Defending the Christian Worldview, Creationism, and Intelligent Design
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Defending the Christian Worldview, Creationism, and Intelligent Design

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Defending the Christian Worldview, Creationism, and Intelligent Design » Origin of life » Index Page: On the origin of Cell factories by the means of an intelligent designer

Index Page: On the origin of Cell factories by the means of an intelligent designer

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Otangelo


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Index Page: On the origin of Cell factories by the means of an intelligent designer

https://reasonandscience.catsboard.com/t2809-on-the-origin-of-cell-factories-by-the-means-of-an-intelligent-designer

Chapter 1

Introduction
God of the gaps
Limited causal alternatives  do not justify to claim of
A God, or no God. That's the question
What's the Mechanism of Intelligent Design?
Is the
Did God create Ex-nihilo?
Intelligence vs no intelligence
Genesis or Darwin?
Naturalists hijack science by imposing philosophical naturalism
Consensus in science
What is life?
The constraint of philosophical naturalism, and consensus science, leads to bullshit science
Paley's watchmaker argument 2.0

Chapter 2
Living Cells are chemical factories
Argument from analogy
Cells are factories in a literal sense, or just as a metaphor?
Cell Metabolism as a production line system
Following would give a good sci-fi movie.
Cells are full of robotic assembly lines: evolved, or created?
Cells superb manufacturing concepts and incredible performance evidences intelligent design
Does the fact that cells self-replicate refute the claim that cells are factories?
The origin of cell factories
Difficulties in top-down approaches: Could life have started simple?
The origin of cell factories
Difficulties in top-down approaches: Could life have started simple?
LUCA, the last universal common ancestor
Nobody knows what LUCA and FUCA looked like
Viruses
Giant Viruses
What are the oldest life forms?
Timeline of the earliest evidence of life
Are the first life forms traced back to submarine vents?
Maybe Cyanobacteria?
Gloeobacter violaceus, a basal cyanobacteria
What does science know about a supposed last bacterial common ancestor (LBCA)?
The first bacterial lineages to diverge were most similar to modern Clostridia
But, after all, how simple can we go, and what is the best model candidate to study the origin of life?
Spontaneous generation of life

Chapter 3

The bottom-up approach
What are the possible mechanisms & causes to explain the origin of life?
Evolution
Physical necessity
Unguided random accidental events
Frozen accidents
Emergent properties:
Time: the naturalist's friend?
Abiogenesis research is a failure
Life requires 1. Matter, 2. Energy, and 3. Information.
There was no prebiotic selection to get the basic building blocks of life
Undesired contamination, and mixtures
Biomolecules decompose and degrade. They do not complexify

Chapter 4

The earth, and the atmosphere, just right for life
Essential elements and building blocks for the origin of life
Energy cycles, how did they
Carbon, essential for life
A finely tuned Carbon-cycle - is essential for life
Origin of carbon fixation.
Origin of ammonia on early earth
The transition to enzymatic fixation of nitrogen
The nitrogen cycle, irreducible interdependence, and the origin of life
Nitrogen levels in the atmosphere must be just right
Oxygen
How could the atmosphere have been aerobic prior the great oxidation event?
From an anaerobic to an aerobic atmosphere
Reactive oxygen species (ROS) & the origin of life
Hydrogen
The faint young sun paradox
Major elements essential for life to start
Calcium
Phosphorus

Chapter 5

Origin of the building blocks of life
Going from prebiotic to biotic synthesis: a major unsolved open question    
Amino acids
Origin of the proteinogenic ( protein creating ) amino acids used in life
Extraterrestrial origins
Panspermia
What about the synthesis of amino acids in hydrothermal vents?
The Miller-Urey experiment
Homochirality
Homochirality, its origin a scientifically longstanding unresolved issue
Why only left-handed, and not right-handed amino acids?
From prebiotic to biotic chirality determination
Aspartate Aminotransferase
How were the 20 proteinogenic amino acids selected on early earth?
Optimality of the amino acid set that is used to encode proteins

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Otangelo


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What came first: Lipid membranes, or membrane proteins?
Eugene V. Koonin (2009): A topologically closed membrane is a ubiquitous feature of all cellular life forms. This membrane is not a simple lipid bilayer enclosing the innards of the cell: far from that, even in the simplest cells, the membrane is a biological device of a staggering complexity that carries diverse protein complexes mediating energy-dependent – and tightly regulated - import and export of metabolites and polymers. Despite the growing understanding of the structural organization of membranes and molecular mechanisms of many membrane proteins, the origin(s) of biological membranes remain obscure. 60

Armen Y. Mulkidjanian (2010) The origins of membrane proteins are inextricably coupled with the origin of lipid membranes. Indeed, membrane proteins, which contain hydrophobic stretches and are generally insoluble in water, could not have evolved in the absence of functional membranes, while purely lipid membranes would be impenetrable and hence useless without membrane proteins. The origins of biological membranes – as complex cellular devices that control the energetics of the cell and its interactions with the surrounding world – remain obscure 61

Eugene V. Koonin: The origin of the cellular membrane itself seems to involve a catch-22: for a membrane to function in a cell, it must be endowed with at least a minimal repertoire of transport systems but it is unclear how such systems could evolve in the absence of a membrane. 62

The challenge to start harvesting energy
Geoffrey Zubay (2000):  Metabolism depends on factors that are external to the organism. The living system must extract nutrients from the environment and convert them to a biochemically useful form. In the next phase of the metabolism, which is internal, small molecules are synthesized and degraded. 63

Jeremy England (2020): EVERY LIFE IS ON FIRE How Thermodynamics Explains the Origins of Living Things: A spring has first to be brought to a compressed state, that is ready to burst apart, forcefully, when properly triggered. When glass and dishes are thrown to the ground, the stored energy is released, but they get smashed, broken, or damaged. Accordingly, people can eat sugar, but not dynamite; plants love sunlight,  but not intense gamma rays. Life needs access to energy, but it has to absorb it in specific ways that are conducive to activating “healthy” motions while avoiding “unhealthy” ones. To get a little bit more technical, it helps to remember that living things are in highly specialized, exceptionally rare configurations of their constituent parts that would not easily be discovered by a random and unbiased search of the space of their possible arrangements. 64

ADDY PROSS (2012) Organized complexity and one of the most fundamental laws of the universe—the Second Law of Thermodynamics—are inherently adversarial. Nature prefers chaos to order, so disorganization is the natural order. Within living systems, however, the highly organized state that is absolutely essential for viable biological function is somehow maintained with remarkable precision. : The living cell is able to maintain its structural integrity and its organization through the continual utilization of energy, which is in fact part of the cell’s modus operandi. . So there is no thermodynamic contradiction in life’s organized high-energy state, just as there is no contradiction in a car being able to drive uphill in opposition to the Earth’s gravitational pull, or a refrigerator in maintaining a cool interior despite the constant flow of heat into that interior from the warmer exterior. Both the car driving uphill and the refrigerator with its cold interior can maintain their energetically unstable state through the continual utilization of energy. In the car’s case the burning of gasoline in the car’s engine is the energy source, while in the case of the refrigerator, the energy source is the electricity supply that operates the refrigerator’s compressor. In an analogous manner, energetically speaking, the body can maintain its highly organized state through the continual utilization of energy from some external source—the chemical energy inherent within the foods we eat, or, in the case of plants, the solar energy that is captured by the chlorophyll pigment found in all plants. But how the initial organization associated with the simplest living system came about originally is a much tougher question. 65

ATP - the Miracle molecule
Geoffrey Zubay (2000): The compound adenosine triphosphate (ATP) is the main source of chemical energy used by living systems. Through hydrolysis, ATP is converted into adenosine diphosphate (ADP) and inorganic phosphate ion (Pi ), and in the process a great deal of free energy is made available to drive other reactions. 63

Daniel Zuckerman: ATP is the most important energized molecule in the cell. ATP is an activated carrier that stores free energy because it is maintained out of equilibrium with its hydrolysis products, ADP and Pi. There is a strong tendency for ATP to become hydrolyzed (split up) into ADP and Pi, and any process that couples to this reaction can be "powered" by ATP - even if that process would be unfavorable on its own. 66

Libretext: ATP is an unstable molecule that hydrolyzes to ADP and inorganic phosphate when it is in equilibrium with water. The high energy of this molecule comes from the two high-energy phosphate bonds. The bonds between phosphate molecules are called phosphoanhydride bonds. They are energy-rich and contain a ΔG of -30.5 kJ/mol. 67

Yijie Deng (2021): Adenosine triphosphate (ATP) is the key energy source for all living organisms, essential to fundamental processes in all cells from metabolism to DNA replication and protein synthesis.  Cellular power consumption varies significantly from approximately 0.8 and 0.2 million ATP/s for a tested strain during lag and stationary phases to 6.4 million ATP/s during exponential phase, indicating ~ 8–30-fold changes of metabolic rates among different growth phases. Bacteria turn over their cellular ATP pool a few times per second during the exponential phase and slow this rate by ~ 2–5-fold in lag and stationary phases. [url=https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-021-01023-2#:~:text=Our model also shows that,under physiological conditions in E.]6[/url]8

ATP was not extant prebiotically. So there had to be a way, a trajectory from non-ATP, to ATP. Prebiotic energy sources were sunlight, chemical compounds, electric discharges, cosmic rays, radioactivity, volcanoes, steam vents, and hydrothermal vents.


Cell membranes, proton gradients, and the origin of life
Every factory needs energy to do its work, and fuel for its machines to operate. So does the living chemical cell factory. It was a long way for researchers to discover how cells tackle this problem and make their energy. It comes out, that the solution is unusual and unexpected. A masterpiece of sophisticated engineering.  

