Preprint Hypothesis Version 3 This version is not peer-reviewed

The ATP Hypothesis: A New Conceptual Framework for the Origin of the Genetic Code

Version 1 : Received: 28 March 2020 / Approved: 29 March 2020 / Online: 29 March 2020 (04:08:22 CEST)
Version 2 : Received: 1 April 2020 / Approved: 2 April 2020 / Online: 2 April 2020 (05:16:09 CEST)
Version 3 : Received: 17 April 2020 / Approved: 19 April 2020 / Online: 19 April 2020 (04:00:24 CEST)

How to cite: Xie, P. The ATP Hypothesis: A New Conceptual Framework for the Origin of the Genetic Code. Preprints 2020, 2020030419 (doi: 10.20944/preprints202003.0419.v3). Xie, P. The ATP Hypothesis: A New Conceptual Framework for the Origin of the Genetic Code. Preprints 2020, 2020030419 (doi: 10.20944/preprints202003.0419.v3).

Abstract

The origin of the genetic code is the key to revealing the origin of life on Earth, as it is a prerequisite for the existence of life. More than half a century has passed since the discovery of the genetic code, but its origin is still one of the greatest mysteries. Is the origin of the genetic code truly unknowable? Does the code truly require external design? Here, a hypothesis is proposed, according to which ATP is at the origin of the genetic code by its coevolution with the pristine biochemical system. ATP has several properties that make it suitable as a plausible initiator of the genetic code. First, ATP is the only energetic product of photosynthesis. Second, ATP is at the heart of the extant biochemical systems. Third, ATP serves as a carrier of both energy and information. Fourth, ATP could energetically elongate chains of both polynucleotides and polypeptides, thus providing a bridge between these molecules and eventually mediating prebiotic biochemical innovation from energy transformation to informatization. This hypothesis shows how primitive life emerged through a series of processes from energy to information flow mediated by ATP. Informatization (processes for creating and managing information) was inevitably coupled with structuralization (processes for organizing or incorporating cellular structures), cyclizing polynucleotides and polypeptides into a feedback loop of reciprocal causation. The triplet codon might be only for stereochemical handling of amino acids through, e.g., Watson–Crick pairing interactions. It is only the evolutionary completion of the genetic code from RNA to DNA that, contrary to the central dogma, marked the dawn of cellular life, when Darwinian evolution began to operate. The ATP hypothesis sheds light on the origin of life, together with the formation of both photosynthetic and biochemical systems, which remains largely unknown thus far.

Subject Areas

origin of genetic codes; ATP-hypothesis; solar energy driven synthesis of chemicals; informatization; structuralization

Comments (13)

Comment 1
Received: 19 April 2020
Commenter: Ping Xie
Commenter's Conflict of Interests: Author
Comment: According to the comments of some experts, I made further revisions to improve the quality of the manuscript. 1) modified the title; 2) added further explanations to "2. ATP-hypothsis"; 3) added figure to graphically show how ATP is at the center of the biochemical system in a modern cell; 4) made major revisons on "Photochemical origin of life" (page 6), especially about the linkage between chlorophyll and the heme of cytochrome. To explain this clearly, I added a new figure (Figure 3); 5) extended the discussion on the various hypotheses on the origin of life (page 8). Detailed English corrections of the text were made by AJE and by an expert.
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Comment 2
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #1 on Version 1
Criticism 1. From the Abstract: “First, ATP is the only energetic product of photosynthesis. Second, ATP is at the heart of the extant biochemical systems. Third, ATP serves as carriers of both energy and information. Fourth, ATP could energetically elongate chains of both polynucleotides and polypeptides, thus providing a bridge between them, and eventually mediating prebiotic transaction from energy to information.”
(1) The Abstract does not contain a mechanism for the origin of the genetic code under the action of ATP. You describe the properties of ATP, but how do these properties help you? (2) What information does ATP carry? ATP is just a molecule. What is information in this context?

Criticism 2. About Section 2. This section of the article is central one (ATP-hypothesis). It begins by listing the six postulates of the hypothesis.
I did not find even single link to articles that would confirm the author’s point of view at least to a small extent.

Criticism 3. The author writes: “Key arguments favoring ATP as the initiator of the origin of genetic codes are its ability to elongate chains of both polynucleotides and polypeptides without additional energy input...”
This key point is groundless. References required.

Criticism 4. Figure 1 is intended to illustrate the origin of the genetic code. This role of Figure 1 meets at least two objections: (1) a picture cannot replace the textual justification of a hypothesis because facts, ideas, and logic can be given in a text, and a picture only illustrates thoughts (a figure instead of logic is unacceptable); (2) Figure 1 shows an already living cell so it already has a genetic code. The question of how this code arose remained unanswered.

