspond to the proposal presented in this manuscript. The hypothesis I advance is, at the very least, original in its synthesis of molecular domains—metabolic, biomolecular, and supramolecular—and in its framing of life as a system–process duality. If this assessment is incorrect, I would be genuinely grateful if the reviewer could provide references to the specific articles in question.
That said, I acknowledge that conceptually related frameworks exist, sharing certain thematic elements with the present work. Several of these have been appropriately cited in the revised version of the manuscript. The primary objective of this contribution is not to provide a comprehensive review of the existing literature, but rather to articulate original ideas concerning the origin of life and the emergence of biodiversity—two intimately interconnected phenomena. In developing this proposal, references to prior studies have been incorporated to provide context and support. While some of the concepts presented here are novel, others may converge with previously established hypotheses, thereby reinforcing the theoretical foundation of this work.
R2 Comment:
- General: The introduction may be redundant. For example, the paragraph starting from L125 seems to be similar to that from L78.
My Answer:
From a general standpoint, the reviewer’s observation is likely valid, as a manuscript of this length may inevitably contain minor redundancies and, in some instances, more substantive ones. These issues will be carefully addressed in the revised version of the manuscript. However, with regard to the specific redundancy highlighted by the reviewer, I do not perceive any repetition in the section referenced.
R2 Comment:
- Ch. 2: Ch. 2 is a bit complex for readers which evolutional stage (OoL, post-OoL, evolution) the target of each paragraph is. This would be because the "life" is undefined in the beginning of the paragraph and the word OoL might habe been used in both the assembly of cells from the prebiotic soup and the cell division of LUCA.
My Answer:
If the reviewer’s comment regarding “Ch. 2” refers to the chapter titled The Miracle of Life, I must express some confusion. The reference to LUCA (Last Universal Common Ancestor) appears to be misplaced, as this hypothetical organism is not discussed in that chapter. I would appreciate further clarification on this point. Should you review the manuscript again, I kindly ask that you indicate the specific section or passage where the inconsistency or difficulty is observed, so that I may address it appropriately in the revised version.
R2 Comment:
- Ch. 4.3: What kind of energy input is considered? It can be either P-O bond energy (ATP), electrochemical potential in hydrothermal vent, photon from the Sun, thunder, volcanic heat, non-ATP molecules synthesized as a consequence of these activities, etc.
My Answer:
The interpretation of evolutionary transitions depends both on the temporal context within the history of life and on the specific types of organisms under consideration. A novel conceptual framework has been proposed by Judson (2017), which organizes the evolutionary history of life on Earth into five distinct “energetic epochs.” Each epoch is defined by the emergence of organisms capable of exploiting a new and increasingly potent energy source—namely, geochemical energy, sunlight, oxygen, flesh, and fire. This framework suggests that the capacity to harness novel energy sources played a pivotal role in enabling the rise of more complex biological forms.
In the revised version of the manuscript, this perspective has been incorporated into the section discussing negentropy, to further support the argument that energy flow and utilization are central to the emergence and diversification of life. Additionally, Section 6.1 discusses the possible energy sources involved in the “cooking” of the prebiotic soup, including geothermal heat, solar radiation, and redox gradients.
R2 Comment:
- Ch.6: What kind of prebiotic soup do you consider? The topics to be consideres are the
chirality of molecules, whether L-enriched or racemic and the possible chiral-enrichment
reactions such as Soai asymmetric autocatalysis, and the mechanism of molecular accumulation. Life is an aqueous assembly of molecules, and the cellular components are, except for (phospho)lipids, water-soluble, and easily dissipates in an aqueous environment. These topics may have been included in the word "PDF", and if so, it is advised to explain the possible PDF.
My Answer:
The reviewer’s observation is valid, as the original manuscript did not explicitly address the role of chirality, despite its fundamental importance in understanding the OoL. While chirality could be implicitly considered within the scope of PDFs, it is essential to make its relevance explicit. Therefore, a new paragraph has been added to Section 6.1.1 in the revised version to highlight the significance of molecular chirality in prebiotic chemistry and early biomolecular evolution.
R2 Comment:
- Fig. 1: Isn't there any PDF between prebiotic soup and each world, and between each
world and organized living matter?
My Answer:
I want to make clear that PDFs are always present, as molecules never lose their atomic essence. The evolutionary forces or emergent properties associated with the life process are added to this physicochemical driving forces, but they do not replace it. Instead, they build upon the persistent molecular dynamics that define the prebiotic chemical landscape.
R2 Comment:
- 6.1.2.1: Ordinary cells in current nature are composed of phospho- or glycolipids. L546
states the existence of fatty acids, which may self-assemble into micelles or vesicles (Geisberger et al. Sci. Rep. 2023, 15227). This may contradict with your hypothesis that the cellular components are similar in PoB cells and current cells. How do you think the
membrane in prebiotic world made of?
My Answer:
I appreciate the reviewer’s suggestion and have incorporated the recommended reference into the revised version of the manuscript. After reviewing the cited article, I found that it does not contradict the statements made in Section 6.1.2.1. On the contrary, it provides complementary and insightful information that enriches the discussion. The reference has been integrated accordingly to strengthen the scientific foundation of the section. The new added text is: “More recently, compartmentalization in aqueous solutions containing mixtures of fatty acids—up to 19 carbon atoms—has been demonstrated under reaction conditions compatible with Hadean Early Earth environments. The resulting vesicle-like structures were capable of encapsulating fluorescent dyes. This self-assembly process likely represents a crucial step in the formation of primitive membranes and protocells, essential for the emergence of metabolism and life.”
Although the precise nature of the membranes that formed in the prebiotic world remains unknown, current biochemical and biophysical evidence supports the reasonable assumption that they were composed of lipid bilayers. These primitive membranes likely consisted of fatty acids and amphiphilic molecules structurally similar or identical to modern phospholipids and glycolipids. Such assemblies would have provided the necessary compartmentalization and dynamic interfaces essential for early biochemical processes and the emergence of life.
R2 Comment:
- L650: Hydrothermal system is of interest not only because of the metal ion abundance but also because of the electrochemical activity that potentially drives electrochemical reactions (Nakamura et al. Angew. Chem. Int. Ed. 2010, 7692, Kitadai et al. Sci. Adv. 2019, eaav7848).
My Answer:
I concur with the reviewer’s observation and, accordingly, have incorporated new content into the revised version of the manuscript, including citations to the two works recommended by the reviewer. The newly added text reads as follows: “One of the most plausible scenarios for OoL posits the existence of a prebiotic autotrophic metabolism in sulfide-rich hydrothermal vent environments. Empirical evidence indicates that hydrothermal vent chimneys are capable of generating electron flow, and that such electron transport may have played a role in the prebiotic synthesis of organic compounds within ancient deep-sea hydrothermal systems [Nakamura]. In this context, it has been proposed that extensive metal production and metal-supported primordial metabolic processes likely emerged as a natural consequence of the intense hydrothermal activity on the Hadean Earth [Kitadai].” (section 6.1.3)
R2 Comment:
- Figure 2: Where are LUCA and LECA? It seems that they are the same as PoB cells.
My Answer:
It is true that what I refer to as PoB cells may bear significant resemblance to the hypothetical organism known as LUCA. However, there are crucial differences when comparing the evolutionary trajectories of LUCA and PoB cells, as discussed in Section 8.2, 'The Roots of Biodiversity.' In fact, PoB cells are more appropriately conceptualized as a heterogeneous population, rather than a single organism, which gave rise to both prokaryotic and eukaryotic lineages. Their inclusion in the figure reflects my proposal to account for the origin of biodiversity.
Minor Comments:
R2 Comments:
L97 Her, ... : Is it a typo of Here,?
L341 and 1213: The definition of PDF is different each other.
L798: Wings are for "directional" flight, otherwise dandelion fluff can be an alternative.
My Answer:
L97: Yes, is “Here”
L341 and L1213: you’re right! In the new version the wording of PDF is physicochemical driving forces
L798: I am not entirely convinced of the validity of that comparison, as dandelion fluffs do not “fly” by intention, but rather are passively dispersed by the wind.
R2 Comment:
Figure 3: Figure caption is not a caption any more. Some of the contents would be better displayed in the main text.
My Answer:
I agree that the caption for Figure 3 is indeed lengthy. However, the information it contains is also present in the main text, albeit in a more distributed form. Given the complexity and originality of the figure, I believe a detailed caption is necessary to facilitate comprehension without requiring repeated reference to the main text.
R2 Comments:
- L1006: An recent example that shows the primitive inter-cellular interaction in archaea (Imachi et al. Nature 2020, 519)
- L1037: What is TACK?
- Abbreviation: LECA and GMO is missing, though only used once each in L904 and L1129. LECA appears in the title of the reference 119 so it may be worth noting, while GMO may not need to be abbreviated.
- Reference: It seems that the reference style is not comprehensive; some lacks issue number and DOI.
My Answer:
- L1006: I would like to thank the reviewer for mentioning Imachi's article, which I find very interesting and have incorporated into the new version of the manuscript as follows: “The evolutionary transition from archaea to eukaryotes remains poorly understood, primarily due to the absence of cultured representatives and the limited physiological data available. Notably, a study published a few years ago may point to the existence of PoEL cells. In that work, the authors reported the decade-long isolation of an Asgard archaeon affiliated with Lokiarchaeota from deep marine sediments [Imachi]. This microorganism exhibits a distinctive metabolism and morphology, which led the authors to propose the entangle–engulf–endogenize model as a framework for explaining the emergence of eukaryotes.”
- L1037: The term TACK archaea refers to a major clade within the domain Archaea, encompassing several phyla: Thaumarchaeota, Aigarchaeota, Crenarchaeota, and Korarchaeota. The acronym "TACK" comes from the initials of these groups. In the new version is clarified the meaning of TACK.
- The meanings of the abbreviations LECA and GMO are explicitly defined within the main text (lines 904 and 1129, respectively). Given that each term is used only once, I opted not to include them in the list of abbreviations.
- References: I will review all of them to ensure their accuracy.
Reviewer 3 Report
Comments and Suggestions for AuthorsThis paper is a strange mixture of several different themes. Much of it is more of a review of origin of life research, than a research paper in its own right: there are large parts of this paper that summarise previous research, and make no new scientific points. Any review is ‘new’ in the sense that it must select and order its material, and a review of OoL must do this more than most because of the breadth and uncertainty in the field, so to some extent, a review of OoL is a valid topic for a research paper. However, the selection of material used here is not clearly justified, and there is no attempt at a balanced coverage (indeed, arguably that is the point of including it – it selects views on the origin of life, intending to construct a coherent but very specific narrative).
Secondly, the subject matter is mainly on origin of life, which I take as meaning how a living organism first emerged. There is however considerable discussion of how living organisms then diverged into the three main branches of life; there is also quite a lot of discussion about the role of humans in shaping the living world, the future of life, and whether life exists elsewhere. These topics are of course related, but it makes the whole thing extremely broad. The discussion moves between these different areas, making it rather unstructured and difficult to follow.
There is new material here. However, much of it is almost mystical, such as the commandments of life, life determinism, assembled world hypothesis (including the Mysterious Earthly Place), and the principle of inexorability. I see no real scientific justification for these concepts, which are just stated as axioms. These need very much more discussion to be acceptable as scientific hypotheses. There is also considerable discussion of different groups of progenitor cells: PoB, PoPL, PoEL, etc, which again have no specific justification, and are not clearly differentiated from LUCA.
