Skip to main content
Have a personal or library account? Click to login
The RNA World Hypothesis: A Critical Reassessment of Prebiotic Plausibility Cover

The RNA World Hypothesis: A Critical Reassessment of Prebiotic Plausibility

By:   
Open Access
|May 2026

References

  1. Gilbert W. Origin of life - the RNA world. Nature. 1986;319: 618–618. doi: 10.1038/319618a0
  2. Fine JL, Pearlman RE. On the origin of life: an RNA-focused synthesis and narrative. RNA. 2023;29(8): 1085–1098. doi: 10.1261/rna.079598.123
  3. Kurland CG. The RNA dreamtime: modern cells feature proteins that might have supported a prebiotic polypeptide world but nothing indicates that RNA world ever was. Bioessays: News and Reviews in Molecular, Cellular and Developmental Biology. 2010;32: 866–871. doi: 10.1002/bies.201000058
  4. Bowman JC, Hud NV, Williams LD. The ribosome challenge to the RNA world. Journal of Molecular Evolution. 2015;80(3–4): 143–161. doi: 10.1007/s00239-015-9669-9
  5. Ding S, Wang P. The life of microRNAs: biogenesis, function and decay in cancer. Biomolecules. 2025;15(10): 1393. doi: 10.3390/biom15101393
  6. Jouravleva K, Zamore PD. A guide to the biogenesis and functions of endogenous small non-coding RNAs in animals. Nature Reviews Molecular Cell Biology. 2025;26: 347–370. doi: 10.1038/s41580-024-00818-9
  7. Will CL, Lührmann R. Spliceosome structure and function. Cold Spring Harbor Perspectives in Biology. 2011;3(7): a003707. doi: 10.1007/BF01654098
  8. Bagi M, Jamalzadegan S, Steksova A, Wei Q. CRISPR–Cas based platforms for RNA detection: fundamentals and applications. Chemical Communications. 2025;61: 13571–13600. doi: 10.1039/D5CC03257A
  9. Nawrocki EP, Petrov AI, Williams KP. Expansion of the tmRNA sequence database and new tools for search and visualization. NAR Genomics and Bioinformatics. 2025;7(1): lqaf019. doi: 10.1093/nargab/lqaf019
  10. Pearce BKD, Pudritz RE, Semenov DA, Henning TK. Origin of the RNA world: the fate of nucleobases in warm little ponds. Proceedings of the National Academy of Sciences. 2017;114(43): 11327–11332. doi: 10.1073/pnas.1710339114
  11. Delsemme AH. Cosmic origin of the biosphere. In: Brack A. (ed.) The molecular origins of life. Cambridge: Cambridge University Press; 1998. p.100–119.
  12. Goldreich P. History of the lunar orbit. Reviews of Geophysics and Space Physics. 1966;4(4): 411–439. doi: 10.1029/RG004i004p00411
  13. Touma J, Wisdom J. Evolution of the Earth–Moon system. The Astronomical Journal. 1994;108(5): 1943–1961. doi: 10.1086/117209
  14. Eulenfeld T, Heubeck C. Constraints on Moon's orbit 3.2 billion years ago from tidal bundle data. Journal of Geophysical Research: Planets. 2023;128: e2022JE007466. doi: 10.1029/2022JE007466
  15. Zorc SA, Roy RN. Origin & influence of autocatalytic reaction networks at the advent of the RNA world. RNA Biology. 2024;21(1): 78–92. doi: 10.1080/15476286.2024.2405757
  16. Mills DR, Peterson RL, Spiegelman S. An extracellular Darwinian experiment with a self-duplicating nucleic acid molecule. Proceedings of the National Academy of Sciences. 1967;58(1): 217–224. doi: 10.1073/pnas.58.1.217
