Fact 2

Prebiotic forces cannot create the basic building blocks needed for the development of the basic cell.

FOUR MOLECULES are needed for life: nucleotides, carbohydrates, proteins, and lipids.

“Nobody has shown a method to make the enantiopure versions of carbohydrates, amino acids, nucleotides or lipids in a prebiotically relevant manner”

— Dr James Tour

Prebiotic Building Blocks

Four Functional Molecules Needed for Life

  • Nucleic Acids (DNA/RNA): To store and transmit genetic information. Nucleotides join together to form polynucleotides (DNA/RNA)

  • Carbohydrates: For energy storage and structural functions. Monomeric sugars (carbohydrates) help for Nucleic Acids and Polysaccharides.

  • Proteins (Enzymes): For catalyzing biochemical reactions. Amino acids join together to form complex polypetide chains ( referred to as Proteins or Enzymes)

  • Lipids (Membranes): To form a protective barrier around the cell and maintain internal conditions.

Molecules are the language of living systems

Prebiotic Building Blocks

The Building Blocks of Building Blocks

Scientists Deceive Public. Dr. Rob Stadler Dissects Origin of Life Science Claims on RNA Replication

Make the simplest cells - 4 building blocks

Carbohydrate

ChatGPT

Carbohydrates are organic molecules made up of carbon (C), hydrogen (H), and oxygen (O), typically with a ratio of 1:2:1 (general formula: ). They are essential for life and serve as a major energy source and structural component for living organisms.

Dr Tour, a synthetic organic chemist from Rice University, discusses many problems with carbohydrate formation.

Primary issues are Instability, selective synthesis, and cross reactivity.

Sugar Problem - random connections (non-covalent bonds)of just 6 sugars can combine in a trillion ways.

The Problem of Carbohydrate Formation in Prebiotic Chemistry

In the context of origin-of-life research, forming carbohydrates under prebiotic conditions is a major challenge because:

1. Instability

Tour argues that no known prebiotic synthesis provides a realistic pathway to form nucleotides—molecules that make up RNA and DNA—under early Earth conditions. He highlights that forming nucleotides requires multiple specific chemical steps, each needing precise conditions (e.g., pH, temperature, and concentration of reactants), which are difficult to envision occurring spontaneously.

2. Selective Synthesis

Prebiotic conditions often produce a mixture of sugars with various chain lengths and structures, making it hard to get only biologically relevant ones.

3. Cross-Reactivity

Sugars can react with other molecules in ways that destroy their usefulness for life.

Dr. James Tour highlights that these challenges make it difficult to explain how carbohydrates, especially complex ones like polysaccharides, could have formed and accumulated in the right conditions to support the emergence of life.

Carbohydrates bonding issues.

Scientists Deceive Public. Dr. Rob Stadler Dissects Origin of Life Science Claims on RNA Replication

Rice Professor Demands Transparency on Origin of Life Chemistry

Episode 5/13: Carbohydrates

Episode 12.1/13: Cell Construction & Assembly Problem

Carbohydrates Summary

  1. Selective Synthesis

  2. Cross reactivity

  3. Carbohydrate - Bonding issues Carbohydrates

  4. Decay in water

  5. Can’t make them - no pathway

Carbohydrates Decay in water

Chat GTP 4/3/25

Stability of Carbohydrates in Water

Carbohydrates, especially sugars like ribose, are chemically unstable in aqueous solution, especially under heat or basic conditions. Here are the issues:

  • Hydrolysis: Water can break glycosidic bonds (if polymers form) or degrade open-chain forms.

  • Degradation: Ribose degrades rapidly, often within hours to days, unless stabilized.

  • Isomerization & Fragmentation: Sugars can isomerize or break down into smaller aldehydes and acids.

Stabilizing Factors:

  • Borate minerals (e.g., colemanite, ulexite): Can bind to sugars like ribose and stabilize them.

  • Low temperatures and low concentrations of reactants can help slow degradation.

  • Dry-wet cycles (e.g., evaporation followed by rehydration) can promote sugar synthesis while limiting breakdown.

