Origin of prebiotic nucleotides - a viable hypothesis ?

Origin of prebiotic nucleotides - a viable hypothesis?

In a paper published in Nature magazine: Searching for lost nucleotides of the pre-RNA World, published in 2018

https://www.nature.com/articles/s41467-018-07389-2

the authors claim: There may have been different nucleotides, and many more of them, on the prebiotic Earth than are found in extant RNA. 1 
The nucleotides of RNA appear to be products of evolution.

Question: How do they know this ?

The origin of the first nucleotides and the origin of RNA are related open questions

My comment: Nice confession

There may have been different nucleotides, and many more of them, on the prebiotic Earth than are found in extant RNA. There could have been a wide variety of molecular building blocks. With this freedom comes the liability of becoming lost in the vast chemical space of possible prebiotic molecules without ever finding the nucleotides that initiated the march toward RNA. 

My comment: That means, in order to have the nucleotides with the four nucleobases, adenine, guanine,  cytosine, uracil, and later, in DNA thymine, used in life, these useful ones would have to be selected out amongst all the different ones that could have existed and occurred naturally on earth. There was however no such chemical evolution or selection process.  The question is: If that is so, how do the authors attempt to explain a prebiotic selection process to sort out the functional nucleotides, and the four bases, used in life? And why would natural processes do such a selection, in face of the fact, that there is no reason why that should occur.

Uncovering the origins of nucleotides and genetic polymers requires understanding the various chemical reactions that produce such molecules

My comment: Indeed. And the outcome had to be the production of the four RNAs used in life, with the four bases, exclusively and joining them in sufficient quantity at the same building site. Since the smallest known genome, mycoplasma genitalum, uses 580 thousand nucleotides, and anything less would not generate a living cell, at least this quantity would have had to be united and joined together.

The RNA-first proponents are limited by the chemical stability, reactivity, and functionality of the molecular subunits that comprise the extant nucleotides. Consequently, the RNA-first proponents must, understandably, sometimes rely on specific minerals (e.g., borate) or geological events (e.g., meteorite impacts) to control, guide, or initiate a particular reaction or reaction sequence.

My comment: Meteorite impacts are chaotic. How can chaotic events control anything? In order to have a functional minimal information-bearing genome, RNA and DNA nucleotide monomers are required. To get functional ones, you need to sort them out between left-handed and right-handed nucleotide configurations ( the homochirality problem). Only right-handed nucleotides are used in cells. There is no selection process known besides the one used in cells by sophisticated enzymes, which produce only right-handed nucleotides.

The chemical structure of the extant RNA nucleotides is modular, with each nucleotide containing three molecular subunits: phosphate, ribose and a nucleobase. This general structure has long inspired chemists to hypothesize that the subunits were formed separately on the early Earth

My comment: There are many problems with this hypothesis, and they are persistent, and unsolved. High-energy precursors to produce purines and pyrimidines would have had to be produced in a sufficiently concentrated form. There is no known prebiotic route to this.   The best-studied mechanism relevant to the prebiotic synthesis of ribose is the formose reaction. Several problems have been recognized for the ribose synthesis via the formose reaction. The formose reaction is very complex. It depends on the presence of a suitable inorganic catalyst. Ribose is merely an intermediate product among a broad suite of compounds including sugars with more or fewer carbons. There would have been no way to activate phosphate somehow, in order to promote the energy dispendious reaction.

....and subsequently joined together by dehydration condensation reactions. That is, both the bond connecting phosphate to ribose and the bond between ribose and the nucleobase release a water molecule as they are formed.

My comment: In order a molecule to be a self-replicator, it has to be a homopolymer, of which the backbone must have the same repetitive units; they must be identical. In the prebiotic world, the generation of a homopolymer was however extremely unlikely, if not impossible. The activated nucleotides (or the nucleotides with coupling agent) now had to be polymerized. In the case of RNA, not only must phosphodiester links be repeatedly forged, but they must ultimately connect the 5 prime‑oxygen of one nucleotide to the 3 prime‑oxygen, and not the 2 prime‑oxygen, of the next nucleotide. .   How could and would random events attach a phosphate group to the right position of a ribose molecule to provide the necessary chemical activity?