  17. Stockbridge RB, Schroeder GK, Wolfenden R. The rate of spontaneous cleavage of the glycosidic bond of adenosine. Bioorganic Chemistry. 2010;38(5): 224–228. doi: 10.1016/j.bioorg.2010.05.003
  18. Moody ERR, Álvarez-Carretero S, Mahendrarajah TA, Clark JW, Betts HC, Dombrowski N, et al. The nature of the last universal common ancestor and its impact on the early Earth system. Nature Ecology & Evolution. 2024;8(9): 1654–1666. doi: 10.1038/s41559-024-02461-1
  19. Ibáñez JD, Kimball AP, OroOró J. Possible prebiotic condensation of mononucleotides by cyanamide. Science. 1971;173: 444–446. doi: 10.1126/science.173.3995.444
  20. Bionumbers. halftime of spontaneous RNA hydrolysis at 25°C. Available from: https://bionumbers.hms.harvard.edu/bionumber.aspx?id=105354&ver=3&utm_source=chatgpt.com
  21. Linjalahti H, Mikkola S. Intra- and intermolecular interactions influence the reactivity of RNA oligonucleotides. Chemistry & Biodiversity. 2007;4(12): 2938–2947. doi: 10.1002/cbdv.200790243
  22. Oivanen M, Kuusela S, Lönnberg H. Kinetics and mechanisms for the cleavage and isomerization of the phosphodiester bonds of RNA by Brønsted acids and bases. Chemical Reviews. 1998;98: 961–990. doi: 10.1021/cr960425x
  23. Dickson KS, Burns CM, Richardson JP. Determination of the free-energy change for repair of a DNA phosphodiester bond. Journal of Biological Chemistry. 2000;275(21): 15828–15831. doi: 10.1074/jbc.M910044199
  24. Orgel LE. Prebiotic chemistry and the origin of the RNA world. Critical Reviews in Biochemistry and Molecular Biology. 2004;39: 99–123. doi: 10.1080/10409230490460765
  25. Schwartz AW, de Graaf RM. The prebiotic synthesis of carbohydrates: a reassessment. Journal of Molecular Evolution. 1993;36: 101–106. doi: 10.1007/BF00166245
  26. Gabel NW, Ponnamperuma C. Model for origin of monosaccharides. Nature. 1967;216: 453–455. doi: 10.1038/216453a0
  27. Reid C, Orgel LE. Model for origin of monosaccharides: synthesis of sugars in potentially prebiotic conditions. Nature. 1967;216: 455. doi: 10.1038/216455a0
  28. Cleaves HJ II. The prebiotic geochemistry of formaldehyde. Precambrian Research. 2008;164: 111–118. doi: 10.1016/j.precamres.2008.04.002
  29. Rodriguez LE. Chapter 4: a geological and chemical context for the origins of life on early Earth. Astrobiology. 2024;24(S1). doi: 10.1089/ast.2021.0139
  30. Omran A, Menor-Salvan C, Springsteen G, Pasek M. The messy alkaline formose reaction and its link to metabolism. Life. 2020;10(8): 125. doi: 10.3390/life10080125
  31. Larralde R, Robertson MP, Miller SL. Rates of decomposition of ribose and other sugars: implications for chemical evolution. Proceedings of the National Academy of Sciences. 1995;92(18): 8158–8160. doi: 10.1073/pnas.92.18.8158
  32. Miyakawa S, James Cleaves H, Miller SL. The cold origin of life: A. Implications based on the hydrolytic stabilities of hydrogen cyanide and formamide. Origins of Life and Evolution of Biospheres. 2002;32: 195–208. doi: 10.1023/A:1016514305984
  33. Levy M, Miller SL. Cytosine deamination and the precipitous decline of spontaneous mutation during Earth's history. Proceedings of the National Academy of Sciences. 2016;113(28): 7897–7901.