On similar lines: Wächtershäuser (cited here in ref 88) often made the point that his ideas on OoL were affected by Popper’s philosophy. I have never been clear what he meant, but presumably he was commenting that any theories on OoL need to be falsifiable, otherwise they do not count as science. I struggle to find any new ideas in here that could be described as falsifiable, in which case it is hard to make the case that this is a viable scientific contribution.
OoL research has a tendency to ignore details and go for the broad picture, and this paper is no exception. In doing so, one still has to remain scientifically honest. To take one example, which is found in much of OoL research, but is brought out clearly here: the paper proposes an early origin of the Vital Factor, which includes some kind of primitive genetic program. It does not however admit reproduction and evolution until a later stage. A genetic program does not just happen by itself: it needs a lot of development and refinement – what would normally be described as evolution. So the timing of different stages does not work, on detailed examination. This sort of problem occurs frequently: take for example figure 1 (the AWL hypothesis), which I think supposes a Biomolecular World, comprising proteins and RNA, existing alongside a Supramolecular world, containing ribosomes (which of course consist of RNA and protein). So these cannot be separate entities, and the construction is an artificial splitting of different features that cannot actually be divided in this way. There are timing problems with many of the details discussed here, including membranes and ribosomes. The author feels that viruses have a specific role in OoL, which I do not see justified here. I can see the value of painting a broad picture, but it has to remain rooted in reality.
I could pick many other examples of unjustified statements and illogical arguments, but I hope I have made my point. This is not a scientifically coherent paper, however scholastic and detailed it may be. It could possibly be fleshed out as a book, and there are parts that might constitute hypotheses, but it should not be considered for publication in anything even remotely resembling its current form.
Author Response
Manuscript ID: life-3882493
Type of manuscript: Hypothesis
Response to Reviewer 3 (R3):
General Comment:
It is evident that this reviewer does not support the proposal presented in the manuscript and does not appear to regard it as a scientific contribution. The review contains no favourable comments or constructive suggestions for improvement; rather, it consists exclusively of disparaging remarks and subjective value judgments.
While I fully respect the reviewer’s right to hold such an opinion, I must respectfully disagree. I would also like to clarify that this work reflects my own scientific perspective, and its content and structure were determined by me—not by external preferences or artificial intelligence. This manuscript is not intended to be, nor should it be interpreted as, a comprehensive review of the existing literature on the topic. Nevertheless, to present the problem and substantiate the claims made, it is necessary to reference specialized literature—as any scientist, anywhere in the world, would do. If additional references are considered necessary, I would greatly appreciate specific suggestions. The literature on prebiotic chemistry, the origin of life, and the emergence of biodiversity is extensive, and it is not my intention to conduct an exhaustive review or cite every publication in the field.
The manuscript presents a conceptual narrative aimed at exploring plausible pathways for the emergence of the first living system and the subsequent development of biodiversity. It is important to clarify that I do not claim to describe the precise origin of the first cell—such knowledge remains beyond our current scientific reach. Rather, my objective is to propose a scientifically informed and original hypothesis regarding how this process might have occurred.
I have introduced several modifications in the revised manuscript:
- A new title that better reflects the conceptual framework of the study.
- A redesigned Figure 1 to illustrate the updated hypotheses.
- A complete rewrite of the text, from the abstract through to the conclusion.
- 27 new references to strengthen the scientific grounding of the discussion.
- New examples that support key aspects of this work.
Having stated these general considerations, I will now proceed to respond point by point to the reviewer’s comments.
Point-by-point Reply
R3 Comment:
This paper is a strange mixture of several different themes. Much of it is more of a review of origin of life research, than a research paper in its own right: there are large parts of this paper that summarise previous research, and make no new scientific points. Any review is ‘new’ in the sense that it must select and order its material, and a review of OoL must do this more than most because of the breadth and uncertainty in the field, so to some extent, a review of OoL is a valid topic for a research paper. However, the selection of material used here is not clearly justified, and there is no attempt at a balanced coverage (indeed, arguably that is the point of including it – it selects views on the origin of life, intending to construct a coherent but very specific narrative).
My Answer:
I do not fully understand the use of the terms “strange” and “mixture” in this context. This manuscript addresses the origin of life and the emergence of biodiversity from my perspective as a scientist—although this may be subject to debate—who has spent many years studying biochemistry and molecular biology, and seeking answers to fundamental biological questions, such as the nature of life and the principles governing living systems, in conjunction with those of physics and chemistry.
While this work can certainly be improved in response to the reviewers’ comments, it is internally consistent—even if that consistency is not recognized or acknowledged. It begins by introducing the problem and proceeds with an approach that is rarely adopted in origin-of-life studies: a reflection on the importance of defining life. Although this may appear trivial to some, I argue that it is not. One can indeed investigate the OoL without a formal definition of life, but doing so limits the depth of inquiry. How can one meaningfully explore the origin of something without first establishing what that “something” is? At what point can we confidently assert that an experimental result represents a living entity rather than a non-living system?
Furthermore, the manuscript introduces what I consider to be key conceptual elements for studying the phenomenon of life, particularly its origin. These include information, negentropy, the system–process duality, and emergence. This reflects my theoretical perspective on how the OoL should be approached. While this view may be subject to disagreement, disagreement alone does not invalidate the approach. I am confident that, over time, theoretical frameworks and experimental findings will converge—either to support or refute the proposal presented here.
Following these reflections, I outline my hypothesis regarding the origin of life. As is customary in scientific inquiry, I apply my own ideas—whether ultimately correct or incorrect—and critically examine the existing literature to support or challenge the concepts I propose. In this way, I develop a hypothesis that shares certain elements with existing models, while also introducing novel aspects that may be experimentally testable once we are able to recreate the conditions of the prebiotic environment and its chemical context. I also present a hypothesis regarding the origin of biodiversity from primitive cells, which differs from the commonly accepted view that eukaryotes emerged from archaea.
I acknowledge the possibility that my proposal may be incorrect—but it may also be correct. If necessary, I would remind the reviewer of the many renowned scientists (I do not consider myself one) whose groundbreaking ideas were initially rejected by the authorities of their time. For example, Peter Mitchell’s chemiosmotic theory, though now widely accepted, initially faced significant skepticism and criticism. When Mitchell proposed the theory in 1961, there was no direct evidence for proton gradients across membranes or for ATP synthase functioning as a rotary motor. The concept of a proton motive force was considered speculative, particularly as most biochemists favored chemical intermediate models for ATP synthesis. Nevertheless, Mitchell’s theory eventually gained widespread acceptance and earned him the Nobel Prize in Chemistry in 1978.
R3 Comment:
Secondly, the subject matter is mainly on origin of life, which I take as meaning how a living organism first emerged. There is however considerable discussion of how living organisms then diverged into the three main branches of life; there is also quite a lot of discussion about the role of humans in shaping the living world, the future of life, and whether life exists elsewhere. These topics are of course related, but it makes the whole thing extremely broad. The discussion moves between these different areas, making it rather unstructured and difficult to follow.
My Answer:
Some aspects of this comment have already been addressed in the previous paragraph. However, I would like to emphasize the human dimension, which I believe is fundamental to research concerning the past, present, and future of life. Are we not human researchers striving to generate the first living cell from inanimate matter in the laboratory? And if we succeed, would that not constitute a recreation of the origin of life—whether on Earth, on Mars, or elsewhere?
When we speak of synthetic biology, we enter a frontier whose boundaries remain undefined. In this context, is it not essential to understand what life is, or what constitutes a living system, in order to guide our search for life beyond Earth? These questions are not merely philosophical—they are central to the scientific endeavour of defining, detecting, and ultimately synthesizing life.
In any case, this is my work, and I have chosen to include these reflections as part of the broader conceptual framework. They represent my perspective on how the origin of life should be approached, and I believe they are relevant to the ongoing dialogue within the scientific community.
R3 Comment:
There is new material here. However, much of it is almost mystical, such as the commandments of life, life determinism, assembled world hypothesis (including the Mysterious Earthly Place), and the principle of inexorability. I see no real scientific justification for these concepts, which are just stated as axioms. These need very much more discussion to be acceptable as scientific hypotheses. There is also considerable discussion of different groups of progenitor cells: PoB, PoPL, PoEL, etc, which again have no specific justification, and are not clearly differentiated from LUCA.
My Answer:
This reviewer describes much of the material presented in this work as 'mystical.' I find this characterization both surprising and bold. Allow me to clarify the non-mystical nature of the ideas I present in this work.
The commandments of life. Perhaps by using the term 'commandments,' the reviewer assumes I am referring to Moses and the Tablets of Jewish Law. If so, this interpretation is entirely mistaken. In 2020, I published an article in which I introduced this term as a synonym for the principles that, in my view, govern life (see reference 6). If you read that work, you will see that it contains no references to esotericism, magic, or religion—quite the opposite, in fact. The seven commandments of life are: the Vital Order, the Principle of Inexorability, the reformulated Central Dogma, the Tyranny of Time, the Evolutionary Imperative, the Conservative Rule, and the Cooperating Thrust.
Life determinism and the principle of inexorability (one of the commandments of life) refers to the idea that the emergence, structure, and behaviour of living systems are governed by deterministic principles—meaning that, given certain initial conditions and laws (physical, chemical, informational), life will inevitably arise and evolve in predictable ways. This concept can be broken down into several key ideas:
- Deterministic Origin of Life: This hypothesis posits that life is a natural and inevitable consequence of the laws of physics and chemistry operating under suitable environmental conditions, rather than the result of random chance or miraculous intervention. Nobel Laureate Christian de Duve expressed this deterministic view succinctly, stating: “Life is a cosmic imperative.” According to this perspective, given the right conditions, the emergence of life is not merely possible—it is expected.
- Predictable Evolutionary Pathways: This concept suggests that biological complexity—including biodiversity and cellular organization—emerges through deterministic patterns shaped by environmental constraints, energy flows, and molecular interactions. It implies that, under similar conditions, evolution may follow comparable trajectories. However, this does not mean that evolution has a predetermined goal or direction. Evolution is inherently blind, driven by natural selection and contingent events, without any intrinsic objective or foresight.
- Information and Negentropy as Drivers: Life determinism often incorporates the role ofinformation processing and negentropy as central to the emergence and maintenance of living systems.
- The Assembled Worlds Hypothesis is a conceptual label used to describe the proposal that the first living entity emerged through cooperative interactions among distinct molecular worlds within the prebiotic soup. These worlds may have originated independently but converged functionally to give rise to life.
- “The Mysterious Earthy Place” is simply a metaphorical designation for the location where life first emerged. This name is justified by three considerations: the origin of life remains a mystery; it occurred on Earth; and the precise site of its emergence is unknown. The use of such terminology is intended to evoke the enigmatic nature of this foundational event, without implying any specific geographic or geological constraints.
- Axioms. It is important to emphasize that my proposal regarding the origin of life is not presented as axiomatic. Rather, it constitutes a conceptual framework that invites discussion, critique, and empirical exploration. As with any scientific hypothesis, agreement or disagreement is part of the natural process of scientific discourse.