The coupling of each nucleotide to a growing RNA polymer also generates a water molecule

My comment: Water is commonly viewed as essential for life, and theories of water are well known to support this as a requirement. So are RNA, DNA, and proteins. However, these biopolymers are corroded by water. For example, the hydrolytic deamination of DNA and RNA nucleobases is rapid and irreversible, as is the base-catalyzed cleavage of RNA in water. This leads to a paradox: RNA requires water to do its job, but RNA cannot emerge in water and cannot replicate with sufficient fidelity in water without sophisticated repair mechanisms in place. There are no solutions in sight to solve this paradox; life needs water that is inherently toxic to RNA necessary for life.


Biological Cells are irreducibly complex:
1. Cell subunits and compartments form a complex system that is useful only in the completion of a much larger system that is able to keep the basic functions of life. A minimal Cell, in order to permit life, according to an article in Science magazine, from 2016, requires a minimal genome of about 473gene products, and at least 438  proteins, each fully set up and functional for specific tasks. A discrete minimal size of each individual protein complex formed by multiple subunits and cofactors is required in order to be functional. And it only operates when interconnected and in a joint venture similar to a robot in a production line, and precise energy supply.
2. Cells must be created and be functional, all at once. As Graham Cairns-Smith noted, this system has to be fixed in its essentials through the critical interdependence of subsystems. Irreducibly complex and interdepend systems cannot evolve but depend on intelligence with foreknowledge on how to build discrete parts with distant goals.
3. Therefore, intelligent design is the best explanation of the origin of living, self-replicating cells.

There is no feasible prebiotic naturalistic unguided route to nucleotide synthesis. And even IF that were the case: These nucleotides would have to be joined in the right order to produce functional instructional information. But even IF that would be the case, what good would there be for a genome without the machinery to transcribe, and translate the information, to produce functional proteins? And even IF that would be the case, what good would functional proteins be good for, if not transported to the right site in the Cell, inserted in the right place, and interconnected to start the fabrication of chemical compounds used in the Cell?  It is clear, that life had to start based on fully operating cell factories, able to self replicate, adapt, produce energy, regulate its sophisticated molecular machinery.

RNA & DNA: It's prebiotic synthesis: Impossible !!  
https://reasonandscience.catsboard.com/t2865-rna-dna-it-s-prebiotic-synthesis-impossible

RNA & DNA: It's prebiotic synthesis: Impossible !! Part 1
https://www.youtube.com/watch?v=-ZFlmL_BsXE

RNA & DNA: It's prebiotic synthesis: Impossible !! Part 2
https://www.youtube.com/watch?v=dv4mUjmuRRU

https://reasonandscience.catsboard.com/t2964-origin-of-prebiotic-nucleotides-a-viable-hypothesis

Walking over 4 Gya: Chemical Evolution from Photochemistry to Mineral and Organic Chemistries Leading to an RNA World

Transfer RNA (tRNA) also plays a crucial role during proteins synthesis. within a molecule of tRNA formed by 4 stems surmounted by 3 loops, numerous non-standard nucleotides are found that could have a distant pre-biotic origin.
We still have to understand how the first nucleotides, formed of a nitrogenous base (purine - A,G - or pyrimidine - U,C -), a sugar (ribose) and phosphoric acid, were assembled.

Despite the massive body of work devoted to research on RNA, the mechanisms of synthesis of the RNA nucleotides and their subsequent polymerization under realistic prebiotic conditions are far from being understood.

The formation of nucleosides, nucleotides, and RNA involves dehydration processes. Thus, these dehydration processes are disadvantageous in aqueous media from a thermodynamic viewpoint.

My comment: That is evidence that the hydrothermal vent hypothesis doesn't work.