Leslie E. Orgel (1999): One day a young scientist unknown to me made an appointment to talk about a theoretical matter that he thought would interest me. He was Peter Mitchell, and he wanted to talk about his ideas on how living cells derive energy: his novel chemiosmotic hypothesis. According to Mitchell's ideas, metabolic energy was used to pump protons across a biological membrane thus establishing a concentration gradient. It was the return of protons down the gradient that led to the synthesis of ATP. Energy could, in principle, be obtained by transporting an ion across a membrane from a more concentrated to a less concentrated solution. His ideas seemed bizarre to most of his contemporaries. They might well have asked, “Are you serious, Dr. Mitchell?” Of course, he was and he was right. 69

Alicia Kowaltowski (2015): Peter Mitchell was awarded the 1978 Nobel Prize in Chemistry for his discovery of the chemiosmotic mechanism of ATP synthesis, a hypothesis he first published in 1961. All groups of lifeforms present today have the genes necessary to build ATP synthases. 70

Kevin Drum (2016): A proton gradient is a complex and highly unusual way of providing energy, but it’s also nearly universal in modern life, suggesting that it goes back to the very beginnings of life. But if it’s so unusual, how did it get its start? 71

Nick Lane (2017): Chemiosmotic coupling – the harnessing of electrochemical ion gradients across membranes to drive metabolism – is as universally conserved as the genetic code. It requires not only a rotor-stator ATP synthase but also (apparently) ion-tight lipid membranes and complex proton pumps to generate electrochemical ion gradients. The claim that the last universal common ancestor had chemiosmotic coupling is treated with reservation.  All that might seem too complex to be primitive, and so it is understandable that most researchers have put the vexed question of its origins aside until more is known. Nonetheless, the fact remains that the ATP synthase is as universally conserved across life as the ribosome itself, and shares the same deep split between the bacteria and archaea. Some form of chemiosmotic coupling probably evolved very early in the history of life, arguably before LUCA; the question is how, and why?   72

Nick Lane (2010): Proton gradients are strictly necessary to the origin of life. The proton gradients that power respiration are as universal as the genetic code itself, giving an insight into the origin of life and the singular origin of complexity. There is a proton gradient across a membrane. It works much like a hydroelectric dam. The energy released by the oxidation of food (via a series of steps) is used to pump protons across a membrane — the dam — creating, in effect, a proton reservoir on one side of the membrane. The flow of protons through amazing protein turbines embedded in this membrane powers the synthesis of ATP in much the same way that the flow of water through mechanized turbines generates electricity. The flow of protons through the membrane turbines rotates the stalk of the ATP synthase, and the conformational changes induced by this rotation catalyze ATP synthesis.  How do bacteria keep their insides different from the outside? Membrane proteins can create gradients across a membrane, and these gradients can in turn power work. Although cells can generate sodium, potassium, or calcium gradients, proton gradients rule supreme. Protons power respiration not only in mitochondria but also in bacteria and archaea. Proton gradients are equally central to all forms of photosynthesis, as well as to bacterial motility (via the famous flagellar motor, a rotary motor similar to the ATP synthase) and homeostasis (the import and export of many molecules in and out of the cell is coupled directly to the proton gradient). [url=https://www.nature.com/scitable/topicpage/why-are-cells-powered-by-proton-gradients-14373960/#:~:text=Recent research suggests that proton,as they do in cells.]7[/url]3

Lane comes to the conclusion: The idea that LUCA was chemiosmotic is not actually particularly challenging, as LUCA certainly had genes and proteins, and the ATP synthase is no more complex than the ribosome. It is a product of natural selection, and presumably the recruitment of subunits with pre-existing functions. 72 He references Eugene Koonin's paper published in 2007, where Koonin writes: We propose that these ATPases originated from membrane protein translocases, which, themselves, evolved from RNA translocases. We suggest that in these ancestral translocases, the position of the central stalk was occupied by the translocated polymer. 73

Is it plausible to believe that RNA translocases would be the product of prebiotic non-designed processes?

Effrosyni Papanikou (2007) The Sec machinery is essential for life. All cells must traffic proteins across their membranes. This essential process is responsible for the biogenesis of membranes and cell walls, motility and nutrient scavenging and uptake. The translocase is an impressively dynamic nanomachine that is the central component that catalyzes transmembrane crossing. This complex, the multi-stage reaction involves a cascade of inter-and intramolecular interactions that select, sort and target polypeptides to the membrane, and use energy to promote the movement of these polypeptides across — or their lateral escape and integration into — the phospholipid bilayer, with high fidelity and efficiency. Metabolic energy in the form of both ATP and the proton motive force is used to power pre-protein movement through the translocase machine  74

ATP synthase, which makes ATP, is explained by the evolution from a translocase, which requires ATP in order to be made. That is a catch22 situation. 

Is a transition from a proton gradient in inorganic compartments in hydrothermal vents, to membrane-based proton gradients a plausible hypothesis? It doesn't seem so. Here is, why: 

Inorganic compartments versus membrane-bounded cells as the means for confining the LUCA 
Eugene V. Koonin (2005): It has been repeatedly argued that the complex molecular composition inferred for LUCA could not have been attained without prior evolution of biogenic-membrane-bounded cells, mainly because (i) compartmentalization is a prerequisite for the evolution of any complex system; and (ii) certain key membrane-associated enzymes, such as the signal recognition particle (SRP) and the proton ATPase, are conserved in eubacteria and archaebacteria. The model of a compartmentalized, but inorganically confined LUCA obviates the first problem. However, the second problem – the conservation of certain membrane-associated functions in all modern forms of life – is more challenging. The ubiquity of the SRP (with its notable RNA component) and the proton ATPase across genomes, together with the clear split between archaebacterial–eukaryotic and eubacterial versions, suggests that these complexes were present in LUCA. Because the SRP inserts proteins into hydrophobic layers and ATPase requires a hydrophobic layer to function, this would seem to imply the existence of membranes in LUCA, apparently in contradiction to arguments concerning the late and independent emergence of lipid biosynthetic pathways. The essential distinction to be made is between a ‘hydrophobic layer’ and a ‘biogenic membrane’. The latter requires elaborate suites of lineage-specific enzymes (given the unrelated isoprene ether versus fatty acid ester chemistries of the membrane lipids in archaebacteria and eubacteria, respectively). 75

J. Baz Jackson (2016):  The hypothesis that a natural pH gradient across inorganic membranes lying between the ocean and fluid issuing from hydrothermal alkali vents provided energy to drive chemical reactions during the origin of life has an attractive parallel with chemiosmotic ATP synthesis in present-day organisms. However, such natural pH gradients are unlikely to have played a part in life’s origin. There is as yet no evidence for thin inorganic membranes holding sharp pH gradients in modern hydrothermal alkali vents at Lost City near the Mid-Atlantic Ridge. Proposed models of non-protein forms of the H+-pyrophosphate synthase that could have functioned as a molecular machine utilizing the energy of a natural pH gradient are unsatisfactory. Some hypothetical designs of non-protein motors utilizing a natural pH gradient to drive redox reactions are plausible but complex, and such motors are deemed unlikely to have assembled by chance in prebiotic times. Small molecular motors comprising a few hundred atoms would have been unable to function in the relatively thick (>1 μm) inorganic membranes that have hitherto been used as descriptive models for the natural pH gradient hypothesis. 76

Tan, Change; Stadler, Rob: The Stairway To Life (2020): The cell uses the proton gradient to charge “batteries” such as adenosine triphosphate (ATP), hence the “coupling” part of chemiosmotic coupling. ATP is a nearly universal battery in life. Once charged, it can be “plugged into” a wide variety of molecular machines to perform a wide variety of functions: activating amino acids for protein synthesis, copying DNA, untangling DNA, breaking bonds, transporting molecules, or contracting muscles. Like rechargeable batteries, ATP cycles frequently between powering gadgets and recharging. Although a human body contains only about sixty grams of ATP at any given moment, it is estimated that humans regenerate approximately their own weight in molecules of ATP every day. Because chemiosmotic coupling is essential for life and is highly conserved across all of life, abiogenesis must include a purely natural means to arrive at chemiosmotic coupling. This requires a membrane, a mechanism for pumping protons across the membrane, and a mechanism for producing or “recharging” ATP. The challenge is particularly onerous because these three components are highly complex in all of life and are interdependent to provide energy for life. In other words, the pumping of protons is of no use unless the membrane is there to maintain a gradient of protons. The membrane has no function for energy generation unless there is a mechanism for pumping protons across it. Similarly, the method of ATP production is of no use without a proton gradient across a membrane. 77

A New Physics Theory of Life?
Natalie Wolchover: A New Physics Theory of Life January 22, 2014
MIT physicist Jeremy England has proposed the provocative idea that life exists because the law of increasing entropy drives matter to acquire life-like physical properties. England, an assistant professor at the Massachusetts Institute of Technology, has derived a mathematical formula that he believes explains this capacity. The formula, based on established physics, indicates that when a group of atoms is driven by an external source of energy (like the sun or chemical fuel) and surrounded by a heat bath (like the ocean or atmosphere), it will often gradually restructure itself in order to dissipate increasingly more energy. This could mean that under certain conditions, matter inexorably acquires the key physical attribute associated with life.

You start with a random clump of atoms, and if you shine light on it for long enough, it should not be so surprising that you get a plant,” England said.
 78

Richard Terrile NASA mission scientist: “Put those ingredients ( for the origin of life) together on Earth and you get life within a billion years 79

Index Page: On the origin of Cell factories by the means of an intelligent designer Lennox12

England did not address the question of the origin of the cell's machinery to harness the energy, like ATP synthase, nor how the proton gradient could have developed prebiotically. In biological processes, ATP is very precisely directed to where energy is required. No explanation was provided how such a state of affairs could have first originated.  

Open questions in prebiotic cell membrane synthesis
How could simple amphiphiles, which are molecules containing a nonpolar hydrophobic region and a polar hydrophilic region will self-assemble in aqueous solutions to form distinct structures such as micelles have been available in the prebiotic inventory if there has never been evidence for this? Furthermore, sources of compounds with hydrocarbon chains sufficiently long to form stable membranes are not known.
How could prebiotic mechanisms have transported and concentrated organic compounds to the pools and construction site?
How could membranous vesicles have self-assembled to form complex mixtures of organic compounds and ionic solutes, if science has no solution to this question?
How could there have been a prebiotic route of lipid compositions that could provide a membrane barrier sufficient to maintain proton gradients? Proton gradients are absolutely necessary for the generation of energy.
How to explain that lipid membranes would be useless without membrane proteins but how could membrane proteins have emerged or evolved in the absence of functional membranes?
How did prebiotic processes select hydrocarbon chains which must be in the range of 14 to 18 carbons in length?  There was no physical necessity to form carbon chains of the right length nor hindrance to join chains of varying lengths. So they could have been existing of any size on the early earth.
How could there have been an "urge" for prebiotic compounds to add unsaturated cis double bonds near the center of the chain?
How is there a feasible route of prebiotic phospholipid synthesis, to the complex metabolic phospholipid and fatty acid synthesis pathways performed by multiple enzyme-catalyzed steps which had to be fully operational at LUCA?
How would random events start to attach two fatty acids to glycerol by ester or ether bonds rather than just one, necessary for the cell membrane stability?
How would random events start to produce biological membranes which are not composed of pure phospholipids, but instead are mixtures of several phospholipid species, often with a sterol admixture such as cholesterol? There is no feasible prebiotic mechanism to join the right mixtures.
How did unguided events produce the essential characteristic of living cells which is homeostasis, the ability to maintain a steady and more-or-less constant chemical balance in a changing environment?  The first forms of life required an effective Ca2+ homeostatic system, which maintained intracellular Ca2+ at comfortably low concentrations—somewhere  ∼10,000–20,000 times lower than that in the extracellular milieu. There was no mechanism to generate this gradient.
How was the transition generated from supposedly simple vesicles on the early earth to the ultracomplex membrane synthesis in modern cells, which would have to be extant in the last universal common ancestor, hosting at least over 70 enzymes?