- LUCA. Firstly, it must be acknowledged that the concept of LUCA (Last Universal Common Ancestor) is a scientific hypothesis—not an indisputable fact. As such, it remains open to reinterpretation, critique, and alternative proposals. The OoL and the emergence of biodiversity are complex phenomena, and the scientific community benefits from diverse theoretical approaches. Secondly, my proposal offers a distinct perspective on these processes, and I assert the freedom to define and name the conceptual entities—such as ancestral cell types—in a manner that best reflects the framework I am developing. This practice is consistent with scientific tradition, where new models often introduce novel terminology to capture unique aspects of the theory.
R3 Comment:
On similar lines: Wächtershäuser (cited here in ref 88) often made the point that his ideas on OoL were affected by Popper’s philosophy. I have never been clear what he meant, but presumably he was commenting that any theories on OoL need to be falsifiable, otherwise they do not count as science. I struggle to find any new ideas in here that could be described as falsifiable, in which case it is hard to make the case that this is a viable scientific contribution.
My Answer:
According to Karl Popper’s philosophy of science, a theory must be falsifiable—that is, capable of being tested and potentially refuted—in order to qualify as a scientific hypothesis. This criterion has long served as a foundational standard for distinguishing scientific inquiry from metaphysical speculation. It is true that many contemporary models addressing the origin of life lack clearly defined, falsifiable predictions, which complicates their classification as strictly scientific contributions.
However, in my view, this limitation does not diminish their intellectual or heuristic value. Even if a theory cannot be directly validated through experimentation, it may still offer conceptual insights, generate new lines of inquiry, and contribute meaningfully to the broader theoretical landscape. Such ideas, when integrated with other frameworks and empirical findings, can incrementally guide us toward a deeper understanding of life’s origins—even if we can never be certain we have reached the ultimate explanation.
How many theories in physics have remained valid and contributed to scientific progress despite not having been experimentally validated? Theoretical constructs such as string theory, multiverse models, or aspects of quantum gravity continue to shape scientific discourse, despite the current lack of direct empirical support. In this light, origin-of-life hypotheses should be evaluated not only by their immediate testability, but also by their capacity to inspire, organize, and advance scientific thought.
R3 Comments:
OoL research has a tendency to ignore details and go for the broad picture, and this paper is no exception. In doing so, one still has to remain scientifically honest. To take one. example, which is found in much of OoL research, but is brought out clearly here: the paper proposes an early origin of the Vital Factor, which includes some kind of primitive genetic program. It does not however admit reproduction and evolution until a later stage. A genetic program does not just happen by itself: it needs a lot of development and refinement – what would normally be described as evolution. So the timing of different stages does not work, on detailed examination. This sort of problem occurs frequently: take for example figure 1 (the AWL hypothesis), which I think supposes a Biomolecular World, comprising proteins and RNA, existing alongside a Supramolecular world, containing ribosomes (which of course consist of RNA and protein). So these cannot be separate entities, and the construction is an artificial splitting of different features that cannot actually be divided in this way. There are timing problems with many of the details discussed here, including membranes and ribosomes. The author feels that viruses have a 1specific role in OoL, which I do not see justified here. I can see the value of painting a broad picture, but it has to remain rooted in reality.
My Answer:
The reviewer’s initial observation is valid, and the underlying rationale is relatively straightforward: we are dealing with a domain of profound uncertainty, primarily because the events that transpired approximately four billion years ago remain unknown. In contemporary biology, we are able to investigate the mechanisms operating within living organisms with exceptional precision, given our understanding of their existence, functional outcomes, and perturbations. However, this level of clarity does not extend to studies concerning the origin of life.
This statement is not intended as a defense of the limitations in my work, but rather as a reflection of the epistemic constraints inherent to the field. I have not delved deeper into specific mechanisms simply because the precise processes remain elusive—not only to myself but to the broader scientific community, including the reviewer. Consequently, I offer a general conceptual framework (as indicated by the title of the manuscript) outlining a plausible scenario for how life might have emerged.
Regarding the concept of the Vital Factor, either my initial explanation was insufficiently clear or the reviewer may have misunderstood its intended meaning. I will clarify it here. The term "Vital Factor" refers to the integration of four essential components that collectively determine whether an organic entity is alive or not. These components were previously outlined in the article. Naturally, this framework represents my own theoretical proposal, which readers may choose to accept or reject. Nonetheless, I think that the concept of vital factor and its implications are clearly articulated within the text. In any case, in the revised version of the manuscript, I have rewritten this section—along with many others—to enhance clarity for the prospective reader.
Reproduction and evolution commenced once the first living system acquired what I refer to as the Vital Factor—that is, when all the requisite structures and processes for life were sufficiently stabilized and organized. This includes the establishment of a cellular architecture, the metabolic pathways necessary for growth and energy production, and the emergence of a primitive genetic system—still in development, yet capable of functional expression. Only when this system reached a sustainable state did it become meaningful to discuss reproduction and evolutionary dynamics.
The concept of "molecular worlds" serves to illustrate the early dynamics of the prebiotic environment. At the initial stages of chemical evolution—what might be termed the 'cooking' of the prebiotic soup—molecules primarily interacted within their own types (e.g., amino acids with amino acids, or RNA molecules with other RNA strands). As the system evolved, cross-interactions began to emerge between distinct molecular domains, such as proteins and RNA, leading to the formation of primitive ribonucleoprotein complexes, including proto-ribosomes. This progressive increase in molecular complexity eventually reached a critical threshold, culminating in the emergence of the first protocell.
The case of viruses. The reviewer states: “The author feels that viruses have a specific role in the origin of life (OoL), which I do not see justified here.” What do I explicitly say regarding the involvement of viruses in the OoL? On page 13 of the original manuscript, the following statement appears: “Although the involvement of viruses in the origin of life remains speculative, their evolutionary impact is unequivocal.”
A few lines later, I add: “It is conceivable that viruses—or virus-like particles—emerged in the prebiotic soup through interactions between RNA and proteins, forming primitive supramolecular assemblies with infectious potential. Such protoviral entities could have persisted until the emergence of the first cells or even contributed to the processes underlying the origin of life.”Is this speculation truly so implausible? Ribosomes are nucleoprotein complexes, as are viruses, and yet the possibility of a prebiotic origin for the simplest ribosomes is rarely questioned. In the context of the origin of life, all hypotheses are inherently speculative—everything is speculation. On page 23 old version (lines 1038–1044), I further state: “Another hypothesis posits that the nucleus originated from the fusion of two ancient archaeon-like cells [127], while a different model suggests that the nucleus descends from a DNA virus that infected the archaeal ancestor of eukaryotes [128, 129]. Notably, a study demonstrated the formation of a nucleus-like compartment during viral infection of a bacterium, wherein proteins involved in DNA replication and transcription were localized inside the compartment, while those involved in translation and nucleotide synthesis remained outside [130].” I cite 3 references to support this hypothesis, which I do not personally endorse, but present as one among several equally plausible models for explaining the origin of the nucleus.
Before concluding this discussion on the potential role of viruses in the origin of life, I would like to highlight three additional works (two of them will be cited in the revised version of the manuscript). First, Pan (2021) presents a compelling argument for the central role of viruses in the co-evolution of life on Earth, emphasizing their unparalleled evolutionary adaptability and influence on host-pathogen dynamics. Second, a feature article in National Geographic explores the provocative hypothesis that giant viruses—such as pithovirus and pandoravirus—may not be evolutionary latecomers but rather ancient entities that contributed foundational components to early cellular life. Finally, the work of Koonin and colleagues introduces the concept of an "ancient virus world," proposing that virus-like genetic elements predated cellular life and played a formative role in the emergence of modern biological systems. These perspectives, while speculative, are grounded in comparative genomics and evolutionary theory, and they underscore the plausibility of considering viruses as active participants in the earliest stages of life’s evolution. While I understand that the reviewer may not share this perspective, I respectfully submit that the inclusion of these ideas is scientifically valid within the context of a discussion on the origin of life, where multiple competing hypotheses coexist. I hope this clarification helps to contextualize the intent and scope of the arguments presented.
-Pan, D. (2021). Virus Origins and the Origin of Life. In: Neubeck, A., McMahon, S. (eds) Prebiotic Chemistry and the Origin of Life. Advances in Astrobiology and Biogeophysics. Springer, Cham. https://doi.org/10.1007/978-3-030-81039-9_8
-Koonin, E.V., Senkevich, T.G. & Dolja, V.V. The ancient Virus World and evolution of cells. Biol Direct 1, 29 (2006). https://doi.org/10.1186/1745-6150-1-29
R3 Comments:
I could pick many other examples of unjustified statements and illogical arguments, but I hope I have made my point. This is not a scientifically coherent paper, however scholastic and detailed it may be. It could possibly be fleshed out as a book, and there are parts that might constitute hypotheses, but it should not be considered for publication in anythingeven remotely resembling its current form.
My Answer:
I appreciate the time and effort the reviewer has dedicated to evaluating my manuscript. However, I must express concern regarding the tone and nature of the feedback provided. While I fully acknowledge the importance of critical review in the scientific process, I found the comments to be uniformly negative and lacking in constructive suggestions that could help improve the manuscript.
It is, of course, entirely valid to disagree with the hypotheses or interpretations presented. Nonetheless, I maintain that the ideas explored in this work—though speculative, as is often the case in origin-of-life research—are grounded in current scientific discourse and supported by relevant literature. I am confident that other readers and experts in the field will recognize the value of the perspectives offered, even if they do not agree with all of them.
I respectfully suggest that more balanced feedback, including acknowledgment of any strengths or novel contributions, would be more conducive to scholarly dialogue and to the advancement of scientific understanding.
Reviewer 4 Report
Comments and Suggestions for AuthorsDear Editor,
This study proposes that life originated as a spontaneous and self-organising phenomenon arising from the structural and functional organisation of the first living system, which enabled the emergence of biological diversity. These findings are significant for understanding the origins of life, the evolution of life on Earth, and future directions in synthetic biology and the search for extraterrestrial life.
Although the work provides a solid foundation, further elaboration and explanation are required to address outstanding questions. The following aspects require further elaboration in this study, which we will outline below in sequential order.
Line 49-60 Could the author please clarify the criteria for rejecting theistic intervention, as well as the implications of the panspermia hypothesis for our understanding of the origin of life? Could they also provide more details or references on the physicochemical mechanisms that led to the emergence of the first living system, and explain what is meant by the 'commandments of life'?
Line 78-92 Could the author provide a detailed explanation of how the "assembled worlds hypothesis" improves our understanding of the origin of life compared to existing hypotheses, with a particular focus on how the stable flow of genetic information from DNA/RNA to proteins was first established in the earliest cells? Also, could the author provide more information on the evidence supporting this hypothesis and explain the connection between the emergence of the first living system and the subsequent development of biodiversity, including the evolutionary forces involved? Could the author also provide a precise explanation of what makes the “assembled worlds hypothesis” novel, specifying how it differs from existing theories on the origin of life and what new insights it provides into early cellular systems and the emergence of biodiversity?
Line 1176-1196 The conclusions presented appear to extend far beyond the scope of the study, failing to clearly reflect the specific findings or hypotheses addressed in the work. Could the author please clarify how the discussion of extraterrestrial life, synthetic organisms, non-carbon life forms, and anthropogenic impacts relates directly to the results of this study? Could the author also specify which insights or evidence from their work substantiate these broad statements and distinguish between speculative considerations and conclusions firmly grounded in the presented research?
Line 148-172 Could the author clarify which specific definition of life is used in this study and how the outlined hallmarks of biological organization are applied to reconstruct a living system from prebiotic conditions?