It is important to explain how ribose, ribonucleosides and phosphate merged in a particular environment suitable for dry conditions or mineral surfaces. For the formation of ribonucleotides, such dehydration processes should have occurred in the presence of phosphate minerals.

https://sci-hub.tw/https://link.springer.com/article/10.1007/s11084-017-9537-2

A plausible mechanism for synthesis of peptide bonds and ester bonds on the prebiotic Earth continues to be a major gap in our understanding of the origin of life. In order to make clear the underlying physical and chemical processes that are relevant to this question, we first need to address the primary hurdles that need to be overcome if non-biological nucleic acid synthesis can be shown to be plausible in the prebiotic environment. Although a source of mononucleotides is still debatable, we will assume that they or similar compounds are present, perhaps by a synthetic pathway similar to that described by Powner et al. 1

. Given a source of ordinary mononucleotides, several obvious questions immediately come to mind:

How can the monomers be sufficiently concentrated and organized to promote polymerization?

What is the source of chemical potential to drive condensation reactions?

How can polymers accumulate even though hydrolysis is thermodynamically favored?

Polymers and monomers such as nucleic acids and mononucleotides are not at thermodynamic equilibrium but instead exist in a steady-state maintained by the input of chemical energy.

Both monomers and polymers can undergo a variety of decomposition reactions that must be taken into account because biologically relevant molecules would undergo similar decomposition processes in the prebiotic environment.

Hydrolysis of ester and peptide bonds has already been described above as a spontaneous reaction that must be compensated in some way by condensation reactions. However, there are two other reactions that can affect mononucleotides as monomers of nucleic acids. Depurination occurs when the glycoside bond is broken that links purines (adenine and guanine) to a ribose or deoxyribose either in a mononucleotide or a nucleic acid. This hydrolysis reaction is spontaneous and occurs continuously in the DNA of all genomes. In a living cell, abasic sites left by depurination are quickly repaired by the action of specific enzymes, but in prebiotic conditions adenine and guanine would be lost at a certain rate from any nucleotide or nucleic acid. Another spontaneous reaction is the deamination of cytosine to produce uracil. This was recognized by Shapiro [80] as an important problem related to the origin of a genetic code.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370405/

Following the unresolved issues of nucleotide biogenesis :

https://reasonandscience.catsboard.com/t2028-origin-of-the-dna-double-helix#3426

(1) Laboratory experiments show that DNA spontaneously and progressively disintegrates over time. Estimates indicate that DNA should completely break down within 10,000 years. Any fossil DNA remaining after this period (especially more than say 100,000 years) must of necessity indicate that the method of dating the fossil is in error. Nature, Vol. 352, August 1, 1991 p:381

(2) The classic evolutionary problem of 'which came first, protein or DNA' has not been solved by the 'self-reproducing' RNA theory as many textbooks imply. The theory is not credible as it was based on laboratory simulations which were highly artificial, and were carried out with a 'great deal of help from the scientists'. Scientific American, February, 1991 p:100-109

(3) DNA can only be replicated in the presence of specific enzymes which can only be manufactured by the already existing DNA. Each is absolutely essential for the other, and both must be present for the DNA to multiply. Therefore, DNA has to have been in existence in the beginning for life to be controlled by DNA. Scott M. Huse, "The Collapse of Evolution", Baker Book House: Grand Rapids (Michigan), 1983 p:93-94

(4) There is no natural chemical tendency for the series of base chemicals in the DNA molecule to line up a series of R-groups in the orderly way required for life to begin. Therefore being contrary to natural chemical laws, the base-R group relationship and the structure of DNA could not have formed by random chemical action. Scott M. Huse, "The Collapse of Evolution", Baker Book House: Grand Rapids (Michigan), 1983 p:94

(5) "The origin of the genetic code is the most baffling aspect of the problem of the origins of life and a major conceptual or experimental breakthrough may be needed before we can make any substantial progress." Written by biochemist Dr Leslie Orgel (Salk Institute, California) in the article "Darwinism at the Very Beginning of Life" in New Scientist, April 15, 1982 p:151

(6) Computer scientists have demonstrated that information does not, and cannot arise spontaneously. Information only results from the input of energy, under the all-important direction of intelligence. Therefore, as DNA is information, it cannot have been formed by natural chemical means. P. Moorhead & M. Kaplan (eds.), "Mathematical Challenges to the Neo-Darwinian Interpretation of Evolution", Wistar Institute: Philadelphia (Pennsylvania), 1967