  34. Voet AB, Schwartz AW. Uracil synthesis via HCN oligomerization. Origins of Life and Evolution of Biospheres. 1982;12: 45–49. doi: 10.1007/BF00926910
  35. Schwartz AW, Joosten H, Voet AB. Prebiotic adenine synthesis via HCN oligomerization in Ice. Bio Systems. 1982;15: 191–193. doi: 10.1016/0303-2647(82)90003-X
  36. Yadav M, Kumar R, Krishnamurthy R. Chemistry of abiotic nucleotide synthesis. Chemical Reviews. 2020;120(11): 4766–4805. doi: 10.1021/acs.chemrev.9b00546
  37. Shapiro R. Prebiotic cytosine synthesis: a critical analysis and implications for the origin of life. Proceedings of the National Academy of Sciences. 1999;96: 4396–4401. doi: 10.1073/pnas.96.8.4396
  38. Oba Y, Takano Y, Furukawa Y, Koga T, Glavin DP, Dworkin JP, et al. Identifying the wide diversity of extraterrestrial purine and pyrimidine nucleobases in carbonaceous meteorites. Nature Communications. 2022;13: 2008. doi: 10.1038/s41467-022-29612-x
  39. Shapiro R. Prebiotic ribose synthesis: a critical analysis. Origins of Life and Evolution of Biospheres. 1988;18: 71–85. doi: 10.1007/BF01808782
  40. Lagoja IM, Herdewijn P. One-step synthesis of hypoxanthine from glycinamide and diformylurea. Chemistry & Biodiversity. 2004;1(1): 106–111. doi: 10.1002/cbdv.200490001
  41. Osumah A, Krishnamurthy R. Diamidophosphate (DAP): a plausible prebiotic phosphorylating reagent with a chem to bioChem potential? Chembiochem: A European Journal of Chemical Biology. 2021;22(21): 3001–3009. doi: 10.1002/cbic.202100274
  42. Gull M, Mehta C, Perez MJH, Seeley A, Rogers KL, Pasek MA. Thermal decomposition and prebiotic formation of adenosine phosphates in simulated early-Earth evaporative settings. Molecules. 2025;30(17): 3587. doi: 10.3390/molecules30173587
  43. Alberty RA. Calculation of standard transformed Gibbs energies and standard transformed enthalpies of biochemical reactants. Archives of Biochemistry and Biophysics. 1998;353(1): 116–130. doi: 10.1006/abbi.1998.0638
  44. Verlander MS, Lohrmann R, Orgel LE. Catalysts for the self-polymerization of adenosine cyclic 2′,3′-phosphate. Journal of Molecular Evolution. 1973;2: 303–316. doi: 10.1007/BF01654098
  45. Verlander MS, Orgel LE. Analysis of high molecular weight material from the polymerization of adenosine cyclic 2′,3′-phosphate. Journal of Molecular Evolution. 1974;3: 115–120.
  46. Tapiero CM, Nagyvary J. Prebiotic formation of cytidine nucleotides. Nature. 1971;231: 42–43. doi: 10.1038/231042a0
  47. Fuller WD, Sanchez RA, Orgel LE. Studies in prebiotic synthesis: VI. synthesis of purine nucleosides. Journal of Molecular Biology. 1972;67: 25–33. doi: 10.1016/0022-2836(72)90383-X
  48. Fuller WD, Sanchez RA, Orgel LE. Studies in prebiotic synthesis. VII. Journal of Molecular Evolution. 1972;1: 249–257. doi: 10.1007/BF01660244
  49. Ingar A-A, Luke RWA, Hayter BR, Sutherland JD. Synthesis of cytidine ribonucleotides by stepwise assembly of the heterocycle on a sugar phosphate. Chembiochem: A European Journal of Chemical Biology. 2003;4: 504–507. doi: 10.1002/cbic.200300554
  50. Bada JL. Amino acid cosmogeochemistry. Philosophical Transactions of the Royal Society. 1991;333: 349–358. doi: 10.1098/rstb.1991.0084
  51. Lohrmann R. Formation of nucleoside 5′-phosphoramidates under potentially prebiological conditions. Journal of Molecular Evolution. 1977;10: 137–154. doi: 10.1007/BF01751807
  52. Mariani A, Russell DA, Javelle T, Sutherland JD. A light-releasable potentially prebiotic nucleotide activating agent. Journal of the American Chemical Society. 2018;140: 8657–8661. doi: 10.1021/jacs.8b05189