Line 204-220 While the text outlines the key molecular constituents that contribute to life, it does not address other potentially essential components or interactions. For example, it does not mention signalling molecules, epigenetic regulators or environmental factors that influence cellular organisation. Could the author clarify which additional components or processes are considered necessary for life to emerge in the context of the assembled worlds hypothesis? Could the author also explain how the temporal and spatial organisation of these components is determined, and how this is justified either experimentally or theoretically?
Line 358-371 Could the author clarify how the "Biomolecular", "Metabolic", and "Supramolecular" worlds are defined and differentiated, provide evidence supporting claims such as primitive viruses or enzyme-free pathways, and explain how these independent worlds transitioned into an integrated living system?
Line 536-560 The text does not clearly explain the mechanistic transition from membrane-free compartments, such as coacervates or micelles, to fully enclosed vesicles, leaving the timing and integration of membranes in prebiotic evolution ambiguous. Additionally, the proposed transmission of compositional information in amphiphilic vesicles and its role in primitive selection lacks sufficient experimental or theoretical support.
Line 601-612 The author should specify which models or hypotheses are referenced for viral origins, provide supporting citations, and clarify the evidence for the proposed prebiotic emergence of virus-like particles.
Line 682-686 The statement that RNA, DNA, ribosomes, and metabolic pathways co-evolved within a membranous structure is presented without supporting citations or evidence. Could the author clarify whether this assertion is based on original data, modelling, or literature, and provide references to substantiate the proposed cooperative and organized transition from chemical to biological evolution in the MEP?
Line 707-733 Could the author clarify whether the four attributes of life are fully and clearly explained in the figure caption, and provide more detail on how each attribute - system-process duality, emergence of the vital process, internal negative entropy, and mutable genetic program - is specifically illustrated and supported by the figure? Additionally, are there other essential attributes that should be considered to more comprehensively represent the "vital factor"?
The sentences in lines 782–789 and lines 1109-1114 are unclear with regard to the author’s intent. Could the author clarify whether this content is intended to be represented visually, for example, as a figure or diagram, or whether it should remain a textual explanation? Additionally, guidance on how best to convey the described relationships or processes would help ensure that the reader correctly interprets the concepts.
Line 822-827 Could the author clarify whether the random events described -mutations, genetic drift and gene flow - are intended to illustrate general stochastic mechanisms in evolution, or whether they are presented too narrowly in relation to human populations (beyond human control)? Could they also provide appropriate references for all examples?
In summary, the work is promising, but could be improved with careful revision and a clearer resolution of key issues.
Author Response
Manuscript ID: life-3882493
Type of manuscript: Hypothesis
Response to Reviewer 4 (R4):
General Comment: I sincerely thank you for your insightful comments and constructive criticism. They have been instrumental in guiding a comprehensive revision of the manuscript, prompting me to reassess several core ideas and ultimately produce a substantially new version of the work.
The principal modifications introduced in the revised manuscript include:
- A new title that better reflects the conceptual framework of the study.
- A redesigned Figure 1 to illustrate the updated hypotheses.
- A complete rewrite of the text, from the abstract through to the conclusion.
- The addition of 27 new references to strengthen the scientific grounding of the discussion.
- Inclusion of new examples that support key aspects of the prebiotic soup hypothesis, particularly those concerning self-organization and the interactions among the proposed molecular worlds.
I wish to emphasize that this manuscript represents my original work, and I retain the right to articulate my ideas in the manner I consider most appropriate. The manuscript presents a conceptual narrative aimed at exploring plausible pathways for the emergence of the first living system and the subsequent development of biodiversity. It is important to clarify that I do not claim to describe the precise origin of the first cell—such knowledge remains beyond our current scientific reach. Rather, my objective is to propose a scientifically informed and original hypothesis regarding how this process might have occurred.
If additional references are considered necessary, I would greatly appreciate specific suggestions. The literature on prebiotic chemistry, the origin of life, and the emergence of biodiversity is extensive, and it is not my intention to conduct an exhaustive review or cite every publication in the field.
With these considerations in mind, I now proceed to address the specific critical comments raised in the review.
R4 Comment:
Line 49-60 Could the author please clarify the criteria for rejecting theistic intervention, as well as the implications of the panspermia hypothesis for our understanding of the origin of life? Could they also provide more details or references on the physicochemical mechanisms that led to the emergence of the first living system, and explain what is meant by the 'commandments of life'?
My Answer:
While the question of whether a divine entity governs the universe lies within the realm of personal belief, the scientific investigation of the origin of life must remain grounded in naturalistic explanations. Faith, by definition, involves belief in that which cannot be empirically observed or tested. Science, in contrast, seeks to understand the natural world through observation, experimentation, and the formulation of testable hypotheses. From this perspective, I maintain that the origin of life was a natural process—one governed by the laws of physics and chemistry, the biological rules and influenced by stochastic events. This view does not preclude metaphysical interpretations, but it emphasizes that scientific inquiry must operate independently of theological frameworks. The goal is not to deny belief, but to ensure that scientific models remain within the bounds of methodological naturalism, which has proven to be a powerful tool for understanding the natural world.
While the panspermia hypothesis offers an intriguing possibility—that life, or its precursors, may have originated elsewhere in the cosmos and been transported to Earth—it ultimately does not resolve the fundamental question of how life began. Even if life were seeded from space, we would still be left without an explanation for the origin of that life, nor would we know where or under what conditions the initial biogenesis occurred. In this sense, panspermia shifts the problem rather than solves it. Therefore, while it remains a topic of legitimate scientific interest, it does not obviate the need to investigate natural, Earth-based scenarios for the origin of life.
In this manuscript, the term “physicochemical driving forces” refers broadly to the ensemble of natural forces and conditions that may have contributed to the formation of complex organic molecules in the prebiotic environment. These include: Energy sources such as geothermal heat, solar radiation, and redox gradients; Chemical gradients that could drive molecular transport and concentration; Temperature fluctuations, which may have facilitated reaction kinetics and phase transitions; Intrinsic chemical reactivity between functional groups of organic molecules; Self-organization processes, including molecular crowding, phase separation, and the spontaneous formation of supramolecular structures. These factors, acting in concert under non-equilibrium conditions, likely played a central role in the emergence of the first living systems. Rather than invoking a single deterministic pathway, this view supports a systems-level approach in which life arose from the dynamic interplay of diverse physicochemical processes.
In this work, the expression “commandments of life” refers to a conceptual framework I introduced in a previous publication (Reference 6, 2020), which outlines the fundamental principles that, in my view, govern the life process. Just as inert matter is subject to the universal laws of physics and chemistry, living systems are governed not only by these same physical laws but also by additional principles that are specific to biology. These biological "commandments" encompass the organizational, functional, and evolutionary rules that distinguish living matter from non-living systems—such as the capacity for self-maintenance, replication, adaptation, and evolution. They serve as a heuristic guide for understanding how life operates and how it may have emerged from prebiotic conditions.
R4 Comments:
Line 78-92 Could the author provide a detailed explanation of how the "assembled worlds hypothesis" improves our understanding of the origin of life compared to existing hypotheses, with a particular focus on how the stable flow of genetic information from DNA/RNA to proteins was first established in the earliest cells? Also, could the author provide more information on the evidence supporting this hypothesis and explain the connection between the emergence of the first living system and the subsequent development of biodiversity, including the evolutionary forces involved? Could the autor also provide a precise explanation of what makes the “assembled worlds hypothesis” novel, specifying how it differs from existing theories on the origin of life and what new insights it provides into early cellular systems and the emergence of biodiversity?
My Answer:
The originality of this hypothesis lies in the proposition that multiple initially independent molecular domains coexisted within the prebiotic soup. Over time, these domains began to interact as a result of intrinsic molecular evolution, increased molecular concentration, and enhanced spatial proximity among the constituents of the prebiotic environment. In essence, three major stages preceded the emergence of the first living system. First, organic matter was synthesized from small inorganic molecules. This organic matter underwent spontaneous transformations, giving rise to simple biomolecules such as monosaccharides, the earliest amino acids, and short-chain fatty acids. These molecules progressively evolved into more complex structures, culminating in what I refer to as disorganized living matter. This disorganized living matter continued to increase in complexity, eventually leading to the emergence of what I term molecular worlds. At this stage, the fundamental molecular components of cellular life were already present. However, a critical feature of living systems was still absent: order, defined as the internal organization and coordination of all molecular components. The establishment of such order necessitated the formation of a membrane capable of encapsulating these molecular worlds, thereby enabling their interaction—initially at the molecular level and subsequently at the cellular level. Through spontaneous self-organization of the entire system, life ultimately emerged.
When presenting the assembled worlds hypothesis, I support the proposal with selected experimental findings referenced in the bibliography. The origin of the central dogma of molecular biology (DNA → RNA → proteins) remains unknown—not only to myself, but to the scientific community at large. Several theoretical models have been proposed, and I restrict my discussion to these within the framework of the hypothesis.
The paper outlines a proposed developmental pathway for the population of precursor cells that underlies biodiversity. It further describes how this cellular population—likely characterized by instability and functional imperfections—had to acquire the capacity for division, thereby enabling the emergence of new populations of heterogeneous cells. From these evolving populations, the cellular lineages that would eventually give rise to prokaryotic and eukaryotic organisms emerged.
R4 Comments:
Line 1176-1196 The conclusions presented appear to extend far beyond the scope of the
study, failing to clearly reflect the specific findings or hypotheses addressed in the work. Could the author please clarify how the discussion of extraterrestrial life, synthetic organisms, non-carbon life forms, and anthropogenic impacts relates directly to the results of this study? Could the author also specify which insights or evidence from their work substantiate these broad statements and distinguish between speculative considerations and conclusions firmly grounded in the presented research?
My Answer:
The reviewer’s comment is entirely valid, and for this reason, the revised conclusion differs significantly from that of the original version. Furthermore, although the manuscript may initially appear to incorporate unrelated elements, it is in fact structured around a unifying theme: life. From its origin to the emergence of biodiversity over millions of years, the narrative maintains a coherent trajectory. Within this framework, the anthropogenic factor becomes increasingly relevant, as the future of biodiversity is no longer governed solely by natural processes, but is now largely influenced by human activity. Importantly, it is also through human intervention and technological advancement that we may gain deeper insights into the origin of life on Earth more than four billion years ago—and into the possibility that similar processes may have occurred elsewhere in the universe.
Although this work also draws upon experimental evidence from the specialized literature, it remains fundamentally speculative—like many others addressing this topic—because I cannot assert that events occurred precisely as described. If such certainty were possible, the nature of this study would be entirely different. It is important to recognize that many foundational laws, principles, and mechanisms in physics and biology were speculative in their early stages. Yet, this did not diminish their scientific relevance or their potential to be transformative.
R4 Comments:
Line 148-172 Could the author clarify which specific definition of life is used in this study and how the outlined hallmarks of biological organization are applied to reconstruct a living system from prebiotic conditions?
My Answer:
The key question is: how can we investigate the origin of life without first establishing what life is? If we argue that a definition of life is unnecessary for studying its origin, then we must ask—what origin are we attempting to uncover? This straightforward line of reasoning underscores the importance of having a conceptual framework for life in order to meaningfully explore its beginnings. While the absence of a universally accepted definition does not preclude laboratory experimentation, it does highlight the philosophical and theoretical challenges inherent in origin-of-life research.