Significance in Origin of Life:

  • The instability of sugars in water challenges the RNA world hypothesis, which depends on stable ribose.

  • Some theories suggest life may have originated in non-aqueous environments or used alternative backbones (e.g., threose or glycolaldehyde-based sugars) that are more stable.

Carbohydrates- Can’t make them - no pathway.

Proteins

Credit: Erin Rod

Proteins are large, complex molecules made of amino acids. They are essential for virtually every biological process, performing structural, enzymatic, transport, and signaling functions in living organisms. The proteins are molecular machines intentionally directed to perform a particular function.  Over a hundred different proteins are needed in a simple cell for life.

Major problems forming these prebiotically.  Prebiotically, the correct structure of Amino acids is not prevalent, instability, improper sequencing and no mechanism to fold up in the correct order.  Here is a simple protein:

Transcription - RNA Polymerase

ChatGPT 2/12/25

RNA polymerase is an enzyme responsible for synthesizing RNA from a DNA template in a process called transcription. It plays a key role in gene expression by copying genetic information from DNA into messenger RNA (mRNA), which is later translated into proteins.

1. Transcription

Synthesizes RNA by adding ribonucleotides (A, U, C, G) in a 5’ to 3’ direction.

2. Initiation

Binds to DNA at the promoter region and starts RNA synthesis.

3. Elongation

Moves along the DNA, adding ribonucleotides to the growing RNA strand.

4. Termination

Stops transcription at specific sequences and releases the RNA molecule. Eukaryotic RNA polymerases are much more complex, consisting of multiple subunits:

  1. RNA Polymerase I – 14 subunits

  2. RNA Polymerase II – 12 subunits

  3. RNA Polymerase III – 17 subunits

Grok3 AI 2/19/25

General Structure

  • Bacterial RNA Polymerase: A well-studied example is Escherichia coli RNAP, which has a core enzyme composed of five subunits: α₂ββ’ω (approximately 400 kDa total). Each subunit is a distinct polypeptide chain made of amino acids.

    • α subunit: ~329 amino acids each (two copies).

    • β subunit: ~1,342 amino acids.

    • β’ subunit: ~1,552 amino acids.

    • ω subunit: ~91 amino acids.

    • A sixth subunit, σ (sigma factor, e.g., σ⁷⁰ with ~613 amino acids), joins temporarily to initiate transcription.

  • Eukaryotic RNA Polymerase II: More complex, with 12 subunits (Rpb1–Rpb12) in humans. The largest subunit, Rpb1, contains ~1,970 amino acids, while smaller subunits range from ~70 to 500 amino acids each.

  • Total Amino Acids: The exact count depends on the species and polymerase type, but bacterial RNAP has roughly 4,000–5,000 amino acids across its subunits, and eukaryotic RNAP II exceeds 5,000.

Transcription video - multiple proteins join together to form the machine, specific location on the DNA must be targeted, the machine rapidly moves, splits the DNA strand, copies the DNA, makes an identical RNA copy and puts the DNA back together.

DNA Transcription (Basic)

You have over 37 trillion living cells in your body, everyone of them is does this process repeatedly throughout the day.

The Origin-of-Life Problem with Proteins

ChatGPT

Dr. James Tour highlights several issues related to protein formation in prebiotic environments:

1. Amino Acid Synthesis

While some amino acids can be synthesized in controlled lab settings, the correct types and chirality (left-handed form for life) are difficult to produce in the right proportions.

2. Peptide Bond Formation

Amino acids must form stable peptide bonds to create functional proteins, but in prebiotic conditions, this reaction is highly inefficient and prone to hydrolysis.

3. Correct Sequencing

Proteins require a specific sequence of amino acids for proper folding and function. Random sequences are unlikely to result in functional proteins.

4. Stability

Even if short peptides form, they are easily broken down in harsh environmental conditions.

