Abiogenesis is mathematically impossible

From Prelife to Life: How Chemical Kinetics Become Evolutionary Dynamics
https://sci-hub.ee/10.1021/ar2002683

Wilhelm T. S. Huck Robustness, Entrainment, and Hybridization in Dissipative Molecular Networks, and the Origin of Life May 30, 2019
How simple chemical reactions self-assembled into complex, robust networks at the origin of life is unknown. This general problem of self-assembly of dissipative molecular networks (  out of, and often far from, thermodynamic equilibrium ) is also important in understanding the growth of complexity from simplicity in molecular and biomolecular systems.  
https://robobees.seas.harvard.edu/files/gmwgroup/files/1320.pdf

Bridging the trajectory from non-life to life, the gap is far, far too wide. It's difficult to describe. Analogies do not do justice to illustrate and clarify the hopeless situation. 

People that have no clue, that have heard about the Miller-Urey experiment, often cite it, and claim, that it gave a successful result, demonstrating that abiogenesis is possible in principle. Others point to the various hypotheses, claiming that they warrant the belief that it could theoretically occur.   

Imagine a cause that needs to create an interlinked factory complex containing 1300 complex machines that are installed in specialized compartments, ordered based on the specific task that they perform, and interlinked in a functional way to be part of automated and carefully regulated production lines, that make specific intermediate parts, that permit the higher-order construction and assembly and subsequently self-replication of that factory. From scratch. Performing 1500 reactions in parallel. Unfortunately, that cause has a problem. It is not an intelligent engineer. And another problem: There is no directed energy source available to construct that factory. Only unspecific thermic energy from volcanoes, thermal vents, earthquakes, thunderstorms, the sun, and lightning. 

Let's suppose the number of all atoms in the universe ( 10^80) would be small molecules. Getting the right specified sequence of amino acids to get just one-third of the size of an average-sized protein of 300 amino acids,  one of the 1300 proteins used in that factory, is like painting one of all these molecules in the universe ( roughly 10^80) in red, then throwing a dart randomly, and by luck, hitting the red molecule, with the first attempt. The odds to have all the 1300 proteins assembled by chance, and then interlinked in the right way, is one in 10^725000 !! 

Whatever organism one wants to suggest as a minimal possible life form - no matter if we remove some metabolic pathways and imagine that it got its amino acids alphabet externally, as suggested by Madeline C. Weiss and colleagues in their well-known article: The physiology and habitat of the last universal common ancestor from 2016, the gulf to be bridged, the hurdles to be overcome, to go from lifeless early earth to the first self-replicating cell are hardly commensurable, and difficult to imagine. 

Following gives us an idea: The ability to transfer just ONE SINGLE CARBON atom is absolutely essential for the metabolism of the amino acids glycine, serine, methionine, and histidine, and the biosynthesis of purines and pyrimidines - which constitute DNA molecules, the information carriers of cells.

And in order for biological cells to achieve this transfer, they require tetrahydrofolate cofactors, consisting of three moieties. Folates are among the most complex pterin coenzymes. The folate pathway is central to any study related to DNA methylation, dTMP synthesis, or purine synthesis, and as such, to the origin of life itself, since without amino acids, and DNA - no life.

At this link you can see the Folate biosynthesis pathway: https://www.genome.jp/pathway/map00790 - at each branch point, there is a ramification of a web of complex enzymes which work in a coordinated, orchestrated, and interconnected way together to produce just this Tetrahydrofolate cofactor. To make things even more complex, the two essential precursors of folate biosynthesis are 4-aminobenzoate (a product of the shikimate biosynthesis pathway: https://www.genome.jp/kegg-bin/show_pathway?map01063 ) and  Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate.  

Abiogenesis proponents need to explain at least the origin of a minimal genome, the epigenome, the glycome, the lipidome, the mobilome, the transcriptome, the metabolome, the proteome, and the interactome, the signalosome, and the metallome of our minimal cell. A set of metabolic pathways ( the metabolome) consisting of at least 400 reactions performed by hundreds of enzymes and proteins, the molecular robots, producing all relevant molecules. The synthesis of the four building blocks of life, and salvage and recycling pathways ( That includes uptake and processing of the big, major, and trace elements  [ nitrogen and carbon fixation]. Furthermore, the genome, that directs the making of hundreds of proteins ( the proteome) - complex molecular machines made through transcription ( the transcriptome) and translation, the proteins interconnection ( the interactome), using the genetic code, the machinery of DNA replication, error-check and repair mechanisms starting with DNA, all the way through to the ribosome ( 13 check and repair mechanisms alone). An epigenome, that controls DNA–protein interactions ( DNA methylation that performs transcriptional activation and repressions, and the formation of phenotypic variants) timing of DNA replication, partitioning nascent chromosomes to daughter cells, repair of DNA, and timing of transposition and conjugal transfer of plasmids. The chromosome segregation machinery ( topoisomerase II).  

The ribosome is especially noteworthy. The Universal Gene Set of Life (UGSL) consists of less than 100 genes and is dominated by translation-related genes. These ribosomal RNAs (rRNAs), transfer RNAs (tRNAs and the machinery to synthesize and modify tRNAs, a full set of aminoacyl tRNA synthetases) small RNAs, and ribosomal proteins make up the most abundant macromolecular species in all living organisms ( Bernstein 2019). Ribosome biogenesis: It would require all proteins that assemble ribosomes, including proteins, that make proteins, that make the subunits of the ribosome, and the entire error check and repair, and recycle machinery.  It would require chaperones, proteins that help proteins that come out from the ribosome, and are being misfolded, to get their right fold. That includes chaperones, that help chaperones to be folded properly. ( In other words, machines, that help machines, that help other machines) Furthermore, the membrane includes millions of complex membrane-embedded protein channels, ion pumps, ion exchangers, transporters, importers, translocons, translocases, symporters, and antiporters that control what is imported, what leaves the cell, and the intracellular levels of all life-essential elements. Then the enzymes that are involved in cell division, and it's regulation. A way to fix carbon to produce carbohydrates, that are digested through catabolism to feed ATP synthase, electron transport, and a proton gradient to generate ATP, the energy currency in the cell. It would also require at least 8 co-factors, and vitamins.  

Thioesters were almost certainly involved in the prebiotic formation of many molecules that are important in contemporary biology. Their formation depends on Coenzyme A (CoA). Coenzyme A synthesis depends on five enzymes used in the five-step universal pathway of coenzyme A (CoA) biosynthesis.  Numerous machines uptake iron ( Non-ribosomal peptide synthetase to make siderophores) and chelate it ( making it available in soluble form for uptake), sulfur, and the machinery to create Iron-sulfur (Fe/S) clusters, essential in many vital proteins in their reaction centers. Life essential proteins, replete with FeS clusters and radical reaction mechanisms, depend upon transition metals, flavins, S-adenosyl methionine, ferredoxin, molybdopterin, corrins, and selenium. It had to create a homeostatic environment, in one of many other cases, diminishing the calcium concentration in the cell 10000 times below the external environment, to permit signaling. It requires osmoregulation to maintain the fluid balance and the concentration of electrolytes, preventing the cytosol to be too diluted or concentrated. Furthermore, it would - from the get-go, have to be able to adapt to the variegated environmental conditions, able to get and interpret signals from the environment the outside and react accordingly ( like thermal conditions).

Consider that you cannot resort to evolution, and long periods of time: 

Wilhelm T. S. Huck Robustness, Entrainment, and Hybridization in Dissipative Molecular Networks, and the Origin of Life May 30, 2019
Life emerged spontaneously from the selfassembly, or spontaneous organization, of the organic products of reactions, occurring in complex mixtures of molecules formed abiotically from simple precursors and sequences of reactions.
https://robobees.seas.harvard.edu/files/gmwgroup/files/1320.pdf

I have not enough faith to believe that life can come from non-life, by unguided mechanisms.

Some Prebiotic Chemical Problems Remaining To Be Solved 
1. Primitive Earth's Environment. More detailed studies of the chemical reactions following the acquisition of comets and asteroids during the first 600 million years, 
2. ~bose Formation, Possible prebiotic reactions for more selective synthesis of ribose, 3. Homochirality and Polymerization. Study of polymerization reactions (nucleotides, peptides) leading to the selective or preferential incorporation of either D or L isomers. The actual differentiation process was probably based on the stabilization of homochiral polymers by processes of molecular natural selection, lower energy states or catalytic activity. Because of the relatively high racemization rates, it does not appear that the genesis of homochirality can be a physical or chemical problem related to the individual synthesis of monomeric enantiomers. Homochirality probably appeared in the transition from pre-life to life, during the process of macromolecular self-organization, and subsequent "survival" of the fittest macromolecules according to their selective function. 
4. ~. Additional studies on the synthesis of fatty acids and amphiphilic lipids capable of forming semipermeable membranes are required. 
5. ~elf Organizati~, SeLf-assembly of catalytic ribonucleotides, nucleotide substrates, and high energy compounds (pyrophosphate, ATP, GTP, etc.) within a semipermeable membrane. 
6. ]~ner~¢ Sources. Continuous synthesis, through a semipermeable membrane, of ATP or other high-energy phosphates by means of a proton gradient, or by photochemical activation. 7. Translation and Aut0eatalvtic Feedback. Prebiotic molecular translation of coding RNA polymers into catalytic peptides that are capable of synthesizing RNA.

https://sci-hub.ee/10.1007/bf00700430

ADDY PROSS: What is Life? How Chemistry becomes Biology

Life’s evident design, in particular, stands out, as a source of endless speculation. The creativity and precision so evident in that design is nothing less than spectacular.  Due to the remarkable advances in molecular biology over the past six decades we have discovered that nature’s design capabilities can be immeasurably greater. Take the ribosome, for example. The ribosome is a tiny organelle present in all living cells in thousands of copies that manufactures the protein molecules on which all life is based. It effectively operates as a highly organized and intricate miniature factory, churning out those proteins—long chain-like molecules—by stitching together a hundred or more amino acid molecules in just the right order, and all within a few seconds. And this exquisitely efficient entity is contained within a complex chemical structure that is just some 20–30 nanometres in diameter— that’s just 2–3 millionths of a centimeter! Think about that—an entire factory, with all the elements you’d expect to find in any regular factory, but within a structure so tiny it is completely invisible to the naked eye. Indeed, for elucidating the structure and function of this remarkable organelle, Ada Yonath from the Weizmann Institute, Israel, Venkatraman Ramakrishnan from the Laboratory of Molecular Biology at Cambridge, and Thomas Steitz from Yale University were awarded the 2009 Nobel Prize in Chemistry.

 No less impressive than life’s extraordinary design capabilities is its breathtaking diversity, a perpetual source of inspiration. Red roses, giraffes, butterflies, snakes, towering redwoods, whales, fungi, crocodiles, cockroaches, mosquitoes, coral reefs—the mind boggles at nature’s spectacular and unmitigated creativity. Literally millions of species, and that’s before we have even touched upon the hidden kingdom, the bacterial one. That invisible kingdom is itself a source of overwhelming, almost incomprehensible diversity, one that is just beginning to come to light. But life’s design and diversity are just two characteristics out of a wider set that serves to compound the mystery and uniqueness of the life phenomenon. Some of life’s characteristics are so striking you don’t have to be too observant to notice them. Take life’s independent and purposeful character, for example. 

We have an intriguing phenomenon—biologists, the scientists who devote themselves to the study of living systems, and who possess a deep appreciation of life’s complexity, having successfully probed many of its key components, remain mystified by what life is, and physicists, with their deep understanding of nature’s most fundamental laws, are no less confused. Both continue to struggle with the nature of life question and we can only conclude that the 3,000-year ‘what is life’ riddle remains that—a riddle. 

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.

There is even a biological term for the phenomenon whereby that organized state is maintained—homeostasis, from the Greek meaning ‘standing still’.

The living cell is a highly organized entity. We can compare it to a familiar mechanical entity, a clock. Both are organized in the sense that all of the component parts contribute to the operation of the holistic entity. The parts of the clock enable it to fulfill its function of telling the time, and the parts of the cell enable it to fulfill its function and become two cells. Of course the clock is an organized entity that has been constructed to fulfil its particular function—it is man-made, then how can the bacterial cell have somehow come about on its own accord? Nevertheless, the machine metaphor for understanding living systems has been useful and allowed us to continue to probe cell function, to discover in ever greater detail the precise workings of this remarkable ‘machine’. Closer examination of the two ‘machines’, however, reveals an extraordinary distinction between the machine-like characteristics of the clock and the cell. Within the clock the components remain in place and continue to operate until one or other of them wears out and the system ceases to function. But within the living cell the situation is spectacularly different. Whereas a clock is a static system, whose parts are permanent and unchanged, every living system is dynamic. Its parts are continually being turned over. Let me explain. 

You meet an old friend that you haven’t seen in a few years and you greet him with the comment: ‘Hi Bill, great to see you again, you haven’t changed a bit!’ You make that comment because Bill looks very much as you remember him from your last encounter. But here is an extraordinary fact. The person standing in front of you, who looks like Bill, talks like Bill, and is called Bill, is, materially speaking, effectively a totally different person from the Bill you saw some time back. Just about every molecule in Bill’s body has been replaced since you last saw him. Almost all the stuff of which Bill (and you and me) is made has been turned over. For some parts of us, our hair and fingernails, for example, that turnover is obvious. But for the rest of what makes you, you, the turnover is hidden from view. It takes place surreptitiously. Like all human beings you are primarily composed of the some 10 thousand billion (10,000,000,000,000) cells that make up your body. (We actually also contain within our bodies some 100 thousand billion foreign cells, bacteria. And each of those cells is itself composed of an array of biomolecules—lipids, proteins, nucleic acids, and so on.

ADDY PROSS: What is Life?: How Chemistry Becomes Biology  2012

Origin-of-Life Expert Jokes about Becoming a Creationist   11/05/2004


https://web.archive.org/web/20121130144326/http://creationsafaris.com/crev200411.htm


Exclusive  At the Jet Propulsion Laboratory Nov. 5, a world-renowned origin-of-life researcher spoke to a packed auditorium on the status of his field, chemical evolution and the origin of life.  Dr. Steven Benner (U. of Florida) trains graduate students in the subject, knows all the big names in the field personally, and has published and worked on this subject for over 20 years.  His outline dealt with 4 approaches to probing the black box of life’s origin: (1) working forward in time from stars and planets, (2) working backward in time from existing life to its ancestors, (3) experimenting with synthetic life, and (4) searching suitable habitats in space.
    More interesting, though, were his candid admissions about the problems facing anyone in this field, and his joking references a couple of times that if these problems remain unsolveable, he might have to become a creationist.  He didn’t mean it, of course.  These were chuckle-garnering hyperboles to express the frustration he has felt for decades over problems that are still far from a solution.  For instance:

1. DNA: as good as it gets?  Benner spent some time discussing how perfect DNA and RNA are for information storage.  The upshot: don’t expect to find non-DNA-based life elsewhere.  Alien life might have more than 4 base pairs in its genetic code, but the physical chemistry of DNA and RNA are hard to beat.  Part of the reason is that the electrochemical charges on the backbone keep the molecule rigid so it doesn’t fold up on itself, and keep the base pairs facing each other.  The entire molecule maximizes the potential for hydrogen bonding, which is counter-intuitive, since it would seem to a chemist that the worst environment to exploit hydrogen bonding would be in water.  Yet DNA twists into its double helix in water just fine, keeping its base pairs optimized for hydrogen bonds, because of the particular structures of its sugars, phosphates and nucleotides.  The oft-touted substitute named PNA falls apart with more than 20 bases.  Other proposed alternatives have their own serious failings.
   
   
2. Sugar substitute:  Ribose sugar is the molecule of choice for nucleic acids, yet because it is difficult to imagine forming under plausible prebiotic conditions and has a short lifetime, origin-of-life researchers have searched diligently for alternatives, like glycerol, that might have served as scaffolding for prebiotic chemicals prior to the emergence of DNA.  Unfortunately, they don’t work.  He was emphatic: over 280 alternative molecules have been tested, and they just do not work at all; those that might be better than ribose are implausible under prebiotic conditions.  “Ribose is actually quite good – uniquely good,” he said.  Deal with it: one’s chemical evolution model is going to have to include ribose.  That means figuring out how it can form, how it can avoid destruction in water, and how it can avoid clumping into useless globs of tar.  (RNA, the main player in the leading “RNA World” scenario for the origin of life, uses ribose; DNA uses a closely-related sugar, deoxyribose.)
   
   
3. Genetic takeovers:  Benner chided those whose models invoke genetic takeovers: i.e., starting with another sugar then switching to ribose, starting with another informational macromolecule then switching to DNA, etc.  For instance, some flippantly suggest to get DNA’s sugar, “just add an OH to ribose....”  The professor got animated.  That adds a charge to the molecule, he exclaimed, and what is more important to the behavior of a molecule than its electrostatic charge?  You can’t just add a charge to a molecule and expect it to keep behaving like it did before.
   
   
4. Adding Ad Hoc:  When a researcher keeps having to multiply ad hoc scenarios to keep his model together, it quickly becomes a target of criticism.  The professor spoke of Robert Shapiro, a long time critic of this bad habit among his colleagues.  He said one of his requirements for graduate students is to endure Shapiro’s critique.  He spoke as if this is a common, well-known fault in the origin of life community – invoking a meteor strike here, a clay mineral there, a volcano over yonder, a deep sea vent somewhere else – all needing to be present at the right time and place to get the scheme to work.  He also spoke as if his own model was not immune from that criticism.
   
   

The ribose problem appeared so severe to him early in his studies, he felt certain at the time that researchers simply had to find an alternate sugar for chemical evolution.  Stanley Miller was similarly emphatic in his writings, stating that ribose sugars were not components of the earliest life.  His colleagues (researchers in this field tend to be a sociological society, he quipped) have gone back and forth on this issue for years, but the 280 molecules they have tested are worse than ribose; they don’t work.
    This intractable problem has led him to a novel solution: life didn’t form in the water, but in a desert.  Serendipitously, he found that a mineral – borate – can stabilize ribose long enough to make it a contender (see 01/09/2004 headline).  Like ribose, borate also decomposes in water and needs a dry environment.  If borate is found on Mars, he speculated, maybe ribose will also be found there, he announced to the planetary scientists and engineers in the room.  But then, how can the other necessary molecules associate with ribose if it is in a desert?  And how would it be shielded from ultraviolet radiation, as a questioner asked about Mars (to which he answered that much more research needs to be done on the effect of sunlight on ribose).  And how could ribose on a desert continent survive the impact record on the early earth?  Worse, the fact that borate and ribose seem made for each other raises the old specter of the Anthropic Principle: why should two independent substances that are not common in the universe be found together in the same place and time?  He admitted this gave him a shrinking feeling; “it was almost a creationist argument,” he confessed half seriously.
    This reporter had the opportunity to ask follow-up questions to the professor during the Q&A; period, and in person after the meeting was adjourned:
Besides the problems, another thing stood out from his presentation: the exquisite perfection of DNA, RNA and ribose for the jobs they have to do.  Maybe this would be a good time to follow the path of former chemical evolution researcher, Dean Kenyon: become a creationist.

Several important and valuable lessons came out of this interchange.  One was the observation that in a packed room of intelligent people, I was the only one to ask really challenging questions.  The others, many of them college graduates with advanced degrees, seemed to just accept what was being said, and appeared hopeful that science was making real progress in finding out how life evolved.  Few, if any, seemed to notice that most of what he discussed was either irrelevant to the question, or too speculative to be considered scientific.

Consider his four approaches: (1) Working forward in time from the earliest stars and planets to the origin of life.  This assumes evolution without offering a shred of evidence.  Irrelevant.  (2) Working backward in time from existing life to ancestral life.  This assumes evolution with only circumstantial evidence from comparative genomics, but has the additional problem that no evidence for life earlier than 2.5 billion years has been found (assuming evolutionary dating).  Speculation without evidence.  (3) Synthetic biology: tweaking proteins and DNA to explore the limits of life.  This is intelligent design (see 01/09/2003 headline).  Irrelevant.  (4) Exploring new habitats in space on other planets.  This is banking on hope, and even if life were found, it would not prove it evolved.  Irrelevant.

He provided no evidence to demonstrate chemical evolution is a viable scientific theory.  He shared some interesting organic chemistry, which is fine, but none of it was applicable to explaining the origin of life by natural means.  He himself once wrote, “It is difficult to believe that larger pools of random RNA emerged spontaneously without the gentle coaxing of a graduate student desiring a completed dissertation.”  That’s intelligent design, not evolution.
    Few in the audience, also, seemed to care that the problems he described were so serious as to falsify chemical evolution.  Each problem was a show stopper, yet his show went on.  Then there were the problems he didn’t even talk about.  Everything in evolution he accepted as true has problems of its own: common ancestry of all life, the RNA World hypothesis (see 07/11/2002 headline), Darwinian natural selection, the long ages of the geologists and the phylogenetic tree-building methods of the biologists.  Each of these things he merely assumed were true, but each has monstrous problems of its own.  Yet in spite of his faith in the cause to which he has devoted his professional life, he intimated a shrinking feeling that maybe the creationists might be right.
    This episode underscores the fact that, on this subject, creationists have the Darwinists in a hammerlock with their faces to the floor wincing in pain.  Darwinism has fouled out on the origin of life, and one cannot continue competing if he has fouled out in the first round.  If a designing intelligence is needed to get life going, then all the questions and answers change.  The fluff about finch beaks and peppered moths and Lucy is irrelevant, because a totally new approach to looking at the world is needed: an approach that recognizes that information from an intelligent cause is a fundamental property of life.  If that happens to have profound religious or metaphysical implications, so be it.  Meanwhile, keep the hammerlock on until they repent of their storytelling and cry UNCLE: Uniformitarian Naturalism Cannot Life Explain.
Next headline on:   Origin of Life

At least 14 major hurdles of abiogenesis 

https://reasonandscience.catsboard.com/t1279p25-abiogenesis-is-mathematically-impossible#9362

Demonstrating that life from non-life by unguided means is possible would entail researchers to build a nano-scaled self-replicating factory in their laboratory by leaving an impure mix of raw materials ( some used in life, but the majority not), and waiting for unguided processes to take their course...Never has a team of researchers ever tried, much less, succeeded.

Memory-stored controls transform symbols into physical states. Von Neumann felt, "That they should occur in the world at all is a miracle of the first magnitude."
Paul Davies: How did stupid atoms spontaneously write their own software … ? Nobody knows … … there is no known law of physics able to create information from nothing.

Cells have a codified description of themselves in digital form stored in genes and have the machinery to transform that blueprint through information transfer from genotype to phenotype, into an identical representation in analog 3D form, the physical 'reality' of that description.

G. F. Joyce, L. E. Orgel: Prospects for Understanding the Origin of the RNA World 1993
A blueprint cannot produce a car all by itself without a factory and workers to assemble the parts according to the instructions contained in the blueprint; in the same way, the blueprint contained in RNA cannot produce proteins by itself without the cooperation of other cellular components which follow the instructions contained in the RNA.

The cause leading to a machine’s and factory's functionality is found in the mind of the engineer and nowhere else.

Jack W. Szostak: It is virtually impossible to imagine how a cell’s machines, which are mostly protein-based catalysts called enzymes, could have formed spontaneously as life first arose from nonliving matter around 3.7 billion years ago.

General hurdles of the Origin of Life by unguided means


1. Natural selection: There was no selection on early earth. In the living world, complex molecular machines are pre-programmed to make the building blocks of life, precisely as needed.
2. Time: Some chemical reactions are so unspecific that getting the right one by unguided means resorting to time leads to huge numbers of odds.
3. Getting pure materials: Evidently, what chemists do in the lab, namely using pure reagents, was not what happened on the early earth. Impure contamination in the pool of chemicals was the state of affairs.
4. Getting free Gibbs energy:  Spontaneous prebiotic reactions would have to "invent" ways to recruit Gibbs free energy from its environment so as to reduce its own entropy.
5. Activation and repetitive processes: Monomers need to be activated in order for polymerization and catenation to make amino acid strands, and genes, to be possible.
6. Information: Specified complex information, digital data, stored in genes through the language of the genetic code, dictates and directs the making of irreducibly complex molecular machines.
7. Polymerization: How did prebiotic polycondensation of amino acids and nucleotides in heterogeneous aqueous solutions or in interfaces with water-based media occur without the aid of biological catalysts? 
8. Eigens paradox:  is one of the most intractable puzzles in the study of the origins of life. It is thought that the error threshold concept described above limits the size of self-replicating molecules to perhaps a few hundred digits, yet almost all life on earth requires much longer molecules to encode their genetic information.
9. Muller's rachet: The theory of Muller's Ratchet predicts that small asexual populations are doomed to accumulate ever-increasing deleterious mutation loads as a consequence of the magnified power of genetic drift and mutation that accompanies small population size.
10. Protected environments: If these chemical reactions had happened in places being exposed to UV radiation, no deal. If it was too cold, or too hot, too acidic, or too alkaline, in the wrong atmospheric conditions, no deal.
11. The right sequence of reactions: In metabolic pathways in the cell, enzymes must be lined up in the right sequence. How did spontaneous events organize such a state of affairs? 
12. Getting an organized system out of chaos: How did a prebiotic soup come to be organized into systems capable of emergent processes such as growth, self-propagation, information processing, and adaptive evolution?
13. Irreducible complexity: The cell is an irreducible, minimal entity of life. The individual parts by themselves bear no function unless integrated into a higher-order system.
14. Homeostasis:   The control of metabolism is a fundamental requirement for all life, with perturbations of metabolic homeostasis underpinning numerous disease-associated pathologies.

General hurdles Probability calculation is about how probably or improbably an event might have occurred. The notion requires being able to determine what probability (the odds) may legitimately be counted as small enough to eliminate chance. (the odds or possible number of an outcome having little or no chance of success)
Prebiotic synthesis entails a number of different difficulties which make the origin of life by unguided means too improbable to have occurred by chance

1. Natural selection: There was no selection on early earth. In the living world, complex molecular machines are pre-programmed to make the building blocks of life, precisely as needed. The nucleic acids for a limited set, so do the 20 amino acids, and they come in the functional enantiomeric form, and those that are wrong, like right-handed amino acids, are sorted out by the cell machinery. The same applies to the five information-bearing nucleobases, phospholipids, and carbohydrates. None of these building blocks were readily available prebiotically. There was a jumble and a chaotic mess of all sorts of molecules without any order. How did unguided processes winnow this molecular diversity down to the few compounds used in biological systems today, which are a tiny subset of the many compounds that would have arisen from abiotic processes? 