  53. Yi R, Hongo Y, Fahrenbach AC. Synthesis of imidazole-activated ribonucleotides using cyanogen chloride. Chemical Communications. 2018;54: 511–514. doi: 10.1039/C7CC08489G
  54. Gibard C, Bhowmik S, Karki M, Kim E-K, Krishnamurthy R. Phosphorylation, oligomerization and self-assembly in water under potential prebiotic conditions. Nature Chemistry. 2018;10: 212–217. doi: 10.1038/nchem.2878
  55. Robertson MP, Joyce GF. The origins of the RNA world. Cold Spring Harbor Perspectives in Biology. 2012;4: a003608. doi: 10.1101/cshperspect.a003608
  56. Sawai H, Orgel LE. Oligonucleotide synthesis catalysed by the Zinc(2+) Ion. Journal of the American Chemical Society. 1975;97: 3532–3533. doi: 10.1021/ja00845a050
  57. Sawai H. Catalysis of internucleotide bond formation by divalent metal ions. Journal of the American Chemical Society. 1976;98: 7037–7039. doi: 10.1021/ja00438a050
  58. Sawai H, Yamamoto K. Lanthanide ion as a catalyst for internucleotide bond formation. Bulletin of the Chemical Society of Japan. 1996;69: 1701–1704. doi: 10.1246/bcsj.69.1701
  59. Ferris JP, Ertem G, Agarwal V. Mineral catalysis of the formation of dimers of 5′-AMP in aqueous solution: the possible role of montmorillonite clays in the prebiotic synthesis of RNA. Origins of Life and Evolution of Biospheres. 1989;19: 165–178. doi: 10.1007/BF01808150
  60. Rajamani S, Vlassov A, Benner S, Coombs A, Olasagasti F, Deamer D. Lipid-assisted synthesis of RNA-like polymers from mononucleotides. Origins of Life and Evolution of Biospheres. 2008;38: 57–74. doi: 10.1007/s11084-007-9113-2
  61. Hassenkam T, Deamer D. Visualizing RNA polymers produced by hot wet-dry cycling. Scientific Reports. 2022;12: 10098. doi: 10.1038/s41598-022-14238-2
  62. Song X, Simonis P, Deamer D, Zare RN. Wet–dry cycles cause nucleic acid monomers to polymerize into long chains. Proceedings of the National Academy of Sciences. 2024;121(49): e2412784121. doi: 10.1073/pnas.2412784121
  63. Mungi CV, Bapat NV, Hongo Y, Rajamani S. Formation of abasic oligomers in nonenzymatic polymerization of canonical nucleotides. Life. 2019;9: 57. doi: 10.3390/life9030057
  64. Rios AC, Yua HT, Tor Y. Hydrolytic fof N-glycosyl bonds: comparing the deglycosylation kinetics of modified, alternative, and native nucleosides. Journal of Physical Organic Chemistry. 2015;28: 173–180. doi: 10.1002/poc.3318
  65. Lindahl T, Nyberg B. Rate of depurination of native deoxyribonucleic acid. Biochemistry. 1972;11: 3610–3618. doi: 10.1021/bi00769a018
  66. Ferris JP. Montmorillonite-catalysed formation of RNA oligomers: the possible role of catalysis in the origins of life. Philosophical Transactions of the Royal Society B: Biological Sciences. 2006;361(1474): 1777–1786. doi: 10.1098/rstb.2006.1903
  67. Ferris JP, Ertem G. Oligomerization of ribonucleotides on montmorillonite: reaction of the 5′-phosphorimidazolide of adenosine. Science. 1992;257: 1387–1389. doi: 10.1126/science.1529338
  68. Jheeta S, Joshi PC. Prebiotic RNA synthesis by montmorillonite catalysis. Life. 2014;5(3): 318–330. doi: 10.3390/life4030318
  69. Zhang SJ, Duzdevich D, Ding D, Szostak JW. Freeze-thaw cycles enable a prebiotically plausible and continuous pathway from nucleotide activation to nonenzymatic RNA copying. Proceedings of the National Academy of Sciences. 2022;119(17): e2116429119. doi: 10.1073/pnas.2116429119
  70. Duzdevich D, Carr CE, Colville BWF, Aitken HRM, Szostak JW. Overcoming nucleotide bias in the nonenzymatic copying of RNA templates. Nucleic Acids Research. 2024;52(22): 13515–13529. doi: 10.1093/nar/gkae982