1. Nick Lane: [url=https://www.nature.com/scitable/topicpage/why-are-cells-powered-by-proton-gradients-14373960/#:~:text=Recent research suggests that proton,as they do in cells.]Why Are Cells Powered by Proton Gradients?[/url] 2010
2. Change Laura Tan, Rob Stadler: The Stairway To Life March 13, 2020
3. Yijie Deng: [url=https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-021-01023-2#:~:text=Our model also shows that,under physiological conditions in E.]Measuring and modeling energy and power consumption in living microbial cells with a synthetic ATP reporter[/url] 17 May 2021
4. Kevin Drum: Proton Gradients and the Origin of Life JULY 25, 2016
5. Nick Lane: Proton gradients at the origin of life 2017 May 15.
6. Eugene V. Koonin: Inventing the dynamo machine: the evolution of the F-type and V-type ATPases November 2007
7. Eugene V. Koonin: Co-evolution of primordial membranes and membrane proteins 2009 Sep 28
8. Armen Y. Mulkidjanian: Structural Bioinformatics of Membrane Proteins 2010
9. Eugene V. Koonin: On the origin of genomes and cells within inorganic compartments 2005 Oct 11.
10. Effrosyni Papanikou Bacterial protein secretion through the translocase nanomachine November 2007
11. J. Baz Jackson: Natural pH Gradients in Hydrothermal Alkali Vents Were Unlikely to Have Played a Role in the Origin of Life 2016 Aug 17
12. Libretext: ATP/ADP
13. Leslie E. Orgel: Are you serious, Dr Mitchell? 04 November 1999
14. Daniel Zuckerman: Synthesis of ATP by ATP synthase
15. ADDY PROSS: What is Life?: How Chemistry Becomes Biology  2012
16. Natalie Wolchover: A New Physics Theory of Life January 22, 2014
17. Jeremy England: EVERY LIFE IS ON FIRE How Thermodynamics Explains the Origins of Living Things  (2020)
18. Alicia Kowaltowski: Redox Reactions and the Origin of Life 05/29/2015
19. Geoffrey Zubay  Origins of Life on the Earth and in the Cosmos 2000
20. Cited by Paul Davies in: The fifth miracle, page 245, (2000)

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Otangelo


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Chapter 6

Linking the building blocks
During DNA replication, in order to make daughter cells, DNA monomers are linked together to form genomes, and chromosomes identical to the mother cell, the information-bearing molecule of life. Using the RNA polymerase machine complex, DNA is transcribed to messenger RNA (mRNA), which are long strands of joined RNA monomers, forming mRNA polymers,  that store the "message" which is sent to the ribosome where the message is translated. The ribosome based on the instructions from mRNA polymerizes amino acids, strands that fold to become proteins, the working horses of the cell. The sequence of mRNA dictates the sequence of amino acids, which is obtained through translation, using the genetic code. 3 nucleotides form a codon "word", that is assigned to one of the 20 amino acids used in life.  In modern cells, ultra-complex machinery does the polymerization work. But prebiotically, these machines were not extant. That raises the question: How did the first RNA, DNA, and amino-acid polymer strands emerge prebiotically? The synthesis of proteins and nucleic acids from small molecule precursors represents one of the most difficult challenges to the model of pre-biological ( chemical) evolution.

Tan, Change; Stadler, Rob. The Stairway To Life (2020): Consistent Linkage of Building Blocks in living organisms, RNA, DNA, and proteins are chains of monomers that are linked together with perfect consistency, like boxcars perfectly aligned on the tracks and interconnected to form a long train. This “homolinkage” of long biopolymers is very difficult to achieve abiotically, even in modern laboratories run by human intellect. Abiotic chemical reactions to link chains of monomers end up looking more like a train derailment unless complex and highly controlled chemical reactions are employed to connect each monomer correctly 1

Prebiotic RNA and DNA polymerization
Another major problem that origin of life research faces is how to explain the transition from monomer ribonucleotides to polynucleotides. The emergence and existence of catalytic polymers are fundamental. Postulates of how polymerization could have occurred on prebiotic earth are, therefore, another essential question that has not been elucidated.  Initially, this could not have happened with a pre-existing polynucleotide template. 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?  Pierre-Alain Monnard (2012): A fundamental requirement of the RNA world hypothesis is a plausible nonenzymatic polymerization of ribonucleotides that could occur in the prebiotic environment, but the nature of this process is still an open issue. 2

In present-day cells, polymerization is carried out by enzymes with high efficiency and specificity. Enzymes are genetically encoded polymers requiring complex, protein-based synthetic machinery.
Observe what Dr. Pierre-Alain Monnard et al. (2012) write: Selection toward highly efficient catalytic peptides, which eventually resulted in present-day enzymes, could have started at a very early stage of chemical evolution. 3

This is an entirely unsupported claim. Readers without training in biochemistry will simply believe it, without further questioning. And that is what goes in basically the entire scientific literature that deals with origins. Nothing besides just-so stories based on evolutionary guesswork !! In living organisms today, adenosine-5'-triphosphate (ATP) is used for the activation of nucleoside phosphate groups, but ATP would not be available for prebiotic syntheses. Joyce and Orgel note the possible use of minerals for polymerization reactions, but then express their doubts about this possibility.

Robert P. Bywater (2012): Despite the wide repertoire of chemical and biological properties of RNA, which make it such an appealing contender for being the first type of molecular species to usher in life onto this planet, there is no explanation for how such a complex chemical species could have arisen in the absence of sophisticated chemical machinery. The generation of complex chemicals requires many millions of cycles of synthesis, partial degradation, concentration, selection, and reannealing in combinatorially new ways such that sufficiently diverse species could be produced and reproduced, from which particularly suitable entities survived 4

Geoffrey Zubay, Origins of Life on the Earth and in the Cosmos (2000): Once the mononucleotide has been made, it must be converted to an activated derivative suitable for incorporation into a polynucleotide chain. In biochemical pathways, the nucleoside triphosphate derivative is usually used. The triphosphate derivative has more than enough chemical energy to power the formation of the phosphodiester linkages found in polynucleotides so there is no thermodynamic problem here. However, these compounds are not very reactive. In biosystems, sophisticated polymerases are essential to catalyze the polymerization of nucleoside triphosphates. Orgel and others have searched for other forms of activated nucleotides that would be reactive under mild conditions and would not require any more than a divalent cation catalyst. Their extensive search has led them to the use of imidazole-activated mononucleotides. Compounds of this type can be synthesized very efficiently by organo-chemical methods but a satisfactory prebiotic route for their synthesis has not been discovered. Because the reaction of imidazole and a mononucleotide involves the loss of a water molecule, a remote possibility is that the phosphorimidazolide is formed under dehydrating conditions. The formation of activated nucleotides by a prebiotically plausible route remains a most challenging problem. 5

Libretext: Phosphodiester bonds are central to all life on Earth as they make up the backbone of the strands of nucleic acid. In DNA and RNA, the phosphodiester bond is the linkage between the 3' prime carbon atom of one sugar molecule and the 5' prime carbon atom of another, deoxyribose in DNA and ribose in RNA. In modern cells, in order for the phosphodiester bond to be formed and the nucleotides to be joined, the tri-phosphate or di-phosphate forms of the nucleotide building blocks are broken apart to give off energy required to drive the enzyme-catalyzed reaction. Once a single phosphate or two phosphates (pyrophosphates) break apart and participate in a catalytic reaction, the phosphodiester bond is formed. 6 

Saidul Islam (2017): Laboratory-based chemical syntheses of ribonucleotides do most, if not all, require manipulation of sugars and nucleobases with protecting group strategies to overcome the thermodynamic and kinetic pitfalls that prevent their fusion. 7

Deamer (2010): The general problem regarding the condensation of small organic molecules to form macromolecules in an aqueous environment is the thermodynamically unfavorable process of water removal. In the current biosphere, these types of reactions are catalyzed by enzymes and energetically driven by pyrophosphate hydrolysis. 8

Deamer interviewed by Suzan Masur ( 2014): In a solution of monomers, such as monomers of RNA or DNA in solution, the laws of thermodynamics do not allow them to polymerize because there is a tremendous energy barrier to getting them to form bonds. 9

Weber, Arthur L.(1998): Obviously, biocatalysts and energy-rich inorganic phosphorus species were not extant on the Earth before life began. In all cases, the starting problem in a prebiotic synthesis would be the fact that materials would consist of an enormous amount of disparate molecules lying around unordered, and would have had to be separated and sorted out. 2

Allaboutscience: The intrinsic nature of the phosphodiester bonds is also finely-tuned. For instance, the phosphodiester linkage that bridges the ribose sugar of RNA could involve the 5’ OH of one ribose molecule with either the 2’ OH or 3’ OH of the adjacent ribose molecule. RNA exclusively makes use of 5’ to 3’ bonding. There are no explanations of how the right position could have been selected abiotically in a repeated manner in order to produce functional polynucleotide chains.  As it turns out, the 5’ to 3’ linkages impart far greater stability to the RNA molecule than do the 5’ to 2’ bonds. Nucleotides can polymerize via condensation reactions.  The activated nucleotides (or the nucleotides with coupling agent) now had to be polymerized. 10

Arthur V. Chadwick, Ph.D. (2005): When produced and condensed with a nucleotide base, a mixture of optical isomers results, only one of which is relevant to pre-biological studies. Polymerization of nucleotides is inhibited by the incorporation of such an enantiomorph. While only 3'-5' polymers occur in biological systems, 5'-5' and 2'-5' polymers are favored in pre-biological type synthetic reactions. 11

A recent paper from Steven Benner and co-workers (2022) claimed: This study shows that various mafic rock glasses almost certainly present on the surface of the Hadean Earth catalyze the formation of polyribonucleic acid in water starting from nucleoside triphosphates. 12

RNA spontaneously forms on basalt lava glass in the presence of nucleoside triphosphates. This is a simple reaction, which is expected to happen spontaneously in various conditions. Nucleoside triphosphates however are compounds that were not around prebiotically - only living cells synthesize them through very complex biosynthesis pathways. They require long chains of complex enzyme-catalyzed reactions, and also energy, which were not around on early earth.