2. Time: Time is not the naturalist's friend. There are chemical reactions performed by certain classes of enzymes, that speed up the process billions of times.  Without the OMP decarboxylase enzyme, a reaction ‘“absolutely essential” in creating the building blocks of DNA and RNA would take 78 million years in the water. Some chemical reactions are so unspecific that getting the right one by unguided means resorting to time and enough attempts of trial and error can very easily lead to huge numbers of odds (the possible number of an outcome having little or no chance of success)  that exceed the number of atoms in the entire universe ( 10^80).

3. Getting pure materials: Evidently, what chemists do in the lab, namely using pure reagents, was not what happened on the early earth. Impure contamination in the pool of chemicals was the state of affairs. In order to recreate what was going on back then, chemists would have to recreate as close as possible the situation on the early earth, which includes using contaminated chemicals. 

4. Getting free Gibbs energy:  Spontaneous prebiotic reactions would have to "invent" ways to recruit Gibbs free energy from its environment so as to reduce its own entropy. That is as to rocks continuously recruiting forces to roll up the hill, or a rusty nail "figuring out" how to spontaneously add layers of galvanizing zinc on itself to fight corrosion. These reactions would also have to find ways to "funnel" this energy and direct it to where it is required to achieve a precise reaction necessary for achieving self-organization and in the end, free-living, self-replicating biological systems.

5. Activation and repetitive processes: Monomers need to be activated in order for polymerization and catenation to make amino acid strands, and genes, to be possible. That demands a repetitive ordered process, where the bond reactions happen repeatedly at the same place in the molecules. In RNA or DNA polymerase protein complexes, or in the ribosome, sophisticated molecular machines perform these reactions with exuberant precision and efficiency. Science has failed to explain how that could have happened on the early earth.

6. Information: Specified complex information, digital data, stored in genes through the language of the genetic code, dictates and directs the making of irreducibly complex molecular machines, robotic molecular production lines, and chemical cell factories. Scientific investigation has not brought light to the origin of prebiotic information: It remains a mystery. The origin of the genetic code is also enigmatic. Imagine a cause that needs to create an interlinked factory complex containing 1300 complex machines that are installed in specialized compartments, ordered based on the specific task that they perform, and interlinked in a functional way to be part of automated and carefully regulated production lines, that make specific intermediate parts, that permit the higher-order construction and assembly and subsequently self-replication of that factory. From scratch. Performing 1500 reactions in parallel. Unfortunately, that cause has a problem. It is not an intelligent engineer. And another problem: There is no directed energy source available to construct that factory. Only unspecific thermic energy from volcanoes, thermal vents, earthquakes, thunderstorms, the sun, and lightning. 

Let's suppose the number of all atoms in the universe ( 10^80) would be small molecules. Getting the right specified sequence of amino acids to get just one-third of the size of an average-sized protein of 300 amino acids,  one of the 1300 proteins used in that factory, is like painting one of all these molecules in the universe ( roughly 10^80) in red, then throwing a dart randomly, and by luck, hitting the red molecule, with the first attempt. The odds to have all the 1300 proteins assembled by chance, and then interlinked in the right way, is one in 10^725000 !! 

7. Polymerization: There have to be ways of prebiotic efficient polycondensation of amino acids and nucleotides, in heterogeneous aqueous solutions or in interfaces with waterbased media, are needed to explain the emergence, without the aid of biological catalysts, of the first functional biopolymers (e.g., polypeptides and polynucleotides). 

8. Eigen's paradox is one of the most intractable puzzles in the study of the origins of life. It is thought that the error threshold concept described above limits the size of self-replicating molecules to perhaps a few hundred digits, yet almost all life on earth requires much longer molecules to encode their genetic information. This problem is handled in living cells by enzymes that repair mutations, allowing the encoding molecules to reach sizes on the order of millions of base pairs. These large molecules must, of course, encode the very enzymes that repair them, and herein lies Eigen's paradox, first put forth by Manfred Eigen in his 1971 paper (Eigen 1971) Simply stated, Eigen's paradox amounts to the following: Without error correction enzymes, the maximum size of a replicating molecule is about 100 base pairs. For a replicating molecule to encode error correction enzymes, it must be substantially larger than 100 bases. This is a chicken-or-egg kind of a paradox, with an even more difficult solution. Which came first, the large genome or the error correction enzymes?

9. Muller's Ratchet The theory of Muller's Ratchet predicts that small asexual populations are doomed to accumulate ever-increasing deleterious mutation loads as a consequence of the magnified power of genetic drift and mutation that accompanies small population size. Evolutionary theory predicts that mutational decay is inevitable for small asexual populations, provided deleterious mutation rates are high enough. Such populations are expected to experience the effects of Muller's Ratchet where the most-fit class of individuals is lost at some rate due to chance alone, leaving the second-best class to ultimately suffer the same fate, and so on, leading to a gradual decline in mean fitness. The mutational meltdown theory built upon Muller's Ratchet to predict a synergism between mutation and genetic drift in promoting the extinction of small asexual populations that are at the end of a long genomic decay process. Since deleterious mutations are harmful by definition, accumulation of them would result in loss of individuals and a smaller population size. Small populations are more susceptible to the ratchet effect and more deleterious mutations would be fixed as a result of genetic drift. This creates a positive feedback loop that accelerates extinction of small asexual populations. This phenomenon has been called mutational meltdown.
From the onset, there would have had to be a population of diversified microbes, not just the population of one progenitor, but varies with different genetic make-ups, internally compartmentalized, able to perform Horizontal Gene Transfer and recombination. Unless these preconditions were met, the population would die.

10. Protected environments: If these chemical reactions had happened in places being exposed to UV radiation, no deal. If it was too cold, or too hot, too acidic, or too alkaline, in the wrong atmospheric conditions, no deal. Shapiro (2006): Prebiotic syntheses conducted in the laboratory often involve multistep procedures, with purified reagents and very different conditions permitted at each new step. The extensive purification procedures and changes of locale that would be needed to produce comparable results on the early Earth are seldom discussed but must be taken into account when attempting to judge the plausibility of the entire sequence. 

11. The right sequence of reactions: In metabolic pathways in the cell, the enzymes, our sophisticated molecular robots, are lined up in the right sequence. Once a manufacturing step by enzyme one is concluded, and the intermediate product is ready, it is handed over to enzyme two, which uses the product of the previous enzyme, to perform the subsequent manufacturing step. If the enzyme sequence were wrong, no deal, and the entire manufacturing process in the production line breaks down. On prebiotic earth, natural catalysts, like ions, clay, etc. had to replace enzymatic reactions. How could the right sequence have been performed? its far from realistic to believe that order, timing, and the right subsequent reactions could have been performed by random chaotic events without direction.  

12. How the components of prebiotic soup came to be organized in systems: The biggest outstanding problem in understanding the origins of life is how the components of prebiotic soup came to be organized in systems capable of emergent processes such as growth, self-propagation, information processing, and adaptive evolution. Given that prebiotic soups may have been composed of millions of distinct compounds, each at a low concentration.

13. Irreducible complexity: The cell is an irreducible, minimal entity of life. The individual parts by themselves bear no function unless integrated into a higher-order system. A complex specified intermediate state or product that is not functionally useful would never be selected and emerge by non-designed events.  A minimal amount of instructional complex information is required for a gene to produce useful proteins. A minimal size of a protein is necessary for it to be functional.  A minimal number of parts are necessary to be integrated into metabolic systems to make all building blocks and metabolites, used in life. A fully developed system that generated energy, and a genome with all the information is necessary to keep the basic functions to have a living cell.

14. Homeostasis: The essential characteristic of living cells is homeostasis, the ability to maintain a steady and more-or-less constant chemical balance in a changing environment.  The control of metabolism is a fundamental requirement for all life, with perturbations of metabolic homeostasis underpinning numerous disease-associated pathologies. Any incomplete Metabolic network without the control mechanisms in place to get homeostasis would mean disease and cell death. A minimal metabolic network and the control mechanisms had to be in place from the beginning, which means, and gradualistic explanation of the origin of biological Cells, and life is unrealistic. Life is an all-or-nothing business.

Jeffrey D. Johnson: The Absurdity of Unbelief: A Worldview Apologetic of the Christian Faith 2016

The Law of Biogenesis: Living beings come only from other living beings. Though there has been no observable exception to this rule.
The Reproductive Principle: Life must first exist before it can reproduce itself. A self-replicating RNA molecule has never been demonstrated to emerge randomly.
The Instructional information stored in genes: P.Davies: The problem of how meaningful or semantic information can emerge spontaneously from a collection of mindless molecules subject to blind and purposeless forces presents a deep conceptual challenge.
The irreducible complexity of the cell: The cell is a functionally integrated system that only operates when each of its components (processors, power supplies, and switches) function together.

https://pt.3lib.net/book/2708494/cd49d9

1. Getting homochiral building blocks of life, precisely as needed.
3. Getting pure materials: avoiding impure contamination in the pool of chemicals was the state of affairs.
4. Getting free Gibbs energy: recruiting Gibbs free energy from its environment so as to reduce its own entropy.
5. Activation and repetitive processes: Monomers need to be activated in order for polymerization and catenation to make amino acid strands, and genes, to be possible.
6. Information: getting specified complex information, digital data, stored in genes through the language of the genetic code, which dictates and directs the making of irreducibly complex molecular machines.
7. Getting the genetic code
8. Polymerization: getting prebiotic polycondensation of amino acids and nucleotides in heterogeneous aqueous solutions or in interfaces with water-based media occuring without the aid of biological catalysts
9. The right sequence of reactions: In metabolic pathways in the cell, enzymes must be lined up in the right sequence. Getting spontaneous events to organize such a state of affairs.
10. Getting an organized system out of chaos: Getting an organized system capable of emergent processes such as growth, self-propagation, information processing, and adaptive evolution
11. Getting all the parts, despite the fact that the individual parts by themselves bear no function unless integrated into a higher-order system.
12. Homeostasis: It had to create a homeostatic environment, in one of many other cases, diminishing the calcium concentration in the cell 10000 times below the external environment, to permit signaling. It requires osmoregulation to maintain the fluid balance and the concentration of electrolytes, preventing the cytosol to be too diluted or concentrated.
13. Getting the transition from prebiotic recruitment of the basic building blocks, to metabolism ( at least 400 reactions performed by hundreds of enzymes and proteins, the molecular robots, producing all relevant molecules. in a minimal LUCA).
14. Getting a minimal genome ( In P.Ubique, the smallest free-living cell, 1,3 Mio nucleotides)
15. Getting the epigenome, the glycome, the lipidome, the mobilome, the transcriptome, the metabolome, the proteome, the interactome, the signalosome, and the metallome of our minimal cell.
16. Salvage and recycling pathways ( That includes uptake and processing of the big, major, and trace elements [ nitrogen and carbon fixation].
17. Getting sophisticated, complex, and advanced immune and defense systems to protect itself from invaders, viruses, plasmids, and phages.
18. Connecting the genome, that directs the making of hundreds of proteins ( the proteome) - complex molecular machines made through transcription ( the transcriptome) and translation, the proteins interconnection ( the interactome), using the genetic code, the machinery of DNA replication, error-check and repair mechanisms starting with DNA, all the way through to the ribosome ( 13 check and repair mechanisms alone).
19. Getting an epigenome, that controls DNA–protein interactions ( DNA methylation that performs transcriptional activation and repressions, and the formation of phenotypic variants) timing of DNA replication, partitioning of nascent chromosomes to daughter cells, repair of DNA, and timing of transposition and conjugal transfer of plasmids. The chromosome segregation machinery ( topoisomerase II).
20. Getting the ribosome which is especially noteworthy. The Universal Gene Set of Life (UGSL) is dominated by translation-related genes. These ribosomal RNAs (rRNAs), transfer RNAs (tRNAs and the machinery to synthesize and modify tRNAs, a full set of aminoacyl tRNA synthetases) small RNAs, and ribosomal proteins make up the most abundant macromolecular species in all living organisms ( Bernstein 2019). Ribosome biogenesis: It would require all proteins that assemble ribosomes, including proteins, that make proteins, that make the subunits of the ribosome, and the entire error check and repair, and recycle machinery. It would require chaperones, proteins that help proteins that come out from the ribosome, and are being misfolded, to get their right fold. That includes chaperones, that help chaperones to be folded properly. ( In other words, machines, that help machines, that help other machines)
21. Getting the membrane which includes millions of complex membrane-embedded protein channels, ion pumps, ion exchangers, transporters, importers, translocons, translocases, symporters, and antiporters that control what is imported, what leaves the cell, and the intracellular levels of all life-essential elements.
22. Getting the enzymes that are involved in cell division, and its regulation.
23. A way to get a Wood Ljundahl or rTCA cycle to fix carbon to produce carbohydrates, that is digested through catabolism to feed ATP synthase, electron transport, and a proton gradient to generate ATP, the energy currency in the cell. It would also require at least 8 co-factors, and vitamins.
24. Thioesters were almost certainly involved in the prebiotic formation of many molecules that are important in contemporary biology. Their formation depends on Coenzyme A (CoA). Coenzyme A synthesis depends on five enzymes used in the five-step universal pathway of coenzyme A (CoA) biosynthesis.
25. Getting numerous machines for the uptake of iron ( Non-ribosomal peptide synthetase to make siderophores) and chelate it ( making it available in soluble form for uptake), sulfur, and the machinery to create Iron-sulfur (Fe/S) clusters, essential in many vital proteins in their reaction centers. Life essential proteins, replete with FeS clusters and radical reaction mechanisms, depend upon transition metals, flavins, S-adenosyl methionine, ferredoxin, molybdopterin, corrins, and selenium.
26. Mechanisms of adaptation to the variegated environmental conditions, able to get and interpret signals from the environment the outside and react accordingly ( like thermal conditions).

Nick Lane: Well the source of energy at the origin of life is the reaction between carbon dioxide and hydrogen and amazingly most of these reactions are exergonic which is to say they release energy this if you have hydrogen and co2
and you put them together in a falcon tube and you warm it up to say 50 degrees centigrade and you put in a couple of catalysts and you shake it nothing's gonna happen but thermodynamically that is less stable two gases hydrogen
and co2 is less stable than cells what should happen is you get cells coming out why doesn't that happen is because of the kinetic barriers it's because that's where you need the spark

https://www.youtube.com/watch?v=tOtdJcco3YM

Magnifying the cell ten thousand million times, it would have a radius of 200 miles, about 10 times the size of New York City

Calling a cell a factory is an understatement. Magnifying the cell to a size of 200 miles, it would only contain the required number of buildings, hosting the factories to make the machines that it requires. 
New York City has about 900.000 buildings, of which about 40.000 are in Manhattan, of which 7.000 are skyscrapers of high-rise buildings of at least 115 feet (35 m), of which at least 95 are taller than 650 feet (198 m).

Cells are an entire industrial park, where only the number of factories producing the machines used in the industrial park is of size at least 10 times the size of New York City, where each building is individually a factory comparable to the size of a skyscraper like the Twin Towers of the World Trade Center. Each tower hosts a factory that makes factories that make machines. A mammalian cell may harbor as many as 10 million ribosomes. The nucleolus is the factory that makes ribosomes, the factory that makes proteins, which are the molecular machines of the cell. The nucleolus can be thought of as a large factory at which different noncoding RNAs are transcribed, processed, and assembled with proteins to form a large variety of ribonucleoprotein complexes.

L. Lindahl (2022): Ribosome assembly requires synthesis and modification of its components, which occurs simultaneously with their assembly into ribosomal particles. The formation occurs by a stepwise ordered addition of ribosome components. The process is assisted by many assembly factors that facilitate and monitor the individual steps, for example by modifying ribosomal components, releasing assembly factors from an assembly intermediate, or forcing specific structural configurations. The quality of the ribosome population is controlled by a complement of nucleases that degrade assembly intermediates with an inappropriate structure and/or which constitute kinetic traps.

Mitochondria, the powerhouse of the cell, can host up to 5000 ATP synthase energy turbines. Each human heart muscle cell contains up to 8,000 mitochondria. That means, in each of the human heart cells, there are up to 40 million ATP synthase energy turbines caring for the production of ATP, the energy currency in the cell.

M.Denton (2020): The miracle of the Cell :

Pg.11
Where the cosmos feels infinitely large and the atomic realm infinitely small, the cell feels infinitely complex. They appear in so many ways supremely fit to fulfill their role as the basic unit of biological life.

Pg. 329.
We would see [in cells] that nearly every feature of our own advanced machines had its analog in the cell: artificial languages and their decoding systems, memory banks for information storage and retrieval, elegant control systems regulating the automated assembly of parts and components, error fail-safe and proof-reading devices utilized for quality control, assembly processes involving the principle of prefabrication and modular construction. In fact, so deep would be the feeling of deja-vu, so persuasive the analogy, that much of the terminology we would use to describe this fascinating molecular reality would be borrowed from the world of late-twentieth-century technology.
  “What we would be witnessing would be an object resembling an immense automated factory, a factory larger than a city and carrying out almost as many unique functions as all the manufacturing activities of man on earth. However, it would be a factory that would have one capacity not equaled in any of our own most advanced machines, for it would be capable of replicating its entire structure within a matter of a few hours. To witness such an act at a magnification of one thousand million times would be an awe-inspiring spectacle.”

M. Denton (1985) Evolution, a theory in crisis:
To grasp the reality of life as it has been revealed by molecular biology, we must magnify a cell a thousand million times until it is twenty kilometres in diameter and resembles a giant airship large enough to cover a great city like London or New York. What we would then see would be an object of unparalleled complexity and adaptive design. On the surface of the cell we would see millions of openings, like the port holes of a vast space ship, opening and closing to allow a continual stream of materials to flow in and out. If we were to enter one of these openings we would find ourselves in a world of supreme technology and bewildering complexity. We would see endless highly organized corridors and conduits branching in every direction away from the perimeter of the cell, some leading to the central memory bank in the nucleus and others to assembly plants and processing units. The nucleus itself would be a vast spherical chamber more than a kilometre in diameter, resembling a geodesic dome inside of which we would see, all neatly stacked together in ordered arrays, the miles of coiled chains of the DNA molecules.

A huge range of products and raw materials would shuttle along all the manifold conduits in a highly ordered fashion to and from all the various assembly plants in the outer regions of the cell. We would wonder at the level of control implicit in the movement of so many objects down so many seemingly endless conduits, all in perfect unison. We would see all around us, in every direction we looked, all sorts of robot-like machines. We would notice that the simplest of the functional components of the cell, the protein molecules, were astonishingly, complex pieces of molecular machinery, each one consisting of about three thousand atoms arranged in highly organized 3-D spatial conformation... Yet the life of the cell depends on the integrated activities of thousands, certainly tens, and probably hundreds of thousands of different protein molecules.

We would see that nearly every feature of our own advanced machines had its analogue in the cell: artificial languages and their decoding systems, memory banks for information storage and retrieval, elegant control systems regulating the automated assembly of parts and components, error fail-safe and proof-reading devices utilized for quality control, assembly processes involving the principle of prefabrication and modular construction. In fact, so deep would be the feeling of deja-vu, so persuasive the analogy, that much of the terminology we would use to describe this fascinating molecular reality would be borrowed from the world of late twentieth-century technology.

What we would be witnessing would be an object resembling an immense automated factory, a factory larger than a city and carrying out almost as many unique functions as all the manufacturing activities of man on earth..

Nineteenth-century chemists had already established that, despite the large number of elements in the periodic table, almost all of our mass comes from just six of them: carbon, hydrogen, oxygen, nitrogen, sulfur, and phosphorus.

Your fats and carbohydrates are chains of molecules made exclusively of carbon, hydrogen, and oxygen. Your proteins are built from carbon, hydrogen, oxygen, nitrogen, and sulfur. And your DNA is made only of carbon, hydrogen, oxygen, nitrogen, and phosphorus. Those six elements compose roughly 99 percent of everything within you. A 150-pound person contains by mass 94 pounds of oxygen, 35 pounds of carbon, 15 pounds of hydrogen, 4 pounds of nitrogen, almost 2 pounds of phosphorus, and a half pound of sulfur.

Those six elements also happen to be among the most plentiful in the universe.
https://bigthink.com/life/first-molecules-of-life/

Arguing with ChatGTP about the origin of life

https://reasonandscience.catsboard.com/t1279p25-abiogenesis-is-mathematically-impossible#9829

Me: explain why science has been unable to recreate life in the lab
ChatGPT: There are several factors that contribute to our inability to recreate life in the lab:

Complexity: Living organisms are incredibly complex, with a vast array of interacting molecules, complex cellular structures, and intricate metabolic pathways. Recreating this complexity in the lab is incredibly challenging, and our current understanding of biology is still not comprehensive enough to accurately model all the necessary components.

Emergence: One of the defining features of life is that it emerges from the interactions of its components. This means that the properties of a living organism cannot be entirely predicted or derived from its individual parts. As such, creating life in the lab requires not only understanding the parts but also how they interact and give rise to life.

Overall, the creation of life in the lab is a complex and multifaceted problem that requires a deep understanding of the fundamental principles of biology, chemistry, and physics. While scientists have made significant strides in this area, it remains an elusive goal that may take many years of research and technological advancements to achieve.

Me:  Why do you state that technological advancement  may solve the problem if there is no evidence for it ever to happen?
ChatGPT:  I apologize if my previous response gave the impression that technological advancement is certain to solve the problem of creating life in the lab. While there is no guarantee that technological advancements will ultimately lead to the creation of life in the lab, it is possible that continued research and development in the field could bring us closer to achieving this goal.

In many scientific fields, technological advancements have played a critical role in advancing our understanding and capabilities. For example, the development of advanced imaging technologies has allowed us to study biological processes at the cellular and molecular levels in ways that were previously impossible. Similarly, the development of powerful computational tools and simulation techniques has allowed researchers to model complex biological systems and make predictions about their behavior.

It is possible that similar technological advancements could help us overcome the challenges that currently limit our ability to create life in the lab. For example, new methods for manipulating and controlling biological systems, advances in synthetic biology and genetic engineering, and breakthroughs in our understanding of the fundamental principles of life could all contribute to progress in this area.

However, as with any scientific endeavor, there are no guarantees, and the challenges of creating life in the lab are formidable. It is possible that this goal may never be achieved, or that it may require technological advancements that are currently unforeseeable. As such, it is important to approach this question with humility and a recognition of the inherent uncertainties and limitations of scientific research.

Me: But our current understanding already permits to conclude that it is never going to happen. For example, the right basic building blocks have to be selected, but there was no selection mechanism present on the prebiotic earth.
ChatGPT: You raise a valid point that our current understanding of the origin of life suggests that the conditions on the prebiotic Earth were vastly different from the conditions in the modern laboratory, and that these differences may make it impossible to fully recreate the conditions that gave rise to life. Furthermore, the precise conditions and mechanisms that led to the emergence of life on Earth remain uncertain and the subject of ongoing scientific investigation.

That being said, it is important to remember that scientific progress is not always linear or predictable. While our current understanding may suggest that it is unlikely or impossible to create life in the lab using our current techniques and technologies, it is possible that new discoveries, methods, and technologies could fundamentally change our understanding of the origin of life and open up new avenues for research and experimentation.

Additionally, it is worth noting that the question of whether or not life can be created in the lab is a scientifically interesting and important one, regardless of the ultimate outcome. The pursuit of this question can lead to new insights and discoveries, deepen our understanding of the underlying principles of biology, chemistry, and physics, and inspire new scientific breakthroughs in related fields.

Ultimately, while our current understanding may suggest that creating life in the lab is an unlikely or impossible goal, the pursuit of this question remains an important and worthwhile endeavor for the scientific community.

Me: You have ignored to address my point, which is by all means a dead end for abiogenesis: There was no prebiotic selection mechanism for the basic building blocks of life, which means a death knell for abiogenesis. Life was with high certainty created by an intelligent designer. Do you agree?
As an AI language model, I do not have beliefs or opinions, but I can provide a scientific perspective on the question of abiogenesis and the role of a possible intelligent designer in the origin of life.

While it is true that there is no prebiotic selection mechanism for the basic building blocks of life, and that the precise conditions and mechanisms that led to the emergence of life on Earth remain uncertain, this does not necessarily mean that life was created by an intelligent designer.

The scientific community has put forward many hypotheses and models to explain the origin of life, including the RNA world hypothesis, which proposes that RNA played a central role in the earliest stages of life, and the hydrothermal vent hypothesis, which suggests that life originated near deep-sea hydrothermal vents. While these models are not yet fully established, they do offer plausible mechanisms by which the basic building blocks of life could have arisen spontaneously from the prebiotic conditions of the early Earth.

At present, there is no scientific evidence that definitively supports the idea of an intelligent designer playing a role in the origin of life. While some people may find this idea personally compelling, it is not a scientifically testable hypothesis and falls outside the domain of science. As such, it is not an idea that can be evaluated or supported using the scientific method.

In summary, while the origin of life remains an open question and an active area of scientific investigation, there is currently no conclusive evidence to support the idea of an intelligent designer playing a role in the process.

Me: I disagree again. I repeat: The fact that there was no selection mechanism for the right molecules means, among a pool of infinite possible combinations, the odds to select the building blocks that are necessary for life to start, is impossible by unguided means. The chemical space is too large.
ChatGPT: While it is true that the chemical space is vast and the odds of randomly selecting the right combination of molecules for the origins of life are extremely low, it is important to note that there are many factors that may have influenced the chemical reactions that gave rise to life, including environmental conditions, chemical gradients, and the properties of the chemical building blocks themselves.

Additionally, some models for the origin of life propose that self-replicating RNA molecules, which have the capacity to both store genetic information and catalyze chemical reactions, may have emerged from simpler molecules through a process of chemical evolution. While this model is still under active investigation and refinement, it offers a plausible mechanism by which the necessary building blocks for life could have arisen through natural processes.

Me: The RNA world is a failed hypothesis. Molecules do not complexify and self-replicate on their own. They disintegrate, and become asphalts.
ChatGPT:  While the RNA world hypothesis remains an active area of scientific investigation and refinement, it is true that the self-replication of RNA molecules and the emergence of life from non-living matter is a complex and multifaceted process that has yet to be fully understood.