Criticism 5. “We contend that driving forces should be energetic, e.g. ATP produced by solar-photon driven synthesis of chemicals.”
Photosynthesis of ATP is possible only in a living cell. The first living cell had photosynthesis, but still had no genetic code?

Criticism 6. You describe the well-known properties of ATP, but are silent about why these properties are useful for the origin of the genetic code.
Criticism 7. “Second, a biomolecule called cytochrome (an electron transport protein with iron porphyrin or heme as a prosthetic group) seems to be imprinted with photosynthesis.”
Your theory inevitably raises the question of the origin of cytochrome.

Criticism 8. “The present ATP- hypothesis, in general agreement with this theory, further details how life began with the evolution of biochemical system driven by photo-chemical synthesis in which ATP played a key role in the transformation from energy to information, leading to the birth of genetic codes.”
This statement is too general. Details and mechanisms are needed, but they have not yet been. However, it was necessary to show this mechanism in the Abstract and in the Introduction.

Criticism 9. “This implies that the formation of ATP in primordial cell had to rely on polypeptide channel that then developed into ATP synthase. In addition, H+ from cleavage of H2O also needed the help of polypeptides.”
This means that at first membrane transport systems should have originated, and after that life originated. How could ATP synthase arise, for example, if it is a very complex protein? How polypeptide channel could develop into ATP synthase? Was this evolution due to God's providence?

Criticism 10. “It may be inferred that there were a series of events randomly occurring in protocells.”
What is the likelihood that a monkey with a computer randomly types the thoughts of Confucius? The universe and the living cell originated in accordance with the laws of physics, and not by chance.

Criticism 11. “It is assumed that these building blocks could form polymers of random sequences or supramolecular aggregates with different properties or functions such as self-replication, catalysis [17]. “
Some people say that God created all things. You say that chance created all things. I don't see any differences between these approaches. In either of these two cases, we give up the search for a physical mechanism.

Criticism 12. “Let us first consider the impermeable lipid vesicle (enclosed by amphiphiles having both polar and non-polar domains) wrapping a plenty of life's building blocks.”
Even a titanium metal membrane is permeable to hydrogen molecules! The impermeability of the lipid membrane is an absolute mistake. Therefore, your further reasoning is erroneous.
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Comment 3
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #2 on Version 1
This is a very interesting area of biology and chemistry……The paper rests on the predicate that life arose via photochemical synthesis, i.e. a primitive kind of photosynthesis was the origin of life. Unfortunately there is no very convincing evidence that is likely – I’ve looked into the literature that you’ve cited in conjunction with this notion, and it deals with steps that must have occurred long after the essential chemistry of life (i.e. primitive energy metabolism) arose. Rather, the most plausible current theory on the origin of life is that which concerns the chemistry of alkaline thermal vents in the sea floor.
I find that, very interesting though your theory is, it rests on a weaker theory as to how the chemistry of life itself originated.
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Comment 4
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #3 on Version 1
It is interesting hypothesis.
1) Energy: ATP
2) Information: DNA & RNA
3) Structure: Phospholipid
Phosphates are surely common origin of basic function of life. Energy rich ATP may have important role as a common starting point (especially 1 and 2). Therefore, your hypothesis sounds very interesting.

(i) If scheme and figures are supplied to each section, this manuscript
becomes much more understandable.
(ii) Genetic code is based on the presence of four bases, A, G, C, T(U).
Without thinking about the other bases, genetic codes cannot be generated.
Contribution of the ATP families such as GMP have also important tasks.

Sorry for such brief comments to your fantastic idea.
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Comment 5
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #4 on Version 1
Do you think SALR clustering might have played some role in this?
I guess my question is whether ATP forms clusters.
In that case, I suspect that ATP, by itself, is not the answer. Amino acids and, I suspect, nucleotides, form giant clusters. Perhaps this is where ATP is involved. Perhaps it can be absorbed into amino acid and/or nucleotide clusters.
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Comment 6
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #5 on Version 1
It seems at first sight extremely interesting, and I wish to congratulate you for having attacked such a difficult problem. I'll read it more carefully and I hope to send you soon a report about it.
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Comment 7
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #6 on Version 1
At any rate, I am attaching a paper of mine on the origin of the genetic code – if you take a look at it you will see that our views are fairly different.
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Comment 8
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #7 on Version 1
The genetic code is only a problem of biology, no chemistry nor physics. The stereochemical hypothesis is related to chemistry, therefore, it cannot be a good explanation. Anyway, I cannot understand how your ATP-hypothesis can solve the origin of the genetic code.
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Comment 9
Received: 19 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Reviewer #5 on Version 2
About “ATP-hypothesis: a new conceptual framework for the origin of genetic codes” by Xie Ping