Protein Stability

Grok3 5/14/25

Dr. James Tour’s Views on Protein Stability in Prebiotic Conditions

Dr. Tour has publicly critiqued the feasibility of complex biomolecules like proteins forming and remaining stable under prebiotic conditions, arguing that the chemical complexity and environmental challenges make it highly improbable without guided processes. His arguments often emphasize:

  • Chemical Instability: Tour highlights that amino acids and peptides are prone to degradation in prebiotic conditions (e.g., high temperatures, UV radiation, or reactive aqueous environments). For instance, peptide bonds can hydrolyze in water, and side chains are susceptible to oxidation or racemization, reducing the likelihood of stable, functional proteins forming spontaneously.

  • Chirality Problem: He stresses that prebiotic chemistry would produce racemic mixtures (equal L- and D-amino acids), but life requires homochiral (L-amino acid) proteins. Maintaining chiral purity in harsh prebiotic conditions is chemically challenging, as racemization occurs readily without enzymatic control.

  • Thermodynamic Barriers: He points out that protein folding into stable, functional conformations is entropically unfavorable without cellular machinery (e.g., chaperones). In prebiotic conditions, misfolding or aggregation would dominate, rendering proto-proteins non-functional.

Polymers

Protein Fold Problem

Proteins are thousands of amino acids long, arranged in a specific order and must fold into shapes to make them operational.

Grok3 5/17/25

Dr. James Tour, a renowned synthetic organic chemist, has extensively discussed the challenges of protein folding in prebiotic conditions, particularly in the context of abiogenesis—the origin of life from non-living matter. His arguments focus on the immense complexity of forming functional proteins under early Earth conditions, emphasizing chemical and stereochemical hurdles. Below is a concise summary of his key points, based on available information, including web sources and discussions relevant to his work:

1. Complexity of Protein Folding

  • Chemical Synthesis Challenges: Tour argues that synthesizing functional proteins prebiotically is extraordinarily difficult. Proteins require specific sequences of amino acids to fold into precise three-dimensional structures, which are critical for their biological function. Under prebiotic conditions, achieving the correct sequence and folding is problematic due to the lack of enzymatic machinery like ribosomes, which modern cells use to ensure accurate protein assembly.

  • Chirality Issue: Proteins in living organisms are composed of left-handed (L) amino acids, a property known as homochirality. In prebiotic conditions, amino acids would form as racemic mixtures (equal parts L and D forms). Tour highlights that incorporating only L-amino acids into a protein chain without a directed mechanism is statistically improbable and chemically challenging, as undirected reactions produce both forms.

  • Side Reactions and Byproducts: Prebiotic chemistry would involve uncontrolled reactions, leading to unwanted byproducts. For example, Tour notes that amino acids like lysine, which has two amino groups, can form incorrect bonds (e.g., ε-linkages instead of α-linkages) under prebiotic conditions, disrupting the formation of functional proteins. These side reactions reduce the yield of correctly folded proteins to negligible levels.

2. Prebiotic Conditions and Environmental Constraints

  • Geochemical Implausibility: Tour critiques the plausibility of prebiotic scenarios, such as the “primordial soup” or hydrothermal vents, for producing and stabilizing proteins. Many proposed reactions require specific conditions (e.g., high pH, thiol catalysts, or pure reactants) that are geochemically unrealistic on the early Earth. For instance, the synthesis of polypeptides from acetylated α-aminonitriles requires conditions and chemicals (like thioacetate) unlikely to be abundant prebiotically.

  • ** Keyword: racemization

  • Racemization: Tour points out that even if amino acids were formed, their specific three-dimensional structures could be lost during reactions due to racemization, rendering them useless for protein formation, as functional proteins require specific chiral configurations.

  • Concentration and Purity: The concentrations of reactants needed for peptide formation in lab experiments are often unrealistically high compared to what would be available on the early Earth. Additionally, purification steps in modern experiments remove byproducts that would interfere with subsequent reactions, a process not feasible in a prebiotic setting.

3. Critique of Origin-of-Life Research

  • Tour argues that the scientific community has overstated progress in understanding prebiotic chemistry. He asserts that “nobody understands” the mechanisms by which proteins could form and fold correctly under prebiotic conditions, and claims of progress are often exaggerated.

  • He calls for humility and honesty in admitting the “massive gaps” in knowledge, suggesting that current models may need a paradigm shift to address these challenges.