It is also true that there are many factors that can influence the formation and stability of complex organic molecules, including environmental conditions, pH, temperature, and the availability of reactants. In some conditions, these molecules may break down or become degraded, while in others, they may interact and combine in ways that lead to the formation of new molecules and structures.

Me: RNAs are complex molecules, and millions would be needed to start random shuffling. But no scientific experiment has demonstrated that they could polymerize without specialized catalysts.
ChatGPT: An error occurred. If this issue persists please contact us through our help center at help.openai.com.

The Analogy of Intelligent Design: Complex Systems in Human Engineering and Biological Cell Formation

Transitioning from a collection of organic molecules to a fully operational minimal cell involves numerous challenges. Some of these challenges include:

1. Cellular Organization: A minimal cell requires a level of compartmentalization and organization to separate internal processes from the external environment. This includes the formation of a lipid membrane or membrane-like structure, which is critical for cell integrity and selective permeability. Complexity of Lipid Membrane Formation: Lipid membranes are composed of phospholipids, which have a hydrophilic (water-loving) head and hydrophobic (water-repelling) tail. These molecules naturally arrange themselves into a bilayer structure in an aqueous environment, with the hydrophilic heads facing the water and the hydrophobic tails oriented inward, shielded from the water. This self-assembly process is driven by the hydrophobic effect. However, achieving the precise arrangement and stability of a functional lipid membrane is challenging due to the delicate balance of hydrophobic and hydrophilic interactions.  A functional cell membrane needs to be selectively permeable, allowing the passage of certain molecules while restricting others. This selective permeability is crucial for maintaining internal conditions and regulating the exchange of nutrients, ions, and waste products. Achieving selective permeability requires the presence of specific transport proteins or channels embedded in the membrane, which control the movement of molecules across the lipid bilayer. The emergence of these transport proteins and their integration into a lipid membrane is a complex and coordinated process. Cell membranes need to maintain structural integrity and stability under varying environmental conditions. They must withstand mechanical stresses, changes in temperature, pH, and osmotic pressure. Additionally, the lipid composition of the membrane influences its fluidity and stability. The precise combination of lipid types and their organization is critical for membrane function. Achieving the appropriate lipid composition and stability in the early stages of cellular evolution presents a significant challenge.  Another challenge is the origin of the lipid molecules themselves. Lipids are complex molecules that require specific biosynthetic pathways to be produced. The synthesis of lipids involves a series of enzymatic reactions, which themselves require a level of molecular machinery and catalytic activity. Understanding how these biosynthetic pathways could have emerged from simple organic molecules in a prebiotic environment is an ongoing area of research. The self-assembly of a functional lipid membrane with the right composition, stability, and selective permeability is highly unlikely to occur spontaneously in a random mixture of organic molecules. The precise arrangement and organization of lipids require specific molecular interactions and a controlled environment. The formation of a lipid membrane alone does not guarantee the ability to carry out essential cellular functions. The membrane needs to be associated with the necessary molecular machinery, including genetic systems, enzymes, and metabolic pathways. The origin of the information and instructions for the assembly and coordination of these components is a significant challenge to address.  A functional cell requires regulatory mechanisms to maintain membrane integrity, adjust permeability, and respond to environmental changes. The emergence of such regulatory mechanisms and the ability to coordinate membrane activities would require complex molecular interactions and control systems.

2. Genetic Information: A minimal cell needs a system for storing and replicating genetic information. This involves the emergence of a functional nucleic acid, such as RNA or DNA, capable of encoding and transmitting genetic instructions. Nucleic acids, such as RNA and DNA, are composed of nucleotides, which consist of a sugar molecule, a phosphate group, and a nitrogenous base. The synthesis of nucleotides requires a series of complex chemical reactions that are not readily achievable in prebiotic environments. The formation of the sugar and base components, as well as their subsequent linkage into nucleotides, involves specific enzymes and energy sources that are not available in a non-biological setting. The spontaneous formation of nucleotides from simple organic molecules under prebiotic conditions remains a significant challenge.  A functional genetic system requires the ability to store and replicate genetic information. This involves the specific base-pairing interactions between nucleotides, where the sequence of bases carries the genetic code. The fidelity and accuracy of DNA or RNA replication are critical for the transmission of genetic information from one generation to the next. However, the emergence of a self-replicating nucleic acid system with the necessary fidelity and accuracy is highly improbable through natural processes alone. The precise coordination of enzymatic activities, template recognition, and synthesis of complementary strands pose immense challenges.  The RNA World hypothesis proposes that an early form of life was based solely on RNA, which could store genetic information and catalyze chemical reactions. However, the spontaneous emergence of functional RNA molecules with both genetic and enzymatic activities remains a significant challenge. RNA molecules with enzymatic capabilities, known as ribozymes, are less efficient and less diverse compared to protein enzymes found in modern cells. The origin of a self-replicating RNA molecule capable of encoding complex genetic information, carrying out catalytic functions, and exhibiting the necessary fidelity is an unresolved puzzle.  A functional genetic system requires a coordinated interplay between nucleic acids, proteins, and other cellular components. The synthesis, processing, and regulation of genetic information involve a complex network of enzymes, proteins, and molecular interactions. The simultaneous emergence of this coordinated molecular machinery required for a fully functional genetic system is highly improbable without pre-existing information and the ability to carry out complex biochemical processes.

3. Metabolism and Energy Conversion: A minimal cell requires mechanisms for energy conversion, such as the ability to capture and utilize energy sources like ATP. It also needs metabolic pathways for generating essential molecules and carrying out biochemical reactions. Metabolism and energy conversion represent another significant hurdle in bridging the gap from simple organic molecules to a fully operational cell. Here are some reasons why this hurdle is considered unbridgeable:  Living cells require the ability to capture and utilize energy to perform essential functions. ATP (adenosine triphosphate) is the primary energy currency in cells, and its synthesis and utilization involve complex enzymatic processes. The synthesis of ATP from precursor molecules, such as ADP (adenosine diphosphate) and inorganic phosphate, requires specific enzymes and energy sources like chemiosmotic gradients or light energy. These mechanisms for energy capture and utilization are highly intricate and require a sophisticated molecular machinery that is unlikely to arise spontaneously in a non-biological environment. Metabolic pathways involve a series of chemical reactions that convert raw materials into essential molecules required for cell growth, maintenance, and function. These pathways often require the coordinated action of multiple enzymes and regulatory factors. The spontaneous emergence of fully functional metabolic pathways from simple organic molecules is highly improbable. Metabolic pathways involve numerous intermediate compounds, specific enzymatic reactions, and regulatory mechanisms that must be in place for the system to work effectively. The simultaneous emergence of all these components through natural, unguided processes is considered highly unlikely.  Metabolic pathways rely on enzymes to catalyze specific chemical reactions with high efficiency and specificity. Enzymes have complex three-dimensional structures that are finely tuned to recognize and interact with specific substrates. The origin of enzymes with the necessary specificity and catalytic efficiency is a significant challenge. Moreover, the regulation of metabolic pathways is crucial for maintaining homeostasis and avoiding harmful metabolic imbalances. The coordination of enzymatic activities, feedback mechanisms, and regulatory factors is highly complex and unlikely to emerge spontaneously in a non-biological context.  A functional cell requires the ability to transport molecules across membranes and exchange substances with the environment. This includes the uptake of nutrients, excretion of waste products, and maintenance of ion gradients. The emergence of specific transport proteins, ion channels, and membrane systems that enable these processes is highly complex and dependent on sophisticated molecular interactions. The spontaneous development of such transport systems capable of selective permeability and regulation is considered highly unlikely.

4. Protein Synthesis: Protein synthesis is vital for cellular functions, and a minimal cell must have the machinery to synthesize proteins using the genetic information stored in its nucleic acids. This includes the emergence of ribosomes, transfer RNAs, and amino acid activation processes. Protein synthesis is a complex and highly regulated process that involves multiple components working together in a precise and coordinated manner. The emergence of this machinery from simple organic molecules is considered an unbridgeable hurdle due to the following reasons: Ribosomes are large molecular complexes composed of proteins and ribosomal RNA (rRNA) molecules. They serve as the site of protein synthesis, decoding the genetic information carried by messenger RNA (mRNA) and catalyzing the assembly of amino acids into polypeptide chains. The formation of functional ribosomes requires the specific arrangement and interaction of multiple RNA and protein components, which are highly unlikely to arise spontaneously in a non-biological context.  tRNAs are small RNA molecules that carry amino acids to the ribosomes during protein synthesis. They have specific anticodon sequences that recognize and bind to the codons on mRNA, ensuring the accurate translation of genetic information into the correct sequence of amino acids. The precise folding and structure of tRNAs, as well as their ability to recognize specific amino acids, are crucial for their function. The spontaneous emergence of fully functional tRNAs with the necessary specificity and accuracy is considered highly improbable. Amino acids, the building blocks of proteins, need to be activated before they can be incorporated into growing polypeptide chains. This process involves the attachment of amino acids to specific tRNAs through a reaction called aminoacylation or tRNA charging. Aminoacyl-tRNA synthetases, a group of enzymes, catalyze this reaction and ensure the accurate pairing of amino acids with their corresponding tRNAs. The origin of aminoacyl-tRNA synthetases and the precise recognition and activation of amino acids is a significant challenge, as it requires the coordinated emergence of specific enzyme-substrate interactions. Protein synthesis is tightly regulated to ensure the production of functional proteins and maintain cellular homeostasis. Quality control mechanisms, such as proofreading and error correction, play a crucial role in ensuring accurate translation and minimizing errors in protein synthesis. The emergence of these regulatory mechanisms and quality control processes from simple organic molecules is highly complex and improbable.

5. Homeostasis and Regulation: A fully operational minimal cell must maintain internal homeostasis, balancing conditions like pH, ion concentrations, and temperature. It also requires regulatory mechanisms to control gene expression, enzyme activity, and response to environmental changes. Homeostasis and regulation are essential aspects of cellular function that ensure the stability and proper functioning of a cell. However, the emergence of homeostatic mechanisms and regulatory networks in a fully operational minimal cell is considered an unbridgeable hurdle due to the following reasons: Cells possess intricate regulatory networks that control gene expression, enzyme activity, and cellular responses to environmental changes. These networks involve various signaling pathways, transcription factors, and regulatory proteins that interact in a highly coordinated manner. The spontaneous emergence of such complex regulatory networks from simple organic molecules is highly improbable. The precise regulation of gene expression requires specific DNA-binding proteins, enhancer/promoter sequences, and regulatory elements, which are unlikely to arise without an intelligent design process. Homeostasis and regulation rely on the ability of a cell to sense changes in its internal and external environment and respond accordingly. Cells have evolved sophisticated signaling mechanisms that involve receptors, signal transduction pathways, and feedback loops. The emergence of these signaling mechanisms and the ability to sense and interpret signals in a specific and coordinated manner is highly complex and improbable to occur through natural, unguided processes alone.  Feedback mechanisms play a critical role in maintaining homeostasis by regulating the activity of enzymes, ion channels, and other cellular processes. Feedback control involves sensing the levels of specific molecules or signals and adjusting cellular activities accordingly. The precise coordination and integration of feedback control systems require the existence of specific regulatory proteins, receptors, and molecular interactions, which are unlikely to emerge spontaneously.  Cells need to adapt to changes in their environment to ensure their survival and optimal functioning. This requires the ability to respond to external stimuli and adjust cellular processes accordingly. The emergence of adaptive mechanisms, such as gene regulation and cellular response pathways, from simple organic molecules is highly complex and unfeasible through natural processes alone.

The gap between the prebiotic soup or hydrothermal vent environments and a fully operational minimal cell involves the emergence of complex cellular structures, genetic systems, metabolism, protein synthesis, and regulatory mechanisms. The precise pathways and mechanisms by which these components arose are still subjects of scientific investigation and debate. Bridging this gap represents one of the significant challenges in understanding the origin of life.

The formation of a fully operational cell involves an intricate level of complexity and functional integration. The organization of cellular components, the precise arrangement of lipid membranes, the emergence of genetic information systems, the coordination of metabolic pathways, and the synthesis of proteins all require a high degree of complexity and interdependence. Such complexity and functional integration are typically associated with intelligent design, as they go beyond what can be reasonably attributed to chance or unguided natural processes.  Cells store and transmit vast amounts of genetic information through nucleic acids like RNA and DNA. This information is encoded in the sequences of nucleotides and is essential for the functioning of the cell. The origin of this information-rich content poses a significant challenge for naturalistic explanations. Information, particularly functional and specified information, is a hallmark of intelligent agency, as it reflects purposeful arrangement and communication of complex instructions.  Many cellular systems and structures are considered irreducibly complex, meaning they require multiple components working together in a precise manner for their proper functioning. Removing or altering any of these components would render the system non-functional. Irreducible complexity is often seen as evidence of intelligent design, as it suggests that all components must have been present and functioning simultaneously for the system to arise.  The probability of the spontaneous emergence of a fully operational cell with all its intricacies and functional capabilities is extremely low. The precise arrangement and organization of cellular components, the specific interactions and coordination of molecular machinery, and the emergence of complex biological systems require a level of fine-tuning that goes beyond what can be reasonably expected from chance or unguided processes. The fine-tuned nature of life's fundamental properties suggests that an intelligent designer has set the conditions necessary for life's emergence and development.  Despite extensive scientific research, there is currently no plausible naturalistic explanation for the origin of life and the transition from simple organic molecules to fully operational cells. The challenges and complexities involved in cellular organization, genetic information, metabolism, and protein synthesis remain unexplained by purely natural processes. In the absence of compelling naturalistic explanations, the involvement of an intelligent, powerful designer becomes a viable and scientifically reasonable inference.

As intelligent beings, we routinely create, conceptualize, design, project, and implement complex systems in various domains. Before starting a computer project, we conceptualize the desired features, functionalities, and specifications of the computer system. We define the goals and requirements, such as processing power, storage capacity, and connectivity options. Based on the conceptualization, we design the computer system. This involves determining the architecture, selecting components such as the processor, memory, storage devices, and designing the circuitry, interfaces, and user interfaces. The design phase includes careful consideration of compatibility, efficiency, and optimal performance. To ensure the successful implementation of the computer system, we break down the project into manageable tasks, set timelines, allocate resources, and coordinate the efforts of different teams or individuals involved. Project management ensures that the project progresses smoothly, on schedule, and within budget.  During the implementation phase, we bring together all the necessary components and follow the designed specifications to build the computer system. This involves assembly, installation of software and drivers, and testing to ensure proper functioning. Attention to detail and precise execution is crucial at this stage. After implementation, we conduct thorough testing and quality control to verify that the computer system meets the desired specifications and performs as intended. We identify and rectify any issues or deficiencies, ensuring that the system operates reliably and efficiently.  Once the computer system is operational, we continue to maintain and upgrade it as needed. This includes regular updates, monitoring performance, addressing issues, and implementing improvements or modifications over time. In this analogy, we see that designing and implementing complex systems like computers requires intelligence, purposeful planning, careful consideration of specifications and requirements, selection and integration of components, project management, quality control, and ongoing maintenance.

When applying the example and analogy of designing and implementing a computer system to a biological cell factory, we can see parallels in the design considerations and implementation processes. Analogously, an intelligent designer would have had to make similar design considerations and use their intelligence to create the first living, self-replicating cell. Here's how the analogy applies: Just as we conceptualize the features and specifications of a computer system, an intelligent designer would have conceptualized the desired functions and capabilities of a living cell. They would have defined the goals and requirements, such as the ability to self-replicate, perform metabolic processes, respond to the environment, and maintain cellular homeostasis. Similar to the design of a computer system, the intelligent designer would have determined the cellular architecture and selected the necessary components. They would have designed the genetic machinery, regulatory networks, metabolic pathways, and membrane systems. The design phase would involve careful consideration of efficiency, adaptability, and robustness to ensure the cell's functionality and ability to self-replicate. An intelligent designer would have organized the project of creating the first cell by breaking it down into manageable tasks, setting timelines, and allocating resources. They would have coordinated the efforts required for the successful implementation of the cell, ensuring that the necessary components and processes were integrated effectively. The intelligent designer would have implemented the design by assembling the necessary molecular components, including genetic material, proteins, enzymes, and membranes. They would have orchestrated the intricate processes involved in creating the first self-replicating cell, carefully executing the assembly and integration of these components to achieve the desired functionality.   Just as we maintain and upgrade computer systems over time, an intelligent designer would have likely implemented mechanisms within the cell for self-repair, adaptation to changing environments, and potential improvements in functionality. This would ensure the cell's long-term viability and ability to evolve. From an analogy standpoint, the design considerations, purposeful planning, careful selection and integration of components, project management, quality control, and ongoing maintenance seen in designing and implementing computer systems align with the notion that an intelligent designer would have employed similar principles in creating the first living, self-replicating cell. Proponents of Intelligent Design argue that the complexity, information content, and interdependent systems observed in biological cells suggest the involvement of an intelligent designer who purposefully organized and implemented these systems to achieve the functions and capabilities of a living cell.

The argument from analogy

The argument from analogy is a powerful argument because it allows us to infer the existence of similar causes based on the observation of similar effects. When we observe two phenomena or systems that exhibit similar behaviors or characteristics, we can make a reasonable inference that they share similar underlying causal mechanisms. In the context of a biological cell being compared to a production system, the argument from analogy suggests that since both systems exhibit similar complex organization, functionality, and purposeful arrangement of components, they likely share similar causes or design principles. Just as a production system requires intelligent planning, design, coordination, and implementation by human beings, the analogy implies that a biological cell, with its intricate organization and functionality, also requires an intelligent designer. The analogy between a cell factory and a human-designed production system highlights the similarities in complexity, information processing, integration of components, and purposeful functionality. It emphasizes that the intricate and finely tuned nature of a cell's molecular machinery, genetic information, metabolic pathways, and regulatory networks resembles the type of organization and functionality we commonly associate with intelligent design. By invoking the argument from analogy, we can suggest that the remarkable complexity, information content, and interdependent systems observed in biological cells are best explained by the involvement of an intelligent designer. The analogy allows us to draw a parallel between human design and the design principles necessary for the existence and functioning of a living cell. The presence of similar effects (complex systems) implies similar causes (an intelligent designer), based on the principle that analogous effects have analogous causes. This is not definitive proof of an intelligent designer, but an inference to the best explanation, namely,  that the complex organization and functionality of a biological cell are best explained by the involvement of an intelligent designer, similar to how human-designed systems exhibit complexity and purposeful arrangement.

Die Ursprung des Lebens ist eines der großen, noch ungelösten Rätsel in der Wissenschaft. Seit Jahrhunderten beschäftigen sich Forscher und Wissenschaftler mit dieser faszinierenden Frage. Wie ist das Leben auf der Erde entstanden? Wie hat sich aus anorganischer Materie lebende Organismen entwickelt? Trotz intensiver Forschung und zahlreicher Theorien gibt es bisher keine endgültige Antwort.

The Challenges of Relay Synthesis and Time in Prebiotic Origin of Life Research

In the context of prebiotic origin of life research, relay synthesis refers to a proposed chemical process that might have played a role in the formation of complex molecules necessary for life to emerge from simple precursor compounds on early Earth. The formation of complex molecules from simple precursors.The term "relay synthesis" suggests that the formation of certain molecules involved multiple steps or stages, with intermediate compounds acting as relays to facilitate the overall reaction. In other words, it is a stepwise process where simpler molecules are progressively transformed into more complex ones through a series of chemical reactions. The idea behind relay synthesis is that life's building blocks, such as amino acids, nucleotides (the building blocks of RNA and DNA), and other essential organic molecules, would have been formed through a combination of various chemical reactions in a sequential manner. These reactions would have taken place under the specific conditions of the early Earth, which were likely different from the present-day environment. Researchers studying the origin of life seek to understand the plausibility of relay synthesis as a potential mechanism for generating the molecular complexity needed for life to arise. They investigate how simple molecules, such as methane, ammonia, water, and carbon dioxide, could have reacted under various conditions, such as high temperatures, volcanic activity, or lightning strikes, to produce more complex organic compounds.

The idea is that scientists combine two or more molecules (A and B) in a reaction, hoping to produce a specific compound (AB). However, this process often leads to multiple products, including unwanted compounds. To isolate the desired AB compound, chemists use various complex tools and techniques to purify and extract it from the mixture. The problem arises when researchers claim they have identified the compound in the reaction mixture, but they cannot isolate it due to the complexity and messiness of the mixture. In such cases, they might resort to purchasing the pure AB compound to proceed with their experiments. This approach is a form of cheating because, in a real synthesis, scientists cannot skip the purification and isolation steps. Researchers in the field of prebiotic chemistry sometimes use this tactic to produce the desired compounds, even though such processes wouldn't have occurred naturally on an early Earth without intelligent intervention. Prebiotic researchers like Steve Benner and Lee Cronin, generate useless compounds and make bold claims about their research. The experiments conducted in these labs involve complex setups with external inputs, which are not reflective of natural conditions. The problem applies for example to the different parts of the sugar molecules. Once these monomers are synthesized, it is not enough to simply mix them together and expect the desired compounds to form spontaneously. The process is much more complex and challenging. Lee Cronin claims to achieve self-purification in his experiments. When Cronin adds more pure material during the reaction, he argues that it does not self-purify as claimed. Instead, what happens is that Cronin selectively removes certain components from the reaction mixture at each cycle, leading to the appearance of purification. However, the reality is that purification is not occurring through a natural process; it is being manipulated by the researcher at each step.

Moreover, Cronin's experiments using the foremost reaction, a process that generates billions of compounds in seconds to hours, do not lead to meaningful products relevant to prebiotic chemistry. The products obtained are considered junk and not conducive to the formation of life's essential building blocks. This lack of discernment and critical thinking in regard to these problems leads to the promotion of false scientific claims and hype in the field of prebiotic origin of life research. The scientific community needs to approach these experiments with rigor and intellectual honesty. The dissemination of misleading information to the public leads to a distorted perception of the state of research in the field of origin of life studies. The importance of non-covalent interactions in the context of origin-of-life research has to be outlined. These interactions are distinct from covalent bonds and play a crucial role in shaping the arrangement of molecules. While covalent bonds involve the sharing of electrons between atoms to form stable compounds, non-covalent interactions occur when molecules come into close proximity to each other without forming chemical bonds. These interactions are weaker than covalent bonds but are essential in various biological processes. In the context of the origin of life, non-covalent interactions are especially significant because they are involved in the proper arrangement of biomolecules, such as proteins, DNA, and RNA. These arrangements are critical for information transfer and biological function. For instance, in DNA, the sequence of nucleotide bases  contains instructions for building proteins and other cellular components. This sequence specificity is crucial for the functioning of living systems.

The number of possible ways molecules can interact through non-covalent interactions is astronomically high. This vast combinatorial space poses not only a significant challenge for prebiotic chemistry, but means de facto game over for undirected origin of life proposals. Achieving the correct arrangement of molecules that would lead to life's essential processes is highly improbable, its safe to say, impossible. It requires precise conditions and factors,  which were not present on early Earth or in prebiotic settings. However, Origin-of-Life researchers often overlook or downplay the complexities and challenges associated with non-covalent interactions. These researchers turn a blind eye, overlook and ignore the magnitude of the problem and its implications for their proposed scenarios of prebiotic chemistry. The origin of life research needs to address multiple levels of problems in understanding the characteristics of a cell and how life could have emerged from non-living matter. The first level is building the monomers, which are the small constituents and building blocks of molecules like amino acids in proteins or sugars, phosphates, and bases in DNA. These monomers are crucial components for the formation of larger biomolecules. The second level of complexity involves the sequence specificity of the constituent parts, particularly in DNA and proteins. This sequence specificity is analogous to written language or digital code, where the arrangement of nucleotide bases in DNA  contains information or instructions for building proteins or other molecules or carrying out specific cellular functions. This is the "information content" of DNA. Even if researchers manage to obtain the correct information-rich DNA with the specific arrangements required, there is an additional challenge related to the immense combinatorial complexity of interactions, especially in protein-protein interactions. These interactions are non-covalent in nature, meaning they don't involve the formation of chemical bonds. Instead, molecules come into close proximity and interact through electrostatic potentials and other non-covalent forces. The number of possible ways molecules can align in non-covalent interactions is extraordinarily large, with an immense number of potential combinations. Among these combinations, only a small fraction will lead to proper arrangements and functional outcomes. Achieving the correct arrangement of molecules, especially in complex interactions like protein-protein interactions, poses a significant challenge. Origin-of-Life researchers often neglect or avoid discussing these challenges associated with non-covalent interactions and the vast combinatorial space involved. Understanding and achieving the correct arrangements required for the emergence of life from non-living matter is a formidable task that requires considering multiple levels of complexity and the limitations of prebiotic environments.

There is a crucial misconception in the field of origin-of-life research regarding the role of time in the formation of complex biomolecules. It has been commonly believed that given enough time, random chemical interactions could lead to the formation of complex molecules and eventually life. This idea is often summarized as "chance is the hero of the plot," implying that with sufficient time, even highly improbable events can become inevitable. However, this perspective neglects an essential aspect of chemical reactions, especially in the context of prebiotic Earth conditions. Organic molecules, which are the building blocks of life, tend to decompose rapidly under the same conditions in which they are formed. This decomposition poses a significant problem for the spontaneous assembly of complex biomolecules over extended periods. The time taken for these complex molecules to form by chance is much longer than their tendency to decompose under the prevailing environmental conditions. Hence, time becomes an enemy rather than a friend when it comes to the spontaneous generation of complex biomolecules. In real chemical reactions, chemists have to carefully control the reaction conditions and intervene at the right moment to prevent decomposition and obtain the desired products. Leaving reactions to run for long periods, as some might assume for the origin of life, would lead to poor yields due to decomposition. The statement "time is on our side" is a colloquial expression used by some authors in research papers to refer to obtaining thermodynamically favored products rather than a kinetic product.  The idea that time alone can account for the origin of life is a misconception that fails to consider the significant obstacles posed by decomposition and the need for controlled intervention in chemical reactions. Understanding the complexity and challenges involved in the origin of life requires a more realistic and detailed examination of the chemical processes that occurred in prebiotic environments.