Index Page: On the origin of Cell factories by the means of an intelligent designer Steve_10
Steven Benner (2008) The red bonds in RNA are each unstable in water. Each of these bonds represents a problem for the prebiotic synthesis of RNA in water, even after the building blocks are in hand since the synthesis of these bonds requires the loss of water. Further, even if the RNA could be made, the red bonds would break in water. In modern life, damage done by water to RNA  and DNA is repaired. Such repair systems were preusumably not present prebiotically. Another paradox. In water, adenine, guanine, and cytosine all eventually lose their NH2 units, the phosphate backbone of  RNA hydrolyzes, and the nucleobases will fall off of ribose. 13

Steven Benner (2012) Current experiments suggest that RNA molecules that catalyze the degradation of RNA are more likely to emerge from a library of random RNA molecules than RNA molecules that catalyze the template-directed synthesis of RNA, especially given cofactors (e.g., Mg2+). This could, of course, be a serious (and possibly fatal) flaw to the RNA-first hypothesis for bio-origins. 14

Steven Benner (2014)The Water Paradox: Water is commonly viewed as essential for life, and theories of water are well known to support this as a requirement. So are biopolymers, like 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 allows us to construct a paradox: RNA requires water to function, but RNA cannot emerge in water, and does not persist in water without repair. Any solution to the “origins problem” must manage the paradox forced by pairing this theory and this observation; life seems to need a substance (water) that is inherently toxic to polymers (e.g. RNA) necessary for life 15

Westheimer (1987) Although RNA is a phosphodiester and carries a negative charge, it is relatively susceptible to hydrolysis; the rate of its spontaneous reaction with water, extrapolated to room temperature, is about 100 times greater than that of DNA 16

Phosphodiester bonds
Activated monomers are essential because polymerization reactions occur in an aqueous medium and are therefore energetically uphill in the absence of activation. A plausible energy source for polymerization remains an open question. Condensation reactions driven by cycles of anhydrous conditions and hydration would seem to be one obvious possibility but seem limited by the lack of specificity of the chemical bonds that are formed. 17

Libretexts: Phosphodiester bonds are central to most life on Earth, as they make up the backbone of the strands of DNA. In DNA and RNA, the phosphodiester bond is the linkage between the 3' carbon atom of one sugar molecule and the 5' carbon atom of another, deoxyribose in DNA and ribose in RNA. Strong covalent bonds form between the phosphate group and two 5-carbon ring carbohydrates (pentoses) over two ester bonds. In order for the phosphodiester bond to be formed and the nucleotides to be joined, the tri-phosphate or di-phosphate forms of the nucleotide building blocks are broken apart to give off energy required to drive the enzyme-catalyzed reaction. When a single phosphate or two phosphates known as pyrophosphates break away and catalyze the reaction, the phosphodiester bond is formed. Hydrolysis of phosphodiester bonds can be catalyzed by the action of phosphodiesterases which play an important role in repairing DNA sequences. 18

Prebiotic phosphodiester bond formation
An often-cited claim is that RNA polymerization could be performed on clay. Robert Shapiro wrote a critique in regards to prebiotic proposals of clay-catalyzed oligonucleotide synthesis (2006): 
An extensive series of studies on the polymerization of activated RNA monomers has been carried out by Ferris and his collaborators. A recent publication from this group concluded with the statement: “The facile synthesis of relatively large amounts of RNA oligomers provides a convenient route to the proposed RNA world. The 35–40 oligomers formed are both sufficiently long to exhibit fidelity in replication as well as catalytic activity”. The first review cited above had stated this more succinctly: “The generation of RNAs with chain lengths greater than 40 oligomers would have been long enough to initiate the first life on Earth”. Do natural clays catalyze this reaction? The attractiveness of this oligonucleotide synthesis rests in part on the ready availability of the catalyst. Montmorillonite is a layered clay mineral-rich in silicate and aluminum oxide bonds. It is widely distributed in deposits on the contemporary Earth. If the polymerization of RNA subunits was a common property of this native mineral, the case for RNA at the start of life would be greatly enhanced. However, the “[c]atalytic activity of native montmorillonites before being converted to their homoionic forms is very poor”. The native clays interfere with phosphorylation reactions. This handicap was overcome in the synthetic experiments by titrating the clays to a monoionic form, generally sodium, before they were used. Even after this step, the activity of the montmorillonite depended strongly on its physical source, with samples from Wyoming yielding the best results. Eventually the experimenters settled on Volclay, a commercially processed Wyoming montmorillonite provided by the American Colloid Company 19

Selecting the binding locations
Once the three components would have been synthesized prebiotically, they would have had to be separated from the confusing jumble of similar molecules nearby, and they would have had to become sufficiently concentrated in order to move to the next steps, to join them to form nucleosides, and nucleotides. 

The phosphate/ribose backbone of DNA is hydrophilic (water-loving), so it orients itself outward toward the solvent, while the relatively hydrophobic bases bury themselves inside. 

Xaktly explains: Additionally, the geometry of the deoxyribose-phosphate linkage allows for just the right pitch, or distance between strands in the helix, a pitch that nicely accommodates base pairing. 20
Lots of things come together to create the beautiful right-handed double-helix structure. Production of a mixture of d- and l-sugars produces nucelotides that do not fit together properly, producing a very open, weak structure that cannot survive to replicate, catalyze, or synthesize other biological molecules. 

Eduard Schreiner (2011): In DNA the atoms C1', C3', and C4' of the sugar moiety are chiral, while in RNA the presence of an additional OH group renders also C2' of the ribose chiral. 21

Rob Stadler (2021): Even in a very short DNA of just two nucleotides, there are dozens of incorrect possible arrangements of the components and only one correct arrangement. The probability of consistent arrangement decreases exponentially as the DNA lengthens. If natural processes could polymerize these monomers, the result would be chaotic “asphalt,” not highly organized, perfectly consistent biopolymers. Think about it — if monomers spontaneously polymerized within cells, the cell would die because all monomers would be combined into useless random arrangements. 22

Pier Luigi Luisi (2014): Attempts to obtain copolymers, for instance by a random polymerization of monomer mixtures, yield a difficult-to-characterize mixture of all different products. To the best of our knowledge, there is no clear approach to the question of the prebiotic synthesis of macromolecules with an ordered sequence of residues. 23

The homochirality problem
A biological system exclusively uses d-ribose, whereas abiotic experiments synthesize both right- and lefthanded-ribose in equal amounts. But the pre-biological building blocks of life didn’t exhibit such an overwhelming bias. Some were left-handed and some right. So how did right-handed RNA emerge from a mix of molecules?  Some kind of symmetry-breaking process leading to enantioenriched bio monomers would have had to exist. But none is known. Gerald Joyce wrote a science paper that was published in Nature magazine, in 1984.  G. F. Joyce (1984):  This inhibition raises an important problem for many theories of the origin of life. 24 His findings suggested that in order for life to emerge, something first had to crack the symmetry between left-handed and right-handed molecules, an event biochemists call “breaking the mirror.” 

To polymerize proteins, it is essential that only left-handed amino acids are added to the chain. The same applies to ribozymes. First, a prebiotic ribozyme ( able to catalyze its self-replication as a template) would have had to emerge and form spontaneously from a pool of racemic mixture of left and right-handed RNA, selecting only enantiomeric pure monomers, incorporating them in the chain. Secondly, in huge sequence space of nonfunctional sequences, it would have to select one that bears function. Once it would start performing template-directed reactions it would have only a racemic mixture at its disposal, monomers of the opposite handedness to the template would be incorporated as chain terminators at the 2′(3′) end of the products. This would end the sequence, and no copy of itself would be the product.

Stu Borman (2014): No known modern-day RNA-based enzyme can assemble RNA from a racemic soup of left- and right-handed RNA building blocks, the form in which RNA likely would have existed prior to the origin of an RNA world. To develop such a ribozyme, chemical biologist Gerald F. Joyce and postdoc Jonathan T. Sczepanski of Scripps Research Institute California used directed evolution. Like modern RNAs, the new ribozyme has d chirality. But unlike them, it catalyzes the template-directed poly­merization of RNAs of opposite handedness, the joining together of l-RNA building blocks bound to an l-RNA template. It ignores d-RNA building blocks that may be around.

Gerald F. Joyce (2014): Thirty years ago it was shown that the non-enzymatic, template-directed polymerization of activated mononucleotides proceeds readily in a homochiral system, but is severely inhibited by the presence of the opposing enantiomer. This finding poses a severe challenge for the spontaneous emergence of RNA-based life.  It is commonly thought that the earliest RNA polymerase and its substrates would have been of the same handedness, but this is not necessarily the case. Replicating D- and L-RNA molecules may have emerged together, based on the ability of structured RNAs of one-handedness to catalyze the templated polymerization of activated mononucleotides of the opposite handedness.  25

The evident problem is outlined a bit later in Stu Borman's article: The study does not directly address how a cross-chiral ribozyme that itself has pure chirality “could have emerged de novo from an achiral mix of nucleotides. Early-world cross-chiral systems “would at some point have to transition to today’s homochiral systems” and that it is difficult to envisage how that could occur.” 

Since then, scientists have largely focused their search for the origin of life’s handedness in the prebiotic worlds of physics and chemistry, not biology - but with no success. So what is the cop-out? Pure chance !! Luck did the job. That is the only thinkable explanation once God's guiding hand is excluded. How could that be a satisfying answer in face of the immense odds? It is conceivable that the molecules were short enough for all possible sequences, or almost, to be realized (by way of their genes) and submitted to natural selection. This is the way de Duve thought that Intelligent Design could be dismissed. This coming from a Nobel prize winner in medicine makes one wondering, to say the least.  De Duve dismissed intelligent design and replaced it with natural selection. Without providing any of evidence. A claim, based on pure guesswork and speculation.

Amino acid peptide bond formation in prebiotic conditions
The formation of proteins in modern cells depends on bonding one amino acid to another, an incredibly precise and efficient reaction catalyzed by ribosomes. The linking bonds of these polymers are peptide and ester bonds. The polymerization reaction is thermodynamically uphill, with hydrolysis being favored. The monomers are chemically activated by the input of metabolic energy so that polymerization is spontaneous in the presence of the enzymes or ribosomes that catalyze polymerization. 

Pier Luigi Luisi (2014): There are no methods described in the literature to efficiently generate long polypeptides, and we also lack a theory for explaining the origin of some macromolecular sequences instead of others. 19 Hui Huang Hui Huang (2019): The viewpoint of amino acids reacting to produce peptides and proteins has always been an unsatisfactory explanation since producing polypeptides via spontaneous reaction of amino acids in aqueous solution is extremely difficult. 26 David Deamer (2017): A plausible mechanism for the 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. 27 Elizabeth C. Griffith (2012): Polymer formation in aqueous environments would most likely have been necessary on early Earth because the liquid ocean would have been the reservoir of amino acid precursors needed for protein synthesis. 28 Fabian Sauer (2021): A critical point in prebiotic reactions is often the required high concentration of reactants, which cannot be reconciled with a dilute ocean or pond on early Earth. 29

Arthur V. Chadwick, Ph.D. (2005): Given an ocean full of small molecules of the types likely to be produced on pre-biological earth with the types of processes postulated by the origin of life enthusiasts, we must next approach the question of polymerization. This question poses a two-edged sword: We must first demonstrate that macromolecule synthesis is possible under pre-biological conditions, then we must construct a rationale for generating macromolecules rich in the information necessary for usefulness in a developing precell.There are many different problems confronted by any proposal. Polymerization is a reaction in which water is a product. Thus it will only be favored in the absence of water. The presence of precursors in an ocean of water favors the depolymerization of any molecules that might be formed. Careful experiments done in an aqueous solution with very high concentrations of amino acids demonstrate the impossibility of significant polymerization in this environment. 30

The water paradox
Water molecules not only serve as a solvent and reactant but can also promote hydrolysis, which counteracts the formation of essential organic molecules. This conundrum constitutes one of the central issues in origin of life.