Conclusion

Dr. James Tour argues that protein folding in prebiotic conditions faces insurmountable chemical, stereochemical, and environmental challenges. The lack of directed mechanisms, the complexity of achieving correct folding, and the implausibility of prebiotic conditions make the spontaneous formation of functional proteins highly unlikely. He urges the scientific community to acknowledge these difficulties and pursue new research paradigms to address them.

Scientists Deceive Public. Dr. Rob Stadler Dissects Origin of Life Science Claims on RNA Replication

Rice Professor Demands Transparency on Origin of Life Chemistry

What are the Scientific Explanations of the Origin of Life?

Formation requires complex enzymes

Grok3 5/17/25

Dr. James Tour, a synthetic chemist, highlights the complexity of protein synthesis in the context of origin-of-life research, particularly the challenge of forming proteins without pre-existing complex enzymes. Here’s a concise overview based on his arguments and the scientific context:

The Protein Synthesis Problem

Proteins are essential macromolecules made of amino acids linked by peptide bonds, forming complex 3D structures critical for biological functions. In modern cells, protein synthesis occurs via translation, where ribosomes (complex molecular machines made of proteins and RNA) read mRNA to assemble amino acids into polypeptides with the help of tRNA and enzymes like aminoacyl-tRNA synthetases. This process is highly precise and depends on numerous enzymes and cofactors.

Tour emphasizes a “chicken-and-egg” paradox in prebiotic chemistry:

  • Enzymes are needed to make proteins: Ribosomes and associated enzymes (e.g., aminoacyl-tRNA synthetases) are required for accurate and efficient protein synthesis in living systems. These enzymes are themselves proteins or protein-RNA complexes.

  • Proteins are needed to make enzymes: The enzymes required for protein synthesis are products of the very process they facilitate, creating a circular dependency.

In a prebiotic world, without these complex molecular machines, forming functional proteins with the correct sequence, chirality (L-amino acids), and folding is a significant challenge. Tour argues that undirected chemical processes (e.g., random polymerization of amino acids) produce mixtures of non-functional peptides with incorrect linkages, racemic amino acids (both L and D forms), and no mechanism for sequence specificity or error correction.

Key Points from Tour’s Perspective

  1. Complexity of Enzymes:

    • Enzymes like aminoacyl-tRNA synthetases are highly specific, attaching the correct amino acid to its corresponding tRNA. Each of the 20 standard amino acids requires a unique synthetase, and these enzymes are large, complex proteins (e.g., hundreds of amino acids long).

    • The ribosome, a massive protein-RNA complex, coordinates peptide bond formation with precision. Its assembly and function depend on numerous proteins and RNAs, which are products of the system itself.

  2. Prebiotic Chemistry Challenges:

    • Selectivity: Proteins in life use only α-linkages between amino acids, but undirected chemistry produces both α and ε linkages (e.g., with lysine) and other non-biological bonds. Achieving exclusive α-linkages without enzymes is unresolved.

    • Chirality: Life uses L-amino acids, but prebiotic reactions yield racemic mixtures (50% L, 50% D). Racemization disrupts protein function, and no robust prebiotic mechanism explains homochirality.

    • Sequence Specificity: Functional proteins require specific amino acid sequences. Random polymerization yields short, non-functional peptides with no mechanism to encode information akin to DNA/RNA.

    • Concentration and Stability: Amino acids and peptides degrade in water, and achieving sufficient concentrations for polymerization in a prebiotic environment (e.g., a “primordial soup”) is geochemically implausible.

  3. The Paradox:

    • Without enzymes, protein synthesis lacks the precision and efficiency seen in cells. Yet, enzymes themselves are proteins requiring the same synthesis machinery.

    • Tour argues that the formation of a self-sustaining protein synthesis system (e.g., a primitive ribosome-like structure) by chance is statistically and chemically implausible due to the complexity and interdependence of the components.