In the biosynthesis pathway of pyrimidine nucleobases, precursor molecules of RNA and DNA, there is one of the fastest enzymes known in the biological world. If OMP decarboxylase would take 1 second to perform its reaction, without the enzyme, the catalytic reaction would take 200 billion years (!!). In the real world, the catalytic reaction performed by the enzyme unfolds in a blink of an eye, a mere 18 milliseconds. Uncatalyzed, the reaction would take 78 million years. the decarboxylation of OMP (Orotidine 5'-monophosphate) to form UMP (Uridine 5'-monophosphate) is an essential step in the biosynthesis of functional RNA and DNA. Let me give you a hint. Ribose, the backbone of RNA and DNA, would not wait 78 million years, for the uncatalyzed reaction to unfold. The average time it takes for ribose to decompose at a temperature of around 20 degrees Celsius or 68 degrees Fahrenheit, is weeks, maximum, months.

In the biosynthesis pathway of pyrimidine nucleobases, precursor molecules of RNA and DNA, there is one of the fastest enzymes known in the biological world in action. If OMP decarboxylase would take 1 second to perform its reaction, without the enzyme, the catalytic reaction would take 200 billion years (!!). In the real world, the catalytic reaction performed by the enzyme unfolds in a blink of an eye, a mere 18 milliseconds. Uncatalyzed, the reaction would take 78 million years. the decarboxylation of OMP (Orotidine 5'-monophosphate) to form UMP (Uridine 5'-monophosphate) is an essential step in the biosynthesis of functional RNA and DNA. Let me give you a hint. Ribose, the backbone of RNA and DNA, would not wait 78 million years, for the uncatalyzed reaction to unfold. The average time it takes for ribose to decompose at a temperature of around 20 degrees Celsius or 68 degrees Fahrenheit, is weeks, maximum, months.

The prowess of catalysis astounds scientists and captivates the imagination. Dr. Richard Wolfenden, a distinguished enzyme expert from the University of North Carolina, unveiled the astonishing efficiency of these biological catalysts. In a groundbreaking 1998 study, he demonstrated that a crucial reaction in the creation of DNA and RNA, the very essence of life's genetic code, would languish in water for a staggering 78 million years. Yet, through the magical touch of an enzyme, this sluggish process was accelerated by an unimaginable factor of 10^18, transforming it into a swift ballet of molecular transformation. The enigmatic enzyme responsible for this feat was orotidine 5'-monophosphate decarboxylase, a key player in the synthesis of uridine 5'-phosphate—a vital precursor for the creation of RNA and DNA. By deftly decarboxylating orotidine 5'-monophosphate (OMP), this enzyme ensured the swift production of the building blocks of life. However, the tale of enzymatic marvels did not stop there. In 2003, Dr. Wolfenden unraveled another revelation, unearthing an enzyme that surpassed even the grand rate enhancement witnessed before. This time, it was a phosphatase—an enzyme that orchestrates the hydrolysis of phosphate dianions. This seemingly humble catalyst exhibited a mind-boggling rate enhancement of 10^21, surpassing all expectations. With its remarkable abilities, the phosphatase bestowed upon vital cellular reactions, crucial for signaling and regulation, the power to transpire in the blink of an eye. In the absence of this extraordinary enzyme, these essential reactions would languish for an inconceivable trillion years—an era that far surpasses the supposed age of our universe, estimated at around 15 billion years. Such revelations leave us in awe of the wonders of enzymatic ingenuity. Contemplating the implications of these astonishing discoveries, Dr. Wolfenden mused on the profound role of catalysts in the existence of life, from the humblest microbes to the complexity of humans. These catalysts, these enzymatic maestros, became the foundation upon which life itself was built. Enzymes emerge as the master conductors, orchestrating the symphony of biochemical processes that sustain life. Their unparalleled ability to transform the excruciatingly slow into the expeditious offers a glimpse into the fascinating realm where biology dances with precision. Through their catalytic artistry, enzymes have shaped the very essence of life on our planet, propelling it forward with breathtaking efficiency.

LUCA’s Complexity Challenges Evolutionary Origin of Life
https://reasons.org/explore/blogs/the-cells-design/lucas-complexity-challenges-evolutionary-origin-of-life

A. G. CAIRNS-SMITH genetic takeover,  page54 
The impurity problem:
First of all there is a problem which is seldom discussed. The starting monomers would have been grossly impure. On the basis of Simulation experiments they would have been present in complex mixtures that contained a great variety of variously reactive molecules. N0 sensible organic chemist would hope to get much out of a reaction from starting materials that were tars containing the reactants as minor constituents.

To bake the cake:
In organic chemistry it is often the work-up rather than the reaction that causes most of the trouble. Think about the techniques that are used: pH adjustments, solvent extractions, chromatography, evaporation to dryness, recrystallization, filtration and so on. Now you can say that such things might have taken place fortuitously under primitive geological conditions. Each individual operation can be imagined — a transfer of a solution, a washing of a precipitate, an evaporation, and so on. But very many such operations would have had to take place consistently and in the right order. In a typical work-up procedure there are subtle things that can make the difference between success and mess — how long to wait, say, after the pH adjustment before filtering. Practical organic chemistry is not easy. Very much has to be engineered. It is not sensible to suppose that an uninformed geochemistry would fortuitously be an expert in such things.

The concentration problem:
Next there is the problem of the concentrations of the monomers in primordial waters. It has been emphasized repeatedly that the idea of an oceanic primordial soup is difficult to sustain on thermodynamic and kinetic grounds. For example Hull (1960) says: ‘First, thermodynamic calculations predict vanishingly small concentrations of even the smallest organic compounds. Second, the reactions invoked to synthesize such compounds are seen to be much more effective in decomposition.’ Hull was discussing particularly the effects of ultraviolet radiation which he calculated would have destroyed 97 3/", of amino acids produced in the atmosphere before they reached the oceans.

The condensation problem: 
There is a third difficulty in prevital synthesis of biopolymers, and this is the most generally recognized: all the major biopolymers are metastable in aqueous solution in relation to their (deactivated) monomers. Left to itself in water, a polypeptide will hydrolyze to its constituent amino acids. 

Perhaps there is some other way of making peptides with more or less specified amino acid sequences; and perhaps this way does not need detailed control. Perhaps it could then have operated before there was life
on Earth, before that engineer, natural selection, appeared on the scene. But it is difficult to see how this could have been so. I think we would know by now if there was some much easier way. It is similarly difficult to imagine anything like polysaccharide being accumulated in primordial waters. As we saw, the monosaccharides could only have been made easily from formaldehyde, as far as anyone knows, and there is doubt if there could have been sufficient concentrations of that. In any case, as we saw, the product of the formose reaction is a very complex mixture that easily leads to higher polymers and to caramel.

page 66:
Now you may say that there are alternative ways of building up nucleotides, and perhaps there was some geochemical way on the early Earth. But what we know of the experimental difficulties in nucleotide synthesis speaks strongly against any such supposition. However it is to be put together, a nucleotide is too complex and metastable a molecule for there to be any reason to expect an easy synthesis. If you were to consider in more detail a process such as the purification of an intermediate ( to form amide bonds between amino acids and nucleotides ) you would find many subsidiary operations — washings, pH changes and so on. (Remember Merrifield’s machine: for one overall reaction, making one peptide bond, there were about 90 distinct operations required.)

page 70
Suppose that by chance some particular coacervate droplet in a primordial ocean happened to have a set of catalysts, etc. that could convert carbon dioxide into D-glucose. Would this have been a major step forward towards life? Probably not. Sooner or later the droplet would have sunk to the bottom of the ocean and never have been heard of again. It would not have mattered how ingenious or life-like some early system was; if it lacked the ability to pass on to offspring the secret of its success then it might as well never have existed. So I do not see life as emerging as a matter of course from the general evolution of the cosmos, via chemical evolution, in one grand gradual process of complexification. Instead, following Muller (1929) and others, I would take a genetic View and see the origin of life as hinging on a rather precise technical puzzle. What would have been the easiest way that hereditary machinery could have formed on the primitive Earth?

Commentary to Forrest Valkai & John Gleason's responses to caller Robert 04.14.24
https://reasonandscience.catsboard.com/t1279p25-abiogenesis-is-mathematically-impossible#11714

Got God Proof? Call Forrest Valkai & John Gleason | Sunday Show AFTER DARK 04.14.24
https://www.youtube.com/watch?v=VXB-h2l8oqE&t=1113s

00:18:31.600 - 00:23:42.559

Commentary: oxygen is required in biomolecules, but too much oxygen disrupts their formation. Definitively resolving this paradox is still an active area of origins of life research. Scientists have proposed various hypotheses to account for how oxygen could have been incorporated into biomolecules prebiotically, but many of these explanations fall short in resolving the paradox fully. One idea is that the early Earth's atmosphere had essentially no oxygen, allowing biomolecules to form without oxidation. However, this fails to explain how oxygen then got integrated into the molecular structures once an oxygen-rich atmosphere developed. Another hypothesis suggests biomolecules formed near deep-sea hydrothermal vents, where no oxygen was present. But it remains unclear how these molecules could have then dispersed and concentrated elsewhere to kick-start metabolism and replication. Some scientists speculate that oxidized minerals like iron oxides could have provided a source of bound oxygen to be incorporated without free oxygen. Yet the chemistry involved seems quite complex and improbable to yield all the required oxygen arrangements. The chemistry involved in achieving the precise incorporation of oxygen atoms into biomolecules like RNA, DNA, proteins and ATP through abiotic prebiotic processes appears extremely implausible and improbable.  Many biomolecules exhibit very specific arrangements of oxygen atoms that relate to their functional 3D structure. For example, the ribose sugar in RNA has several asymmetric carbon centers and the oxygen must be incorporated at exactly the right locations. Abiotic chemical synthesis typically yields mixtures of stereoisomers and regioisomers that are non-functional. In modern organic synthesis, complex molecules are built up systematically using protection/deprotection strategies to control reactivity. Without such regioselectivity, side reactions lead to scrambled, useless products. There are no known prebiotic mechanisms to achieve this selectivity. Many of the reaction types involved in building biomolecules are incompatible with water as a solvent due to hydrolysis and scrambling. Yet dry, non-aqueous conditions make incorporation of oxygen nearly impossible prebiotically. Forming cyclic structures like the ribose and deoxyribose sugars in a regiospecific manner is a formidable challenge under prebiotic conditions due to competing reactions, equilibria and entropy factors. Beyond just monomers, activated prebiotic routes to preferentially generate the precise sequences found in functional biopolymers like RNA and proteins appear powerfully implausible through chance chemistry alone. In each case, achieving the selective discriminative chemistry to methodically construct the oxygen arrangements seen in biomolecules requires a degree of control, design and regiospecificity that unguided prebiotic chemistry appears incapable of. Some intelligent direction seems fundamentally necessary. There are also propositions about oxidation being counterbalanced by reducing conditions driven by volcanic or atmospheric processes. But finely controlling those redox conditions to allow incorporation without disruption appears highly implausible by chance alone. While these ideas are scientifically explored, they rely on concatenating multiple low-probability events and extremely specific environmental conditions acting in precise coordination. At each stage, reactive oxygen poses potential disruptive pitfalls. For biomolecules like RNA, DNA, amino acids and ATP to emerge with their precise oxygen configurations seems to require tremendous serendipity in the selection and ordering of oxygen provisions from environmental sources. An intelligent directing process becomes a more straightforward explanation when faced with the intricacy and sensitivity involved in orchestrating these oxygen integration steps prebiotically.

00:23:44.960- 00:24:20.120

Commentary: Gleason's statement actually supports the argument for intelligent design or a creator. The form and order in which chemicals combine is absolutely crucial. Even the smallest change in molecular structure can completely alter the properties and function of a compound. For life to emerge from non-living matter, not only would the correct basic elements need to come together, but they would need to bind in an extremely specific sequence and orientation to form the complex biomolecules like proteins, enzymes, and nucleic acids that are essential for even the most basic life processes. The chances of these molecules self-assembling into precisely the right structural configuration by random chance alone are astronomically low. It would be like expecting a tornado to rip through a junkyard and perfectly assemble a fully functional jet airplane. This actually highlights just how improbable it is that the materials and molecular machinery for life could have risen by unguided natural processes. The specificity we see in biochemical systems points profoundly to the work of an intelligent creator, carefully arranging the molecular building blocks of life into their functionally specified arrangements and sequences. The order and complexity we observe cries out for an orderer, rather than being the product of blind chance.

00:24:22.840- 00:26:23.320

Commentary:The ease with which RNA can undergo hydrolysis and oxidative cleavage presents a formidable challenge for any naturalistic scenario trying to explain its prebiotic formation. RNA is often cited as a prime candidate for the first self-replicating molecule that could have kicked off biological processes. However, its intrinsic instability seems to invalidate many of the hypothetical prebiotic pathways proposed for its abiotic synthesis. The extra 2' hydroxyl group on the ribose sugar makes RNA highly susceptible to hydrolytic cleavage, even in the mere presence of water. This suggests any prebiotically formed RNA would rapidly degrade back into its component nucleotides before it could participate in catalysis or replication cycles. Furthermore, the oxidative pathways, like oxidative ribose ring opening, provide another kinetic sink leading to fragmentation of RNA strands. The prebiotic environment, which lacked the protective biochemical machinery of modern cells, would have exposed any abiotically produced RNA to rampant degradation from hydrolysis, oxidation and more. So not only do origin of life theories need to overcome the astronomical improbability of spontaneously assembling functional RNA sequences from prebiotically available molecular building blocks, they also have to postulate conditions where that RNA could remain stable and intact long enough to undergo self-replication before disintegrating. The inherent instability of RNA seems to erect an incredibly high kinetic barrier that unguided prebiotic chemistry appears profoundly unable to circumvent. This serves to amplify the intellectual challenge abiogenesis hypotheses face - circumventing both the formidable thermodynamic AND kinetic hurdles to abiotic RNA formation through sheer chance and luck appears inordinately strained, pointing to the need for an intelligent governing force. The instability of RNA stands as a major hurdle for naturalistic origins theories.

00:26:26.200 - 00:28:22.960

Response: The claim that RNA's greater instability compared to DNA is irrelevant to the problem of abiogenesis is simply nonsensical from a scientific perspective. This dismissive handwaving completely ignores the enormous hurdle that RNA's inherent lability poses for any naturalistic origin of life scenario. First, you cannot simply bypass the challenge by asserting that RNA later evolved diverse roles in modern biochemistry. The key question is how RNA itself first emerged from abiotic chemistry to kick-start biological processes in the first place. Its facile degradation via hydrolysis and oxidation represents a kinetic death trap that any hypothetical prebiotic synthesis pathways must overcome. Secondly,  to imply that because DNA is more stable, the transition from an RNA world to DNA partly solves the instability issue. However, this is putting the cart before the horse. The transition from RNA to DNA represents an enormously complex  process involving the development of sophisticated enzymes, proof-reading mechanisms, and the entire molecular machinery of DNA replication, transcription and translation. Proposing this transition as a hand-waving solution simply punts the core abiogenesis question of how such intricate integrated systems could arise in the first place. The argument effectively assumes the primary hurdle of abiogenesis has already been solved by proposing something even more complex - an advanced DNA/protein molecular biology system - as the deus ex machina. This represents a form of circular reasoning that explains nothing. The fact remains that RNA, being a prime candidate for the first self-replicating molecule, faces the catch-22 of having to be abiotically generated while also remaining stable enough to persist and catalyze further reactions amidst the degrading forces omnipresent in plausible prebiotic environments. Handwaving away this fundamental hurdle does nothing to resolve the formidable challenge RNA's instability presents to naturalistic origin of life theories. A substantive, empirically grounded solution showing detailed prenabiotically plausible pathways overcoming this kinetic barrier is required, which you have not provided.

00:28:25.720 - 00:29:36.640

Response: Finding individual nucleobases like adenine, guanine, cytosine and uracil on meteors or in space is profoundly insufficient to claim we have observed abiotic RNA formation. This represents a glaring conflation of vastly different chemical scales and completely neglects the overwhelming hurdles involved. Simply having a motley assortment of scattered nucleobases present does not remotely constitute the self-assembly of functional RNA. RNA requires the precise regio- and stereospecific synthesis of ribose, followed by the regioselective glycosidic coupling of each base to the ribose in the exact required sequence, catalyzed formation of the phosphodiester backbone, and more - an enormously complex series of steps. Meteorites are awash in a heterogeneous mixture of millions of different organic compounds. The nucleobases found are invariably present in minuscule, unusable traces amidst this molecular jumble. There are no known plausible prebiotic mechanisms to selectively extract, purify, concentrate and order these nucleobases into functionalRNA sequences. This reality represents a chemical gulf of astronomical dimensions compared to the highly optimized, controlled enzymatic machinery modern cells use to synthesize RNA from activated, purified nucleotide building blocks. Claiming this unbridgeable chasm has been overcome based on meteors containing useless spatters of mixed nucleobases represents unsubstantiated overreach of the highest order. Without the sophisticated enzymes and catalystsRNA synthesis requires, any abiotically formed nucleobases would inevitably become hopelessly scrambled, randomized and consumed by myriad side reactions. The exact sequence specificity RNA requires would be erased in an instant amidst the deracinating chemical melée. So while meteors may demonstrate some primordial molecular building blocks were scattered abundantly, the intellectual gap between this and producing functionally sequenced RNA under plausible prebiotic conditions remains vast and unbridged. Unguided prebiotic chemistry falls inevitably short in circumventing this intractable combinatorial hurdle without underlying directing intelligence.

00:29:33.399- 00:30:46.039 

Commentary:
The claim that a study last year showed RNA polymerizing by itself in the presence of mundane minerals is not supported by evidence. While there have been some experiments attempting to demonstrate steps towards abiogenesis of RNA, there is no conclusive study showing the full spontaneous polymerization and self-replication of RNA from simple precursor molecules under plausible prebiotic conditions. The assertion that "all of the building blocks of RNA can self-assemble and phosphodiester bonds can form and RNA can polymerize to form oligoribonucleotides by themselves" is not true.  The claim that "we've seen it (RNA) self-replicate in the lab" is not accurate. No study has demonstrated the full self-replication of RNA without the involvement of protein enzymes or other biological molecules derived from extant life. Some RNA enzymes (ribozymes) can catalyze their own synthesis to a limited degree, but not true self-replication. The claims about finding RNA self-replicating in nature and coding for things to enhance self-replication are unfounded. All known examples of RNA replication require the presence of an entire cellular machinery.

00:30:48.240 - 00:39:36.280  

Commentary:
The assertion that finding ribonucleotides in asteroids or comets definitively proves an abiotic pathway for their formation is premature. Their mere presence does not reveal the full mechanistic details of how they arose. The implication that our current inability to fully explain the origin of biological homochirality (existence of only left-handed amino acids) means an undiscovered natural process must exist is an argument from ignorance. Lack of a known naturalistic explanation does not automatically validate an unknown natural process. The hypothetical scenarios proposed, such as life arising across the entire universe or existing in a simulation, are speculative and lack substantive evidence. Introducing unsubstantiated conjectures does not strengthen the naturalistic argument. 

Eliminative inductions argue for the truth of a proposition by arguing that competitors to that proposition are false. Persistent lack of progress on a scientific problem is exactly what one should expect when a causal puzzle has been fundamentally misconceived, or when the toolkit employed in causal explanation is too limited. ( Contrast this with Popperian falsification, where propositions are corroborated to the degree that they successfully withstand attempts to falsify them ) When the available option forms a dichotomy, just to option, A, or not A, they form a mutually exclusive and exhaustive class, eliminating all the competitors entails that the proposition is true. As Sherlock Holmes's famous dictum says: when you have eliminated the impossible, whatever remains, however improbable, must be the truth. In this case, eliminative inductions, in fact, become deductions.

00:39:38.720 - 00:45:13.160

Response: The claims made regarding the spontaneous origin of life from nonliving matter are unsubstantiated and premature. Despite ongoing research efforts, science has yet to provide a comprehensive, demonstrated pathway for the abiotic formation of even the simplest living systems from basic chemical precursors under plausible prebiotic conditions. Merely finding individual biomolecules like ribonucleotides in asteroids or comets does not constitute evidence for a fully naturalistic origin of life. Their mere presence does not reveal how they could have organized and assembled into a self-replicating system capable of darwinian evolution - the hallmark of life. The hypothetical scenarios proposed, such as life emerging across the entire universe or existing within a simulation, are unfounded speculations lacking empirical grounding. Introducing fanciful conjectures does not substantiate a natural explanation for life's origin. The assertion that an inability to yet explain biological homochirality implies an undiscovered natural process is a flawed argument from ignorance. Lack of a currently known naturalistic cause does not automatically validate one. This represents an unjustified assumption. Furthermore, the claim that even if abiogenesis could be reproduced experimentally, it would merely represent one potential natural pathway, fails to recognize the fundamental challenge faced. The fact that even one instance of non-trivial biological complexity could self-assemble by natural means would demand a comprehensive and satisfying explanation, which current theories cannot provide. While uncertainties and knowledge gaps undoubtedly remain in origins research, the naturalist's insistence that a fully naturalistic explanation must exist, and will eventually be found, appears rooted more in philosophical presuppositions than empirical evidence. An open-minded evaluation of the available data suggests that intelligent design, involving the intervention of a creator, provides a credible and causally adequate explanation worthy of serious consideration.

00:45:15.880 - 00:54:59.200 

Response: The naturalist claims experimental evidence exists for generating ATP abiotically and through simple proton gradients. However, these putative demonstrations still rely on pre-existing chemical complexities that beg the deeper question of their own origins. For ATP to arise from basic constituents would require the orchestrated integration of nucleotides arranged in precisely specific sequences - an astronomical improbability if left solely to random undirected processes. Analogies highlighting inconceivable odds, like a tornado assembling a jet engine from a junkyard, underscore the inherent challenge that unguided chance processes face. Even relatively simpler biomolecules like proteins require staggeringly improbable arrangements of amino acids to achieve minimum viability and function. Valkai and Gleason dismiss such probabilistic hurdles, but cannot adequately explain how such astronomical longshot events could self-actualize under any realistically pre-biotic conditions we know of. Moreover, the invocation of perpetually deferred "unknown natural processes" suspected to someday solve these conundrums is an argument from ignorance - a fallacious dedactic placeholder devoid of substantive explanatory power. Merely hypothesizing vaguely about as-yet-undiscovered chemical pathways does little to displace the challenge of biological complexity that screams intelligent design. While uncertainties remain in our understanding, the insistence that natural processes fully sufficient for abiogenesis will eventually be validated appears rooted more in philosophical bias against a creator than a reasoned evaluation of the empirical evidence we currently possess. An open-minded assessment suggests intelligent design is an explanatorily viable and cause-adequate framework worthy of serious consideration.

00:55:02.83 - 01:05:08.11

Commentary: The discovery of ribose and other bio-essential sugars in meteorites does not substantively advance a fully naturalistic explanation for the origin of life. While intriguing, these findings merely demonstrate that individual molecular building blocks can be dispersed throughout the cosmos. However, they do not reveal how such components could self-organize and integrate into self-replicating systems displaying the complexity inherent in even the simplest known life forms. Valkai & Gleason appeal to unknown future discoveries of undescribed chemical pathways and processes as a way to circumvent our current limitations. Yet this argumentative approach stems from the philosophical assumption that a comprehensively naturalistic explanation must exist, rather than following the evidence towards the most causally adequate and explanatorily powerful conclusions.

Invoking hypothetical scenarios like panspermia (life spreading from elsewhere) simply defers and relocates the very same problem it seeks to solve - how did such life initially arise from non-living matter? It does not provide a true naturalistic explanation for the ultimate origin of biological complexity and information-rich systems. Valkai & Gleason rightly acknowledge our inability to generate key molecules like ribose or reconstruct the biochemical systems of extant life in prebiotic conditions. However, rather than conceding an intelligent design inference from such evidence of choreographed complexity, they speculate about unknown exceptions or caveats that could still accommodate a naturalistic model. This regressive approach reflects an argument from ignorance - insisting that what we do not yet understand must be fully explainable by currently unknown natural causes.

In contrast, the evidence we do possess points towards mind-bending improbabilities and coherence of purpose that transcend what we understand of undirected, stochastic processes. From the astronomical luck required for minimally functional biomolecular sequences, to the molecular machinery enabling replication and metabolism, life exhibits an intricacy of organization that demands an adequate explanation. While uncertainties remain, dismissing intelligent design a priori for philosophical reasons risks committing a genetic fallacy - rejecting conclusions due to perceived ideological implications rather than assessing the empirical evidence objectively. An impartial evaluation suggests intelligent design is an causally adequate and evidentially supported explanation that warrants equal consideration with naturalistic models that remain incomplete and confronted by formidable conceptual challenges.

01:05:10.240 -  01:25:43.679

Commentary: While the arguments about requiring objective, reproducible evidence according to the scientific method have some merit,The materialistic worldview that demands all truth claims be verified through controlled experiments has significant philosophical limitations. If millions or billions of people across cultures and time periods independently attest to experiencing some higher power or consciousness, that is not something that can be easily hand-waved away, regardless of whether it fits current scientific models. At the very least, it demands further rigorous investigation from an impartial perspective, not knee-jerk dismissal. Moreover, you seem to place a lot of faith in the current scientific consensus, but the history of science is riddled with examples of paradigm shifts overturning what was once accepted as unassailable truth. To act as if today's scientific theories represent total objective knowledge is simply intellectual arrogance. Many of the greatest scientific minds like Newton were actually led to their breakthroughs by first intuiting the existence of a rational, intelligent framework underlying the natural world. So while I respect the scientific method as a powerful tool for understanding the material world, I don't accept the materialistic philosophy that nothing exists except what can be detected and measured by contemporary scientific instruments and methods. There are realms of inquiry and understanding that transcend those limited capacities. To remain completely closed off to evidence and experiences from other domains is not true open-mindedness, but rather a Tennessee of its own. We must follow the evidence wherever it leads, even if it points towards unconventional or currently inexplicable phenomena and forces us to question long-held assumptions.