Michael Marshall (2020): Although water is essential for life, it is also destructive to life’s core components. There’s a fundamental problem: life’s cornerstone molecules break down in water. This is because proteins, and nucleic acids such as DNA and RNA, are vulnerable at their joints. Proteins are made of chains of amino acids, and nucleic acids are chains of nucleotides. If the chains are placed in water, it attacks the links and eventually breaks them. In carbon chemistry, “water is an enemy to be excluded as rigorously as possible”, wrote the late biochemist Robert Shapiro in his totemic 1986 book Origins, which critiqued the primordial ocean hypothesis. This is the water paradox. Today, cells solve it by limiting the free movement of water in their interiors. Everything is incredibly scaffolded in cells, and it’s scaffolded in a gel, not a water bag. 31

Martina Preiner (2020): Water is essential for all known forms of life. As the solvent for life, it provides protons (H+) and hydroxyl groups (OH–) for myriad reactions but it creates a central problem when it comes to life’s origin: hydrolysis. Water molecules dissociate chemical bonds and thereby break larger molecules or polymers into their monomeric components. In free solution, condensation reactions that generate water are thermodynamically unfavorable. Both protons and hydroxide ions can catalyze hydrolysis reactions, making them highly pH-dependent processes. Water molecules can easily cleave ester and amide bonds and thus hydrolyze nucleic acids and proteins or they affect the half-life of reactants. 32

Steven Benner (2012): The “water problem”. Many bonds in RNA are thermodynamically unstable with respect to hydrolysis in water. Thus, even if these are made in water, they will fall apart. Indeed, examples of RNA molecules that catalyze the template-directed synthesis of RNA are not accepted as a “final proof” of the RNA-first hypothesis in part because they work at high concentrations of Mg2+, which in turn catalyzes hydrolysis of product RNA. 33
Steven Benner (2014): Water is commonly viewed as essential for life, and theories of water are well known to support this as a requirement. So are biopolymers, like 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 allows us to construct a paradox: RNA requires water to function, but RNA cannot emerge in water, and does not persist in water without repair. Any solution to the “origins problem” must manage the paradox forced by pairing this theory and this observation; life seems to need a substance (water) that is inherently toxic to polymers (e.g. RNA) necessary for life. 34

G. Waechtershaeuser (1998): Under the dilute aqueous conditions most relevant for the origin of life, activation of the amino acids by coupling with hydrolysis reactions notably of inorganic polyphosphates has been suggested. It is, however, not clear how under hot aqueous conditions such hydrolytically sensitive coupling compounds, if geochemically available at all, could resist rapid equilibration. 35

Index Page: On the origin of Cell factories by the means of an intelligent designer Peptid11
Formation of a peptide bond  Creative Commons CC0 License

1. The synthesis of proteins and nucleic acids from small molecule precursors, and the formation of amide bonds without the assistance of enzymes represents one of the most difficult challenges to the model of pre-vital ( chemical) evolution, and for theories of the origin of life.
2. The best one can hope for from such a scenario is a racemic polymer of proteinous and non-proteinous amino acids with no relevance to living systems.
3. Polymerization is a reaction in which water is a product. Thus it will only be favored in the absence of water. The presence of precursors in an ocean of water favors the depolymerization of any molecules that might be formed.
4. Even if there were billions of simultaneous trials as the billions of building block molecules interacted in the oceans, or on the thousands of kilometers of shorelines that could provide catalytic surfaces or templates, even if, as is claimed, there was no oxygen in the prebiotic earth, then there would be no protection from UV light, which would destroy and disintegrate prebiotic organic compounds. Secondly, even if there would be a sequence, producing a functional folding protein, by itself, if not inserted in a functional way in the cell, it would have absolutely no function. It would just lay around, and then soon disintegrate. Furthermore, in modern cells proteins are tagged and transported on molecular highways to their precise destination, where they are utilized. Obviously, all this was not extant on the early earth.
5. To form a chain, it is necessary to react bi-functional monomers, that is, molecules with two functional groups so they combine with two others. If a uni-functional monomer (with only one functional group) reacts with the end of the chain, the chain can grow no further at this end. If only a small fraction of uni-functional molecules were present, long polymers could not form. But all ‘prebiotic simulation’ experiments produce at least three times more uni-functional molecules than bifunctional molecules.

The RNA world
The term “RNA world” was first coined in the science paper: Origin of life: The RNA world, published in 1986 by Walter Gilbert 36. It is probably not only the most extensively investigated hypothesis for the origin of life but is also the most popular, hailed by many as the most plausible of how cells emerged on the early earth, and kickstarted life. 

For example, Harold S Bernhardt (2012) wrote in a paper giving the title: The RNA world hypothesis: the worst theory of the early evolution of life (except for all the others) still wrote in the concluding remarks: 
I have argued that the RNA world hypothesis, while certainly imperfect, is the best model we currently have for the early evolution of life. [url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495036/#:~:text=However%2C the following objections have,of RNA is too limited.]37[/url] Others express the same opinion. For example:
Florian Kruse (2019): The RNA world hypothesis is the central consensus in the origins of life research, although many questions arising from this hypothesis have not yet been answered. 38
Jessica C. Bowman (2015): An RNA World that predated the modern world of polypeptide and polynucleotide is one of the most widely accepted models in origin of life research.  

The RNA World Hypothesis is actually a group of related models, with a variety of assumptions and definitions. In all variations of the RNA World Hypothesis, RNA enzymes (ribozymes) predate protein enzymes. Ribozymes performed a variety of catalytic functions in the RNA World, from metabolite biosynthesis to energy conversion. The defining ribozyme of the RNA World, which unites all RNA World models, performed template-directed synthesis of RNA: in the RNA World, RNA self-replicated. 
39

Not all researchers are however that enthusiastic. Italian chemist and OoL researcher Pier Luigi Luisi, for example, interviewed by Suzan Mazur, responded (2012): The most popular view of Origin of Life, by way of the RNA world, to me and to many others is and always has been a fantasy. This is the theory by which self-replicating RNA arose by itself. Self-replicating also means Darwinian evolution. This, according to the story, produces ribozymes, nucleic acid also capable of catalysis. Ribozymes capable of catalyzing the synthesis of DNA and protein. How did self-replicating RNA arise? And, even granted that, how do we go from this to our DNA/protein cells? It is all in the air, still. 40

Life would coincide with the start of a first self-replicating entity, a jack-of-all-trades super-RNA molecule, which would as a world's first, rule and dominate, and somehow promote both, genetics and catalysis, operating initially both functions performed by DNA and proteins, starting to generate and process information, in parallel replicating, performing metabolic transformations and functions ( similar to proteins) and evolve through natural selection. 

Harris Bernstein:  (2020): In early protocellular organisms the genome is thought to have consisted of ssRNAs (genes) that formed folded structures with catalyic activity (ribozymes) 41

Such a transitional state of affairs, from non-life to life, has never been observed. The imagination led very far. According to the narrative, after the emergence of replicating molecules (replicases) that could self-replicate, short amino acid peptides from the prebiotic soup would have joined RNAs, and given rise to the RNA-peptide world, enhancing its catalytic efficiency.  Westheimer (1987) hypothesized that:  the greater structural variety of amino acids permitted better catalytic properties in protein enzymes than in those composed of RNA 42 and given rise to the much more complex DNA–RNA–proteins interdependence, genetic information directing the making and operation of proteins, and subsequent descendant generations would undergo further mutations, creating metabolic networks, promoting growth and division, the fittest survive, gaining new abilities and getting more complex, and evolve into a progenote, into a cenansestor, a first, and a last universal common ancestor, that then would give rise to the three domains of life. 

Index Page: On the origin of Cell factories by the means of an intelligent designer Rna_wo10
Creative Commons CC0 License; 
Hannes Mutschler (2019): A schematic representation of the classical RNA world hypothesis. 
Initially, synthesis and random polymerization of nucleotides result in pools of nucleic acid oligomers, in which template-directed non-enzymatic replication may occur. Recombination reactions result in the generation of longer oligomers. Both long and short oligomers can fold into structures of varying complexity, resulting in the emergence of functional ribozymes. As complexity increases, the first RNA replicase emerges, and encapsulation results in protocells with distinct genetic identities capable of evolution. In reality, it is likely that multiple processes occurred in parallel, rather than in a strictly stepwise manner, and encapsulation may have occurred at any stage. 43

Museum of science: Until relatively recently, it was thought that proteins were the only biological molecules capable of catalysis.  In the early 1980s, however, research groups led by Sidney Altman and Thomas Cech independently found that RNAs can also act as catalysts for chemical reactions. This class of catalytic RNAs is known as ribozymes, and the finding earned Altman and Cech the 1989 Nobel Prize in Chemistry. [url=https://exploringorigins.org/ribozymes.html#:~:text=The discovery of ribozymes supported,and to catalyze chemical reactions.]44[/url]

Could RNA substitute proteins in an RNA world?
RNA can perform various catalytic functions. RNA riboswitches regulate gene expression and perform peptidyl-transfer reactions in the ribosome, self-splicing Group I intron ribozymes remove intron sequences in genes,  RNA ligases, and polymerase ribozymes ( they break and catalyze phosphodiester bonds), etc. The thing is, ribozymes are extremely good and specialized in what they are doing. They are all encoded in DNA in modern cells and preordained to do what they do with specificity.  How would they emerge spontaneously from a messy primordial soup by random chance?

Timothy J. Wilson (2020): What is arguably the most important reaction in the cell, the condensation of amino acids to form polypeptides by the peptidyl transferase activity of the ribosome is catalyzed by RNA in the large subunit . Another example is the splicing of mRNA, where the U2/U6 snRNA complex is a ribozyme. RNase P is a ribozyme that processes the 5' end of tRNA in all domains of life. Some of the small nucleolytic ribozymes are widespread, such as the hammerhead and twister ribozymes. RNA can accelerate phosphoryl transfer reactions by a millionfold or more. This is achieved by one or other of two main broad strategies. The group I self-splicing introns use divalent metal ions to organize the active center, activate the nucleophile, and stabilize the transition state and the group II introns and RNase P also appear to function as metalloenzymes. By contrast, the nucleolytic ribozymes use general acid-base catalysis most frequently utilizing nucleobases. Even though the natural pKa values of the nucleobases are either low (adenine and cytosine) or high (guanine and uracil), generally resulting in a low fraction of active catalyst at physiological pH, a ribozyme like twister has its active center to impose an in-line geometry for attack by the O20 nucleophile, stabilize the phosphorane transition state and perform nucleobase-mediated general acid-base catalysis to achieve a substantial rate acceleration. Peptidyl transferase activity in the large ribosomal subunit does not use nucleobase-mediated catalysis, but the reaction appears to involve proton transfer mediated by a 20 -hydroxyl of tRNA. 