Introduction
I must first warn that I am not a biologist nor a chemist, but a communication engineer. All my research work up to my retirement, in 1997, was devoted to communication, especially by means of error-correcting codes, within the framework of information theory. Since then, I tried to apply my acquired experience to the understanding of life, without belonging to any institution. It is why my comments will mainly concern questions related to information for lack of a sufficient knowledge of biochemistry. It turns out that information theory and error-correcting codes are poorly known outside the engineering community, although I think they could be extremely useful in biology and even in physics. They are moreover difficult matters which need a deep reflection. For lack of a sufficient knowledge of biochemistry, I cannot formulate valid opinions about the hypotheses you state. I can only ask questions and suggest that further explanations are given.
I’ll also make some remarks regarding English. Although I can easily grasp the broad lines of your text, I am often stopped in my reading by minor grammatical errors. I thus think that the text should be much improved as regards English. Being French, I am not as proficient in this matter as a native English or American, but I have a long practice of it which, I hope, can be somewhat helpful to you.
General remarks
When I began reading the paper, I was impressed by its ambitious goal. I was also delighted to read that information was considered in it as essentially needed to deal with life, together with matter and energy. The quest for origins may indeed be considered as an impossible task for lack of conclusive proofs. However, a plausible scenario is already a valuable result as far as it has testable consequences in today’s living world. Instead of being positively validated, this scenario is then not disproved.
To begin with, I tried to rewrite your abstract with a double purpose: pinpoint some crucial questions, and correct some linguistic errors. In this rewritten abstract, I wrote in italics the changes I made and appended to it a number which refers to a comment below. These changes should also be useful to help correcting the main text. First of all, I replaced your “I present" by an impersonal phrase, in accordance with the general usage.

Rewriting the abstract.
The origin of the genetic code (1) is the key to reveal life’s origin on Earth (2) as a prerequisite to the existence of life. More than half a century passed since the discovery of the genetic code, while its origin is still one of the greatest mysteries of biology. Are the origins of the genetic code really unknowable? Does it actually require an external design? Here, a hypothesis (3) is proposed according to which ATP is at the origin of the genetic code by its coevolution with the pristine biochemical system. ATP has several properties that make it a plausible (4) initiator of the genetic code. First, ATP is the only energetic product of photosynthesis. Second, ATP is at the heart of the extant biochemical systems. Third, ATP serves as a carrier (5) of both energy and information (6). Fourth, ATP could energetically elongate chains (7) of both polynucleotides and polypeptides, thus providing a bridge between them, and eventually mediating prebiotic biochemical transition (8) from energy to information. This hypothesis shows how primitive life emerged through a series of ATP-mediated processes from energy to information (9). Informatization (10) (processes of creating and managing information) was inevitably coupled with structuralization (processes of organizing or incorporating into a cellular structure), making polynucleotides and polypeptides involved into a feedback loop (11) of reciprocal causation. The triplet codon might just be for stereo-chemical handling of amino acids through e.g. Watson{Crick pairing interactions. It is an evolutionary completion for the genetic code from RNA to DNA which, inverting (12) the Central Dogma, marked the dawn of cellular life where Darwinian evolution began to operate. The ATP-hypothesis sheds (13) light on the origin of life, together with the formation of both photosynthesis and biochemical systems, which remains yet largely unknown (14).

Related comments.
(1) I replaced your “I present” by an impersonal phrase, in accordance with the general usage. I have also been rather puzzled by the fact that you use the plural when writing “genetic codes” in the title and in the abstract, and alternatively the plural and the singular in the main text. The singular usually refers to the “standard” correspondence rule between the codons and the 20 amino acids which are the regular constituents of proteins. Doing so, one ignores the several known variants of it, e.g., the mitochondrial one. Or does the plural refer to something else? I understood your use of the plural in order to mean by “code” any correspondence rule between a codon and an amino acid. It is generally agreed in the English language literature that “genetic code”, in the singular, designates the set of all these 64 particular rules.
If I am right, I suggest that you conform to this usage and thus use everywhere the singular.
(2) The capital E in “on Earth” is intended to designate the planet.
(3) You cannot write “an ATP-hypothesis”, with the indeterminate article, since the hypothesis is a well defined one. I changed the text accordingly.
(4) “The initiator of the origin” is pleonastic. “Initiator” suffices.
(5) “Carrier” should be in the singular.
(6) A single molecule cannot by itself carry information. An alphabet must exist.
(7) How?
(8) The word “transaction” you use is clearly improper. I suggest “transition” but I am not satisfied with it. I would wish a more precise description of this process.
(9) and (10) I think a longer phrase to explain what is meant here would be needed.
(11) I think that “system” is unnecessary.
(12) I found the phrase unclear, and I propose this one.
(13) The correct expression is “to shed light”. “Shade” sounds almost the same but means lack of
light!
(14) I hope this phrase is better.