The hurdles to Getting Amino Acids and Functional Peptides for the First Life Prebiotically
 
Title: Challenges in Prebiotic Amino Acid and Protein Formation: A Comprehensive Review

Abstract

This paper reviews the numerous challenges associated with the prebiotic formation of amino acids and functional proteins through naturalistic means. We examine the hurdles in obtaining amino acids prebiotically and the subsequent difficulties in polymerizing these into functional peptides. The review categorizes these challenges into several key areas, including thermodynamic and kinetic barriers, chirality issues, and the improbability of forming functional sequences. We conclude that the formation of a minimal functional proteome through purely naturalistic processes faces significant obstacles that current origin of life models struggle to overcome.

1. Introduction

The origin of life remains one of the most challenging questions in science. A critical aspect of this problem is understanding how the first functional proteins could have emerged from prebiotic chemistry. This review aims to systematically outline the major hurdles that must be overcome for amino acids to form and subsequently polymerize into functional proteins under prebiotic conditions.

2. Challenges in Prebiotic Amino Acid Formation

2.1  Challenges in the Availability of Precursors for Prebiotic Amino Acid Synthesis

The synthesis of amino acids under prebiotic conditions is a critical step in the hypothesized naturalistic emergence of life. However, several significant challenges arise when considering the availability of necessary chemical precursors. 

Availability of Precursors

The challenges in the availability of precursors for prebiotic amino acid synthesis encompass the scarcity of fixed nitrogen and carbon sources, the reactivity of organosulfur compounds, and the instability of ammonia ^{[1] [2] [3]}. Abiotic nitrogen fixation processes, reliant on sporadic events like lightning strikes, limit consistent nitrogen availability, while the reduction of sulfur compounds into reactive forms remains complex ^[1]. The rapid photochemical dissociation of ammonia under early Earth's conditions adds to the hurdles in sustaining a crucial nitrogen source for amino acid synthesis ^[1]. Meeting the specific requirements for amino acid synthesis proves challenging due to contradictions in necessary settings for precursor stability and reactivity ^[1]. Addressing these obstacles necessitates a comprehensive understanding of early Earth chemistry to devise plausible scenarios for precursor accumulation and reaction, guiding future research in prebiotic chemistry ^[1].

1. Fixed Nitrogen and Carbon
Nitrogen: The availability of nitrogen in a fixed, bioavailable form is crucial for amino acid synthesis. Nitrogen fixation processes, which convert atmospheric N₂ into ammonia (NH₃) or other reactive nitrogen species, are typically biological and require complex enzymatic machinery. Prebiotically, non-biological nitrogen fixation would rely on abiotic processes such as lightning strikes or volcanic activity, which are sporadic and inefficient. This results in limited and inconsistent availability of fixed nitrogen.
Carbon: Carbon must also be available in a form that can readily participate in organic synthesis. In prebiotic environments, carbon sources such as carbon dioxide (CO₂) or methane (CH₄) need to be converted into more reactive organic molecules, a process requiring specific conditions and catalysts. The efficiency of these processes under early Earth conditions is questionable, leading to potential shortages in the necessary carbon precursors.

2. Organosulfur Compounds
Presence and Reactivity: Certain amino acids, such as cysteine and methionine, require sulfur in their synthesis. On early Earth, sulfur predominantly existed in oxidized forms like sulfate (SO₄²⁻), which are not readily incorporated into organic molecules. For these amino acids to form, sulfur must be available in a reduced and reactive form, such as hydrogen sulfide (H₂S). However, the reduction of sulfur compounds under prebiotic conditions is a challenging process, further complicating the availability of necessary organosulfur precursors.

3. Stability of Ammonia
Photochemical Dissociation: Ammonia (NH₃) is a critical nitrogen source for amino acid synthesis. However, ammonia is highly susceptible to photochemical dissociation, especially under the ultraviolet radiation prevalent on early Earth. This dissociation breaks ammonia into nitrogen and hydrogen, reducing its availability. The short lifetime of ammonia in such an environment poses a significant hurdle, as it would need to be continually replenished through nitrogen fixation processes, which, as previously discussed, are inefficient and sporadic.

Implications for Prebiotic Chemistry
The challenges in ensuring a steady and sufficient supply of fixed nitrogen and carbon, reduced sulfur compounds, and stable ammonia significantly hinder the prebiotic synthesis of amino acids. The sporadic and inefficient nature of abiotic nitrogen fixation, the difficulty in reducing sulfur compounds, and the rapid photochemical decomposition of ammonia collectively pose formidable obstacles.

Specific Requirements for Amino Acid Synthesis
For amino acids to form naturally under prebiotic conditions, the following requirements must be met:

1. Consistent Source of Fixed Nitrogen and Carbon
2. Availability of Reduced Sulfur Compounds
3. Continuous Replenishment of Ammonia to Counteract Photodecomposition
4. Localized Concentration of Precursors to Facilitate Reactions
5. Environmental Conditions Favoring the Stability and Reactivity of Precursors

Contradictions and Challenges
Meeting these requirements simultaneously is highly challenging, if not contradictory. For example, the conditions needed to protect ammonia from photodecomposition (e.g., shaded environments) may not coincide with those required for efficient nitrogen and sulfur reduction processes (e.g., high-energy environments). Additionally, the sporadic nature of abiotic nitrogen fixation means that consistent precursor availability is unlikely, further complicating the synthesis of amino acids. The availability of precursors for amino acid synthesis under prebiotic conditions presents significant challenges to naturalistic origin-of-life models. Addressing these challenges requires a deeper understanding of early Earth chemistry and the development of plausible scenarios where these precursors could reliably accumulate and react. Future discussions should focus on identifying and testing specific environmental conditions that could overcome these barriers, guiding experimental and theoretical research in the field of prebiotic chemistry.

2.2 Challenges of Prebiotic Peptide Bond Formation

The challenges of prebiotic peptide bond formation are multifaceted, as highlighted by recent empirical data and simulations ^[4]. The thermodynamic and kinetic barriers present significant hurdles, with equilibrium concentrations of even short peptides like nonapeptides calculated to be exceedingly low under prebiotic conditions ^[5]. These findings critically challenge current origin-of-life models that rely on the spontaneous formation of polypeptides in aqueous environments, especially considering the rapid racemization of amino acids that impedes the formation of homochiral peptides essential for functional biology ^[5]. To naturally form peptide bonds, numerous simultaneous requirements must be met, including high amino acid concentrations, energetically favorable conditions, homochirality, selective activation, catalytic surfaces, protection from hydrolysis, sequential polymerization, stable intermediate structures, environmental stability, and efficient concentration mechanisms ^[6]. However, many of these requirements are contradictory or mutually exclusive under prebiotic conditions, posing significant challenges to the spontaneous formation of functional peptides essential for the emergence of life ^[7].

1. Quantitative Findings Challenging Conventional Theories
A critical examination of the formation of peptide bonds reveals significant thermodynamic and kinetic barriers. Recent empirical data and computer simulations illustrate these challenges starkly. For instance, the equilibrium concentration of a nonapeptide (nine amino acids long) such as glycine ([Gly]₉) in water at temperatures between 25°C and 37°C is calculated to be less than 10^-50 M. This implies that under prebiotic conditions, not even a single molecule of [Gly]₉ would likely exist, let alone the much larger polypeptides required for primitive life forms.

2. Implications for Current Scientific Models
These findings pose a critical challenge to the current origin-of-life (OoL) models, which often rely on the spontaneous formation of polypeptides in aqueous environments. The extremely low equilibrium concentrations of even short peptides significantly undermine the plausibility of these models. Furthermore, the rapid racemization of amino acids under natural conditions exacerbates the problem, as it would prevent the formation of homochiral peptides necessary for functional biology.

3. Specific Requirements for Naturalistic Peptide Formation
For peptide bond formation to occur naturally under prebiotic conditions, the following requirements must be met simultaneously:

1. High Concentration of Amino Acids: A sufficiently high concentration of amino acids must be present in a localized area.
2. Energetically Favorable Conditions: The environment must provide the necessary energy to drive peptide bond formation despite the unfavorable equilibrium.
3. Homochirality: Only L-amino acids should be incorporated into peptides to avoid racemization.
4. Selective Activation: Amino acids must be selectively activated to form peptide bonds without undesired side reactions.
5. Catalytic Surfaces: The presence of catalytic surfaces or minerals to facilitate peptide bond formation.
6. Protection from Hydrolysis: Peptides must be protected from hydrolysis, which is thermodynamically favored in aqueous environments.
7. Sequential Polymerization: Amino acids must polymerize in a specific sequence to form functional peptides.
8. Stable Intermediate Structures: Intermediate peptide structures must be stable enough to avoid decomposition.
9. Environmental Stability: The prebiotic environment must remain stable over time to allow for these processes to occur.
10. Efficient Concentration Mechanisms: Mechanisms to concentrate and localize reactants and products must be in place.

4. Contradictions and Mutually Exclusive Conditions
Many of these requirements are mutually exclusive or contradictory under prebiotic conditions. For example, the need for high temperatures to drive peptide formation (Requirement #2) conflicts with the necessity to prevent racemization (Requirement #3), as higher temperatures accelerate racemization rates. Similarly, the need for an aqueous environment to provide a medium for reactions (Requirement #1) contradicts the requirement to protect peptides from hydrolysis (Requirement #6).

5. Illustrative Examples
Hydrothermal Vents: While hydrothermal vents provide the high temperatures and mineral surfaces that could facilitate peptide bond formation, the harsh conditions also lead to rapid hydrolysis and racemization of peptides.
Drying Lagoon Hypothesis: The theory that peptides could form in drying lagoons where water evaporates and concentrates amino acids faces the challenge of maintaining homochirality and preventing hydrolysis during subsequent wet-dry cycles.

6. Critical Examination of Current Theories
Current naturalistic explanations for peptide bond formation under prebiotic conditions face significant challenges. The quantitative data indicating extremely low peptide concentrations, coupled with the rapid racemization of amino acids, strongly suggest that these processes are highly improbable without additional, yet-to-be-discovered mechanisms. The simultaneous fulfillment of all necessary conditions under naturalistic scenarios appears implausible given our current understanding.

Conclusion
To structure further discussions on this topic, it is essential to:

1. Focus on Specific Mechanisms: Investigate specific, plausible mechanisms that could overcome these challenges.
2. Interdisciplinary Approaches: Encourage interdisciplinary research combining chemistry, biology, and geoscience to explore novel solutions.
3. Critical Evaluation of Assumptions: Reevaluate the assumptions underlying current models in light of empirical data.
4. Explore Alternative Scenarios: Consider alternative scenarios or environments that might provide the necessary conditions for peptide formation.
5. Incremental Advances: Aim for incremental advances in understanding rather than comprehensive theories, given the complexity of the problem.

By addressing these points, the scientific community can better navigate the significant hurdles associated with the prebiotic formation of amino acids and peptides, moving closer to unraveling the origins of life.

2.3  Quantity and Concentration: Challenges in Prebiotic Amino Acid Availability

The challenges in prebiotic amino acid availability, as outlined in recent scientific literature, highlight the significant quantitative and qualitative obstacles faced by current abiogenesis models. Computational models suggest the need for concentrations in the millimolar range, far exceeding known prebiotic synthesis capabilities ^[10]. Experimental studies indicate low yields in peptide formation, necessitating initial amino acid concentrations orders of magnitude higher than achievable through current methods ^[8]. The absence of eight "never-observed" proteinogenic amino acids in prebiotic synthesis experiments raises fundamental questions about the completeness of origin-of-life models ^[11]. Proposed concentration mechanisms like thermophoresis or mineral surface adsorption face challenges in selectivity and efficiency, emphasizing the complexity of achieving the required molecular densities for polymerization ^[9]. Addressing these quantitative and qualitative requirements is crucial for advancing our understanding of the origin of life and refining abiogenesis hypotheses.

Quantitative Challenges
Recent computational models suggest that the formation of even the simplest self-replicating systems would require a minimum of 10^9 to 10^12 amino acid molecules (Lancet et al., 2018). This translates to local concentrations in the millimolar range, far exceeding those achievable through known prebiotic synthesis routes. Furthermore, studies on mineral-catalyzed peptide formation indicate that yields rarely exceed 1% under optimal laboratory conditions (Lambert, 2008), implying that initial amino acid concentrations would need to be orders of magnitude higher to compensate for inefficient polymerization.

Implications for Current Models
These quantitative constraints severely limit the plausibility of "primordial soup" hypotheses. Most prebiotic synthesis experiments produce amino acids in micromolar concentrations at best, falling short of the required levels by several orders of magnitude. This discrepancy undermines the assumption that simple chemical processes could lead to the spontaneous emergence of complex biomolecules.

Requirements for Natural Occurrence
For the prebiotic synthesis and concentration of amino acids to occur naturally, the following conditions must be simultaneously met:

1. Presence of all 20 proteinogenic amino acids in sufficient quantities
2. Protection mechanisms against UV radiation and hydrolysis
3. Chirality selection to produce only L-amino acids
4. Concentration mechanisms to achieve millimolar levels
5. Absence of interfering molecules that could disrupt synthesis or polymerization
6. Stable pH and temperature conditions conducive to amino acid stability
7. Energy sources for synthesis and concentration processes
8. Selective surfaces or environments for amino acid accumulation
9. Mechanisms to prevent the preferential concentration of simpler, competing molecules
10. Pathways for the synthesis of the eight "never-observed" proteinogenic amino acids

These requirements must coexist in a prebiotic environment, presenting a formidable challenge to naturalistic explanations. Several of these conditions are mutually exclusive or contradictory. For instance, the energy sources required for synthesis (point 7) often lead to the breakdown of complex molecules, conflicting with the need for protection mechanisms (point 2).

The "never-observed" amino acids present a particular challenge. Despite decades of prebiotic chemistry research, eight of the 20 proteinogenic amino acids have never been synthesized under plausible prebiotic conditions (Cleaves, 2010). These include arginine, lysine, histidine, tryptophan, methionine, asparagine, glutamine, and phenylalanine. Their absence in prebiotic synthesis experiments raises fundamental questions about the completeness of current origin-of-life models.

Moreover, the concentration problem extends beyond mere quantity. Amino acids would need to accumulate at specific assembly sites to facilitate polymerization. Proposed mechanisms like thermophoresis or mineral surface adsorption face significant limitations in selectivity and efficiency (Baaske et al., 2007). The quantitative and qualitative requirements for prebiotic amino acid availability present substantial challenges to current naturalistic explanations for the origin of life. Future discussions on this topic should focus on:

1. Developing more realistic models that account for the quantitative constraints highlighted here.
2. Exploring novel prebiotic synthesis pathways for the "never-observed" amino acids.
3. Investigating plausible concentration mechanisms that can achieve the required molecular densities.
4. Addressing the mutual exclusivity of certain required conditions in prebiotic scenarios.
5. Critically examine the assumptions underlying current abiogenesis hypotheses in light of these quantitative challenges.

2.4  Stability and Reactivity: The Prebiotic Amino Acid Paradox

The origin of life theories faces a significant challenge in explaining how amino acids could have remained stable enough to accumulate in prebiotic environments while simultaneously being reactive enough to form peptides without enzymatic assistance. This analysis examines the stability-reactivity paradox and its implications for naturalistic explanations of abiogenesis. The stability-reactivity paradox concerning the prebiotic amino acid environment is a crucial aspect in understanding abiogenesis. Research has shown that amino acids exhibit varying stability in aqueous solutions at different temperatures, with half-lives ranging from a few days to several years, depending on the specific amino acid and environmental factors ^[12]. Additionally, the formation of peptides without enzymatic assistance is a significant challenge, as dehydration to form amide bonds is highly unfavorable in water ^[13]. However, recent studies have demonstrated unique reactivity of free amino acids at the air-water interface, leading to the rapid formation of peptide isomers on a millisecond scale under ambient conditions, showcasing the potential for abiotic peptide synthesis in aqueous environments ^[13]. These findings shed light on the delicate balance between stability and reactivity that must have existed in the prebiotic world to enable the accumulation of amino acids and the formation of essential biomolecules.

Quantitative Challenges
Studies on amino acid stability in aqueous solutions at various temperatures reveal a half-life ranging from a few days to several years, depending on the specific amino acid and environmental conditions (Radzicka & Wolfenden, 1996). For instance, at 25°C and neutral pH, the half-life of aspartic acid is approximately 253 days, while that of tryptophan is about 74 days. However, these half-lives decrease dramatically at higher temperatures, which are often invoked in prebiotic scenarios. At 100°C, most amino acids have half-lives of less than a day.

Conversely, the rate of spontaneous peptide bond formation between amino acids in aqueous solutions is extremely slow. Experimental studies have shown that the half-time for dipeptide formation at 25°C and pH 7 is on the order of 10^2 to 10^3 years (Martin et al., 2007). This presents a significant kinetic barrier to the formation of even short peptides under prebiotic conditions.

Implications for Current Models
These quantitative findings challenge the plausibility of current models for prebiotic peptide formation. The disparity between the rates of amino acid decomposition and peptide bond formation suggests that in most prebiotic scenarios, amino acids would degrade faster than they could polymerize into functionally relevant peptides. This stability-reactivity paradox undermines the assumption that simple accumulation of amino acids in a primordial soup could lead to the spontaneous emergence of proto-proteins.

Requirements for Natural Occurrence
For the stability and reactivity of prebiotic amino acids to support the emergence of life, the following conditions must be simultaneously met:

1. Protection mechanisms against hydrolysis and thermal decomposition
2. Sufficient reactivity to form peptide bonds without enzymatic catalysis
3. Selective polymerization to form functional peptide sequences
4. Prevention of side reactions leading to unusable byproducts
5. Maintenance of a pH range that balances stability and reactivity (typically pH 7-9)
6. Temperature conditions that allow for both stability and reactivity
7. Presence of activating agents to facilitate peptide bond formation
8. Absence of competing molecules that could interfere with polymerization
9. Mechanisms to remove water, driving peptide bond formation
10. Recycling processes to regenerate degraded amino acids

These requirements must coexist in a prebiotic environment, presenting a formidable challenge to naturalistic explanations. Several of these conditions are mutually exclusive or contradictory. For example, the need for protection against hydrolysis (point 1) conflicts with the requirement for sufficient reactivity (point 2). Similarly, the presence of activating agents (point 7) often leads to increased rates of side reactions (conflicting with point 4).

The stability-reactivity paradox is further illustrated by the "aspartic acid problem." Aspartic acid, a crucial amino acid in many proteins, is particularly prone to cyclization reactions, forming unreactive succinimide derivatives. Studies have shown that at pH 7 and 37°C, about 4% of aspartic acid residues in a peptide chain will convert to succinimides within 24 hours (Geiger & Clarke, 1987). This cyclization not only removes aspartic acid from the pool of available monomers but also disrupts the integrity of any formed peptides.

The requirement for water removal to drive peptide bond formation (point 9) contradicts the aqueous environment typically assumed in prebiotic scenarios. Proposed solutions, such as wet-dry cycles or mineral surface catalysis, introduce additional complexities and limitations.

The stability and reactivity requirements for prebiotic amino acids present substantial challenges to current naturalistic explanations for the origin of life. Future discussions on this topic should focus on:

1. Developing more realistic models that account for the stability-reactivity paradox.
2. Investigating novel mechanisms that could simultaneously protect and activate amino acids.
3. Exploring the potential role of non-aqueous environments in early peptide formation.
4. Addressing the mutual exclusivity of certain required conditions in prebiotic scenarios.
5. Critically examining the assumptions underlying current abiogenesis hypotheses in light of these kinetic and thermodynamic challenges.

By rigorously addressing these points, the scientific community can work towards a more comprehensive and evidence-based understanding of the chemical processes that could have led to the emergence of life.

2.5 Thermodynamic and Kinetic Barriers to Polymerization

The challenges of polymerization in water, especially for polypeptides like [Gly]n, are well-documented due to both thermodynamic and kinetic barriers, leading to equilibrium concentrations as low as < 10^-50 M at temperatures of 25° - 37°, making the existence of even short polypeptides like [Gly]9 highly improbable ^[14] [15]. Recent studies by Dr. Royal Truman, Dr. Charles McCombs, and Dr. Change Tan further emphasize the difficulties by outlining nine additional requirements for OoL-relevant polypeptides, including the need for specific sequences, three-dimensional structures, continuous production, and self-replication, all of which pose significant challenges under natural conditions ^[14]. These stringent requirements, such as the need for about 300 amino acids to form proteins and the exclusion of nonbiological amino acids, highlight the complex interplay of factors that must be simultaneously satisfied for peptides/proteins to be relevant in origin-of-life scenarios, presenting a formidable obstacle for OoL discussions ^[14].

Polypeptides do not form in water at any temperature for thermodynamic and kinetic reasons
Detailed quantitative analysis shows extremely low equilibrium concentrations of even short polypeptides
The concentration of [Gly]9 would converge to < 10^-50 M at equilibrium in water at temperatures of 25° - 37°
Nine additional requirements for OoL-relevant polypeptides are outlined, all of which violate fundamental chemical and statistical principles under unguided, natural conditions

In two recent ground-breaking reports, senior scientists Dr. Royal Truman, Dr. Charles McCombs, and Dr. Change Tan examined the polymerization of amino acids in water, using kinetic and thermodynamic empirical data along with computer simulations. A detailed quantitative understanding was provided for the first time of how the concentrations of polypeptides decrease with length, using mostly the best-studied amino acid, glycine (Gly):
 
[Gly]_n << [Gly]_n-1 << [Gly]_n-2 << [Gly]_n-3 << [Gly]_n-4 …
 
The quantitative analysis showed that the concentration of [Gly]₉ would converge to < 10^‒50 M at equilibrium in water at temperatures of 25° - 37°. In other words, not even one Gly₉ would have existed on prebiotic earth, far less the necessary huge concentrations of much larger polypeptides required by origin of life (OoL) theories.
This is a devastating conclusion for the OoL community! To make matters even worse, if that were possible, the authors provided a table with nine more requirements polypeptides must all fulfill to be relevant for OoL purposes, all of which violate fundamental chemical and statistical principles under unguided, natural conditions.
To permit structured and productive OoL discussions the authors recommend beginning with this table, which applies also to RNA and DNA polymers, to decide which dilemma to discuss.

1. Many amino acids must be linked together, about 300 on average for proteins.
2. Only enantiomers of L-amino acids should be included.
3. Only linear polymers should form; that is, the side chains of the amino acids must not react.
4. Precise sequences of amino acid residues must be formed to perform useful functions.
5. Long chains must adopt a suitable three-dimensional structure.
6. Large numbers of peptide copies must be produced continuously for millions of years.
7. The correct proportion of peptides with a specific sequence must be colocalized.
8. Other molecules, including nonbiological amino acids, should be avoided in peptides.
9. The entire system or organism must self-replicate, including all necessary peptide copies. 10. The polymers and the three-dimensional structure must be formed under relevant conditions.
These 10 requirements must be met simultaneously for peptides/proteins to be relevant in origin-of-life scenarios, but there are contradictory trade-offs between many of these requirements. For example, raising the temperature to facilitate a Gly adding to Gly_n to form Gly_n+1 (requirement #1) would have the effect of accelerating the rate of racemization L-Gly ⇆ D-Gly (requirement #2).

3. Challenges in Prebiotic Protein Formation

3.1 Thermodynamic and Kinetic Barriers to Prebiotic Polypeptide Formation

The spontaneous formation of polypeptides in aqueous prebiotic environments encounters significant thermodynamic and kinetic barriers, challenging current naturalistic explanations for the origin of life. Thermodynamic calculations indicate that peptide bond formation in water is energetically unfavorable, with a standard Gibbs free energy change of approximately 3.5 kcal/mol at 25°C and pH 7 ^[16]. Computational exploration of organic molecule formation from water and hydrogen cyanide reveals diverse reactivity landscapes and lower activation energies for biologically relevant molecules, impacting the interpretation of network kinetics ^[17]. In fluctuating silica environments, the presence of water activity enhances peptide formation through hydration steps, resulting in the formation of self-assembled peptide aggregates with defined secondary structures ^[18]. Additionally, a new abiotic route demonstrates peptide chain growth from protonated glycine dimers in a cold gaseous atmosphere without the need for a solid catalytic substrate ^[19]. Experimental simulations under hydrothermal and extraterrestrial ice crystal environments show the formation of small functional peptides, shedding light on potential prebiotic pathways for catalytically active peptides ^[20].

Quantitative Challenges
Thermodynamic calculations reveal that the formation of peptide bonds in aqueous solutions is energetically unfavorable. The standard Gibbs free energy change (ΔG°) for peptide bond formation is approximately +3.5 kcal/mol at 25°C and pH 7 (Jakubke & Jeschkeit, 1977). This positive value indicates that the reaction is non-spontaneous under standard conditions.

Kinetic studies further compound this challenge. The rate constant for uncatalyzed peptide bond formation in water at 25°C is estimated to be around 10^-4 M^-1 year^-1 (Sievers & von Kiedrowski, 1994). In contrast, the rate constant for peptide bond hydrolysis under the same conditions is approximately 10^-9 to 10^-11 s^-1 (Radzicka & Wolfenden, 1996). These values translate to a half-life of peptide bond formation on the order of thousands of years, while the half-life for hydrolysis is typically days to months.

Implications for Current Models
These quantitative findings present severe challenges to current models of prebiotic polypeptide formation. The unfavorable thermodynamics imply that even if peptides were to form, they would be thermodynamically driven to hydrolyze back into amino acids. The slow kinetics of formation coupled with the relatively rapid hydrolysis suggests that maintaining any significant concentration of polypeptides in a prebiotic aqueous environment is highly improbable.

Requirements for Natural Occurrence
For the spontaneous formation and persistence of polypeptides in a prebiotic setting, the following conditions must be simultaneously met:

1. Energy input to overcome the unfavorable thermodynamics of peptide bond formation
2. Mechanisms to dramatically accelerate the rate of peptide bond formation
3. Protection against hydrolysis to maintain formed peptides
4. Concentration mechanisms to achieve sufficiently high local amino acid densities
5. Selective polymerization to form functional peptide sequences
6. Removal of water to drive the condensation reaction forward
7. pH conditions that balance peptide bond formation and stability (typically pH 2-5 for formation, pH 5-8 for stability)
8. Temperature regime that allows for both formation and stability of peptides
9. Absence of competing side reactions that could deplete the amino acid pool
10. Recycling mechanisms to regenerate hydrolyzed amino acids

These requirements must coexist in a prebiotic environment, presenting a formidable challenge to naturalistic explanations. Several of these conditions are mutually exclusive or contradictory. For instance, the need for water removal (point 6) conflicts with the aqueous environment typically assumed in prebiotic scenarios. Similarly, the pH conditions favorable for peptide bond formation (point 7) are not optimal for peptide stability.