This demonstrates how all extant ribozymes are highly complex and specified to perform their designated catalytic functions with high specificity, precision, and efficiency. All enzymes that use metal co-factors require enormously complex biosynthesis pathways that are similar to robotic production lines. They orchestrate the synthesis of the co-factors, and the precise insertion into the reaction centers, the pockets, where the catalytic reaction occurs. How could the origin of such a state of affairs be explained by chance events? 

Timothy J. Wilson continues: According to the simplest version of the RNA world hypothesis (W. Gilbert, 1986) ribozymes would have catalyzed all cellular chemical reactions in a primitive metabolism. This would have required RNA to catalyze a far wider range of chemistry than we currently are aware of in nature, and it would have required relatively difficult reactions such as carbon–carbon bond formation. Many of the reactions available to the organic chemist for this purpose would be highly improbable for RNA catalysts. 45

Limited catalytic possibilities of RNAs
Ronald R. Breaker (2020): Only a few classes of ribozymes are known to contribute to the task of promoting biochemical transformations. The RNA World theory hypothesis encompasses the notion that earlier forms of life made use of a much greater diversity of ribozymes and other functional RNAs to guide complex metabolic states long before proteins had emerged in evolution. 46

Jessica C. Bowman (2015): Although RNA in extant biology is seen to catalyze only RNA cutting and ligation along with peptidyl transfer (within the ribosome), a wide variety of chemical transformations can be catalyzed by ribozymes selected in vitro. 47

Selecting ribozymes in the laboratory
Timothy J. Wilson (2020):  To explore what might be possible by way of RNA-mediated catalysis of novel chemical reactions there have been many investigations in which in vitro evolution methods have been used to select RNA species that will accelerate a given reaction from a random pool of sequences. These experiments have generally been carried out in a similar manner in which one reactant is tethered to an RNA oligonucleotide whose sequence has been partially or totally randomized, while the other is linked to biotin. If an RNA within the pool can catalyze formation of a bond between the reactants this connects the RNA to the biotin, allowing it to be isolated by binding to streptavidin. This can then be amplified and a second round of selection performed. Something like 15–20 such cycles will be performed after which the reactant will be disconnected from the RNA to see if it will catalyze a reaction in trans. Clearly this strategy is limited to bond-forming reactions, and we can divide this into reactions leading to the formation of C-C, C-N, and C-S bonds. 

Carbon–carbon bond formation. Ribozymes have been selected that can catalyze C-C bonds by the non-natural Diels– Alder cycloaddition reaction, the aldol reaction and related Claisen condensation. 
Carbon–nitrogen bond formation. Selected ribozymes catalyzing C-N bond formation include one that alkylates itself at a specific guanine N7, amide and peptide bond formation and glycosidic bond formation. Very recently Höbartner and colleagues have selected an RNA that catalyzes methyl transfer from O6 -methylguanine to adenine N1. 
Carbon–sulfur bond formation. C-S bond formation has been demonstrated by selected RNA species catalyzing Michael addition and CoA acylation. The estimated rate enhancements vary, being strongly dependent on the estimation of the uncatalyzed rate, but are frequently around 1000-fold. They are probably relatively unsophisticated catalysts. It is likely to be much easier to find an RNA that can exploit metal ions in catalysis than one that uses nucleobases as chemical participants for example. 48

TM.Tarasow ( 1997): Carbon–carbon bond formation and the creation of asymmetric centres are both of great importance biochemically, but have not yet been accomplished by RNA catalysis. (DAase activity) was carried out with a library of 10^14 unique sequences. The RNA molecules were constructed of a contiguous 100-nucleotide randomized region 49

That means nature would have had to shuffle in sequence space of 10^14 possible combinations, to find one that would be able to catalyze a Carbon-carbon bond formation. Considering an estimate of the age of the universe which is 13,7 Billion years, that would be = 1 x 10^16 seconds. A prebiotic soup would have had to try potentially one reaction per second, for 13,7 billion years, to find a functional sequence. That far stretches plausibility. 

Requirement of cofactors and coenzymes for ribozyme function
The Achilles heel of all these experiments is that there was no prebiotic selection, and biotin is a Vitamin B7, an enzyme co-factor. The synthesis of biotin is very complex, depending on a series of complex enzymes ( BioC, BioH BioF, BioA, BioD, and BioB, and SAH, S-adenosylhomocysteine; SAM, S-adenosyl-L-methionine; AMTOD, S-adenosyl-2-oxo-4-thiomethylbutyrate; 5’-DOA, 5′-deoxyadenosine.) Evidently, these enzymes and cofactors were not swimming in the prebiotic soup, synthesizing biotin, ready to be linked to the random nucleotide chains.

Daniel N. Frank (1997): Despite the occurrence of a wide variety of structures and mechanisms among catalytic RNAs (ribozymes), most are metalloenzymes that require divalent metal cations for catalytic function. The ribozyme RNase P for example absolutely requires divalent metal ions for catalytic function. Multiple Mg2+ ions contribute to the optimal catalytic efficiency of RNase P, and it is likely that the tertiary structure of the ribozyme forms a specific metal-binding pocket for these ions within the active site. Divalent metals are thought to play two critical roles in ribozyme function. First, they promote the proper folding of RNA tertiary structures. Second, metals can participate directly in catalysis by activating nucleophiles, stabilizing transition states, and stabilizing leaving groups  50

Gerald F. Joyce (2018): Divalent metal cations appear to be essential for efficient RNA copying, but the poor affinity of the catalytic metal for the reaction center means that very high concentrations of these ions are required, which causes problems for both the RNA (degradation, hydrolysis of activated monomers) and for the fatty acid–based membranes. RNA polymerase enzymes solve these problems by binding and precisely positioning the metal ion for catalysis . A prebiotically plausible means of achieving effective metal ion catalysis at low ambient concentration would greatly simplify the development of model protocells. 51

Coenzymes and cofactors are molecules that help an enzyme or protein function appropriately. Coenzymes are organic molecules and quite often bind loosely to the active site of an enzyme and aid in substrate recruitment, whereas cofactors do not bind the enzyme. Cofactors are "helper molecules" and can be inorganic or organic in nature. These include metal ions and are often required to increase the rate of catalysis of a given reaction catalyzed by the specific enzyme. These coenzymes and cofactors play an integral role in a number of cellular metabolism reactions playing both structural and functional roles to aid in the catalysis. [url=https://www.biovision.com/products/metabolism-assays/coenzymes-cofactors.html#:~:text=Coenzymes and cofactors are molecules,do not bind the enzyme.]5[/url]2

HAROLD B. WHITE, III (1975): Coenzymes are complex organic molecules that are essential for many enzyme-catalyzed reactions. At least 52% of the nearly 1750 enzymes recently cataloged (IUPAC-IUB, 1972) require a coenzyme for activity. I propose that coenzymes are the surviving vestiges of nucleic acid enzymes which preceded the evolution of ribosomal protein synthesis. 51

If the RNA world were true, ribozymes would have had to catalyze a wide range of catalytic reactions which subsequently were substituted by proteins. About half would only obtain the necessary catalytic activity by recruiting and employing cofactors and coenzymes ( which, as we see, also depend on complex biosynthesis pathways, and alternative non-enzymatic emergence would be very unlikely).  It is as if a Software engineer had to learn to become a mechanical engineer and assemble complex machines. There is no evidence that RNAs, made of just four different building blocks ( the four nucleobases), were ever able to catalyze the widely different enzymatic and metabolic reactions required for life to thrive. There is no evidence, that that somehow, prebiotic shuffling created a pool of millions of repetitive complex nucleotides, all with the repetitive configuration of purine and pyrimidine bases. There is no chemical logic that makes it appear plausible, that a gradual chemical evolutionary process would have promoted the emergence of an RNA world, followed by an RNA-peptide world. There is a wide unexplained gap between the RNA world, and the modern DNA - RNA - protein state of affairs in modern cells. Can this gap be bridged with new hypotheses and the advance in abiogenesis investigations? That prediction looks rather unlikely. Only time will tell. 
 
Solving a chicken & egg problem?
Supposedly, the RNA world hypothesis solved a long-standing chicken & egg, or catch22 problem ( J.Wells [2006]: In Joseph Heller’s novel about World War II, Catch-22, an aviator could be excused from combat duty for being crazy. But a rule specified that he first had to request an excuse, and anyone who requested an excuse from combat duty was obviously not crazy, so such requests were invariably denied. The rule that made it impossible to be excused from combat duty was called “Catch-22.”  ) In 1965, Sidney Fox wrote a scientific article, asking: How, when no life existed, did substances come into being which today are absolutely essential to living systems, yet which can only be formed by those systems?  He was referring to a problem, outlined by Jordana Cepelewicz (2017): For scientists studying the origin of life, one of the greatest chicken-or-the-egg questions is: Which came first — proteins or nucleic acids like DNA and RNA? 27 This problem arises because DNA and RNA direct the synthesis of enzymes and proteins. But proteins synthesize the making of RNA and DNA. 

Jessica C. Bowman (2015) claimed: The RNA World Hypothesis resolves the putative chicken and egg dilemma: which came first, polynucleotide or polypeptide? The simultaneous emergence from whole cloth of two functional biopolymers, one encoding the other, seems improbable. A single type of ancestral biopolymer (polynucleotide), performing multiple roles, appears to be characterized by high parsimony. A ‘‘Polymer Transition’’, a progression of biology from one polymer type (polynucleotide) to two polymer types (polynucleotide and polypeptide), is consistent with an expectation that ancient biology transitioned from simple to complex. 53





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1. Change Laura Tan, Rob Stadler: The Stairway To Life: An Origin-Of-Life Reality Check  March 13, 2020 
2. Weber, Arthur L.: [size=12]Prebiotic Polymer Synthesis and the Origin of Glycolytic Metabolism 1998-01-01
[/size]
3. Dr. Rafał Wieczorek: [size=12][size=13]Formation of RNA Phosphodiester Bond by Histidine-Containing Dipeptides[/size] 18 December 2012
[/size]
4. Robert P. Bywater writes in: On dating stages in prebiotic chemical evolution 15 February 2012

5. Geoffrey Zubay:[size=12]Origins of Life on the Earth and in the Cosmos  2000
[/size]
6. [url=https://chem.libretexts.org/Courses/Sacramento_City_College/SCC%3A_Chem_309_-_General_Organic_and_Biochemistry_(Bennett)/Text/13%3A_Functional_Group_Reactions/13.10%3A_Phosphoester_Formation#:~:text=an ester bonds.-,Phosphodiesters,the strands of nucleic acid.][size=12]Phosphoester Formation[/url]
[/size]
7. Saidu lIslam: Prebiotic Systems Chemistry: Complexity Overcoming Clutter  13 April 2017
8. David Deamer: Bioenergetics and Life's Origins 2010 Feb; 2
9. Suzan Mazur: The Origin of Life Circus: A How To Make Life  November 30, 2014
10. All about science
11. Arthur V. Chadwick, Ph.D.: Abiogenic Origin of Life: A Theory in Crisis 2005
12. Steven A. Benner: Catalytic Synthesis of Polyribonucleic Acid on Prebiotic Rock Glasses 8 Jun 2022
13. Steven A. Benner: Life, the Universe and the Scientific Method 2008
14. Steven A. Benner: [size=12]Asphalt, Water, and the Prebiotic Synthesis of Ribose, Ribonucleosides, and RNA March 28, 2012
[/size]
15. Steven A. Benner: [size=12]Paradoxes in the Origin of Life 5 December 2014
[/size]
16. F H Westheimer: [size=12]Why nature chose phosphates  1987 Mar 6
[/size]
17. David Deamer: Bioenergetics and Life's Origins 2010 Feb; 2