Further comments.
I list here the main questions I ask.
• How do lipid vesicles originate?
• What is precisely meant by “informatization”?
• What is the detailed process of elongation of chains (of nucleotides or of amino acids) by means of ATP?
• How does ATP generate the nucleotides of RNA and DNA?
Some of these questions probably result from my lack of competence in biochemistry. It is why I do
not wish to debate about them.
Another important point where I can be more useful to you is about language. As it is, your text
cannot be published unless its English is carefully improved. Here are some points I noticed.
Use of the plural. Besides your use of the plural in “genetic codes”, I found in your text many cases where the plural and the singular are misused. I quoted below a few of them. In the present, the verb which has as subject a name in the singular should end with “s", but not if this subject is in the plural.
Use of the articles. This is a difficult point, but a proper use of the articles is important in order to make a text understandable. The definite article \the", in the singular as well as in the plural, should be used with a name which refers to a precisely identified object or entity. The undefinite article, “a” or “an”, refers on the contrary to any member of some broad class, and can be used only in the singular. In the plural, the lack of any article has the same function as the undefinite article in the singular. Not using an article in the singular is possible and is frequent, e.g., in newspapers. In my opinion, using an article is better, although omitting the article is current practice when dealing with broad entities like energy or information.
“To call” is transitive. This means that “as” should not be used after “call”.
Place of adjective and adverbs. An adjective is generally placed before the noun, and an adverb is generally before the verb.
“Hereditable” is not an English word. You may use “heritable” or “hereditary”.
About the ATP molecule. The ATP molecule plays a central role in your work. Although ATP is a well known acronym, I think that its meaning should be recalled, as well as that of ADP and AMP. Moreover, I think that its chemical formula should be given, which would help understanding some parts of the text. Also, you refer to ATP as a nucleotide, although it is only a part of it, adenine, which is actually one the the bases in RNA and DNA.
Miscellaneous remarks
Notice that the indications of page and line below refer to the first version of the text, except for pages
11 and 12.
Page 2 I suggest to rewrite the first sentence as follows: The genetic information is recorded in chemical
memories (ARN or ADN) by means of triplets of nucleotides named codons.
Line 4: on Earth.
Line 7: first key
Line 10: in their majority
Line 11: may ever
Line 24: declare (there are several authors)
Line 25: describes
Line 35: even by extending the vision
Page 3 Line 5: misleading as regards
Lines 7-8: on the primitive Earth
Line 16: I have been unable to understand the sentence “It is great . . .
Line 19: hypothesis, referred to as ATP-hypothesis,
Line 28: “initiator of the origin” is pleonastic.
Line 37: it is an undeniably important
Page 4 Line 5: there existed plenty of (no article before “plenty”)
Line 13: carrier
Line 15: be cycled (2 words?)
Line 17: inverting the central dogma
Page 5 Line 5: codons
Line 6: I am afraid that \mire" is too strong. I would suggest: into the religious belief
Line 7: to be these ones
Line 11: a language is a much more complex entity than the genetic code. I suggest “a chemical correspondence rule”.
Line 25: Near abyssal thermal sources, there are living things that do not receive their energy from the sun, so “all” is a bit exaggerated.
Line 28: called photosynthesis
Line 29: in any biochemical system is more important than ATP.
Line 34: Krebs cycle)
Page 6 Line 28: I am afraid that “dissipate the solar spectrum” is not the proper wording.
Line 34: I already noticed that “transaction” is improper. I suggested “transition” but I am afraid that it has little meaning. I think that more developments are needed.
Line 37: “how” can advantageously be suppressed.
Page 7 Line 34: “as” should be suppressed.
Line 41: “a” should be suppressed.
Line 42: electrons and protons,
Page 8 Line 40: hereditary
Page 9 Line 5: Yes, but why does the number of the usual amino acids is 20?
Line 8: hereditary or heritable
Line 11: I think that “achieved” would be better than “obtained”.
Line 21: I have been unable to understand the last sentence.
Line 27: differences between them.
Page 10 Line 3: because the need of a difference
Line 4: Contrary to DNA, RNA can fold
Line 5: catalyse
Line 11: mRNAs.
Line 22: the RNA world hypothesis
Line 28: similarly
Line 39: the ability of early RNAs
Page 11 (version 2) Line 2: similarly
Line 7: systems
Line 13: the technical ability
Line 18: the validity of the statement that
Line 19: RNA existed earlier
Line 21: the RNA world
Line 28: happens
Line 31: development of the
Line 41-42: photosynthetic, chemosynthetic or heterotrophic. The ATP hypothesis
Page 12 Line 6: “an” instead of ‘in”.
Line 25: the origin of life
Line 26: hypothesis
Line 32: human beings will never stop
Line 33: codons
Lines 38 and 40: The ATP hypothesis
Line 1: understanding of
Conclusion
Your hypothesis is undeniably appealing. I think it deserves to be widely known and debated. An improvement of your text seems to me necessary to give it its maximum impact.
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Comment 10
Received: 19 April 2020
Commenter: James V. Kohl
Commenter's Conflict of Interests: I own the domains RNA-mediated.com, Autophagy.pro, MicroRNA.pro, Pheromones.com, ScentofEros.com and Chemogenetics.com
Comment: It's not a hypothesis, McEwen et al., (1964) linked God's Creation of anti-entropic virucidal light to the ATP-dependent creation of RNA and RNA interference, which biophysically constrains viral latency across kingdoms.