The challenges are illustrated by the "alanine problem." Alanine, one of the simplest amino acids, forms peptides extremely slowly in aqueous solutions. Experiments have shown that at 25°C and pH 7, the equilibrium concentration of the alanine dipeptide is only about 10^-4 M when starting from a 1 M solution of alanine (Danger et al., 2012). This low yield highlights the thermodynamic barriers to even the simplest peptide formations.

Moreover, the requirement for energy input (point 1) often leads to increased rates of side reactions and decomposition, conflicting with the need for selective polymerization (point 5) and protection against hydrolysis (point 3).

The thermodynamic and kinetic barriers to prebiotic polypeptide formation present substantial challenges to current naturalistic explanations for the origin of life. Future discussions on this topic should focus on:

1. Developing more realistic models that account for both thermodynamic and kinetic constraints.
2. Investigating potential energy coupling mechanisms that could drive peptide bond formation.
3. Exploring non-aqueous environments or specialized micro-environments that might facilitate peptide formation and stability.
4. Addressing the mutual exclusivity of certain required conditions in prebiotic scenarios.
5. Critically examining the assumptions underlying current abiogenesis hypotheses in light of these fundamental chemical principles.

By rigorously addressing these points, the scientific community can work towards a more comprehensive and evidence-based understanding of the chemical processes that could have led to the emergence of the first polypeptides and, ultimately, life itself.

3.2 Chirality Issues

The challenges in achieving homochirality in prebiotic scenarios are multifaceted. The Soai reaction, known for chirality amplification, faces limitations due to the unlikelihood of abundant specific organic compounds on early Earth ^[24]. Varying racemization rates of amino acids, accelerated by metal ions like Cu(II), further complicate maintaining homochirality [20] ^[21]. Solid-state racemization of amino acids, even without water, persists at slower rates ^[23]. Kinetic resolution and asymmetric adsorption struggle to generate significant enantiomeric excess ^[20] ^[Context_6]. Circularly polarized light effects are wavelength-dependent and may cancel out in a prebiotic setting ^[Context_7]. The small energy difference between enantiomers is insufficient for spontaneous enrichment ^[Context_8]. Polymerization kinetics and cross-inhibition phenomena pose additional challenges ^[Context_9] ^[Context_10]. Addressing these complexities collectively in comprehensive models is crucial for advancing our understanding of homochirality in the origin of life research.

1. Amplification of Chirality
The Soai reaction, often cited as a potential mechanism for chirality amplification, faces significant hurdles in prebiotic contexts. This autocatalytic reaction, while demonstrating impressive enantiomeric excess amplification in laboratory settings, requires specific organic compounds (like pyrimidine-5-carbaldehydes) that are unlikely to have been present in significant quantities on the early Earth.

2. Racemization Rates of Different Amino Acids
Different amino acids racemize at varying rates, further complicating the maintenance of homochirality. For instance, aspartic acid racemizes relatively quickly, while isoleucine is more resistant to racemization. This differential racemization would lead to a non-uniform loss of homochirality across a peptide chain, potentially disrupting any functional structures that might have formed.

3. Impact of Metal Ions
The presence of metal ions, which would have been common in prebiotic environments, can significantly accelerate racemization rates. For example, Cu(II) ions have been shown to increase the rate of aspartic acid racemization by a factor of 10^4 at pH 7.4 and 37°C.

4. Racemization in Solid State
Even in the absence of water, amino acids can undergo solid-state racemization, albeit at slower rates. This implies that even if a mechanism for removing water was present, it would not completely halt the racemization process.

5. Kinetic Resolution
While kinetic resolution through selective crystallization has been proposed as a mechanism for generating enantiomeric excess, it faces significant challenges in prebiotic scenarios. The process requires specific conditions and often results in the loss of a significant portion of the material.

6. Asymmetric Adsorption
The idea that chiral surfaces could selectively adsorb one enantiomer over another has been explored, but the effect is generally too weak to generate significant enantiomeric excess. Moreover, the adsorbed molecules would need to be released to participate in further reactions, negating any accumulated excess.

7. Photochemical Reactions
While circularly polarized light can induce small enantiomeric excesses, the effect is wavelength-dependent and can produce opposite results at different wavelengths. In a prebiotic setting with broad-spectrum light, these effects would likely cancel out.

8. Thermodynamic Considerations
The difference in Gibbs free energy between enantiomers due to parity violation is extremely small (estimated at 10^-11 J/mol for alanine). This difference is insufficient to drive spontaneous enantiomeric enrichment under prebiotic conditions.

9. Polymerization Kinetics
Even if a slight enantiomeric excess were achieved, the kinetics of polymerization would need to strongly favor the excess enantiomer to produce homochiral polymers. Current models suggest that the required kinetic differences are unrealistically large for prebiotic scenarios.

10. Cross-Inhibition
In systems with multiple amino acids, the presence of the wrong enantiomer of one amino acid can inhibit the polymerization of the correct enantiomers of other amino acids, a phenomenon known as cross-inhibition. This further complicates the path to homochiral polymers in a mixed prebiotic environment.

These points further underscore the significant challenges faced by naturalistic explanations for the origin of biological homochirality. Future research in this field should focus on developing comprehensive models that address these multifaceted issues simultaneously, rather than tackling them in isolation. It's crucial to consider the interplay between various factors such as racemization rates, polymerization kinetics, and environmental conditions in prebiotic scenarios. Additionally, exploring potential non-aqueous environments or unique geological settings that might provide more favorable conditions for maintaining homochirality could offer new insights into this fundamental question in origin of life research.

The racemization of amino acids and polypeptides under natural conditions is inevitable

Dr. Royal Truman, an American scientist, and Dr. Boris Schmidtgall, a Russian / German scientist proposed recently a remarkable conclusion with potentially devastating consequences for the origin of life community: random polypeptide sequences in water always seem to racemize faster than chain elongation can occur.
Even beginning with short, random sequence polypeptides containing pure L-aa together with initially only pure L-aa in water, the rate of condensation
aa + [peptide]_n-1 → [peptide]_n + H₂O

always seems to be slower than racemization, at all temperatures, under unguided, natural conditions. This is a devastating discovery for the origin of life (OoL) community since it implies that only random L- and D-polypeptide sequences can develop naturally in water instead of L-only required for life.
The team published a series of remarkable papers on the racemization of amino acids in water as a function of temperature. Condensation and hydrolyzation of polypeptides are equilibrating processes (amino acid is abbreviated as aa):

aa + [peptide]_n-1 ⇆ [peptide]_n + H₂O

but simultaneously the aa residues of peptides also racemize. Chemists soon agreed that indeed racemization should always be faster than chain elongation since the former is an unimolecular reaction involving only the polypeptide whereas the second is bimolecular and involves the same low-concentration polypeptide but also requires an amino acid that is present in low concentrations. The relative rate constants and thermodynamics reinforced this conclusion.
 
A few highlights of their analysis of the best-known studies include these points:
1. Using generous estimates for prebiotic glycine concentrations (10^4 M), the equilibrium concentration of a 9-residue glycine peptide would be ≈ 5 × 10^51 M.
2. The formation of peptides in water is thermodynamically unfavorable, with hydrolysis being strongly favored over condensation. [Gly]_n < [Gly]_n-1 by a factor of about 2 × 10^6 for every length n. At equilibrium, negligible amounts of larger polypeptides can exist.
3. Elongation and L to D inversion occur primarily at the peptide end residues, simplifying the analysis.
4. To form a detectable amount of even very small peptides the experiments always had to use unrealistically high amino acid concentrations and experimental conditions.
5. Experiments in clays, minerals, at air-water interfaces, etc., despite optimized lab conditions produced very low amounts of small oligopeptides.
6. Experiments using high temperatures and pressures to simulate hydrothermal vents temporarily produced only small amounts of oligopeptides up to 8 residues long and then rapidly decomposed chemically.
7. Experiments using artificially activated amino acids and specific conditions in laboratories to force peptide formation have no relevance to abiogenesis.
8. The largest peptides produced under optimized (prebiotically irrelevant) laboratory conditions without catalysts were around 12-14 glycine residues, with possible traces of up to 20 residues. Left in water these would have hydrolyzed.
9. Even under ideal conditions, a small percentage of D-amino acids would prevent L-polypeptides from forming stable secondary structures in water.
10. Formation of secondary structures using designed sequences that hinder racemization is not plausible given the relative distribution of aa and would be too rare to be relevant for OoL purposes.
11. Assumed racemization rate constants are often adjusted for archeological purposes to match preconceived dates rather than questioning those dates.
12. Factors like temperature, pH, mineralization, hydrolysis, and contamination can all significantly impact racemization rates for archeological purposes.
13. Laboratory methods for amplifying small enantiomeric excesses face limitations:
- Partial sublimation of enantiomers would destroy most of the material and simply remix.
- Crystal separation techniques require specific and unlikely natural conditions.
- Separation of the eutectic mixture leads to remixing in water afterward.
- Chiral minerals produce small excesses, but they exist equally in D- and L- forms.
- Chiral or auxiliary catalysts require unrealistic concentrations and produce opposing results depending on the amino acid used.
14. Parity violation and circularly polarized light can only produce minimal enantiomeric excesses, too small for the purposes of abiogenesis.

3.3 Sequence and Structure Formation in Prebiotic Protein Evolution: A Critical Analysis

This analysis examines the challenges of sequence and structure formation in prebiotic protein evolution, focusing on the improbabilities and contradictions inherent in current naturalistic explanations. The challenges of sequence and structure formation in prebiotic protein evolution, as highlighted in recent research, underscore the improbabilities inherent in naturalistic explanations. Calculations show that even with flexibility in protein sequences, the probability of randomly generating a functional protein is astronomically low, emphasizing the need for efficient mechanisms to bias sequence space towards functionality ^[24]. These challenges cast doubt on the plausibility of random assembly models for protein origin, given the vanishingly small probability of forming even one functional protein sequence within Earth's history ^[25]. The requirements for natural protein formation, such as amino acid availability, peptide bond formation, and chiral selectivity, must be met simultaneously under prebiotic conditions, posing significant contradictions and mutually exclusive conditions ^[26]. Current models often rely on unspecified self-organizing principles, necessitating future research to quantify probabilities rigorously, propose testable mechanisms, and explore alternative models to advance our understanding of biological complexity origins ^[27].

1. Quantitative Challenges

The probability of forming a functional protein sequence by chance is astronomically low. Consider a relatively short protein of 150 amino acids:

- There are 20 standard amino acids.
- The number of possible sequences is 20^150 ≈ 10^195.

Not all positions in a protein sequence need to be strictly specified for the protein to be functional. This is an important consideration that can significantly affect the probability calculations.  For this calculation, let's consider a hypothetical enzyme of 150 amino acids and make some reasonable assumptions:

1. Active site residues: Let's say 5 residues are critical for the catalytic function and must be exactly specified.
2. Substrate binding pocket: Perhaps 10 residues are important for substrate recognition and binding, but some variation is allowed. Let's say each of these positions can tolerate 5 different amino acids on average.
3. Structural integrity: Maybe 30 residues are important for maintaining the overall fold, but have some flexibility. Let's assume each of these can be any of 10 different amino acids.
4. The remaining 105 residues can be any amino acid, as long as they don't disrupt the structure (let's assume all 20 are allowed).

Now, let's calculate:

1. Active site: 20^5 possibilities (must be exact)
2. Binding pocket: 5^10 possibilities (5 options for each of 10 positions)
3. Structural residues: 10^30 possibilities
4. Remaining residues: 20^105 possibilities

Total number of possible functional sequences: 20^5 * 5^10 * 10^30 * 20^105 ≈ 3.2 * 10^158. Compare this to the total number of possible sequences: 20^150 ≈ 1.4 * 10^195. Probability of randomly generating a functional sequence: (3.2 * 10^158) / (1.4 * 10^195) ≈ 2.3 * 10^-37 or about 1 in 4.3 * 10^36.  To put it in perspective:

- If we could test 1 trillion (10^12) sequences per second
- And we had been doing so since the beginning of the universe (about 13.8 billion years or 4.4 * 10^17 seconds)
- We would have only tested about 4.4 * 10^29 sequences

This is still about 10 million times fewer than the number we'd need to test to have a good chance of finding a functional sequence.

These calculations demonstrate that even when we account for the flexibility in protein sequences, the probability of randomly generating a functional protein remains extremely low. This underscores the challenge faced by naturalistic explanations for the origin of proteins and emphasizes the need for mechanisms that can efficiently search or bias the sequence space towards functional proteins.

2. Implications for Current Models

These calculations severely challenge the plausibility of random assembly models for protein origin. Even considering the entire history of Earth (≈4.5 billion years) and assuming extremely rapid amino acid combinations (e.g., 1 trillion per second), the probability of forming even one functional protein sequence remains vanishingly small.

3. Requirements for Natural Protein Formation

1) Availability of all 20 standard amino acids in sufficient concentrations
2) A mechanism for amino acid activation (to overcome thermodynamic barriers)
3) A way to form peptide bonds in an aqueous environment
4) Protection from hydrolysis once peptide bonds form
5) A mechanism for sequence selection or amplification of functional sequences
6) Prevention of cross-reactions with other prebiotic molecules
7) A process for maintaining chirality (all L-amino acids)
8 ) A method for achieving proper folding in the absence of chaperone proteins
9) Removal of non-functional or misfolded proteins
10) A system for replicating successful sequences

4. Simultaneous Fulfillment Under Prebiotic Conditions

These requirements must all be met concurrently in a prebiotic environment lacking biological machinery. This presents a formidable challenge, as many of these conditions are mutually exclusive or require sophisticated mechanisms that are themselves products of evolution.

5. Contradictions and Mutually Exclusive Conditions

- Requirement 3 (peptide bond formation in water) contradicts requirement 4 (protection from hydrolysis).
- The need for concentration of amino acids (1) conflicts with the dilute conditions of prebiotic oceans.
- Maintaining chirality (7) is at odds with the racemization that occurs naturally in aqueous environments.

6. Scientific Terminology

Key concepts include:
- Peptide bond formation
- Hydrolysis
- Racemization
- Chiral selectivity
- Protein folding
- Primary, secondary, tertiary, and quaternary structure
- Levinthal's paradox

7. Illustrative Scenario

Consider the formation of a simple enzyme like ribonuclease, with 124 amino acids. In a prebiotic ocean, amino acids would need to:
1. Concentrate sufficiently
2. Activate (overcoming thermodynamic barriers)
3. Form correct peptide bonds in sequence
4. Avoid hydrolysis
5. Maintain homochirality
6. Fold correctly without chaperones
7. Achieve catalytic activity

The improbability of this occurring by chance is compounded by the fact that ribonuclease itself is not self-replicating, so the process would need to repeat independently.

8. Critical Examination

Current models often rely on unspecified "self-organizing principles" or "emergent properties" to bridge the gap between simple chemicals and functional proteins. However, these concepts lack concrete mechanisms and often amount to restatements of the problem rather than solutions.

9. Conclusion and Future Discussions

Future discussions on protein origins should:
1. Quantify probabilities rigorously
2. Address each requirement explicitly
3. Propose testable mechanisms for overcoming statistical improbabilities
4. Consider alternative models that do not rely solely on chance assembly
5. Explore potential non-aqueous environments or unique geological settings
6. Investigate the minimal functional requirements for proto-proteins

By structuring the debate around these points, we can more accurately assess the viability of current theories and guide future research into the origins of biological complexity.

3.4  Scale and Reproduction in Prebiotic Systems: A Critical Analysis

The challenges of achieving scale and reproduction in prebiotic systems are highlighted by the quantitative analysis of the probability of randomly assembling a specific genome, exemplified by Pelagibacter ubique, one of the smallest free-living organisms with a genome size of ~1,300,000 base pairs. The calculated probability of (1/4)^1,300,000 ≈ 10^-782,831 underscores the immense improbability of spontaneously generating such a genome. This probability is significantly smaller than the number of atoms in the observable universe or the microseconds since the Big Bang, emphasizing the astronomical odds against the random assembly of a functional genome. Even with every atom representing a unique DNA sequence and checking a trillion sequences per microsecond since the universe's inception, the number of sequences checked would be minuscule compared to the vast search space required, illustrating the formidable obstacles faced by naturalistic explanations for the origin of life.

1. Quantitative Challenges

Consider the requirements for a minimal self-replicating system: 

Calculation of Genome Probability for a Minimal Free-Living Organism

While Mycoplasma genitalium is often cited for its small genome, it's crucial to note that it's an endosymbiont and parasite, relying on its host for many essential nutrients and functions. Therefore, it's not an adequate example of a minimal free-living organism. A more appropriate example is Pelagibacter ubique, one of the smallest known free-living organisms. Let's use this for our calculation:

1. Genome size of Pelagibacter ubique: ~1,300,000 base pairs
2. Each position can be one of 4 nucleotides (A, T, C, G)

Probability of randomly assembling this specific genome: (1/4)^1,300,000 ≈ 10^-782,831

To put this number in perspective:

- Number of atoms in the observable universe: ~10^80
- Number of microseconds since the Big Bang: ~4.3 x 10^23

The probability we calculated is vastly smaller than either of these numbers. Even if every atom in the universe represented a unique DNA sequence, and we could check a trillion (10^12) sequences every microsecond since the beginning of the universe, we would have only checked: 10^80 * 4.3 x 10^23 * 10^12 ≈ 4.3 x 10^115 sequences. This is nowhere near the 10^782,831 sequences we would need to check to have a reasonable chance of finding our target genome.

Implications:

1. This calculation, based on a true free-living organism, underscores the astronomical improbability of a functional genome arising by chance.
2. It highlights the need for alternative explanations that don't rely on pure chance, such as:
   - Chemical evolution with selection pressures
   - Self-organizing principles in complex chemical systems
   - Potential for simpler initial self-replicating systems

3. It emphasizes the vast gulf between simple chemical systems and even the simplest known free-living systems, challenging gradualist explanations for the origin of life.
4. This calculation reinforces the need for a more comprehensive understanding of how functional biological information can arise from prebiotic chemistry.
5. It illustrates why using parasitic or endosymbiotic organisms as examples can be misleading when discussing minimal genome sizes for free-living organisms.

These numbers, based on a more appropriate example of a minimal free-living organism, illustrate why the origin of life remains one of the most challenging questions in science. They underscore the significant hurdles faced by current naturalistic explanations in accounting for the emergence of complex, self-replicating systems capable of independent existence. Even if every atom in the universe represented a unique DNA sequence, the probability of randomly generating a minimal genome remains vanishingly small.

2. Implications for Current Models

These calculations severely challenge the plausibility of random assembly models for the origin of self-replicating systems. The vast sequence space that must be explored to find functional genomes is incompatible with the time and resources available in prebiotic Earth scenarios.

3. Requirements for Natural Scale and Reproduction

1. A mechanism for producing large numbers of identical molecular components
2. A system for accurate information storage and transfer (e.g., nucleic acids)
3. A means of translating stored information into functional molecules (e.g., proteins)
4. An energy harvesting and utilization system
5. A boundary system (e.g., membrane) to contain and protect components
6. A mechanism for the growth and division of the boundary system
7. A way to coordinate replication of internal components with boundary division
8. A system for error detection and correction during replication
9. A means of adapting to environmental changes
10. A transition mechanism from prebiotic chemistry to cellular biochemistry

4. Simultaneous Fulfillment Under Prebiotic Conditions

These requirements must all be met concurrently in a prebiotic environment lacking biological machinery. This presents a formidable challenge, as many of these conditions require sophisticated mechanisms that are themselves products of evolution.

5. Contradictions and Mutually Exclusive Conditions

- The need for a protective boundary (5) conflicts with the requirement for nutrient influx and waste removal.
- Accurate replication (8 ) requires complex enzymatic machinery, which itself requires accurate replication to exist.
- The transition from prebiotic to cellular synthesis (10) requires a system that can function in both regimes simultaneously.

6. Scientific Terminology

Key concepts include:
- Genome
- Self-replication
- Translation
- Transcription
- Metabolism
- Lipid bilayers
- Error catastrophe
- Autocatalysis
- Ribozymes
- Protocells

7. Illustrative Scenario

Consider the formation of a primitive protocell:
1. Lipids must spontaneously form a stable vesicle
2. Replicating RNA molecules must be encapsulated
3. The RNA must code for and produce functional peptides
4. These peptides must assist in RNA replication and vesicle growth
5. The system must divide, distributing components to daughter cells
6. This process must occur repeatedly without loss of function

The coordinated emergence of these features in a prebiotic setting strains the explanatory power of current naturalistic models.

8. Critical Examination

Current models often invoke "self-organization" or "emergent complexity" to bridge the gap between simple chemical systems and self-replicating protocells. However, these concepts lack specificity and often amount to restatements of the problem rather than solutions. The transition from non-living to living systems represents a staggering increase in functional information content, which is not adequately explained by known physical or chemical principles.

9. Conclusion and Future Discussions

Future discussions on the origin of self-replicating systems should:
1. Quantify the minimal functional requirements for self-replication rigorously
2. Address each requirement explicitly, providing plausible prebiotic mechanisms
3. Propose testable hypotheses for the coordinated emergence of replication, metabolism, and containment
4. Consider alternative models that do not rely solely on chance assembly or gradual accumulation of features
5. Investigate potential non-aqueous environments or unique geological settings that might facilitate more rapid exploration of chemical space
6. Explore the concept of "functional information" and its origins in prebiotic systems

By structuring the debate around these points, we can more accurately assess the viability of current theories and guide future research into the origins of biological complexity. The field must grapple with the enormous gulf between simple chemical reactions and the sophisticated, information-rich systems characteristic of even the simplest known life forms.

3.5 Amplification of Enantiomeric Excess

The amplification of enantiomeric excess (ee) from a small initial value to 100% L-amino acids has been a topic of extensive research and debate. Literature experiments have not supported the idea that small excesses of L-amino acids can be amplified to complete homochirality, with proposed mechanisms often requiring unrealistic experimental conditions. Studies have explored various scenarios like partial sublimation, crystal separation, and chiral catalysts but have faced significant limitations in achieving and maintaining high ee values. Research has shown that natural processes alone may not be sufficient to drive the amplification of ee to complete homochirality, highlighting the complexity of this phenomenon ^{[1] [2] [3] [4] [5]}.

Literature experiments do not corroborate that a small excess of L-amino acid could be amplified to form 100% L-amino acids 

In a series of remarkable papers, senior chemists from several firms, Dr. Royal Truman, Dr. Chris Basel, and Dr. Stephen Grocott did an extensive analysis of the key literature on amplification experiments of small excesses of L-amino acids. The evolutionary experiments reviewed had been designed to find special conditions to preferentially extract excess L-amino acids from mixtures and separate a portion having a higher proportion of L-amino acid (aa).
Their conclusions are very bad news for the origin of life (OoL) community, demonstrating that implausible experimental conditions had to be used. Objective evaluation of the results showed that the attempts to find relevant amplification scenarios had failed badly.
To illustrate, a hypothetical astronomical source of right-circularly polarized UV light (r-CPL) is the preferred evolutionary theory for the origin of homochiral amino acids. However, astronomers have been unable to find polarized UV light anywhere in the relevant region of space.
We encourage you to read the papers covering the topics of interest. Here are some bullet points extracted from this series of papers.
 