18. Libretext: Phosphoester Formation

19. Robert Shapiro: Small Molecule Interactions Were Central to the Origin of Life Review 2006
20. Xaktly: DNA & RNA: The foundation of life on Earth
21. Eduard Schreiner: Stereochemical errors and their implications for molecular dynamics simulations 2011
22. Rob Stadler: Long Story Short — A Strikingly Unnatural Property of Biopolymers December 1, 2021
23. Pier Luigi Luisi : OPEN QUESTIONS IN ORIGIN OF LIFE: EXPERIMENTAL STUDIES ON THE ORIGIN OF NUCLEIC ACIDS AND PROTEINS WITH SPECIFIC AND FUNCTIONAL SEQUENCES BY A CHEMICAL SYNTHETIC BIOLOGY APPROACH February 2014
24. G. F. Joyce: Chiral selection in poly(C)-directed synthesis of oligo(G) 16 August 1984
25. Gerald F. Joyce A cross-chiral RNA polymerase ribozyme 29 October 2014
26. Hui Huang, Siwei Yang: Photocatalytic Polymerization from Amino Acid to Protein by Carbon Dots at Room Temperature October 22, 2019
27. David Deamer: [size=12]The Role of Lipid Membranes in Life’s Origin 2017 Jan 17
[/size]
28. Elizabeth C. Griffith: [size=12]In situ observation of peptide bond formation at the water–air interface August 6, 2012
[/size]
29. Fabian Sauer: [size=12]From amino acid mixtures to peptides in liquid sulphur dioxide on early Earth 2021 Dec 10
[/size]
30. Arthur V. Chadwick, Ph.D.: Abiogenic Origin of Life: A Theory in Crisis 2005

31. Michael Marshall: [size=12]How the first life on Earth survived its biggest threat — water 09 December 2020
[/size]
32. Martina Preiner: [size=12]The ambivalent role of water at the origins of life 16 May 2020
[/size]
33. Steven A. Benner: Asphalt, Water, and the Prebiotic Synthesis of Ribose, Ribonucleosides, and RNA March 28, 2012

34. Steven A. Benner [size=12]Paradoxes in the Origin of Life 5 Dec. 2014
[/size]
35. G. Waechtershaeuser: [size=12]Peptides by Activation of Amino Acids with CO on (Ni,Fe)S Surfaces: Implications for the Origin of Life 31 JULY 1998
[/size]
36. Walter Gilbert: [size=12]Origin of life: The RNA world 20 February 1986
[/size]37. Harold S Bernhardt:[url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495036/#:~:text=However%2C the following objections have,of RNA is too limited.] The RNA world hypothesis: the worst theory of the early evolution of life (except for all the others)a[/url] 2012 Jul 13
38. Prof. Dr. Oliver Trapp: Direct Prebiotic Pathway to DNA Nucleosides 26 May 2019
39. Jessica C. Bowman: The Ribosome Challenge to the RNA World  20 February 2015
40. Suzan Mazur: Pier Luigi Luisi: Origin of Life Mindstorms Needed 19 December 2012
41. Harris Bernstein: Origin of DNA Repair in the RNA World October 12th, 2020
42. F H Westheimer: Why nature chose phosphates  1987 Mar 6
43.Harris Bernstein: Origin of DNA Repair in the RNA World October 12th, 2020
44. [url=https://exploringorigins.org/ribozymes.html#:~:text=The discovery of ribozymes supported,and to catalyze chemical reactions.]Exploring life's origins[/url]
45. Timothy J Wilson: The potential versatility of RNA catalysis 2021 May 5
46. Ronald R. Breaker: Imaginary Ribozymes 2020 Aug 21
47. Jessica C. Bowman: The Ribosome Challenge to the RNA World  20 February 2015
48. Timothy J Wilson: The potential versatility of RNA catalysis 2021 May 5
49. T M Tarasow: RNA-catalysed carbon-carbon bond formation 1997 Sep 4
50. Daniel N. Frank: In vitro selection for altered divalent metal specificity in the RNase P RNA 1997 Dec 23
51. Gerald F. Joyce: Protocells and RNA Self-Replication 2018
52. Coenzymes & Cofactors
53. Jessica C. Bowman: The Ribosome Challenge to the RNA World  20 February 2015











9. T M Tarasow: RNA-catalysed carbon-carbon bond formation 1997 Sep 4
5. David Deamer: Bioenergetics and Life's Origins  January 13, 2010
9. Robert Shapiro: Small Molecule Interactions Were Central to the Origin of Life Review 2006
26. S W FOX: A Theory of Macromolecular and Cellular Origins 1965
27. Jordana Cepelewicz: Life’s First Molecule Was Protein, Not RNA, New Model Suggests November 2, 2017

37. Jonathan Wells: The Politically Incorrect Guide to Darwinism and Intelligent Design August 21, 2006
39. [url=https://exploringorigins.org/ribozymes.html#:~:text=The discovery of ribozymes supported,and to catalyze chemical reactions.]Exploring life's origins[/url]
40. Stu Borman: Ribozyme May Hint At The Origin Of Life November 17, 2014 

48. 

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Under naturalism, the only possible explanation for the complexity seen in biochemistry is gradualism: From the simple to the complex. Gradually moving from chemistry to biology. A sudden appearance of all the complex interdependent intricacies observed in the living cannot be explained by a biochemical Big bang. It is untenable. Therefore, under the framework of philosophical naturalism, answers have to be found that confer with the gradualistic scenario. Only the model of intelligent design permits the hypothesis of instant creation by an intelligent agency. Giving up gradualism means giving up naturalism. 

Eugene V Koonin (2007): The origin of the translation system is, arguably, the central and the hardest problem in the study of the origin of life, and one of the hardest in all evolutionary biology. The problem has a clear catch-22 aspect: high translation fidelity hardly can be achieved without a complex, highly evolved set of RNAs and proteins but an elaborate protein machinery could not evolve without an accurate translation system. 13

Paul C. W. Davies (2013): Because of the organizational structure of systems capable of processing algorithmic (instructional) information, it is not at all clear that a monomolecular system, where a single polymer plays the role of catalyst and informational carrier, is even logically consistent with the organization of information flow in living systems because there is no possibility of separating information storage from information processing (that being such a distinctive feature of modern life). As such, digital-first systems (as currently posed) represent a rather trivial form of information processing that fails to capture the logical structure of life as we know it.  The real challenge of life's origin is thus to explain how instructional information control systems emerge naturally and spontaneously from mere molecular dynamics. 15

Self-replication in the RNA world
Despite the current celebrity status, there are several reasons that raise doubts that RNAs would self-assemble into ribozyme polymerases with function-bearing sequences, obtaining the right chemical structures with autocatalytic properties, and being apt to start self-replication. 

Harold S Bernhardt (2012): The following objections have been raised to the RNA world hypothesis: (i) RNA is too complex a molecule to have arisen prebiotically; (ii) RNA is inherently unstable; (iii) catalysis is a relatively rare property of long RNA sequences only; and (iv) the catalytic repertoire of RNA is too limited. 12

Since the various problems of prebiotic RNA monomers have been outlined in the previous chapter, we will address now the issues with RNA self-replication.  Steven Benner (2013): Catalysis and genetics place contradicting demands on any single molecular system asked to do both. For example, catalytic molecules should fold, to surround a transition state. Genetic molecules should not fold, to allow them to template the synthesis of their complements. Catalytic molecules should have many building blocks, to create versatile catalytic potential. Genetic molecules should have few building blocks, to ensure that they are copied with high fidelity 11

Jack W Szostak (2012): The first RNA World models were based on the concept of an RNA replicase - a ribozyme that was a good enough RNA polymerase that it could catalyze its own replication. Although several RNA polymerase ribozymes have been evolved in vitro, the creation of a true replicase remains a great experimental challenge. 6

Hannes Mutschler (2019): It has not yet been possible to demonstrate robust and continuous RNA self-replication from a realistic feedstock (i.e. activated mono- or short mixed-sequence oligonucleotides). In the case of ribozymes, only ‘simple’ ligation or recombination-based RNA replication from defined oligonucleotides has been demonstrated. Such systems have only a limited ability to transmit heritable information and so are not capable of open-ended evolution — the ability to indefinitely increase in complexity like living systems. Open-ended evolution requires that a replicase must at least be able to efficiently copy generic sequences longer than that required to encode its own function. RNA in isolation (including ribozymes) is simply not sufficient to catalyze its own replication, and substantial help from either other molecules or the environment is essential. 7

The annealing problem
Jordana Cepelewicz (2019): As a first step toward making a copy of itself, a single strand of RNA can take up complementary nucleotide building blocks from its surroundings and stitch them together. But the paired RNA strands then tend to bind to each other so tightly that they don’t unwind without help, which prevents them from acting as either catalysts or templates for further RNA strands. “It’s a real challenge,” Sutherland said. “It’s held the field back for a long time.” 8

Gerald F. Joyce (2018): Because the product of template copying is a double-stranded RNA, there must be some means of either strand separation or strand displacement synthesis. Transient temperature fluctuations could lead to thermal strand separation, but long RNA duplexes (≥30 base pairs) are difficult to denature thermally. 10

In modern cells, ribonuclease H enzymes destroy annealed RNAs but evidently, they were not around on prebiotic earth.

The Eigen paradox
Jaroslaw Synak (2022): Another challenge is the maintenance of genetic information in RNA sequences over many rounds of imperfect replication. In order to survive, RNA polymerase must be copied faster than it is hydrolyzed and accurately enough to preserve its function. In the early stages of molecular evolution, due to the lack of reliable replication mechanisms, the mutation rate was likely very high and the critical amount of information could not have been stored in long RNA sequences; on the other hand, the short ones could not be efficient enzymes. Maynard Smith estimated that the maximum length of the RNA replicase is approximately 100 nucleotides, assuming nonenzymatic replication with a copying fidelity of one base of up to 0.99. In order to further increase this length, the copying fidelity would have to be increased, which requires the presence of specific enzymes. This is known as Eigen’s paradox and is often equivalently formulated as: no enzymes without a large genome and no large 5

Indeed. But the problem is not only to maintain genetic information but for the first replicator to obtain it in the first place!