Conclusion

The protein synthesis problem, as articulated by Tour, underscores the difficulty of explaining the origin of complex enzymes and molecular machines in a prebiotic world. The interdependence of proteins and enzymes creates a significant hurdle for abiogenesis, with no definitive prebiotic pathway yet demonstrated. While hypotheses like the RNA World offer potential solutions, they face their own chemical challenges. Tour’s call for transparency about these gaps resonates with the need for rigorous, critical examination in origin-of-life research.

Peptides - Inconceivable

Proteins Summary

  1. Amino acid synthesis

  2. Peptide bond formation

  3. Correct sequencing

  4. Stability in water and harsh conditions

  5. Folding problem Protein fold

  6. Formation requires complex enzymes

Amino Acid Fold

Lipids

ChatGPT

Lipids are a diverse group of hydrophobic or amphiphilic molecules, primarily composed of carbon, hydrogen, and oxygen. They play crucial roles in energy storage, membrane structure, and signaling.

Lipids in Origin-of-Life Research

In the origin-of-life debate, the formation and organization of lipids into protocells (primitive cell-like structures) is a key focus. However, there are major challenges:

1. Prebiotic Synthesis

The formation of complex lipids (like phospholipids) under prebiotic conditions is difficult and poorly understood.

2. Selective Assembly

For life to emerge, lipids must form stable, selectively permeable membranes—a challenging feat without cellular machinery.

3. Membrane Stability

Early membranes would be prone to degradation in harsh environments, reducing the chances of forming and maintaining protocells. Despite these challenges, lipids are considered vital to the emergence of the first cells, as they provide compartmentalization, a critical step toward organized biochemical processes.

Lipid Prebiotic Synthesis

Grok3 5/17/25

Key Points from Dr. James Tour on Lipid Synthesis in Prebiotic Conditions

  1. Complexity of Lipid Bilayer Formation:

    • Lipids, particularly phospholipids, are essential for forming the lipid bilayer that encapsulates cells. Tour argues that synthesizing these molecules and assembling them into a functional bilayer under prebiotic conditions is extraordinarily difficult.

    • The lipid bilayer is not just a passive barrier; it is a complex structure with precise stereochemistry, embedded proteins, and specific saccharide interactions. Tour highlights that even with modern synthetic chemistry, constructing a lipid bilayer from scratch is beyond current capabilities, let alone under the uncontrolled conditions of a prebiotic Earth.

  2. Prebiotic Synthesis Challenges:

    • Tour points out that while some studies claim to have synthesized simple lipids (e.g., fatty acids or amphiphilic compounds) under prebiotic conditions, these experiments often rely on highly controlled environments, pure reagents, and human intervention, which do not reflect the chaotic and impure conditions of early Earth.

  3. Purity and Chirality Issues:

    • Lipids, like other biomolecules, require specific stereochemistry (chirality) to function in biological systems. Tour emphasizes that prebiotic chemistry would produce racemic mixtures (equal amounts of left- and right-handed molecules), which are not conducive to forming functional membranes. Achieving homochirality without enzymes is a major unsolved problem.

    • Even if lipids were synthesized, their purity would be compromised by side reactions and complex mixtures of byproducts, making it difficult for them to self-assemble into stable vesicles or micelles.

  4. Environmental Constraints:

    • Tour critiques the assumption that prebiotic molecules could conveniently accumulate in one location (e.g., a “warm little pond” or hydrothermal vent) without degradation from environmental factors like UV radiation, oxygen, or water. Lipids are particularly susceptible to hydrolysis and oxidation, which would disrupt their formation and assembly.

    • He argues that scenarios like hydrothermal vents or meteorite delivery of organic compounds do not solve the problem, as they still fail to provide the specific conditions needed for selective synthesis and assembly.

  5. Lack of Mechanisms for Self-Assembly:

    • Even if lipids were available, Tour argues that their spontaneous assembly into functional membranes is not straightforward. Modern cells rely on complex enzymatic and protein-mediated processes to form and maintain membranes. Without these, prebiotic lipids would likely form disordered aggregates rather than selectively permeable bilayers.

    • The integration of other molecules (e.g., proteins, nucleic acids) into a lipid bilayer to create a protocell adds further layers of complexity that remain unexplained.