Among the many existing definitions of life, I have chosen to adopt two (Refs. 27, 28) presented in the first version of this manuscript as reference points. Of these, the second and more recent represents an evolution of the first, and serves as the basis for describing the characteristics of the earliest living system. However, I must note that I have recently submitted a new article to another journal, in which I attempt—perhaps for the third and final time—to formulate what I consider to be the most accurate definition of life. Some conceptual elements from that work have already been incorporated into the present manuscript. As the new article is still under review, I am unable to cite it at this time.
Regardless of what may ultimately constitute the most accurate definition of life, I wish to emphasize—and maintain as fundamental—the importance of having a clear conceptual understanding of life in any research aimed at investigating its origin. While experimental approaches can proceed without a universally accepted definition, such clarity is essential for framing meaningful questions and interpreting results within a coherent theoretical context.
R4 Comment:
Line 204-220 While the text outlines the key molecular constituents that contribute to life, it does not address other potentially essential components or interactions. For example, it does not mention signalling molecules, epigenetic regulators or environmental factors that influence cellular organisation. Could the author clarify which additional components or processes are considered necessary for life to emerge in the context of the assembled worlds hypothesis? Could the author also explain how the temporal and spatial organisation of these components is determined, and how this is justified either experimentally or theoretically?
My Answer:
The reviewer notes that the manuscript does not address signalling molecules, epigenetic regulators, or environmental factors influencing cellular organization. It is true that I do not discuss signalling molecules or epigenetic regulators, primarily because the manuscript is already extensive and adding further detail would compromise its focus. That said, I do not consider these factors to have played a significant role in the origin of life. Cellular signalling mechanisms became increasingly relevant as biological complexity grew, particularly with the emergence of multicellular organisms. As for the point at which epigenetic processes began contributing to the development of biodiversity, I must acknowledge that this remains uncertain, at least to me. Environmental factors, however, are discussed in the context of both the origin of life and the subsequent development of biodiversity. Their influence is considered essential in shaping early biochemical systems and driving evolutionary processes.
I believe I have addressed all the factors that, in my view, have played a significant role both in the origin of life and in the emergence and evolution of biodiversity. While the scope of this work necessarily limits the inclusion of every possible variable, the elements discussed reflect those I consider most relevant to the central questions explored in the manuscript. In response to the reviewer’s final question, I believe the temporal sequence of the processes—specifically, which events occurred first—is clearly outlined in the manuscript. Regarding the spatial organization of the molecular worlds, my position is that all such systems coexisted within the same prebiotic environment. , It was within this shared context that molecular assemblies began to self-organize and interact cooperatively, ultimately giving rise to the first living system.
R4 Comments:
Line 358-371: Could the author clarify how the "Biomolecular", "Metabolic", and "Supramolecular" worlds are defined and differentiated, provide evidence supporting claims such as primitive viruses or enzyme-free pathways, and explain how these
independent worlds transitioned into an integrated living system?
My Answer:
This question addresses a fundamental aspect of the manuscript. The concept of "molecular worlds" is introduced and elaborated upon, including the composition of each type. In the initial version (lines 279–281), a molecular world is defined as “a set of structurally and functionally related molecular entities that interact through catalytic, autocatalytic, and/or self-assembly processes.” While direct empirical evidence for their existence is lacking, if we accept the hypothesis of a prebiotic soup as the origin of life, it follows that this primordial environment contained a wide variety of biomolecules.
The central idea proposed here is that groups of structurally similar organic molecules initially interacted among themselves, forming distinct molecular worlds. Over time, these molecular worlds began to interact with other types of organic molecules, potentially through processes involving positive feedback. One speculative example of such interaction could be the association between amino acids and RNA molecules, possibly leading to the emergence of the first proteins. However, this remains hypothetical, as do most theories concerning the origin of life.
In the specific case of the metabolic world, there exists indirect evidence supporting its plausibility: namely, the demonstration of metabolic-like pathways occurring in the absence of enzymes, as cited in the manuscript.
The role of viruses in both the origin of life and the evolution of species is well-established in evolutionary biology. Regarding the emergence of the first living systems, the involvement of viruses remains a hypothesis. Nonetheless, it has been experimentally demonstrated that viruses can be assembled in vitro from mixtures of proteins and DNA, even in the absence of cellular machinery. Whether viruses played a role in the genesis of the first cell remains an open question—one that may persist unresolved for many years, or perhaps indefinitely.
R4 Comments:
Line 536-560 The text does not clearly explain the mechanistic transition from membrane-free compartments, such as coacervates or micelles, to fully enclosed vesicles, leaving the timing and integration of membranes in prebiotic evolution ambiguous. Additionally, the proposed transmission of compositional information in amphiphilic vesicles and its role in primitive selection lacks sufficient experimental or theoretical support.
My Answer:
There is no doubt that membranous vesicles were essential in the transition from prebiotic chemistry to cellular life. In the new version of the manuscript, I have changed the entire section on membranes: new wording, four new references, new data, and new explanations. In addition, one of the references cited indirectly supports my proposal regarding the existence of “molecular worlds” and the interactions between them.
R4 Comments:
Line 601-612 The author should specify which models or hypotheses are referenced for viral origins, provide supporting citations, and clarify the evidence for the proposed prebiotic emergence of virus-like particles.
My Answer:
From a retrospective perspective, it is reasonable to hypothesize that in a prebiotic environment where nucleic acids and proteins coexisted, these biomolecules could have interacted to form complex assemblies such as ribosomes or, conceivably, viruses. However, there is no empirical evidence to support this scenario, nor is it likely that such evidence will ever be obtainable—just as there is no direct proof of the prebiotic existence of ribosomal structures.
In any case, the section on viruses has been rewritten and some new references have been added.
R4 Comments:
Line 682-686 The statement that RNA, DNA, ribosomes, and metabolic pathways co-evolved within a membranous structure is presented without supporting citations or evidence. Could the author clarify whether this assertion is based on original data, modelling, or literature, and provide references to substantiate the proposed cooperative and organized transition from chemical to biological evolution in the MEP?
My Answer:
I acknowledge the reviewer’s concerns and questions; however, I regret that I am unable to provide a fully satisfactory response. My perspective is informed both by specialized literature and by my own intuition as a biochemist. While the hypothesis is speculative, it is grounded in a synthesis of current experimental findings and conceptual reasoning derived from biochemical principles.
It is evident that the hypothesis I am proposing is not grounded in direct experimental evidence. Nonetheless, there are two conceptual arguments that may support this claim. First, it seems reasonable to assume—at least from my perspective—that the emergence of the first living system required a membranous structure capable of enclosing the key components of biological activity. These would include the elements responsible for the storage and expression of genetic information, as well as a rudimentary metabolic system capable of generating energy and synthesizing molecules essential for sustaining the nascent life process. Second, throughout the manuscript, particularly in the sections addressing molecular worlds, several references are made to experimental studies demonstrating that, under plausible prebiotic conditions, all essential components of life—including membranes, RNA, peptides, ribosomes, and metabolic pathways resembling those found in contemporary organisms—could have emerged. If such components were enclosed within a semipermeable membrane and capable of self-organization, it is conceivable that a living system might have arisen. Admittedly, this remains speculative; I do not claim to know the answer, and it is fair to say that no one does.
In any case, that section has also been thoroughly revised.
R4 Comments:
Line 707-733 Could the author clarify whether the four attributes of life are fully and clearly explained in the figure caption, and provide more detail on how each attribute - system-process duality, emergence of the vital process, internal negative entropy, and mutable genetic program - is specifically illustrated and supported by the figure? Additionally, are there other essential attributes that should be considered to more comprehensively represent the "vital factor"?
My Answer:
Figure 2 has been removed from the revised version of the manuscript, as it was not well-designed and did not effectively support the argument. I believe that the four attributes which collectively define what I refer to as the vital factor—a term that, I should clarify, bears no relation to the vitalist doctrine or dogma of the 19th century—are sufficient to determine whether a vital process is present. However, to assess whether a system can be classified as truly living, additional criteria may be required. References 28 and 44 specifically address the distinction between 'life' and a 'living system', which may help clarify this conceptual boundary.
R4 Comments:
The sentences in lines 782–789 and lines 1109-1114 are unclear with regard to the author’s intent. Could the author clarify whether this content is intended to be represented visually, for example, as a figure or diagram, or whether it should remain a textual explanation? Additionally, guidance on how best to convey the described relationships or processes would help ensure that the reader correctly interprets the concepts.
My Answer:
I understand that the reviewer is referring to the definition of evolutionary forces. However, the specific concern remains unclear to me. In the revised version of the manuscript, the section on evolutionary forces has been expanded and supplemented with additional examples to enhance clarity and comprehensiveness.
Section 9, Perspectives on the future of life research, offers a brief reflection on the future of research related to life and the future of life on our planet, which is highly conditioned by what I call the anthropogenic factor.
R4 Comments:
Line 822-827 Could the author clarify whether the random events described -mutations,
genetic drift and gene flow - are intended to illustrate general stochastic mechanisms in
evolution, or whether they are presented too narrowly in relation to human populations
(beyond human control)? Could they also provide appropriate references for all examples?
My Answer:
In the original version of the manuscript, the first sentence reads: “Random events, as referred to in this context, denote inherently stochastic phenomena—those that are unpredictable and beyond human control.” I think it is clear that I am not referring to processes resulting from human intervention. In any case, I have modified this section (Random Events) in the new version of the manuscript. I have not gone into further detail because the work is already very extensive, but if this reviewer and the editor consider that I should expand on it further, there would be no problem.
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsI must say that I suspect most manuscript submissions to this particular issue will probably suffer from many of my same critiques as for this manuscript. I do not wish to be overly critical to the point of making acceptance of any submission practically impossible.
The rewrite is respectable. Historical science presents many challenges different from bench science papers. The author’s perspective is certainly mainstream. With life-origin papers, we expect every submission to have empirical and even theoretical shortcomings. I trust the author profited some from my extreme critique that will refine and refocus some his future work. I trust he will explore more thoroughly the source of Prescriptive Information (PI) in an inanimate environment blind to function. What was the source of the executable commands of programmed genomics and epigenomics? This programming of computational halting must precede the existence of any naturally selectable organism. Evolution is nothing more than the differential survival and reproduction of the fittest already-programmed, already-cybernetically processed, already-living organisms. Life is computed, which has nothing to do with numbers, although numbers can be used to represent decision-node choices. Evolution tells us absolutely nothing about life origin. Even molecular evolution requires active selection, not secondary passive natural selection. Nothing is alive yet to differentially survive. What orchestrated the proto-metabolism required for life to come into existence?
I have no problem with letting the readers decide the worth of this paper if the editors decide to accept the rewrite. The author has put a great deal of effort into his work. He defends his thesis respectably. It's already "type-set." I would let the readers decide its value and publish it.
Author Response
Manuscript ID: life-3882493 – Second Revision
Type of manuscript: Hypothesis
Response to Reviewer 1 (R1):
I would first like to express my sincere gratitude to the reviewer for their thoughtful comments, which—despite our differing perspectives—have prompted a thorough reflection and substantial revision of the manuscript. I fully concur with the observation that evolutionary theory does not address the origin of life.