Natalia Szostak (2017): Researchers have performed many attempts to create RNA polymerase ribozyme, recently resulting in a cross-chiral RNA polymerase ribozyme and a system of cooperative RNA replicators, as well as RNA polymerase ribozyme that is able to synthesize structured functional RNAs, including aptamers and ribozymes. However, these molecules are too large to be maintained in a quasispecies population, as they exceed the 100 nucleotide error threshold, which is the maximum length polynucleotide molecule that can be accurately replicated without high fidelity polymerases. Eigen suggested hypercycles as a solution to the error threshold problem mentioned above. However, even if the traditional hypercycle model formulation based on ordinary differential equations is ecologically stable, it is proved to be evolutionarily unstable. To evolve life as we know it, separation of the roles performed by replicases, information storage, and replication of the information, into two molecules appears to be one of the crucial events that had to occur early in the stages leading to life. 4

A remarkable admission !!

Sami EL Khatib (2021): Countless challenges are faced by an RNA self-replicating cycle; for it to be a fully chemically and  enzymatically free reaction, the cycle loses rate and fidelity, so much that it does not even reach the critical threshold for the sustenance of life, meaning the RNA nucleotides break apart faster than the incorporation of nucleotides takes place, thus is the case when experimenting with modern substrates, that do not leak out of cells and are very polar with the regularly known triphosphate ester, this is advantageous to the modern cell where it uses enzymes to catalyze the release of di-phosphate, but not for the primitive cell as the substrates are found in the environment and require continuous dynamic exchange. The RNA world hypothesis has been criticized mostly because of the belief that long RNA sequences are needed for the catalytic function of RNA. These long sequences are enormous and are needed to isolate the catalytic and biding functions of the overall ribozyme. For example the best ribozyme replicase created so far, which is able to replicate an impressive 95-nucleotide stretch of RNA, is ~190 nucleotides in length, which is by far too large a number to have risen in any random assembly, thus in vitro selection experiments had to be designed where 10,000,000,000,000 – 1,000,000,000,000,000 of randomized RNA molecules are required as the starting point for the isolation of ribozymic and/or binding activity. This experiment clearly contradicts the probable prebiotic situation. 14

Index Page: On the origin of Cell factories by the means of an intelligent designer Sem_tz34

Eugene Koonin (2012):  The primary incentive behind the theory of self-replicating systems that Manfred Eigen outlined was to develop a simple model explaining the origin of biological information and, hence, of life itself. Eigen’s theory revealed the existence of the fundamental limit on the fidelity of replication (the Eigen threshold): If the product of the error (mutation) rate and the information capacity (genome size) is below the Eigen threshold, there will be stable inheritance and hence evolution; however, if it is above the threshold, the mutational meltdown and extinction become inevitable (Eigen, 1971). The Eigen threshold lies somewhere between 1 and 10 mutations per round of replication; regardless of the exact value, staying above the threshold fidelity is required for sustainable replication and so is a prerequisite for the start of biological evolution. Indeed, the very origin of the first organisms presents at least an appearance of a paradox because a certain minimum level of complexity is required to make self-replication possible at all; high-fidelity replication requires additional functionalities that need even more information to be encoded. However, the replication fidelity at a given point in time limits the amount of information that can be encoded in the genome. What turns this seemingly vicious circle into the (seemingly) unending spiral of increasing complexity—the Darwin-Eigen cycle.  The crucial question in the study of the origin of life is how the Darwin-Eigen cycle started—how was the minimum complexity that is required to achieve the minimally acceptable replication fidelity attained? In even the simplest modern systems, such as RNA viruses with the replication fidelity of only about 10^3 and viroids that replicate with the lowest fidelity among the known replicons (about 10^2), replication is catalyzed by complex protein polymerases. The replicase itself is produced by translation of the respective mRNA(s), which is mediated by the immensely complex ribosomal apparatus. Hence, the dramatic paradox of the origin of life is that, to attain the minimum complexity required for a biological system to start on the Darwin-Eigen spiral, a system of a far greater complexity appears to be required. How such a system could evolve is a puzzle that defeats conventional evolutionary thinking, all of which is about biological systems moving along the spiral; the solution is bound to be unusual.

When considering the origin of the first life forms, one faces the proverbial chicken-and-egg problem: What came first, DNA or protein, the gene or the product? In that form, the problem might be outright unsolvable due to the Darwin-Eigen paradox: To replicate and transcribe DNA, functionally active proteins are required, but production of these proteins requires accurate replication, transcription, and translation of nucleic acids. If one sticks to the triad of the Central Dogma, it is impossible to envisage what could be the starting material for the Darwin-Eigen cycle. Even removing DNA from the triad and postulating that the original genetic material consisted of RNA (thus reducing the triad to a dyad), although an important idea, does not help much because the paradox remains. For the evolution toward greater complexity to take off, the system needs to somehow get started on the Darwin-Eigen cycle before establishing the feedback between the (RNA) templates (the information component of the replicator system) and proteins (the executive component). The brilliantly ingenious and perhaps only possible solution was independently proposed by Carl Woese, Francis Crick, and Leslie Orgel in 1967–68: neither the chicken nor the egg, but what is in the middle—RNA alone. The unique property of RNA that makes it a credible—indeed, apparently, the best—candidate for the central role in the primordial replicating system is its ability to combine informational and catalytic functions. Thus, it was extremely tempting to propose that the first replicator systems—the first life forms—consisted solely of RNA molecules that functioned both as information carriers (genomes and genes) and as catalysts of diverse reactions, including, in particular, their own replication and precursor synthesis. This bold speculation has been spectacularly boosted by the discovery and subsequent study of ribozymes (RNA enzymes), which was pioneered by the discovery by Thomas Cech and colleagues in 1982 of the autocatalytic cleavage of the Tetrahymena rRNA intron, and by the demonstration in 1983 by Sydney Altman and colleagues that RNAse P is a ribozyme. Following these seminal discoveries, the study of ribozymes has evolved into a vast, expanding research area. 

Despite all invested effort, the in vitro evolved ribozymes remain (relatively) poor catalysts for most reactions; the lack of efficient, processive ribozyme polymerases seems particularly troubling. An estimate based on the functional tolerance of well-characterized ribozymes to mutations suggest that, at fidelity of 10^3 errors per nucleotide per replicase cycle (roughly, the fidelity of the RNA-dependent RNA polymerases of modern viruses), an RNA “organism” with about 100 “genes” the size of a tRNA (80 nucleotides) would be sustainable. Such a level of fidelity would require only an order of magnitude improvement over the most accurate ribozyme polymerases obtained by in vitro selection 3

Lack of prebiotic RNA repair mechanisms
Harris Bernstein (2020): Persistence and replication of even the simplest forms of RNA life must have depended on preserving the information content of the RNA genome from damage (a form of informational noise). Damage to the RNA genome likely occurred in a variety of ways including spontaneous hydrolysis, exposure to UV light and exposure to reactive chemicals. 9

Where did the energy come from?
Jack Szostak, interviewed by Suzan Mazur (2014): The problem is RNA falls apart. The activated nucleotides we use to do the non-enzymatic replication -- they react with water, so they fall apart. There needs to be a way to bring energy back into the system to essentially keep the battery charged. To keep all the nucleotides activated and to keep things running. 1

PHILIP BALL (2020): It’s an alluring picture – catalytic RNAs appear by chance on the early Earth as molecular replicators that gradually evolve into complex molecules capable of encoding proteins, metabolic systems and ultimately DNA. But it’s almost certainly wrong. For even an RNA-based replication process needs energy: it can’t shelve metabolism until later. And although relatively simple self-copying ribozymes have been made, they typically work only if provided with just the right oligonucleotide components to work on. What’s more, sustained cycles of replication and proliferation require special conditions to ensure that RNA templates can be separated from copies made on them. Perhaps the biggest problem is that self-replicating ribozymes are highly complex molecules that seem very unlikely to have randomly polymerized in a prebiotic soup. And the argument that they might have been delivered by molecular evolution merely puts the cart before the horse. The problem is all the harder once you acknowledge what a complex mess of chemicals any plausible prebiotic soup would have been. It’s nigh impossible to see how anything lifelike could come from it without mechanisms for both concentrating and segregating prebiotic molecules – to give RNA-making ribozymes any hope of copying themselves rather than just churning out junk, for example. In short, once you look at it closely, the RNA world raises as many questions as it answers.  The best RNA polymerase the researchers obtained this way had a roughly 8% chance of inserting any nucleotide wrongly, and any such error increased the chance that the full chain encoded by the molecule would not be replicated. What’s more, making the original class I ligase was even more error-prone and inefficient – there was a 17% chance of an error on each nucleotide addition, plus a small chance of a spurious extra nucleotide being added at each position. These errors would be critical to the prospects of molecular evolution since there is a threshold error rate above which a replicating molecule loses any Darwinian advantage over the rest of the population – in other words, evolution depends on good enough replication. Fidelity of copying could thus be a problem, hitherto insufficiently recognized, for the appearance of a self-sustaining, evolving RNA-based system: that is, for an RNA world. Maybe this obstacle could have been overcome in time. But my hunch is that any prebiotic molecule will have been too inefficient, inaccurate, dilute and noise-ridden to have cleared the hurdle. 2

1. Suzan Mazur: The Origin of Life Circus: A How To Make Life Extravaganza  November 30, 2014
2. PHILIP BALL: Flaws in the RNA world  12 FEBRUARY 2020
3. Eugene Koonin: The Logic of Chance: The Nature and Origin of Biological Evolution  31 agosto 2011
4. Natalia Szostak: Simulating the origins of life: The dual role of RNA replicases as an obstacle to evolution July 10, 2017
5. Jaroslaw Synak: RNA World Modeling: A Comparison of Two Complementary Approaches 11 April 2022
6. Jack W Szostak: The eightfold path to non-enzymatic RNA replication 03 February 2012
7. Hannes Mutschler: The difficult case of an RNA-only origin of life AUGUST 28 2019
8. Jordana Cepelewicz: Origin-of-Life Study Points to Chemical Chimeras, Not RNA September 16, 2019
9. Harris Bernstein: Origin of DNA Repair in the RNA World October 12th, 2020
10. Gerald F. Joyce: Protocells and RNA Self-Replication 2018
11. Steven A. Benner: The ‘‘Strong’’ RNA World Hypothesis: Fifty Years Old 2013 Apr;13
12. Harold S Bernhardt:[url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495036/#:~:text=However%2C the following objections have,of RNA is too limited.] The RNA world hypothesis: the worst theory of the early evolution of life[/url] (except for all the others) 2012 Jul 13
13. Eugene V Koonin: On the origin of the translation system and the genetic code in the RNA world by means of natural selection, exaptation, and subfunctionalization 2007 May 31
14. Sami EL Khatib: Assumption and Criticism on RNA World Hypothesis from Ribozymes to Functional Cells March 12, 2021
15.  Paul C. W. Davies: The algorithmic origins of life 2013 Feb 6

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