  71. Cohen ZR, Ding D, Zhou L, DasGupta S, Haas S, Sinclair KP, et al. Natural soda lakes provide compatible conditions for RNA and membrane function that could have enabled the origin of life. Proceedings of the National Academy of Sciences Nexus. 2024;3(3): gae084. doi: 10.1093/pnasnexus/pgae084
  72. Angyal SJ. The composition of reducing sugars in solution: current aspects. Advances in Carbohydrate Chemistry and Biochemistry. 1991;49: 19–35. doi: 10.1016/S0065-2318(08)60180-8
  73. Miyakawa S, Cleaves HJ, Miller SL. The cold origin of life: B. Implications based on pyrimidines and purines produced from frozen ammonium cyanide solutions. Origins of Life and Evolution of Biospheres. 2002;32: 209–218. doi: 10.1023/A:1019514022822
  74. Levy M, Miller SL, Brinton K, Bada JL. Prebiotic synthesis of adenine and amino acids under Europa-like conditions. Icarus. 2000;145: 609–613. doi: 10.1006/icar.2000.6365
  75. Brewer TE, Albertsen M, Edwards A, Kirkegaard RH, Rocha EPC, Fierer N. Unlinked rRNA genes are widespread among bacteria and archaea. The ISME Journal. 2020;14: 597–608. doi: 10.1038/s41396-019-0552-3
  76. Stoddard SF, Smith BJ, Hein R, Roller BR, Schmidt TM. rrnDB: improved tools for interpreting rRNA gene abundance in bacte-ria and archaea and a new foundation for future development. Nucleic Acids Research. 2015;43(Database issue): D593–598. doi: 10.1093/nar/gku1201
  77. Brosius J, Dull TJ, Sleeter DD, Noller HF. Gene organization and primary structure of a ribosomal RNA operon from Escherichia coli. Journal of Molecular Biology. 1981;148(2): 107–127. doi: 10.1016/0022-2836(81)90508-8
  78. Pei A, Nossa CW, Chokshi P, Blaser MJ, Yang L, Rosmarin DM, et al. Diversity of 23S rRNA genes within individual prokaryotic genomes. Plos One. 2009;4(5): e5437. doi: 10.1371/journal.pone.0005437
  79. Szymanski M, Barciszewska MZ, Erdmann VA, Barciszewski J. 5S ribosomal RNA database. Nucleic Acids Research. 2002;30(1): 176–178. doi: 10.1093/nar/30.1.176
  80. Espejo RT, Plaza N. Multiple ribosomal RNA operons in bacteria; their concerted evolution and potential consequences on the rate of evolution of their 16S rRNA. Frontiers in Microbiology. 2018;9: 1232. doi: 10.3389/fmicb.2018.01232
  81. Apirion D, Miczak A. Processing of bacterial rRNA precursors. FEBS Letters. 1981;125(1): 1–9. doi: 10.1016/0014-5793(81)80984-2
  82. Takada H, Shimada T, Dey D, Quyyum MZ, Nakano M, Ishiguro A, et al. Differential regulation of rRNA and tRNA transcription from the rRNA-tRNA composite operon in Escherichia coli. Plos One. 2016;11(12): e0163057. doi: 10.1371/journal.pone.0163057
  83. Nissen P, Hansen J, Ban N, Moore PB, Steitz TA. The structural basis of ribosome activity in peptide bond synthesis. Science. 2000;289: 920–930. doi: 10.1126/science.289.5481.920
  84. Sutton SM, Pulletikurti S, Lin H, Krishnamurthy R, Liotta CL. Abiotic aldol reactions of formaldehyde with ketoses and aldoses—implications for the prebiotic synthesis of sugars by the formose reaction. Chemistry. 2025;11(11): 102553. doi: 10.1016/j.chempr.2025.102553
  85. Costanzo G, Saladino R, Crestini C, Ciciriello F, Di Mauro E. Nucleoside phosphorylation by phosphate minerals. Journal of Biological Chemistry. 2007;282(23): 16729–16735. doi: 10.1074/jbc.M611346200
Language: English
Page range: 25 - 42
Published on: May 16, 2026
In partnership with: Paradigm Publishing Services

© 2026 Royal J. Truman, published by The Israel Biocomplexity Center
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.