(7) The transformation of one species into another by viruses transferring small sections of the DNA of another species could not cause evolution for three reasons:- (1) if genes for a particular feature or action were transmitted as a small piece of DNA, the animal would not be able to utilize the code unless it had all the other structures present to support that feature, (2) there is no guarantee that without the rest of the supporting DNA code, that the feature would appear in the right place, and (3) the information transmitted would already be in existence and would not lead to the formation of a species with totally new features. Reader's Digest, March 1980

(8 "A scientist who won the Nobel Prize for his discovery of the DNA technique that inspired (the film) Jurassic Park was asked how likely it was that in the future, a dinosaur could be re-created from ancient DNA trapped in amber, as in the movie. Dr Kary Mullis replied in essence that it would be more realistic to start working on a time machine to go back and catch one." From Creation Ex Nihilo, Vol. 16, No. 2, March 1994, p:8, summarizing The Salt Lake Tribune, December 5, 1993

Life uses just five nucleobases to make DNA and RNA. Two purines, and three pyrimidines. Purines use two rings with nine atoms, pyrimidines use just one ring with six atoms. Hydrogen bonding between purine and pyrimidine bases is fundamental to the biological functions of nucleic acids, as in the formation of the double-helix structure of DNA. This bonding depends on the selection of the right atoms in the ring structure. Pyrimidine rings consist of six atoms: 4 carbon atoms and 2 nitrogen atoms. Purines have nine atoms forming the ring: 5 carbon atoms and 4 nitrogen atoms.

Remarkably, it is the composition of these atoms that permit that the strength of the hydrogen bond that permits to join the two DNA strands and form Watson–Crick base-pairing, and well-known DNA ladder. Neither transcription nor translation of the messages encoded in RNA and DNA would be possible if the strength of the bonds had different values. Hence, life, as we understand it today, would not have arisen.

Now, someone could say, that there could be no different composition, and physical constraints and necessity could eventually permit only this specific order and arrangement of the atoms. Now, in a recent science paper from 2019, Scientists explored how many different chemical arrangements of the atoms to make these nucleobases would be possible. Surprisingly, they found well over a million variants. The remarkable thing is, among the incredible variety of organisms on Earth, these two molecules are essentially the only ones used in life. Why? Are these the only nucleotides that could perform the function of information storage? If not, are they perhaps the best? One might expect that molecules with smaller connected Carbon components should be easier for abiotic chemistry to explore.

According to their scientific analysis, the natural ribosides and deoxyribosides inhabit a fairly redundant ( in other words, superfluous, unnecessary, needless, and nonminimal region of this space. This is a remarkable find and implicitly leads to design. There would be no reason why random events would generate complex, rather than simple, and minimal carbon arrangements. Nor is there physical necessity that says that the composition should be so. This is evidence that a directing intelligent agency is the most plausible explanation. The chemistry space is far too vast to select by chance the right finely-tuned functional life-bearing arrangement.

In the mentioned paper, the investigators asked if other, perhaps equally good, or even better genetic systems would be possible. Their chemical experimentations and studies concluded that the answer is no. Many nearly as good, some equally good, and a few stronger base-pairing analog systems are known. There is no reason why these structures could or would have emerged in this functional complex configuration by random trial and error. There is a complete lack of scientific-materialistic explanations despite decades of attempts to solve the riddle.

What we can see is, that direct intervention, a creative force, the activity of an intelligent agency, a powerful creator, is capable to have the intention and implement the right arrangement of every single atom into functional structures and molecules in a repetitive manner, in the case of DNA, at least 1,300,000 nucleotides to store the information to kick-start life, exclusively with four bases, to produce a storage device that uses a genetic code, to store functional, instructional, complex information, functional amino acids, and phospholipids to make membranes, and ultimately, life. Lucky accidents, the spontaneous self-organization by unguided coincidental events, that drove atoms into self-organization in an orderly manner without external direction, chemical non-biological are incapable and unspecific to arrange atoms into the right order to produce the four classes of building blocks, used in all life forms.