Regarding the concept of Prescriptive Information raised by the reviewer, I would like to offer two reflections. First, I must acknowledge some difficulty in fully grasping the precise definition and relevance of this concept to the origin of life. Living systems are not computational devices in the conventional sense, and molecular interactions are fundamentally governed by the laws of physics and chemistry. For instance, when a mixture containing DNA, DNA polymerase, primers, nucleotides, and other necessary components is placed in a test tube and subjected to appropriate thermal cycling conditions, the system self-organizes to produce millions of copies of a specific DNA segment defined by the primers. This process occurs without the need for any external algorithm or guiding intelligence. While this example is admittedly a simplification of the broader problem, it illustrates that molecular systems are capable of executing highly coordinated and complex tasks through intrinsic chemical and physical interactions, without requiring intentional design or symbolic instruction.
Second, I agree with the reviewer on the importance of addressing fundamental questions concerning how and when the information that governs biological processes was established, and how such information came to be interpreted in a structured and biologically meaningful way. These are indeed central issues in understanding the emergence of life. In response, the revised manuscript now includes a brief reflection on the concept of Prescriptive Information and its potential implications for the origin-of-life (section 3.1: Information and Life).
In conclusion, with the incorporation of this new discussion, I believe the present work has been substantially strengthened. Although I do not claim to have a definitive answer to the question of how systems transitioned from purely physicochemical self-organization to algorithmically controlled, information-driven biochemistry, I consider this question to be of central importance in origin-of-life research. Its resolution would significantly advance our understanding of the emergence of biological complexity and the foundational principles underlying living systems.
Reviewer 2 Report
Comments and Suggestions for AuthorsThank you for the sincere revision. The manuscript has been improved much and has become easier to read through as an overview paper from the OoL to the biodiversity and evolution. I agree that the topic is very diverse and is impossible for a single paper to comprehensively describe the related studies, and I think the authors neutrally distilled the essence of these fields.
After re-reading, I noticed several minor points.
L102 Here is the first point where AWH appears, though not abbreviated. It may be possible to show the abbreviation of AWH here, rather than L385.
L463 The increase in concentration would be as important as the chemical complexity; reaction rate depends on concentration, and there is a certain threshold concentration to form micelle/ vesicle (related to L487).
L502 Please add one or some case examples or the original development paper of the IVTT kit, if any.
L561 Compared to the Assembled World Hypothesis in L385, which capitalized letters to be abbreviated, is there any specific intention to capitalize the RNA World Hypothesis? Same for L1049 and L1050.
L957 (comment) Does the author consider the primitive life autotroph or heterotroph? §3.4 states that life maintains the biological order by decreasing internal entropy, which alone does not determine which type emerged first. Of course, it depends on where the first life emerged.
L997 I remember there was a descriptive figure of the evolving "worlds", and it is now integrated in Fig3. I wonder whether it is correct to write an arrow from Prebiotic soup to Extinct prebiotic worlds (EPW); EPW may also be a byproduct of PW and EW, and from the definition no AW-EPW line. The complexity of the figure appears as a more-than-a-page-long figure legend. If there is a need to put more lines around the central EnW triangle, the current Fig 3 may be a bit crowded, and it may be suitable to separate EnW formation and evolution from EnW nodes.
L1278 Why not use pre-defined PW and EW?
Author Response
Manuscript ID: life-3882493 – Second Revision
Type of manuscript: Hypothesis
Response to Reviewer 2 (R2):
I am sincerely grateful for your comments, which have contributed to the improvement of this manuscript. Below, I provide my responses to your latest observations:
L102: The reviewer is right, and this error has been corrected in the new version.
L463: The reviewer is right, and in the new version the wording of this phrase has been changed to include the term “concentration”.
L502: Concerning the IVTT kit, in the new version I have included this reference:
Tuckey C, Asahara H, Zhou Y, Chong S. Protein synthesis using a reconstituted cell-free system. Curr. Protoc. Mol. Biol. 2014 108:16.31.1-16.31.22. doi: 10.1002/0471142727.mb1631s108.
L561: In the revised version of the manuscript, I have adopted the expression RNA world hypothesis to align with prevailing conventions in the scientific literature.
L385: My intention in capitalising the names ‘Life Determinism’ and ‘Principle of Inexorability’ was to highlight them. In the new version, they are written in lower case.
L957: At this point, it is pertinent to address a key question raised by the reviewer: does the author consider primitive life to be autotroph or heterotroph? In the revised version, I explore this issue by discussing whether PoB cells were autotrophs, heterotrophs, or facultative autotrophs. Given the environmental variability and the limited availability of organic substrates in early Earth conditions, it is plausible that the earliest life forms exhibited facultative autotrophy—a metabolic flexibility allowing them to switch between autotrophic and heterotrophic modes depending on resource availability.
L997: This comment pertains to Figure 3. While I acknowledge that it is a complex figure, I also consider it to be readily comprehensible. I do not believe it would be beneficial to separate its components, as its strength lies in presenting a holistic view. Concerning the extinct prebiotic worlds (EPWs), I must say that the term EPWs refer exclusively to molecular worlds that emerged throughout the entire process preceding the formation of the first viable living system. From this standpoint, it would be inappropriate to associate EPWs with the three living worlds, as the latter are not prebiotic in nature. However, the inclusion of EPWs may introduce ambiguity and does not significantly enhance the explanation of the biodiversity formation process. Therefore, I have removed the EPWs from the figure 3.
L1278: The reviewer's observation is correct, and the abbreviations PW and EW are now used.
Reviewer 3 Report
Comments and Suggestions for AuthorsIn this revision, the author has made many changes, with a number of new points. However the fundamental nature of the paper is not changed. There is a large literature on OoL, so any consistent hypothesis / plausible scenario needs to be selective. This manuscript is not selective, and therefore is also not consistent. Let me provide some examples.
- In line 812, the author concludes that there has been a long co-evolutionary process between RNA and protein. However, much of the discussion preceding this has been about separate RNA world and protein worlds.
- Again, in line 523 he cites (with approval) a study showing a shared origin for RNA, protein and lipid. Which contradicts the separate Worlds for RNA and protein.
- In line 668, he suggests that lipid membranes arose long before the emergence of nucleic acids or proteins. But earlier (eg line 466), he says that phospholipid vesicles arose after the arrival of ‘molecular worlds’.
- The whole concept of separate Worlds is unclear and contradictory. As I pointed out in my earlier review, Figure 2 describes a Metabolic World, in which metabolites are produced – elsewhere described as being for example monomeric sugars, amino acids, nucleotides and lipids. It also describes a Biomolecular World, which contains polymers of these metabolites. Surely there must be a connection between these worlds? It also describes a Supramolecular World, containing membranes and ribosomes. These are of course made of lipids, RNA and protein, so one would again expect a connection between these Worlds. Yet the author clearly describes them as separate things, which only come together later (a ‘sequential pathway’, line 398; ‘distinct’ worlds, line 1214). Either they are initially separate or they are not – which? In either case, there seems to me a logical inconsistency in the whole idea of distinct Worlds.
- In a similar way, in several places the author states that ‘molecular interactions initially occurred preferentially among chemically similar species’ (line 520). He does not justify this statement, which I find very unlikely.
- Not unique to this paper, but particularly prominent here, is a general difficulty with timescales. One assumes (and this paper explicitly says so) that prebiotic development begins with simple things, that then become more complex. The ‘more complex’ molecules surely include polymeric molecules that depend for their function on their having a specific (and genetically defined) sequence, for example proteins and ribozymes/ribosomes. Yet for example the author suggests that metabolites only emerged after the genetic code and gene synthesis (line 642); and that the systems that generate energy (which currently all require gradients of ions across membranes, as discussed in the paper) arose before the membranes (line 946). Ribozymes must surely come after the metabolic processes that generate nucleic acid monomers. In my first review I described this point as a need for scientific honesty. I do not mean to imply that the author is in any way being dishonest, but I do feel that he has not fully thought through some of his arguments.
- The author goes into considerable detail about ‘deterministic’ biology. Section 1 appears to agree with de Duve that life is a ‘cosmic imperative’. However, section 2 describes life as a miracle, which the author explains as meaning ‘extremely unusual’. He also quotes Crick and Hoyle. I am not sure what Hoyle meant (biology not being his strong point), but Crick certainly meant that life did not originate in one big event, but as multiple small events, and was not implying that life is inherently unlikely. Life Determinism and the Principle of Inexorability suggests that ‘certain biological outcomes are inevitable given the constraints imposed by natural laws’ (Line 1029). The following section 7.2.1 describes some of these ‘predictable pathways’. These are (1) Wings. I agree that the functional need to fly necessitates the evolution of wings. However in detail the wings of different animals are very different: in the body parts used, in the material used, in the way they are moved, etc. So there is a functional convergence (as indicated by the fact that they are all called wings), but the pathway (as opposed to the phenotype) is very varied and not at all predictable. (2) Glycolysis. Glucose does not undergo spontaneous conversion to pyruvate. If you heat glucose for example, a small proportion does convert to pyruvate, but the majority oxidises, polymerises and turns into black tar. And it certainly does not produce energy. So none of this is ‘predictable’. (3) The genetic code. Yes there is good evidence that certain features of the genetic code are meaningful and quite possibly a consequence of physical laws. But I cannot think of anyone who has suggested that it is deterministic, or ‘the best code’. (4) The eye. As for the wing, there are very many independent origins of vision, and the extant forms of the eye are numerous and very different. They all require some form of photoreceptor, but other properties are very variable and not at all determined. (5) Human bipedal locomotion. The best explanation I have seen is that it enabled humans to maintain a sustained running speed for many hours and thus catch up with prey who could run faster over short distances but ran out of energy on a longer timescale. And combined with hairlessness and sweat glands, stopped them overheating. So, not deterministic but a lucky invention.
In his response, the author asks me to provide more balanced feedback, including acknowledgment of strengths or novel contributions. Yes there are some strengths: primarily the language, which is almost poetic at times, and has a fairly consistent grandeur to it, helped by what I termed the mysticism: Mysterious Earthly Place; Assembled Worlds; Life Determinism; Vital Factor (note the capitalisation, which gives it a more mythic feel); system-process duality. I like the attempt to describe what life is. And there are indeed novel contributions – mainly the terms listed above, which have a certain grandeur, but sadly not much scientific clarity. The main weaknesses are the logical and narrative inconsistencies described above; and a tendency to indulge his favorite themes (the anthropogenic factor; the future of life; the role of viruses) which distract from the main argument. There is also a tendency to state his own views as being the accepted truth.
And a small complaint: On several occasions the author refers to ‘prebiotic soup’, a term that reflects Darwin’s mention of ‘some warm pond’. My personal conviction is that life began in hydrothermal vents – very far from prebiotic soup – because of the need for large throughput of energy to drive the origin of life. The author is entitled to his views, but I feel the downplaying of the role of hydrothermal vents is an omission that should be remedied.
In summary, the author has not dealt with the major criticisms that I raised before – and nor did I expect him to, because my criticisms are of the underlying structure and concepts and not of specific details. I therefore still recommend rejection.
Author Response
Manuscript ID: life-3882493
Type of manuscript: Hypothesis
Response to Reviewer 3 (R3):
R3: In this revision, the author has made many changes, with a number of new points. However the fundamental nature of the paper is not changed. There is a large literature on OoL, so any consistent hypothesis / plausible scenario needs to be selective. This manuscript is not selective, and therefore is also not consistent. Let me provide some examples.
My Answer:
The reviewer begins their critique with a flawed syllogism: “... any consistent hypothesis / plausible scenario needs to be selective. This manuscript is not selective, and therefore is also not consistent.” I disagree with this reasoning. The modifications introduced in the manuscript are indeed selective, and moreover, the consistency of a scientific work does not depend solely on its degree of selectivity.