See: Dependence of RNA synthesis in isolated thymus nuclei on glycolysis, oxidative carbohydrate catabolism and a type of “oxidative phosphorylation” https://www.sciencedirect.com/science/article/pii/0926655064901665

"The synthesis of RNA in isolated thymus nuclei is ATP dependent."
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Response 1 to Comment 10
Received: 20 April 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Thank you for your comments! Unfortunately, I don’t think this could be a reliable evidence against my hypothesis.
Comment 11
Received: 6 June 2020
Commenter: Ping Xie
The commenter has declared there is no conflict of interests.
Comment: Comments from an expert

Dear Sir,

Many thanks first for the full text of your ATP theory.
The principle of entropy requires an energy supply to go from disorder to order and the source you chose the ATP is especially credible in this role. A solar energy driven start and maintenance in operation of the RNA World is particularly interesting because there is no other really plausible energy source at the time and in addition the four nucleotides can be considered as derived from ATP. If we now consider a remarkable experience like that of the Benard rolls about disorder to order it appears that it is well the arrival of energy that causes the transition but what happens is determined by the only geometry. So your theory provides a fine explanation about how life began with the RNA world as a first step and the driving force to continue. In this first step ATP provides energy and and geometry.
For the next step to the genetic code I think that it is necessary to consider in addition the existing geometry and in particular the contours of the molecules candidates to a link between nucleotides and amino acids . In my theory between codon and amino acid it is each time a group of amino acids ( 2 +1 ejected in opposite direction ) that mediated the assignment of codons to the different acids. Evolution then retained at both sides nucleotides and amino acids molecules capable of participating in this group recognition with amino acid contour encoded in the form of nucleotide triplets.

Kind regards
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Comment 12
Received: 2 July 2020
The commenter has declared there is no conflict of interests.
Comment: Comments from an expert:

Your hypothesis deals with a fundamental question that is very challenging and interesting. Unfortunately, there are a few problems about your claims that tampered our enthusiasm:

First, in your hypothesis, ATP is synthesized by the primitive photosynthesis chemical system, and is the initiator of other nucleotides, and also promotes the formation of peptide and RNA polymers. However, research from Sutherland's group gives a plausible pre-biotic origin of pyrimidine nucleotides (& AA & lipids) that does not depend on ATP (or purines): see below for these papers. And these earliest components of nucleotides (even their polymers) can be synthesized chemically, which seems a lot earlier than the appearance of the primitive photosynthesis system.
1) Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions. Powner MW, Gerland B, Sutherland JD. Nature. 2009 May 14;459(7244):239-42. doi: 10.1038/nature08013
2) Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism. Patel BH, Percivalle C, Ritson DJ, Duffy CD, Sutherland JD. Nat Chem. 2015 Apr;7(4):301-7. doi: 10.1038/nchem.2202. Epub 2015 Mar 16.

Secondly, are there any experimental evidences supporting that other nucleotides were derived from ATP?

Thirdly, does this primitive photosynthesis system operate to produce ATP without the involvement of proteins at all? How was the photosynthesis system propagated in early life without involving DNA, or even RNA?

I agree that the primitive photosynthesis system plays a pivotal role in transforming life on the earth - Would you be interested in addressing the origin of photosynthesis and its role played in evolution?
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