  6. Critique of Overstated Claims:

    • Tour is critical of what he perceives as overconfident claims in the origin-of-life field, where researchers suggest that lipid synthesis and membrane formation are well-understood. He argues that such claims misinform the public and students, as the actual mechanisms remain speculative and unproven.

    • He calls for greater humility and transparency about the “massive gaps” in our understanding, suggesting that exposing these gaps could inspire new research or paradigms in prebiotic chemistry.

Conclusion

Dr. James Tour argues that the synthesis and assembly of lipids under prebiotic conditions remain unsolved problems due to the complexity of forming functional lipid bilayers, the need for stereochemical purity, and the lack of plausible mechanisms for self-assembly in uncontrolled environments. He views these challenges as emblematic of broader gaps in origin-of-life research, urging scientists to acknowledge the unknowns to foster more honest and innovative inquiry.

Cell Membrane

The Complex Cellular Membrane

ChatGPT

  • Researchers have identified thousands of different lipid structures in cell membranes.
    When making synthetic vesicles-synthetic lipid bilayer membranes-mixtures with monoacyl lipids can destabilize the system- so how are these avoided?

  • Lipid bilayers surround subcellular organelles, such as nuclei and mitochondria, which are themselves microsystem assemblies. Each of these has their own lipid composition, different from the host vesicle.

  • Lipid bilayers have a non-symmetric distribution between inner and outer surfaces.

  • Protein-lipid complexes are the required passive transport sites and active pumps for the passage of ions and molecules through bilayer membranes, often with high specificity.

  • All lipid bilayers have vast numbers of polycarbohydrate appendages, known as glycans. These are essential for cell regulation. Consider the hexamer of the carbohydrate D-pyranose→ >1 trillion constitutional and stereochemical isomers. Eliminating any class of carbohydrates from an organism results in its death.

Lipid Route

Molecules Decompose

CISS

The Assembly Problem

Lipid Summary

  1. Prebiotic Synthesis

  2. Selective Assembly

  3. Membrane stability

  4. Complex cell membrane

Fact 2 Summary

Building blocks of the building blocks have not been made.

Rice Professor Demands Transparency on Origin of Life Chemistry

Episode 6/13: The Building Blocks of Building Blocks

Episode 11/13: Chiral-induced Spin Selectivity

Synthesis is Hard

The Synthesis Problem

Episode 5/13: Carbohydrates

Polymer Stability- Building Blocks Decay and Disassemble

Rice Professor Demands Transparency on Origin of Life Chemistry

Episode 1/13: Introduction to Abiogenesis

Molecular Evolution - Molecules Don’t Seek Life

Rice Professor Demands Transparency on Origin of Life Chemistry

Polymerization Not Seen or Possible Prebiotically

Episode 12.1/13: Cell Construction & Assembly Problem

Non-Covalent Interactions Cannot Be Explained

Rice Professor Demands Transparency on Origin of Life Chemistry

CISS - Chiral-Induced-Spin-Selectivity

Rice Professor Demands Transparency on Origin of Life Chemistry

Summary

  1. Building blocks of the building blocks have not been made.

  2. Synthesis is Hard

  3. Polymer stability- Buiding blocks decay and disassemble.

  4. Molecular evolution - molecules don’t seek life

  5. Polymerization not seen or possible prebiotically

  6. Non covalent interactions cannot be explained.

  7. CISS - Chiral-induced-spin-selectivity

  8. Carbohydrate - Selective Synthesis, Cross reactivity, Bonding issues Carbohydrates; Decay in water; Can’t make them - no pathway.

  9. Proteins - Amino acid synthesis, Peptide bond formation, Correct sequencing, Stability in water; Folding problem; formation requires complex enzymes

  10. Lipids- No known route to form, Selective Assembly, Membrane stability, Must be organized with other complex molecules. Complex membrane.

We have discussed that none of these building blocks required for life have been made in prebiotic conditions. We will now discuss the most amazing fact of all. How did random processes align the DNA nucleotides in a specific way that produces required information for Life.

FACT 3 - Prebiotic forces cannot arrange DNA nucleobases that contain the stored information of the DNA strand.