To illustrate this point with an analogy from biochemistry literature: one may author a highly focused monograph on haemoglobin, a somewhat broader volume on allosteric proteins, a general book on proteins, or a comprehensive biochemistry textbook that includes proteins among many other topics. Each of these works can be internally consistent and scientifically rigorous, regardless of their degree of selectivity.
R3-1: In line 812, the author concludes that there has been a long co-evolutionary process between RNA and protein. However, much of the discussion preceding this has been about separate RNA world and protein worlds.
My Answer:
My conclusion regarding the prolonged co-evolutionary relationship between RNA and proteins is supported by established scientific literature (see, for example, references 75, 76, 79, 100, and 101). It is reasonable to infer that prior to the molecular convergence of RNA and peptides, these entities must have existed in distinct molecular 'worlds.' Therefore, the reviewer’s claim of inconsistency is unfounded.
Moreover, the notion of separate molecular domains preceding convergence is not only conceptually sound but also consistent with widely accepted models of early molecular evolution. The manuscript builds upon this foundation to propose a coherent scenario that aligns with current biochemical and evolutionary evidence. Thus, the critique appears to overlook both the selective nature of the proposed modifications and the broader theoretical context in which they are situated.
R3-2: Again, in line 523 he cites (with approval) a study showing a shared origin for RNA, protein and lipid. Which contradicts the separate Worlds for RNA and protein.
My Answer:
I believe the reviewer may have misunderstood the rationale behind my citation of the work by Patel et al. (Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Nat. Chem. 2015). This study is highly relevant, as it demonstrates that a single chemical environment can give rise to a diverse array of biomolecular precursors.
My interpretation builds on this finding by suggesting that, once synthesized, these molecules would naturally follow distinct evolutionary trajectories, leading to the emergence of separate molecular worlds. These worlds would eventually converge and contribute to the formation of the first living system.
In conclusion, the coexistence and interaction of distinct molecular domains within a shared chemical environment is not only plausible but supported by empirical evidence. The emergence of complexity through convergence is a fundamental principle in biology. My proposal seeks to explore this principle within the context of prebiotic chemistry. While I acknowledge the possibility of interpretative error, I respectfully maintain that the reviewer’s critique overlooks this integrative perspective. I invite a reconsideration based on the scientific merits of the argument rather than on subjective interpretations.
R3-3: In line 668, he suggests that lipid membranes arose long before the emergence of nucleic acids or proteins. But earlier (eg line 466), he says that phospholipid vesicles arose after the arrival of ‘molecular worlds’.
My Answer:
The reviewer’s statement is incorrect. The content referenced in line 668 pertains to the GARD model (see reference 84), which is not part of my original proposal. My proposal is presented in line 466 and in the surrounding sections, both preceding and following that point. It is essential to distinguish between the citation of existing models and the development of a novel conceptual framework. The GARD model is cited to provide context and contrast, not as a representation of my own hypothesis.
R3-4: The whole concept of separate Worlds is unclear and contradictory. As I pointed out in my earlier review, Figure 2 describes a Metabolic World, in which metabolites are produced – elsewhere described as being for example monomeric sugars, amino acids, nucleotides and lipids. It also describes a Biomolecular World, which contains polymers of these metabolites. Surely there must be a connection between these worlds? It also describes a Supramolecular World, containing membranes and ribosomes. These are of course made of lipids, RNA and protein, so one would again expect a connection between these Worlds. Yet the author clearly describes them as separate things, which only come together later (a ‘sequential pathway’, line 398; ‘distinct’ worlds, line 1214). Either they are initially separate or they are not – which? In either case, there seems to me a logical inconsistency in the whole idea of distinct Worlds.
My Answer:
I acknowledge that I may not have explained clearly what is meant by “molecular worlds.” It is also possible that the reviewer’s critique stems from a misinterpretation of the concept, perhaps due to a lack of alignment with the ideas presented in this work. Regardless, I appreciate the opportunity to clarify the notion.
The concept of molecular worlds is intended as a metaphor for biochemical reality. Just as in cell biology we distinguish functional domains—such as the cytoskeleton, transport systems, or the mitochondrial respiratory chain—these domains, while studied separately, coexist and interact within the same cellular environment, ultimately contributing to a unified goal: the survival and function of the cell. In the context of this work, a molecular world refers to a set of structurally and functionally related molecular entities that interact through catalytic, autocatalytic, and/or self-assembly processes. Over time, these molecular worlds would increase in complexity and begin to converge, ultimately giving rise to novel structures and processes that culminated in the emergence of the first living system.
This framework is consistent with the sequential logic observed in biochemical evolution. For example, before membranes could form, phospholipids had to be synthesized; and prior to phospholipids, their precursors—such as fatty acids and glycerol—must have emerged. Similarly, the formation of a ribosome presupposes the prior existence of RNAs and proteins, which in turn require nucleotides, and before that, nitrogenous bases and ribose. This progression reflects a natural increase in chemical and structural complexity.
To further illustrate, consider an analogy from metabolism: we study the metabolic pathways of carbohydrates, lipids, nucleotides, and other biomolecules separately. However, this compartmentalization does not preclude their integration into a unified metabolic network, which is tightly regulated both internally and externally. For instance, glucose initially participates in carbohydrate metabolism (e.g., glycolysis, pentose phosphate pathway). Only after its conversion to acetyl-CoA does it enter lipid metabolism. Thus, while these metabolic domains are distinct, they are interconnected and ultimately part of a single, coherent system.
In conclusion, the coexistence and interaction of distinct molecular domains within a shared chemical environment is not only plausible but supported by empirical evidence. The emergence of complexity through convergence is a fundamental principle in biology. My proposal seeks to explore this principle within the context of prebiotic chemistry. While I acknowledge the possibility of interpretative error, I respectfully maintain that the reviewer’s critique overlooks this integrative perspective. I invite a reconsideration based on the scientific merits of the argument rather than on subjective interpretations.
R3-5: In a similar way, in several places the author states that ‘molecular interactions initially occurred preferentially among chemically similar species’ (line 520). He does not justify this statement, which I find very unlikely.
My Answer:
I do not fully understand the reviewer’s criticism, and it is possible that my explanation was unclear or that the reviewer misinterpreted my intended meaning. What I am proposing is that, prior to interactions between structurally distinct molecules—such as a ribonucleotide and an amino acid—more homogeneous interactions may have occurred. For instance, nucleotides could have interacted among themselves to give rise to primitive RNA structures, and amino acids may have similarly assembled into early peptides or proteins.
This scenario is, of course, speculative, and I acknowledge that it cannot be empirically verified given the unknown nature of the prebiotic environment. Nonetheless, it represents a plausible hypothesis within the broader framework of molecular evolution. It is grounded in the principle that molecular complexity likely emerged through gradual, stepwise processes involving increasingly sophisticated interactions among simpler precursors.
I hope this clarification helps to resolve any misunderstanding and highlights the conceptual coherence of the proposed framework.
R3-6: Not unique to this paper, but particularly prominent here, is a general difficulty with timescales. One assumes (and this paper explicitly says so) that prebiotic development begins with simple things, that then become more complex. The ‘more complex’ molecules surely include polymeric molecules that depend for their function on their having a specific (and genetically defined) sequence, for example proteins and ribozymes/ribosomes. Yet for example the author suggests that metabolites only emerged after the genetic code and gene synthesis (line 642); and that the systems that generate energy (which currently all require gradients of ions across membranes, as discussed in the paper) arose before the membranes (line 946). Ribozymes must surely come after the metabolic processes that generate nucleic acid monomers. In my first review I described this point as a need for scientific honesty. I do not mean to imply that the author is in any way being dishonest, but I do feel that he has not fully thought through some of his arguments.
My Answer:
I must express my concern regarding what I perceive as a subtle insinuation in the reviewer’s comments, suggesting the possibility of scientific dishonesty. While I fully acknowledge my limitations as a researcher and accept that my proposal may be speculative and imperfect, I cannot accept any implication that questions my integrity. Scientific disagreement is both expected and welcome in academic discourse, but it must be grounded in mutual respect and focused on the merits of the work. I find this remark inappropriate and not conducive to constructive scientific dialogue.
Returning to the scientific discussion, I would like to respond to the reviewer’s comments. In my view, the first polymeric molecules—such as peptides and nucleic acids—likely arose through stochastic processes and the inherent chemical reactivity of their monomeric precursors. At this early stage, I do not believe that the correspondence between RNA/DNA sequences and protein sequences (i.e., the genetic code) had yet been established. That mechanism likely emerged later in evolutionary history. Resolving this question remains one of the central challenges in origin-of-life research and will be crucial to understanding and potentially recreating the conditions under which life first appeared.This reviewer attributes conclusions to my work that are not accurate. For example, the comment referring to line 642 misrepresents the content; I do not make the claim the reviewer suggests. Similarly, the interpretation of line 946 is incorrect—I do not state what the reviewer asserts in that comment either. In my opinion, in the earliest cells, energy acquisition systems must have been diverse and likely involved mechanisms such as chemiosmotic processes and substrate-level phosphorylation. These pathways represent plausible early bioenergetic strategies, consistent with current understanding of primitive metabolic systems.
Finally, I do not understand the basis of the reviewer’s assertion that “ribozymes must surely come after the metabolic processes that generate nucleic acid monomers.” This point seems self-evident, as ribozymes are composed of nucleotides, and therefore their formation necessarily depends on the prior availability of nucleotide monomers. I fail to see the conceptual conflict implied by the reviewer. The sequence of molecular emergence proposed in this work is consistent with the fundamental chemical logic: monomers must precede polymers, and functional assemblies such as ribozymes must arise from the components generated by earlier processes.
R3-7: The author goes into considerable detail about ‘deterministic’ biology. Section 1 appears to agree with de Duve that life is a ‘cosmic imperative’. However, section 2 describes life as a miracle, which the author explains as meaning ‘extremely unusual’. He also quotes Crick and Hoyle. I am not sure what Hoyle meant (biology not being his strong point), but Crick certainly meant that life did not originate in one big event, but as multiple small events, and was not implying that life is inherently unlikely. Life Determinism and the Principle of Inexorability suggests that ‘certain biological outcomes are inevitable given the constraints imposed by natural laws’ (Line 1029). The following section 7.2.1 describes some of these ‘predictable pathways’. These are (1) Wings. I agree that the functional need to fly necessitates the evolution of wings. However in detail the wings of different animals are very different: in the body parts used, in the material used, in the way they are moved, etc. So there is a functional convergence (as indicated by the fact that they are all called wings), but the pathway (as opposed to the phenotype) is very varied and not at all predictable. (2) Glycolysis. Glucose does not undergo spontaneous conversion to pyruvate. If you heat glucose for example, a small proportion does convert to pyruvate, but the majority oxidises, polymerises and turns into black tar. And it certainly does not produce energy. So none of this is ‘predictable’. (3) The genetic code. Yes there is good evidence that certain features of the genetic code are meaningful and quite possibly a consequence of physical laws. But I cannot think of anyone who has suggested that it is deterministic, or ‘the best code’. (4) The eye. As for the wing, there are very many independent origins of vision, and the extant forms of the eye are numerous and very different. They all require some form of photoreceptor, but other properties are very variable and not at all determined. (5) Human bipedal locomotion. The best explanation I have seen is that it enabled humans to maintain a sustained running speed for many hours and thus catch up with prey who could run faster over short distances but ran out of energy on a longer timescale. And combined with hairlessness and sweat glands, stopped them overheating. So, not deterministic but a lucky invention.