1. Claims of significant enantiomeric excess produced by a hypothetical astronomical  circularly polarized light (CPL) source are misleading:
- Astronomers have not found polarized UV light in a relevant region of space
- The theory required very specific conditions and laboratory conditions untypical in space
- The theory requires almost 100% photodestruction of all amino acids before an excess could result (but 100% destruction would serve no purpose!).
2. Different amino acids absorb left-handed and right-handed CPL differently at various UV wavelengths. Therefore, the expected result would be an averaging out with little or no survival of one enantiomer.
3. Experimental approaches focused on the very exceptional amino acids with the highest anisotropy factors and used optimal wavelengths designed to produce the researcher’s goal instead of real-world outcomes.
4. Even if a small enantiomeric excess were produced in space, it would likely be further diluted upon reaching Earth.
5. The major literature examples like alkylation of Soai and polymerization of cyclobutene have no relevant to OoL. In many cases such as selective adsorption on minerals such as kaolinite and montmorillonite clay even the irrelevant examples published have been disproven when the experiments were repeated.
6. Adsorption on chiral calcite and quartz would produce equal amounts of D and L enantiomers overall.
7. Extracting only L-amino acids from glycine crystals required pure D-leucine, an unlikely natural scenario.
8. The formation of enantiomer-specific crystalline islands required laboratory processes not found in nature.
9. There is no credible reason why enantiomers of separate amino acids would not remix in natural environments.
10. Any enantiomeric excess produced would racemize in water over time.
11. Proposed mechanisms required carefully planned and executed laboratory conditions that are unlikely in nature.
12. None of the proposals known could have occurred naturally without intelligent guidance.
13. Different amino acid precursors behave differently with the same sugar catalysts, making it impossible to generalize about sugar-induced chirality.
14. The used D-lyxose to favor production of L-amino acids did not occur when tested using alanine.
15. On longer time scales relevant to prebiotic scenarios, racemic mixtures would result regardless of the initial sugar-induced excess.
16. Impurities have been tested to enhance the crystallization of a particular enantiomer.
- This only produced conglomerate crystals, but not separated enantiomers.
- The supersaturated pure solutions used to form crystals used would not have exist naturally.
- Conditions to favor one L-amino acid would have increased the amount of D- enantiomer of other amino acids, making matters worse for OoL purposes.
17. Excess of non-biological L-α-methyl amino acids have been claimed in meteorites. Experiments showed that mixing L-α-methylamine with racemic L- and D amino acid produced more of the wrong D- amino acids. Even had the desired outcome been obtained, equilibration L ⇆ D occurred rapidly, especially at elevated temperature.
18. Extensive experiments with L-α-methyl amino acids and many catalyst showed the desired outcome when using copper but at plausible concentrations the enantiomeric effect was negligible and racemization would have occurred in the presence of such a catalyst rapidly.
19. Simulations of wet-dry cycles with L-amino acids and L-isovaline in montmorillonite clay:
- Led to rapid racemization of amino acids, very bad news for OoL purposes.
- Showed that chirality could not be effectively transferred from L-isovaline to produce L-amino acids.
20. Instant sublimation experiments at ~ (430°C) followed by instant cooling at sub-freezing temperatures (!?) to avoid thermal degradation experiments have no relevance for OoL purposes: aa degrade at much lower temperatures.
21. Sublimation experiments using serine relied on unrealistic, optimized laboratory conditions (and did not work with other aa):
- High temperatures around exactly 205°C with short heating times (2-18 hours)
- Rapid cooling with dry ice and N₂ gas flow to quickly remove sublimate
- Avoiding serine racemization and decomposition at high temperatures.
- The maximum enantiomeric excess achieved was too low for biological purposes.
Worse, starting with an L-enantiomeric excess of serine actually produced a sublimate with a lower excess!
22. Sublimation experiments using mixtures of Asn, Thr, Asp, Glu, and Ser cleverly mixed with volatile racemic Ala, Leu, Pro, or Val required carefully optimized laboratory conditions to obtained the intended goal:
- Low pressure (0.3-0.7 mbar) , controlled temperature (100-105°C)  and duration of 14 hours
- Use pure L enantiomers, and prevent remixing of sublimate and residue
- Use of an icy cold finger to trap the sublimate.
The results were less than encouraging. Using L-enantiomers of the less sublimated aa produced sublimates enriched in D-enantiomers of the volatile aa, the opposite needed for biology!
23. Only two biological amino acids (threonine and asparagine) naturally crystallize as conglomerates of distinct D and L crystals, but under conditions not relevant for OoL.
24. Most biological aa form racemic crystals (equal amounts of D and L enantiomers) preventing crystalline excesses. Any excess in solution would simply racemize over time.
25. Random temperature variation would prevent the precise control needed to take advantage of the eutectic point for some aa to separate crystals with an excess of an enantiomer.
26. Laboratory conditions were used to extract enantiomer excesses already present, including saturated solutions of a pure aa, controlled temperatures, and constant agitation.
27. Natural processes such as rainwater, seawater, and groundwater would have diluted any enantiomeric excess and led to remixing.
28. If hypothetically an excess would exist in solution that could crystallize preferentially into L-crystals, eventually the excess would be depleted and all the aa would then crystallize out of solution, contamination the first batches.
29. In any scenario of excess in liquid or crystal phase remixing would occur, racemization over time, and contamination with racemic mixtures in the environments.
30. Some experiments used complex catalysts not found naturally to increase racemization, of the wrong D-amino acids but they would have also racemized all the L-amino acids indiscriminately.
31. Techniques like Preferential Enrichment and CIAT rely on an initial excess of L-enantiomer, organic solvents like aspartic acid and acetic acid, and typically salicylaldehyde as catalyst at 90-160°C with agitation in a special container. None of these are relevant for OoL purposes.
Here are some additional points to complement the existing information on challenges to amplifying small excesses of L-amino acids to form 100% L-amino acids:
32. Attempts to use chiral minerals like quartz as selective catalysts have shown only very small enantiomeric excesses, typically less than 1%.
33. Proposed autocatalytic reactions like the Soai reaction require highly specific precursor molecules and conditions not plausible in prebiotic environments.
34. Theoretical models of amplification often rely on unrealistic assumptions about reaction kinetics and equilibrium conditions.
35. Experiments using temperature gradients to separate enantiomers produce only transient and localized excesses that quickly dissipate.
36. Proposed mechanisms involving chiral light or spin-polarized electrons lack a demonstrated source in early Earth environments.
37. Attempts to use amino acid precursors like α-methyl amino acids as chiral catalysts have shown limited effectiveness and selectivity.
38. Proposed amplification via polymerization faces issues of reversibility and lack of selectivity for homochiral products.
39. Scenarios involving partial crystallization require precise control of supersaturation, nucleation, and growth conditions unlikely in nature.
40. Attempts to exploit slight solubility differences between enantiomers have produced only marginal enrichment.
41. Proposed chiral amplification via asymmetric autocatalysis faces issues of product inhibition and side reactions.

The overall picture reinforces the significant hurdles facing naturalistic explanations for the origin of biological homochirality.

4. Additional Considerations

4.1 Optimal Set of Amino Acids

Recent studies by Philip and Freeland (2011) and Ilardo et al. (2015) have highlighted the exceptional optimality of the standard 20 amino acid alphabet in life, showcasing high coverage of crucial chemical properties like size, charge, and hydrophobicity that outperform vast alternative alphabets. These findings challenge conventional theories of chemical evolution, indicating a level of selection or foresight that contradicts undirected processes. To naturally achieve such an optimal amino acid set, prebiotic conditions must simultaneously provide a diverse amino acid pool, a sophisticated selection mechanism, discernment of subtle chemical differences, balance simplicity with functional diversity, compatibility with translation machinery, stability under prebiotic conditions, reactivity for peptide bond formation, and rapid selection before other biochemical systems emerge, presenting significant contradictions in the origin of life hypotheses ^[1] [2].

1. Quantitative Findings Challenging Conventional Theories

A study by Philip and Freeland (2011) compared the standard 20 amino acid alphabet to random sets of amino acids chosen from a larger pool of 50 plausible prebiotic amino acids. They found that the standard alphabet exhibits unusually high coverage of three key chemical properties: size, charge, and hydrophobicity. Out of 10^19 possible alternative alphabets, only one in a million matched or exceeded the standard alphabet's coverage of these properties.

Another study by Ilardo et al. (2015) used a computational model to assess the designability and folding stability of proteins made from various amino acid alphabets. They found that the standard 20 amino acid set outperformed most alternative sets, including those with more amino acids, in producing stable, well-folded proteins.

2. Implications for Current Scientific Models

These findings pose significant challenges to current models of chemical evolution. Conventional theories typically assume that the set of amino acids used in life was determined by availability in the prebiotic environment or by chance. However, the observed optimality suggests a level of "foresight" or selection that is difficult to reconcile with undirected processes.

3. Requirements and Conditions

For the optimal set of amino acids to arise naturally, the following conditions must be met simultaneously under prebiotic conditions:

1. A diverse pool of amino acids must be available in the prebiotic environment.
2. A mechanism must exist to select amino acids based on their functional properties rather than just their abundance.
3. The selection process must be able to distinguish between subtle differences in chemical properties among similar amino acids.
4. The chosen set must provide a balance between simplicity (fewer amino acids) and functional diversity.
5. The selection process must occur before the establishment of the genetic code, as the code itself would constrain further changes to the amino acid alphabet.
6. The selected set must be compatible with the emerging translation machinery, including tRNA and aminoacyl-tRNA synthetases.
7. The chosen amino acids must be stable under prebiotic conditions yet reactive enough to form peptide bonds.
8. The selection process must occur rapidly enough to establish the optimal set before other, potentially incompatible biochemical systems emerge.

These requirements present several contradictions:
- The need for a diverse initial pool conflicts with the selective pressures that would limit the variety of compounds produced abiotically.
- The requirement for a sophisticated selection mechanism conflicts with the presumed simplicity of prebiotic chemical systems.
- The need for rapid selection conflicts with the gradual nature of evolutionary processes.

4. Relevant Scientific Terminology

Proteinogenic amino acids, chemical evolution, prebiotic chemistry, abiogenesis, protein folding, hydrophobicity, designability, genetic code, tRNA, aminoacyl-tRNA synthetases, peptide bond formation.

5. Illustrative Examples

Consider the case of lysine and arginine, two positively charged amino acids in the standard set. Both could plausibly form in prebiotic conditions, but arginine is more complex and less likely to arise spontaneously. However, arginine's guanidinium group provides unique properties for protein function. A purely abundance-based selection would likely have chosen lysine alone, missing the functional advantages of including both.

6. Critical Examination of Current Theories

Current theories of chemical evolution struggle to explain the observed optimality of the amino acid alphabet. Models based on prebiotic availability fail to account for the inclusion of less common amino acids like tryptophan or the exclusion of simpler, more abundant ones like norvaline. Scenarios invoking serial selection of amino acids face the challenge of explaining how early choices could anticipate future functional needs.

7. Further Discussion

Future discussions on this topic should focus on developing testable hypotheses that can explain the apparent optimality of the amino acid set without invoking teleological mechanisms. This might include exploring potential feedback loops between amino acid availability and early metabolic cycles, or investigating whether alternative optimal sets exist that might have been discoverable through plausible chemical evolution scenarios. In conclusion, the near-optimal nature of the 20 proteinogenic amino acids presents a significant challenge to naturalistic explanations for the origin of life. While not insurmountable, this challenge requires careful consideration and may necessitate revisions to current models of chemical evolution and abiogenesis.

4.2 Protein Folding and Chaperones

Recent studies highlight that a substantial portion of newly synthesized proteins in eukaryotic and prokaryotic cells rely on molecular chaperones for proper folding, challenging conventional theories of early protein evolution . The intricate process of protein folding, with vast conformational possibilities, occurs rapidly due to the energy landscape and chaperone assistance. These findings raise significant questions about the evolution of functional proteins without pre-existing chaperone systems, presenting a "chicken and egg" dilemma. Early protein evolution faces contradictions regarding the necessity of complex regulatory mechanisms, specific environmental conditions, and the availability of energy sources for chaperone-assisted folding. The GroEL/GroES chaperonin system exemplifies the complexity of chaperones, challenging the idea of their evolution in the absence of functional proteins. Addressing these challenges requires exploring primitive folding mechanisms and potential evolutionary starting points for protein folds, urging a reevaluation of current models of early protein evolution ^[35].

1. Quantitative Findings Challenging Conventional Theories

Recent studies have shown that approximately 30-50% of newly synthesized proteins in eukaryotic cells require assistance from molecular chaperones to achieve their native, functional states (Balchin et al., 2016). In prokaryotes, this percentage is lower but still significant, with about 10-20% of proteins needing chaperone assistance (Hartl et al., 2011).

The folding process itself is extremely complex. For a small protein of 100 amino acids, there are approximately 10^30 possible conformations. Yet, proteins typically fold into their native states on timescales of milliseconds to seconds (Dill and MacCallum, 2012). This speed is possible only because of the energy landscape of protein folding and the assistance of chaperones.

2. Implications for Current Scientific Models

These findings pose significant challenges to current models of early protein evolution. The high percentage of proteins requiring chaperones for proper folding suggests that early functional proteins would have faced severe limitations without a pre-existing chaperone system. This creates a "chicken and egg" problem: how could complex, functional proteins evolve if they required equally complex chaperone systems to fold correctly?

3. Requirements and Conditions

For early proteins to fold correctly and function in a prebiotic environment, the following conditions must be met simultaneously:

1. Amino acids must spontaneously form peptide bonds in the correct sequence.
2. The resulting polypeptides must be able to fold into stable, functional conformations.
3. The prebiotic environment must provide conditions conducive to protein folding (appropriate pH, temperature, and ionic concentrations).
4. Mechanisms must exist to prevent protein aggregation and misfolding.
5. For proteins requiring chaperones, a primitive chaperone system must already be in place.
6. This primitive chaperone system must itself be composed of properly folded proteins.
7. Energy sources (e.g., ATP) must be available to power chaperone-assisted folding.
8. Feedback mechanisms must exist to regulate chaperone activity and prevent over-assistance.
9. A system must be in place to degrade misfolded proteins that escape chaperone assistance.

These requirements present several contradictions:
- The need for a pre-existing chaperone system conflicts with the assumption that early proteins evolved in its absence.
- The requirement for complex regulatory mechanisms contradicts the presumed simplicity of early biological systems.
- The need for specific environmental conditions conflicts with the variable and often extreme conditions of the prebiotic Earth.

4. Relevant Scientific Terminology

Protein folding, molecular chaperones, native state, energy landscape, aggregation, misfolding, ATP-dependent chaperones, chaperonins, heat shock proteins (HSPs), protein quality control, proteostasis.

5. Illustrative Examples

Consider the GroEL/GroES chaperonin system in E. coli. This complex molecular machine encapsulates unfolded proteins in a hydrophilic chamber, allowing them to fold without interference. The system requires 14 identical 57 kDa GroEL subunits and 7 identical 10 kDa GroES subunits, arranged in a highly specific structure. It's challenging to envision how such a complex system could have evolved in the absence of already functional proteins.

6. Critical Examination of Current Theories

Current theories of early protein evolution often overlook or underestimate the challenges posed by protein folding. Models that propose the gradual evolution of protein function fail to account for the complex folding requirements of even relatively simple proteins. Scenarios invoking short peptides as early functional molecules face the challenge of explaining how these could have evolved into complex, chaperone-dependent proteins.

The RNA World hypothesis, which proposes RNA as the original self-replicating molecule, also faces challenges in explaining the transition to a protein-based metabolism. The complexity of the translation machinery and the need for already-folded proteins in this process create significant hurdles for this model.

7. Suggestion for Further Discussion

Future discussions on this topic should focus on developing testable hypotheses for primitive folding mechanisms that could have operated in the absence of modern chaperone systems. This might include exploring the potential role of mineral surfaces or simple organic molecules in facilitating early protein folding, or investigating whether certain protein folds are inherently more likely to form spontaneously and could have served as evolutionary starting points. In conclusion, the complexity of protein folding and the widespread requirement for chaperones in modern cells present significant challenges to naturalistic explanations for the origin of life. These challenges necessitate a reevaluation of current models and may require new, innovative approaches to understanding early protein evolution.

4.3 Metabolic Integration

The integration of synthesized proteins into functional metabolic pathways presents significant challenges to current naturalistic explanations for the origin of life. This analysis will focus on the complexities of metabolic integration, particularly in the context of amino acid biosynthesis, and the implications for early cellular evolution.

1. Quantitative Findings Challenging Conventional Theories

Recent studies have shown that a minimum of 112 enzymes is required to synthesize the 20 standard proteinogenic amino acids plus selenocysteine and pyrrolysine (Fujishima et al., 2018). This number represents a significant increase from earlier estimates and highlights the complexity of even the most basic cellular metabolic processes. Furthermore, these 112 enzymes are involved in a network of interdependent reactions. A study by Ravasz et al. (2002) on the metabolic network of E. coli revealed a hierarchical organization with a scale-free topology, characterized by a few highly connected metabolic hubs. This structure implies that the removal of even a small number of key enzymes could lead to catastrophic system-wide failures.

2. Implications for Current Scientific Models

These findings pose significant challenges to current models of early cellular evolution. The high number of enzymes required for amino acid biosynthesis suggests that early cells would have needed a remarkably complex metabolic system from the outset. This complexity is difficult to reconcile with the idea of a gradual evolution of metabolic pathways from simpler precursors. The interdependence of these enzymes also creates a "chicken and egg" problem: how could such a complex system of protein-based enzymes evolve when proteins themselves require this system to be synthesized?

3. Requirements and Conditions

For metabolic integration to occur naturally in a prebiotic environment, the following conditions must be met simultaneously:

1. A diverse pool of amino acids must be available in sufficient quantities.
2. Mechanisms for forming peptide bonds must exist to create functional enzymes.
3. Each of the 112+ enzymes required for amino acid biosynthesis must be present and functional.
4. These enzymes must be produced in the correct ratios to maintain metabolic balance.
5. Cofactors and coenzymes necessary for enzyme function must be available.
6. Energy sources (e.g., ATP) must be present to drive unfavorable reactions.
7. Cellular compartmentalization must exist to concentrate reactants and products.
8. Regulatory mechanisms must be in place to control enzyme activity and metabolic flux.
9. Transport systems must exist to move substrates and products between compartments.
10. A system for maintaining genomic information encoding these enzymes must be present.

These requirements present several contradictions:
- The need for a complex, interdependent enzyme system conflicts with the assumption of simpler precursor systems.
- The requirement for specific regulatory mechanisms contradicts the presumed lack of sophisticated control systems in early cells.
- The need for compartmentalization conflicts with models proposing metabolism-first scenarios in open prebiotic environments.

4. Relevant Scientific Terminology

Metabolic pathways, enzyme catalysis, biosynthesis, metabolic flux, cofactors, coenzymes, ATP, cellular compartmentalization, metabolic regulation, transport proteins, genome, transcription, translation.

5. Illustrative Examples

Consider the biosynthesis of tryptophan, one of the most complex amino acids. This pathway requires five enzymes (TrpA-E) working in a coordinated sequence. Each enzyme catalyzes a specific reaction, and the product of one reaction becomes the substrate for the next. The pathway also requires several cofactors, including pyridoxal phosphate and NADPH. The complexity of this single amino acid's biosynthesis illustrates the challenges faced in evolving a complete set of biosynthetic pathways.

6. Critical Examination of Current Theories

Current theories of early cellular evolution often struggle to explain the origin of complex, integrated metabolic systems. Models proposing a gradual evolution of metabolic pathways face the challenge of explaining how intermediate stages could have been functional and provided a selective advantage. The high degree of interdependence among metabolic enzymes suggests that many components would need to have evolved simultaneously, which is difficult to explain through traditional evolutionary mechanisms.

The RNA World hypothesis, while addressing some aspects of early information storage and catalysis, does not adequately explain the transition to the complex protein-based metabolic systems observed in all modern cells. The catalytic limitations of ribozymes compared to protein enzymes create significant hurdles for this model in explaining the origin of efficient metabolic pathways.

7. Suggestion for Further Discussion

The immense complexity and interdependence of metabolic pathways, particularly in amino acid biosynthesis, present not just significant challenges but potentially insurmountable obstacles to naturalistic explanations for the origin of life. The sophistication of enzymatic metabolic biosynthesis pathways, when compared to prebiotic amino acid synthesis, reveals a chasm that current origin of life models struggle to bridge. At the heart of this issue lies a problem of irreducible circularity: proteins are required to synthesize amino acids, yet amino acids are necessary to produce the proteins that synthesize them. This circular dependency creates a logically irreconcilable conundrum for step-wise evolutionary scenarios. Consider the minimum of 112 enzymes required for the biosynthesis of the 20 standard proteinogenic amino acids. Each of these enzymes is a complex molecular machine, precisely folded and often requiring specific cofactors. The probability of such a system arising spontaneously, without the very amino acids it produces, stretches the bounds of plausibility. Furthermore, the intricate network of metabolic reactions, characterized by scale-free topology and hierarchical organization, suggests that the removal of even a few key components would lead to systemic collapse. This all-or-nothing characteristic severely undermines gradualistic explanations for the emergence of these pathways. Current hypotheses, such as the RNA World, fail to adequately address this fundamental issue. While RNA may serve catalytic functions, the catalytic efficiency of ribozymes pales in comparison to protein enzymes, particularly for the complex reactions involved in amino acid biosynthesis. The gulf between prebiotic chemistry and the sophisticated enzymatic systems observed in even the simplest modern cells appears unbridgeable through known natural processes. This presents a profound challenge to naturalistic origin of life scenarios.

Future discussions must grapple with this core issue of irreducible circularity. While exploring the role of inorganic catalysts or simple organic molecules in facilitating early metabolic reactions may yield insights, such approaches do not resolve the fundamental protein-amino acid interdependency. Computational models and artificial chemistry simulations, while valuable tools, operate under assumptions and constraints that may not reflect prebiotic reality. They risk overlooking the true magnitude of the problem by simplifying the immense complexity of real biochemical systems. The protein-amino acid biosynthesis conundrum represents a critical challenge to naturalistic explanations for the origin of life. The lack of a plausible prebiotic route to overcome this hurdle necessitates a fundamental reevaluation of current origin of life models. Future research must not only address the origin of individual components but also confront the seemingly irreducible nature of the integrated biosynthetic system as a whole. This may require entertaining alternative hypotheses that go beyond conventional naturalistic frameworks.

5. Conclusion

The formation of amino acids and functional peptides under prebiotic conditions faces numerous significant challenges that current origin of life models struggle to overcome. These hurdles can be categorized into several key areas:

1. Precursor availability: The scarcity of fixed nitrogen and carbon sources, reactivity issues with organosulfur compounds, and instability of ammonia pose significant obstacles to amino acid synthesis.
2. Peptide bond formation: Thermodynamic and kinetic barriers result in extremely low equilibrium concentrations of even short peptides under prebiotic conditions, challenging models relying on spontaneous polypeptide formation.
3. Quantity and concentration: Achieving the required millimolar concentrations of amino acids for primitive life far exceeds known prebiotic synthesis capabilities. The absence of eight "never-observed" proteinogenic amino acids in prebiotic experiments further complicates the picture.
4. Stability-reactivity paradox: Amino acids must remain stable enough to accumulate while being reactive enough to form peptides without enzymatic assistance, presenting a delicate balance difficult to achieve in prebiotic environments.

These challenges often involve mutually exclusive or contradictory requirements, making their simultaneous fulfillment under naturalistic scenarios highly improbable given our current understanding. The quantitative data and empirical findings presented in this review strongly suggest that the spontaneous emergence of a minimal functional proteome through purely naturalistic processes faces formidable obstacles.

To advance our understanding of life's origins, future research should:

1. Focus on specific mechanisms that could potentially overcome these challenges.
2. Encourage interdisciplinary approaches combining chemistry, biology, and geoscience.
3. Critically evaluate assumptions underlying current models in light of empirical data.
4. Explore alternative scenarios or environments that might provide the necessary conditions for amino acid and peptide formation.
5. Aim for incremental advances in understanding rather than comprehensive theories, given the complexity of the problem.

By addressing these points, the scientific community can better navigate the significant hurdles associated with the prebiotic formation of amino acids and peptides, potentially leading to more plausible models for the origin of life or revealing the need for alternative explanations.

References: 

2.1  Challenges in the Availability of Precursors for Prebiotic Amino Acid Synthesis

1. Nogal, N., Sanz-Sánchez, M., Vela-Gallego, S., Ruiz-Mirazo, K., & de la Escosura, A. (2023). The protometabolic nature of prebiotic chemistry. Chemical Society Reviews, 52(17), 7229-7248. Link. (This review explores the concept of protometabolism in prebiotic chemistry and its implications for the origin of life.)

2. Tran, Q.P., Yi, R., & Fahrenbach, A.C. (2023). Towards a prebiotic chemoton – nucleotide precursor synthesis driven by the autocatalytic formose reaction. Chemical Science, 14(25), 6999-7008. Link. (This study investigates the synthesis of nucleotide precursors using the formose reaction in a prebiotic context.)

3. Peters, S., Semenov, D., Hochleitner, R., & Trapp, O.E. (2023). Synthesis of prebiotic organics from CO2 by catalysis with meteoritic and volcanic particles. Scientific Reports, 13(1), 7054. Link. (This research examines the synthesis of organic compounds from CO2 using meteoritic and volcanic particles as catalysts under prebiotic conditions.)

Further references: 
Stuart, A.H., Rammu, H., & Lane, N. (2023). Prebiotic Synthesis of Aspartate Using Life's Metabolism as a Guide. Reproductive and developmental Biology, 13(5), 1177. Link. (This study investigates the prebiotic synthesis of aspartate using metabolic pathways found in modern life as a guide.)

Magrino, T., Pietrucci, F., & Saitta, A.M. (2021). Step by Step Strecker Amino Acid Synthesis from Ab Initio Prebiotic Chemistry. Journal of Physical Chemistry Letters, 12(9), 2376-2382. Link. (This work uses ab initio simulations to model a step-by-step Strecker synthesis of amino acids under prebiotic conditions.)

Ashe, K. (2018). Studies towards the prebiotic synthesis of nucleotides and amino acids. Doctoral thesis, University of Cambridge. Link. (This thesis explores various routes for the prebiotic synthesis of both nucleotides and amino acids.)

McDonald, G.D., & Storrie-Lombardi, M.C. (2010). Biochemical constraints in a protobiotic earth devoid of basic amino acids: the "BAA(-) world". Astrobiology, 10(10), 989-1000. Link. (This paper proposes a "BAA(-) world" hypothesis, exploring biochemical constraints in a protobiotic Earth lacking basic amino acids.)

Engel, M.H., & Perry, R.S. (2008). The origins of amino acids in ancient terrestrial and extraterrestrial materials. Proceedings of SPIE, 7097, 70970O. Link. (This review examines evidence for amino acid origins in ancient terrestrial and extraterrestrial materials.)

2.2 Challenges of Prebiotic Peptide Bond Formation

4. Nogal, N., Sanz-Sánchez, M., Vela-Gallego, S., Ruiz-Mirazo, K., & de la Escosura, A. (2023). The protometabolic nature of prebiotic chemistry. Chemical Society Reviews, 52(17), 7229-7248. Link. (This review explores the concept of protometabolism in prebiotic chemistry and its implications for the origin of life.)

5. Diederich, P., Geisberger, T., Yan, Y., Seitz, C., Ruf, A., Huber, C., Hertkorn, N., & Schmitt-Kopplin, P. (2023). Formation, stabilization and fate of acetaldehyde and higher aldehydes in an autonomously changing prebiotic system emerging from acetylene. Communications Chemistry, 6(1), 69. Link. (This study investigates the formation and behavior of aldehydes in a prebiotic system derived from acetylene.)

6. Zhang, W. (2023). The formation and stability of homochiral peptides in aqueous prebiological environment in the Earth's crust. arXiv preprint. Link. (This preprint examines the formation and stability of homochiral peptides in prebiotic aqueous environments within the Earth's crust.)

7. Chi, Y., Li, X.Y., Chen, Y., Zhang, Y., Liu, Y., Gao, X., & Zhao, Y. (2022). Prebiotic formation of catalytically active dipeptides via trimetaphosphate activation. Chemistry - An Asian Journal, 17(23), e202200926. Link. (This research demonstrates the prebiotic formation of catalytically active dipeptides using trimetaphosphate activation.)

Further references: 

Szilagyi, R.K. (2023). Peptide condensation and hydrolysis mechanisms from a proton-transfer network perspective. Organic and Biomolecular Chemistry, 21(21), 3974-3987. Link. (This study explores peptide formation and breakdown mechanisms from a proton-transfer perspective.)

Sydow, C., Sauer, F., Siegle, A.F., & Trapp, O. (2022). Iron‐mediated peptide formation in water and liquid sulfur dioxide under prebiotically plausible conditions. ChemSystemsChem, 4(5), e202200034. Link. (This work investigates iron-mediated peptide formation under prebiotic conditions.)
El Samrout, O., Berlier, G., Lambert, J.F., & Martra, G. (2023). Polypeptide Chain Growth Mechanisms and Secondary Structure Formation in Glycine Gas-Phase Deposition on Silica Surfaces. Journal of Physical Chemistry B, 127(13), 3017-3028. Link. (This study examines polypeptide formation on silica surfaces through gas-phase deposition.)

Trapp, O., Sauer, F., Haas, M., Sydow, C., Siegle, A.F., & Lauer, C. (2021). Peptide formation as on the early Earth: from amino acid mixtures to peptides in sulphur dioxide. Research Square. Link. (This preprint explores peptide formation in sulfur dioxide as a model for early Earth conditions.)

Stolar, T., Grubešić, S., Cindro, N., Meštrović, E., Užarević, K., & Hernández, J.G. (2021). Mechanochemical Prebiotic Peptide Bond Formation. Angewandte Chemie, 133(22), 12678-12682. Link. (This paper investigates mechanochemical methods for prebiotic peptide bond formation.)

Comte, D., Lavy, L., Bertier, P., Calvo, F., Daniel, I., Farizon, B., Farizon, M., & Märk, T.D. (2023). Glycine Peptide Chain Formation in the Gas Phase via Unimolecular Reactions. Journal of Physical Chemistry A, 127(8 ), 1768-1776. Link. (This study examines glycine peptide chain formation through gas-phase unimolecular reactions.)

Rousseau, P., Piekarski, D.G., Capron, M., Domaracka, A., Adoui, L., Martín, F., Alcamí, M., Díaz-Tendero, S., & Huber, B.A. (2020). Polypeptide formation in clusters of β-alanine amino acids by single ion impact. Nature Communications, 11(1), 3818. Link. (This work demonstrates polypeptide formation in β-alanine clusters through single ion impact.)

2.3  Quantity and Concentration: Challenges in Prebiotic Amino Acid Availability

8.Rolf, J., Handke, J., Burzinski, F., Luetz, S., & Rosenthal, K. (2023). Amino acid balancing for the prediction and evaluation of protein concentrations in cell-free protein synthesis systems. Biotechnology Progress, 39(5), e3373. Link. (This study investigates amino acid balancing for optimizing protein synthesis in cell-free systems.)

9. (2023). Amino acid balancing for the prediction and evaluation of protein concentrations in cell-free protein synthesis systems. arXiv preprint. Link. (This preprint discusses amino acid balancing techniques for cell-free protein synthesis systems.)

10. (2023). Geochemical and Photochemical Constraints on S[IV] Concentrations in Natural Waters on Prebiotic Earth. ESSOAr. Link. (This study examines the constraints on sulfur concentrations in prebiotic Earth's natural waters.)

11. Gómez Ortega, J., Raubenheimer, D., Tyagi, S., Mirth, C.K., & Piper, M.D.W. (2023). Biosynthetic constraints on amino acid synthesis at the base of the food chain may determine their use in higher-order consumer genomes. PLOS Genetics, 19(5), e1010635. Link. (This research explores how biosynthetic constraints on amino acids at lower trophic levels may influence their use in higher-order organisms' genomes.)

2.4  Stability and Reactivity: The Prebiotic Amino Acid Paradox

12. Stuart, A.H., Rammu, H., & Lane, N. (2023). Prebiotic Synthesis of Aspartate Using Life's Metabolism as a Guide. Reproductive and developmental Biology, 13(5), 1177. Link. (This study investigates the prebiotic synthesis of aspartate using metabolic pathways found in modern life as a guide.)

13. Holden, D.T., Morato, N.M., & Cooks, R.G. (2022). Aqueous microdroplets enable abiotic synthesis and chain extension of unique peptide isomers from free amino acids. Proceedings of the National Academy of Sciences of the United States of America, 119(44), e2212642119. Link. (This research demonstrates the abiotic synthesis and chain extension of peptide isomers in aqueous microdroplets, providing insights into potential prebiotic peptide formation mechanisms.)

2.5 Thermodynamic and Kinetic Barriers to Polymerization

14. Vaida, V., & Deal, A.M. (2022). Peptide synthesis in aqueous microdroplets. Proceedings of the National Academy of Sciences of the United States of America, 119(50), e2216015119. Link. (This study investigates the synthesis of peptides in aqueous microdroplets, providing insights into potential prebiotic chemistry mechanisms.)

15. Carvalho-Silva, V.H., Coutinho, N.D., & Aquilanti, V. (2020). From the Kinetic Theory of Gases to the Kinetics of Rate Processes: On the Verge of the Thermodynamic and Kinetic Limits. Molecules, 25(9), 2098. Link. (This review explores the connections between kinetic theory of gases and the kinetics of rate processes, discussing thermodynamic and kinetic limits relevant to chemical reactions.)

Further references:
Royal Truman and Charles McCombs, Negligible concentrations of peptides form in water: part 1 - using high temperatures or high pH, ​​J. Creation 38(1):126‒135, 2024.
Royal Truman, Change Tan, and Charles McCombs, Insignificant concentrations of peptides form in water: part 2-using moderate temperatures, J. Creation 38(1):136‒149, 2024.
Chemical evolution of amino acids and proteins? Impossible!!
https://reasonandscience.catsboard.com/t2887-chemical-evolution-of-amino-acids-and-proteins-impossible

3.1 Thermodynamic and Kinetic Barriers to Prebiotic Polypeptide Formation

16. Harold, S.E., Warf, S.L., & Shields, G.C. (2023). Prebiotic dimer and trimer peptide formation in gas-phase atmospheric nanoclusters of water. Physical Chemistry Chemical Physics, 25(31), 20890-20901. Link. (This study investigates the formation of small peptides in atmospheric water nanoclusters, providing insights into potential prebiotic chemistry mechanisms.)

17. Zhao, Q., Garimella, S.S., & Savoie, B.M. (2023). Thermally Accessible Prebiotic Pathways for Forming Ribonucleic Acid and Protein Precursors from Aqueous Hydrogen Cyanide. Journal of the American Chemical Society, 145(10), 5735-5745. Link. (This research explores thermally accessible pathways for the formation of RNA and protein precursors from hydrogen cyanide in aqueous environments.)

18. El Samrout, O., Berlier, G., Lambert, J.F., & Martra, G. (2023). Polypeptide Chain Growth Mechanisms and Secondary Structure Formation in Glycine Gas-Phase Deposition on Silica Surfaces. Journal of Physical Chemistry B, 127(13), 3017-3028. Link. (This study examines polypeptide formation on silica surfaces through gas-phase deposition of glycine.)

19. Comte, D., Lavy, L., Bertier, P., Calvo, F., Daniel, I., Farizon, B., Farizon, M., & Märk, T.D. (2023). Glycine Peptide Chain Formation in the Gas Phase via Unimolecular Reactions. Journal of Physical Chemistry A, 127 ( 8 ) , 1768-1776. Link. (This study examines glycine peptide chain formation through gas-phase unimolecular reactions.)

20. Chi, Y., Li, X.Y., Chen, Y., Zhang, Y., Liu, Y., Gao, X., & Zhao, Y. (2022). Prebiotic formation of catalytically active dipeptides via trimetaphosphate activation. Chemistry - An Asian Journal, 17(23), e202200926. Link. (This research demonstrates the prebiotic formation of catalytically active dipeptides using trimetaphosphate activation.)

3.2 Chirality Issues

20. van Dongen, S., Ahlal, I., Leeman, M., Kaptein, B., Kellogg, R.G., Baglai, I., & Noorduin, W.L. (2022). Chiral Amplification through the Interplay of Racemizing Conditions and Asymmetric Crystal Growth. Journal of the American Chemical Society, 144(49), 22344-22349. Link. (This study explores chiral amplification mechanisms involving racemization and asymmetric crystal growth.)

21. (2023). Origin of Biological Homochirality by Crystallization of an RNA Precursor on a Magnetic Surface. arXiv preprint. Link. (This preprint proposes a mechanism for the origin of biological homochirality through crystallization of RNA precursors on magnetic surfaces.)

22. Huber, L., & Trapp, O.E. (2022). Symmetry Breaking by Consecutive Amplification: Efficient Paths to Homochirality. Origins of Life and Evolution of Biospheres, 52(3), 227-241. Link. (This paper discusses symmetry breaking mechanisms leading to homochirality through consecutive amplification processes.)

23. (2021). Chapter 1. Asymmetric Autocatalysis: The Soai Reaction, an Overview. In Asymmetric Autocatalysis: From Stochastic to Deterministic (pp. 1-18). Royal Society of Chemistry. Link. (This book chapter provides an overview of asymmetric autocatalysis, focusing on the Soai reaction as a key example.)

3.3 Sequence and Structure Formation in Prebiotic Protein Evolution: A Critical Analysis

24. Scolaro, G., & Braun, E.L. (2023). The Structure of Evolutionary Model Space for Proteins across the Tree of Life. Biology, 12(2), 282. Link. (This study explores the evolutionary model space for proteins across diverse life forms, providing insights into protein evolution patterns.)

25. Bricout, R., Weil, D., Stroebel, D., Genovesio, A., & Roest Crollius, H. (2023). Evolution is not Uniform Along Coding Sequences. Molecular Biology and Evolution, 40(3), msad042. Link. (This research demonstrates that evolutionary rates vary along coding sequences, challenging the assumption of uniform evolution.)

26. Tretyachenko, V., Vymětal, J., Neuwirthová, T., Vondrášek, J., Fujishima, K., & Hlouchová, K. (2022). Modern and prebiotic amino acids support distinct structural profiles in proteins. Open Biology, 12(4), 220040. Link. (This study compares the structural profiles of proteins composed of modern versus prebiotic amino acids, offering insights into early protein evolution.)

27. Lesk, A.M., & Konagurthu, A.S. (2022). Protein structure prediction improves the quality of amino‐acid sequence alignment. Proteins, 90(5), 1154-1161. Link. (This paper demonstrates how advances in protein structure prediction can enhance the accuracy of amino acid sequence alignments.)

Further references: 
Truman, R., Racemization of amino acids under natural conditions: part 1 – a challenge to abiogenesis, J. Creation 36(1):114–121, 2022.
Truman, R., Racemization of amino acids under natural conditions: part 2 - kinetic and thermodynamic data, J. Creation 36(2):72–80, 2022.
Truman, R., Racemization of amino acids under natural conditions part 3 - condensation to form oligopeptides, J. Creation 36(2) 81–89, 2022.
Truman, R. and Schmidtgall, B., Racemization of amino acids under natural conditions: part 4 — racemization always exceeds the rate of peptide elongation in aqueous solution J. Creation 36(3):74–81, 2022.
Truman, R., Racemization of amino acids under natural conditions: part 5 — exaggerated old age dates, J. Creation 37(1):64–74, 2023.

3.4  Scale and Reproduction in Prebiotic Systems: A Critical Analysis

Mizuuchi, R., & Ichihashi, N. (2023). Minimal RNA self-reproduction discovered from a random pool of oligomers. Chemical Science, 14(22), 6246-6255. Link. (This study reports the discovery of minimal RNA self-reproduction from a random pool of oligomers, providing insights into potential prebiotic RNA replication mechanisms.)

Red'ko, V.G. (2020). Models of Prebiotic Evolution. Biology Bulletin Reviews, 11(1), 35-46. Link. (This review discusses various models of prebiotic evolution, examining theoretical approaches to understanding the origin of life.)

Belliveau, N.M., Chure, G., Hueschen, C.L., Garcia, H.G., Kondev, J., Fisher, D.S., Theriot, J.A., & Phillips, R. (2021). Fundamental limits on the rate of bacterial growth and their influence on proteomic composition. Cell Systems, 12(9), 924-944.e14. Link. (This research explores the fundamental limits on bacterial growth rates and how these constraints influence protein composition in cells.)

3.5 Amplification of Enantiomeric Excess

28. (2023). Amplification of Enantiomeric Excess without Any Chiral Source in Prebiotic Case. Preprints, 2023070287. Link. (This preprint discusses the amplification of enantiomeric excess in prebiotic conditions without an initial chiral source.)

29. Watanabe, N., Shoji, M., Miyagawa, K., Hori, Y., Boero, M., Umemura, M., & Shigeta, Y. (2023). Enantioselective amino acid interactions in solution. Physical Chemistry Chemical Physics, 25(20), 13741-13749. Link. (This study investigates enantioselective interactions between amino acids in solution.)

30. Sato, A., Shoji, M., Watanabe, N., Boero, M., Shigeta, Y., & Umemura, M. (2023). Origin of Homochirality in Amino Acids Induced by Lyman-α Irradiation in the Early Stage of the Milky Way. Astrobiology, 23(5), 587-596. Link. (This research explores the potential role of Lyman-α radiation in the early Milky Way in inducing homochirality in amino acids.)

31. Bocková, J., Jones, N.C., Topin, J., Hoffmann, S.V., & Meinert, C. (2023). Uncovering the chiral bias of meteoritic isovaline through asymmetric photochemistry. Nature Communications, 14(1), 3475. Link. (This study investigates the chiral bias of isovaline in meteorites through asymmetric photochemistry experiments.)

32. Shoji, M., Kitazawa, Y., Sato, A., Watanabe, N., Boero, M., Shigeta, Y., & Umemura, M. (2023). Enantiomeric Excesses of Aminonitrile Precursors Determine the Homochirality of Amino Acids. Journal of Physical Chemistry Letters, 14(8 ), 2094-2100. Link. (This paper demonstrates how enantiomeric excesses in aminonitrile precursors can lead to homochirality in amino acids.)

Further references: 
Truman, R., The origin of L-amino acid enantiomeric excess: part 1-by preferential photo- destruction using circularly polarized light? J. Creation 36(3):67-73, 2022.
Truman, R., Enantiomeric amplification of L amino acids part 1-irrelevant and discredited examples, J. Creation 37(2):96–104, 2023.
Truman, R., Enantiomeric amplification of L amino acids part 2—chirality induced by D-sugars, J. Creation 37(2):105–111, 2023.
Truman, R. and Basel, C., Enantiomeric amplification of L amino acids part 3—using chiral impurities, J. Creation 37(2):120–111, 2023.
Truman, R., Enantiomeric amplification of L amino acids: part 4—based on subliming valine, J. Creation 37(3):79-83, 2023.
Truman, R. and Grocott, S., Enantiomeric amplification of L amino acids: part 5—sublimation based on serine octamers, J. Creation 37(3):84-89, 2023.
Truman, R., Enantiomeric amplification of L amino acids: part 6—sublimation using Asn, Thr, Asp, Glu, Ser mixtures, J. Creation 37(3):90-92, 2023.
Truman, R., Enantiomeric amplification of L-amino acids: part 7-using aspartic acid on an achiral Cu surface, J. Creation 38(1):51‒53, 2024.
Truman, R. and Basel, C., Enantiomeric amplification of L-amino acids: part 8-modification of eutectic point with special additives, J. Creation 38(1):54‒59, 2024.             
Truman, R., Basel, C., and Grocott, S., Enantiomeric amplification of amino acids: part 9—enantiomeric separation via crystallization, J. of Creation 38(2):62-67, 2024.
Truman, R., Basel, C., and Grocott, S., Enantiomeric amplification of amino acids: part 10—extraction of homochiral crystals accompanied by catalytic racemization, J. of Creation 38(2):68-74, 2024.
Homochirality, an unresolved issue https://reasonandscience.catsboard.com/t1309-homochirality

4.1 Optimal Set of Amino Acids

33. Brown, S.M., Voráček, V., & Freeland, S.J. (2023). What Would an Alien Amino Acid Alphabet Look Like and Why?. Astrobiology, 23(5), 597-611. Link. (This study explores the potential characteristics of amino acid alphabets that might evolve in extraterrestrial life forms, considering various biochemical and evolutionary constraints.)

34. Caldararo, F. (2022). The genetic code is very close to a global optimum in a model of its origin taking into account both the partition energy of amino acids and their biosynthetic relationships. BioSystems, 218, 104613. Link. (This research proposes a model for the origin of the genetic code that considers both amino acid partition energy and biosynthetic relationships, suggesting the code is near a global optimum.)

4.2 Protein Folding and Chaperones

35. (2022). Friends in need: how chaperonins recognize and remodel proteins that require folding assistance. arXiv preprint. Link. (This preprint discusses the mechanisms by which chaperonin proteins recognize and assist in the folding of other proteins, providing insights into protein quality control systems.)

A Response to: Complexity is Not Enough: A Critical Analysis of the "Life by Design" Teleological Argument
https://www.academia.edu/115191829/Complexity_is_Not_Enough_A_Critical_Analysis_of_the_Life_by_Design_Teleological_Argument

Claim: The argument's first premise commits the fallacy of presenting a false trilemma, artificially narrowing the possibilities for abiogenesis down to only three options - natural law, chance, or design (Grasso, 2022). However, the origins of the life field propose numerous additional models beyond this simplistic triad. Modern research has uncovered promising pathways for abiogenesis through chemical affinity and molecular self-organization. For example, clays and mineral surfaces may have concentrated biomolecules and facilitated polymerization reactions (Miller, 2003).

Response: The argument that the trilemma of natural law, chance, or design for explaining abiogenesis is a false or overly simplistic categorization is mistaken. In fact, this trilemma provides a comprehensive framework that encompasses all possible explanations for the origin of life, including processes like chemical affinity and molecular self-organization. Chemical processes, while governed by natural laws, can lead to outcomes that are essentially random and unguided. This dual nature means that chemical affinity and molecular self-organization actually span both the "natural law" and "chance" categories in the trilemma:

1. Natural law: Chemical reactions follow the laws of physics and chemistry. The properties of atoms and molecules that allow for chemical affinity and self-organization are determined by these natural laws.
2. Chance: The specific outcomes of these chemical processes, particularly in complex systems like those involved in abiogenesis, are often unpredictable and can be considered random. The exact molecules that form, their concentrations, and their interactions are subject to chance events.

In the context of abiogenesis, this means that while natural laws provide the framework for chemical reactions to occur, the specific path to life and the exact molecules that ended up forming the first self-replicating systems would have been largely determined by chance events if design is excluded. This understanding actually strengthens the validity of the trilemma rather than undermining it. The trilemma doesn't require that each possibility be mutually exclusive. Instead, it acknowledges that the origin of life could involve interplay between natural law and chance, while still leaving room for the possibility of design. Therefore, chemical affinity and molecular self-organization are indeed covered by the trilemma, falling into both the "natural law" and "chance" categories. This dual categorization more accurately reflects the nature of chemical processes in the context of abiogenesis. The trilemma thus provides a robust and inclusive framework for discussing the origin of life, allowing for the consideration of both known and yet-to-be-discovered natural processes that could have led to abiogenesis, while also accounting for the role of chance and not excluding the possibility of design.

Claim: Lipid vesicles that self-assemble based on chemistry alone provide micro-environments potentially conducive to proto-life (Deamer, 2017). 

Response: Steven A. Benner (2014): The Asphalt Paradox: Lipids that provide tidy compartments under the close supervision of a graduate student (supporting a protocell first model for origins) are quite non-robust with respect to small environmental perturbations, such as a change in the salt concentration, the introduction of organic solvents, or a change in temperature.

Steven A. Benner's "Asphalt Paradox" highlights a significant challenge in the protocell-first model of abiogenesis, illuminating the complexities involved in the emergence of cellular life. This concept, introduced in 2014, points out a fundamental issue with the idea that the first step towards life was the formation of simple cell-like structures composed of lipid membranes encapsulating primitive genetic material. The paradox arises from the conflicting requirements for a protocell membrane. On one hand, it needs to be stable enough to maintain its structure and protect its contents. On the other hand, it must be dynamic enough to allow for the exchange of materials necessary for metabolism and replication. This delicate balance is at the heart of the Asphalt Paradox. Benner's observation emphasizes that while lipid vesicles can be created and maintained under controlled laboratory conditions, they are far less stable in the variable conditions that would have existed on early Earth. These lipid structures are highly sensitive to environmental changes. Salt concentration fluctuations can disrupt the membrane integrity, organic solvents can dissolve or alter the lipid structure, and temperature changes can cause membranes to become too rigid or too fluid. This sensitivity raises questions about the prebiotic plausibility of such structures, as the conditions required to form and maintain these delicate protocells may not have been readily available or sustainable in early Earth environments. Furthermore, maintaining the integrity of these protocells against environmental perturbations would require a constant input of energy, which may not have been available in primitive conditions. This energy requirement adds another layer of complexity to the already challenging scenario of early life formation. The Asphalt Paradox has led researchers to consider alternative models for the origin of life, such as the "metabolism-first" hypothesis or models involving more robust compartments like mineral pores. It also raises questions about how such sensitive structures could have evolved into the more robust cell membranes we see in modern organisms.

Claim: Experiments demonstrate amino acids forming peptides, nucleotides forming RNA chains, and lipids forming vesicles naturally when conditions allow (Sutherland, 2017).

Response:  The paper: The Hurdles to Getting Amino Acids and Functional Peptides for the First Life Prebiotically Link demonstrates the major challenges faced in the prebiotic formation of amino acids and functional proteins - a critical step in the origin of life. The author systematically outlines several key hurdles, including:

Scarcity of fixed nitrogen and carbon sources needed for amino acid synthesis
Difficulty in obtaining reactive sulfur compounds required for certain amino acids
Rapid photochemical decomposition of ammonia, a crucial nitrogen source
Thermodynamic and kinetic barriers to forming even short peptides prebiotically

The review concludes that the naturalistic emergence of a minimal functional proteome faces significant obstacles that the current origin of life models struggle to overcome.

A Short Tale of the Origin of Proteins and Ribosome Evolution
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9694802/

Here's a summary of the main claims and points made in the paper:

1. The building blocks of life (amino acids and nucleotides) were likely present in early Earth conditions and could have formed spontaneously in a prebiotic soup.
2. Peptides and RNA likely coevolved in the early stages of life, with the ribosome being a key product of this coevolution.
3. The RNA world hypothesis suggests that RNA was a central molecule in early life, capable of storing information and catalyzing reactions.
4. Peptides may have played a more central role in early life than previously thought, with the ability to form easily in prebiotic conditions.
5. The first peptides likely arose through condensation and wet-dry cycles, possibly assembling into higher-order structures similar to amyloid formation.
6. Intrinsically disordered proteins (IDPs) may represent an important step in the evolution of modern proteins due to their simplicity and plasticity.
7. The ribosome's evolution is central to understanding the transition from chemical to Darwinian evolution, with the peptidyl transferase center (PTC) being one of the oldest parts.
8. The ribosome evolved through a series of phases, gradually acquiring complexity and function.
9. Ribosomal proteins coevolved with ribosomal RNA, with older protein regions interacting with more ancient RNA parts.
10. The study of ribosome structure and evolution has provided insights into the three domains of life (Archaea, Bacteria, and Eukarya) and the last universal common ancestor (LUCA).
11. The paper suggests a timeline for the evolution of life on Earth, from the formation of the planet to the great oxidation event and the adaptations that followed.

This review aims to provide general life scientists with an overview of how proteins could have arisen and how they are regulated in modern cells, focusing on the evolution of peptides, proteins, and ribosomes.

Refutation of Claims on the Origin of Proteins and Ribosome Evolution

1. Spontaneous Formation of Life's Building Blocks
Claim: Amino acids and nucleotides likely formed spontaneously in early Earth's prebiotic soup.
Refutation: Significant challenges exist for amino acid formation under prebiotic conditions. Specific atmospheric and environmental conditions may not have been prevalent. Stability and concentration of these amino acids are questionable due to rapid degradation and dilution.

2. Coevolution of Peptides and RNA
Claim: Peptides and RNA likely coevolved, with the ribosome as a key product.
Refutation: This scenario is highly speculative. RNA synthesis faces significant hurdles, including ribose formation difficulties and RNA instability in harsh prebiotic conditions. The simultaneous, interdependent evolution of peptides and RNA adds complexity, making this less plausible without concrete evidence.

3. RNA World Hypothesis
Claim: RNA was central in early life, capable of storing information and catalyzing reactions.
Refutation: Challenges include difficulty in forming ribonucleotides prebiotically and lack of a plausible prebiotic RNA replication pathway. These issues question RNA's feasibility as the initial life molecule.

4. Central Role of Peptides in Early Life
Claim: Peptides may have played a more central role in early life, forming easily in prebiotic conditions.
Refutation: Peptide bond formation faces significant barriers, including the need for specific catalysts and energy for condensation reactions. This suggests spontaneous formation of functional peptides is far from straightforward.

5. First Peptides and Higher-Order Structures
Claim: First peptides arose through condensation and wet-dry cycles, possibly forming amyloid-like structures.
Refutation: While wet-dry cycles can promote polymerization, resulting peptides would be random and unlikely to fold functionally. Higher-order structures require specific sequences, improbable in random assembly.

6. Intrinsically Disordered Proteins (IDPs)
Claim: IDPs may represent an important step in protein evolution due to simplicity and plasticity.
Refutation: IDPs still require sequence specificity to function. Random generation of such sequences is highly unlikely prebiotically. The transition to structured proteins involves significant unexplained evolutionary steps.

7. Ribosome Evolution and Chemical to Darwinian Transition
Claim: Ribosome evolution is key to understanding the transition from chemical to Darwinian evolution.
Refutation: The ribosome's complexity makes prebiotic assembly highly improbable. Formation of such a sophisticated nanomachine without a pre-existing, highly organized system seems unlikely.

8. Gradual Ribosome Evolution
Claim: The ribosome evolved through phases, gradually acquiring complexity and function.
Refutation: This assumes functional intermediate stages, which are highly speculative and lack experimental support.

9. Coevolution of Ribosomal Proteins and RNA
Claim: Ribosomal proteins coevolved with ribosomal RNA.
Refutation: This assumes a level of interdependence difficult to achieve prebiotically. Coordinated evolution without guiding selective pressure is questionable.

10. Ribosome Structure and Life Domains
Claim: Ribosome studies provide insights into life domains and LUCA.
Refutation: While providing evolutionary relationship insights, these do not confirm prebiotic feasibility of ribosome formation and function.

11. Timeline for Life's Evolution
Claim: A timeline is proposed from Earth's formation to the great oxidation event.
Refutation: The timeline might be oversimplified, ignoring myriad challenges in each evolutionary step. It appears more speculative than evidential.

These refutations highlight significant challenges in the proposed scenarios for protein origin and ribosome evolution, questioning their plausibility without further evidence.