My Answer:
Yes, I concur with Christian de Duve’s assertion that “life is a cosmic imperative,” meaning that, given the appropriate physicochemical conditions, the emergence of life is not merely possible but inevitable. This perspective underscores the idea that life is a natural outcome of the laws of chemistry and physics, and that its origin is a predictable consequence of molecular complexity under favourable environmental circumstances.
Regarding the use of the term miracle, I would like to clarify that it is employed in a metaphorical and secular sense. If the reviewer consults the Merriam-Webster dictionary, one of the definitions provided is: “an extremely outstanding or unusual event, thing, or accomplishment.” Therefore, to describe the origin of life as a “miracle” is not incompatible with de Duve’s assertion that “life is a cosmic imperative.” This usage reflects the extraordinary nature of the origin of life, without implying any form of divine intervention. Describing the origin of life as a “miracle” is not at odds with this scientific perspective; it simply acknowledges the remarkable and rare nature of the event.
With regard to the references to F. Crick and F. Hoyle, I would like to clarify that my intention is to interpret their words within the context of this work. Only Crick and Hoyle knew precisely what they meant, and I do not claim to speak on their behalf. However, their statements are part of the historical and philosophical discourse surrounding the origin of life, and I believe they offer valuable perspectives. Hoyle’s famous quote is often interpreted as expressing scepticism about the likelihood of life arising purely by chance and suggesting the possibility of a guiding principle or higher order. While Hoyle was not a biologist, he was a distinguished scientist, and his views on the origin of life—an event that precedes biology and is deeply rooted in physics and chemistry—deserve consideration. What I interpret from his statement is the extraordinary, perhaps even “miraculous,” nature of life’s emergence. As for Francis Crick, who also was not a biologist by training, his use of the term “miracle” appears to reflect an awareness of the vast number of favourable conditions required for life to originate. This does not imply divine intervention but rather highlights the complexity and improbability of the event. If the reviewer assumes that I am advocating for a supernatural explanation, that interpretation is entirely mistaken. In this context, describing the origin of life as a “miracle” aligns with the Merriam-Webster definition. It is a metaphorical expression of the profound and rare nature of the transition from chemistry to biology, not a theological claim.
I strongly believe in a form of vital determinism, which I refer to as the principle of inexorability. This principle posits that many aspects related to life and living systems occur in specific ways due to the constraints imposed by natural laws. In other words, the emergence and behaviour of biological systems are not arbitrary but are shaped and limited by the fundamental properties of matter and energy. To support this principle scientifically, I will present several examples that illustrate how physical and chemical laws guide biological outcomes—whether on Earth, Mars, or Ganymede. These examples aim to demonstrate that life, if it emerges, must do so within the boundaries set by universal principles. You may disagree with this interpretation, and I respect that. However, I would appreciate a more substantive argument in support of your disagreement, rather than a dismissal without engagement with the underlying reasoning.
Wings. I am unable to follow the reviewer's line of reasoning. It is unclear what specific aspect is being criticized regarding vital determinism and the presence of wings. The principle of inexorability simply states that if an organism is to fly, it must possess wings. Furthermore, it implies that if life exists in another galaxy and includes flying organisms, those organisms will necessarily have wings. This principle does not pertain to the design or morphological specifics of wings, which are governed by genetic mutations and natural selection, rather than by vital determinism.
Glycolysis. None of the reviewer’s comments reflect my own views. Once again, I find the reviewer’s reasoning difficult to follow. The remarks concerning what occurs when glucose is heated are irrelevant to the scope of the manuscript. Had the reviewer consulted the section dedicated to the “metabolic world,” they would have found references to pertinent literature, including the work of Keller et al. (Keller, M. et al. Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean. Mol. Syst. Biol. 2014, 10, 725) among others. This paper presents evidence that early forms of glycolysis and the pentose phosphate pathway could have occurred spontaneously in the Archean ocean through non-enzymatic reactions catalysed by metal ions. The study found that a solution mimicking the Archean ocean's chemical composition could catalyse interconversions between sugar phosphates, producing key metabolites like ribose 5-phosphate, erythrose 4-phosphate, and eventually pyruvate and glucose. This suggests that the basic structure of these essential metabolic networks may have emerged from the chemical and physical conditions of prebiotic Earth, with iron playing a particularly important catalytic role.
Genetic Code. The hypothesis of determinism in the origin of the genetic code is a proposal I put forward, and to the best of my knowledge, it has not been explicitly formulated by other researchers. This idea arises from a fundamental question: why is the genetic code universal, and why has it remained largely unchanged since the earliest stages of life on Earth? Despite the theoretical possibility of alternative coding schemes, molecular evolution has consistently preserved this configuration. This persistence suggests that the genetic code may not be a product of arbitrary historical contingencies alone. While the precise mechanisms underlying its conservation remain unknown—and indeed, may be beyond current scientific understanding—it is plausible to consider that the genetic code reflects a form of biological informational determinism. In this view, the structure of the code may be constrained by deeper principles inherent to the nature of biological information processing, rather than being solely shaped by evolutionary chance. While the standard genetic code is nearly universal across all known life, there are documented examples of non-standard or variant genetic codes. Here are some notable examples (mitochondrial genetic code, ciliate nuclear code, mycoplasma and other bacteria, archaea and some protists). These examples show that while the genetic code is highly conserved, it is not absolutely fixed. However, the rarity and limited scope of these variations reinforce the idea that the standard code is under strong evolutionary constraints—possibly supporting the hypothesis of biological informational determinism.
The Eye. My response to the reviewer’s comments regarding the evolution of eyes is analogous to my response concerning the evolution of wings. In both cases, the principle of inexorability applies: if an organism is to perform a specific function—such as flight or vision—it must possess the corresponding structures, such as wings or eyes. The emergence and design of these structures are governed by evolutionary mechanisms, including mutation and natural selection, rather than by vital determinism.
Human bipedal locomotion. The example of bipedal locomotion as an instance of life determinism in humans may be considered somewhat speculative; however, it remains a fact that no known Homo sapiens, nor any of their hominid ancestors, have ever possessed three legs. This anatomical consistency suggests that certain structural constraints are deeply embedded in our evolutionary lineage. What appears to lack scientific rigor is the reviewer’s characterization of bipedal locomotion as merely a “fortunate invention.” Such a statement oversimplifies the intricate evolutionary processes that led to this trait and overlooks the anatomical, biomechanical, and environmental pressures that shaped it through natural selection. Bipedalism is not a random occurrence but the result of a long and complex adaptive trajectory, influenced by selective pressures and functional necessities. To dismiss it as a stroke of luck undermines the explanatory power of evolutionary biology.
R3 says: “there are some strengths: primarily the language, which is almost poetic at times, and has a fairly consistent grandeur to it, helped by what I termed the mysticism: Mysterious Earthly Place; Assembled Worlds; Life Determinism; Vital Factor (note the capitalisation, which gives it a more mythic feel); system-process duality.”
My Answer:
The reviewer states that my manuscript employs poetic and mystical language. I am unsure of the basis for this claim, as I do not perceive my writing in such terms. I do not intend to spend further effort justifying the terminology used in the manuscript, as these names are already explained and supported within the text. I would, however, invite the reviewer to reflect on the broader context of scientific nomenclature. For instance, genes such as sonic hedgehog, enzymes like catalase, and proteins such as huntingtin have all been assigned names that, while unconventional or even whimsical, are widely accepted in the scientific community. The use of creative or metaphorical terminology does not inherently undermine scientific rigor, provided the concepts are clearly defined and consistently applied.
These types of comments convey a tone of condescension toward me as the author that is difficult to reconcile with the principles of constructive scientific criticism. Scientific review should aim to engage with the content of the work objectively and respectfully, fostering dialogue rather than dismissiveness.
R3 says: “And there are indeed novel contributions – mainly the terms listed above, which have a certain grandeur, but sadly not much scientific clarity. The main weaknesses are the logical and narrative inconsistencies described above; and a tendency to indulge his favourite themes (the anthropogenic factor; the future of life; the role of viruses) which distract from the main argument. There is also a tendency to state his own views as being the accepted truth.”
My Answer:
This comment is inappropriate and inaccurate. It reflects a level of subjectivity and contempt that is incompatible with the standards of academic discourse and scientific respect. Constructive criticism should be grounded in objective analysis and aimed at improving the quality of the work, not at undermining the author through disparaging remarks. Scientific dialogue should be based on mutual respect and intellectual exchange, not on condescension or appeals for leniency.
R3 says: “On several occasions the author refers to ‘prebiotic soup’, a term that reflects Darwin’s mention of ‘some warm pond’. My personal conviction is that life began in hydrothermal vents – very far from prebiotic soup – because of the need for large throughput of energy to drive the origin of life. The author is entitled to his views, but I feel the downplaying of the role of hydrothermal vents is an omission that should be remedied.”
My Answer:
Once again, this comment suggests that the reviewer has not read the manuscript carefully. Had they done so, such remarks would likely not have been made. A thorough and attentive reading is essential for providing constructive and informed criticism, and the absence of such engagement undermines the validity of the review.
Nowhere in the manuscript does it say that prebiotic soup is equivalent to the warm pond Darwin spoke of. In fact, I call the place where life originated the Mysterious Earthly Place, and I call it mysterious because we do not know where life originated, and in this work I do not rule out any possibility, including the one suggested by this reviewer.
In relation to hydrothermal vents, lines 884-894 in the version reviewed by this reviewer, it is said: “Several hypotheses have been proposed regarding the origin of the metabolic world. One prominent model suggests its emergence within hydrothermal systems, where metal ions—abundant in oceanic environments—could have catalysed key chemical reactions [116–118]. In this context, one of the most plausible scenarios for the OoL posits the existence of a prebiotic autotrophic metabolism within sulfide-rich hydrothermal vent environments. Empirical evidence indicates that hydrothermal vent chimneys can generate electron flow, and that such electron transport may have facilitated the abiotic synthesis of organic compounds in ancient deep-sea hydrothermal systems [119]. It has therefore been proposed that extensive metal production and metal-supported primordial metabolic processes likely arose as a natural consequence of the intense hydrothermal activity on the Hadean Earth [120]. In light of this revised and evidence-based formulation, do you still maintain your previous criticism?
R3 says: In summary, the author has not dealt with the major criticisms that I raised before – and nor did I expect him to, because my criticisms are of the underlying structure and concepts and not of specific details. I therefore still recommend rejection.
My Answer:
The reviewer recommends rejection of this manuscript, even if some of the arguments presented are based on misinterpretations or inaccuracies regarding the content and intent of the work. It is evident that the reviewer has not acknowledged the substantial revisions made to the manuscript or the detailed responses provided to previous comments.
Reviewer 4 Report
Comments and Suggestions for AuthorsDear Editor,
The author has carefully considered all previous comments and made the necessary revisions. Having reviewed the updated version, I am satisfied with the changes and have no further comments or suggestions.
Author Response
Manuscript ID: life-3882493 – Second Revision
Type of manuscript: Hypothesis
Response to Reviewer 4:
I am sincerely grateful for your constructive feedback and insightful comments, which have played a valuable role in enhancing the quality of this manuscript.
