Making Nucleotides

Powner, Matthew W. et al.  “Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions.”  Nature 459:239–242.  May 14, 2009.  Five years earlier Orgel had written the sentence this paper falsified, in a review of prebiotic chemistry (Critical Reviews in Biochemistry and Molecular Biology 39 (2004): 99–123):  “The synthesis of nucleosides from ribose and the nucleoside bases is the weakest link in the chain of prebiotic reactions leading to oligonucleotides.”  Section Abstract:  “Here we show that activated pyrimidine ribonucleotides can be formed in a short sequence that bypasses free ribose and the nucleobases, and instead proceeds through arabinose amino-oxazoline and anhydronucleoside intermediates.  The starting materials for the synthesis—cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphate—are plausible prebiotic feedstock molecules, and the conditions of the synthesis are consistent with potential early-Earth geochemical models.”  A laboratory synthesis from John Sutherland's group at Cambridge, which made activated pyrimidine ribonucleotides, the RNA building blocks with pyrimidine bases, from five simple feedstocks: cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and phosphate.  The route bypasses free ribose and the nucleobases, and the article uses it to show that the claim that no one has ever made a nucleotide is out of date.  The article takes all its experimental conditions from the supplementary information.  Guanine remains awkward:  Sutherland's later route gives inosine-type purines as deoxyribonucleosides (Xu, Jianfeng, et al., Nature 582 (2020): 60–66), and no published route makes all four canonical ribonucleotides from one-carbon feedstocks in one environment. ↩ ↩ ↩

1. 1a.

   Section One-pot formation of the aminooxazolines 12 and 21 in the presence of phosphate:  “Glycolaldehyde 10 (60 mg, 1.0 mmol) was dissolved in a D₂O solution of sodium deuterium phosphate solution (1.0M, 1 mL, pD = 7.0), cyanamide 8 (42 mg, 1.0 mmol) was added, and the resulting solution was incubated at 60°C for 3 h.  rac-Glyceraldehyde 9 (90 mg, 1.0 mmol) was added, and the solution was heated at 40°C for a further 16 h.”  The product distribution, from the same passage: 70% overall conversion to 2-aminooxazole (4%), arabinose aminooxazoline (15%), ribose aminooxazoline (25%), xylose aminooxazoline (6%), two lyxose aminooxazolines (2% each), and two pentose oxazoles (11% and 9%).  Arabinose aminooxazoline is the intermediate the nucleotide route needs. ↩ ↩

2. 1b.

   “D-Arabinofuranosyl-2,2′-anhydrocytidine 13 (32.3 mg, 0.12 mmol), ammonium dihydrogen phosphate (17 mg, 0.12 mmol), and urea (72 mg, 1.2 mmol) were dissolved in H₂O (0.5 mL), and the resultant solution applied evenly to glass fibre discs (25 mm × 0.68 mm, 0.25 mL per disc).  The discs were dried at 40ºC for 2 d, then heated at 100ºC for 24 h.  The discs were then washed with H₂O (10 mL), and the washings were lyophilized.”  Yields of β-ribocytidine-2′,3′-cyclic phosphate from this step are 14% by one procedure and 32% by another. ↩

3. 1c.

   The supplementary information says irradiation used.  “a low pressure, cold cathode mercury lamp (primary emission at 254 nm),”.  with irradiation times running to 82 hours at pH 6.5. ↩

Richert, Clemens.  “Prebiotic chemistry and human intervention.”  Nature Communications 9:5177.  2018.  Page 1:  “When Diego Maradona was asked about having used his hand to score a goal in the quarter-finals of the 1986 soccer World Cup, he initially claimed that there had been divine intervention, and the term 'Hand of God Goal' was coined.—There had been manual intervention, and there had been an understandable interest of the player not to admit it.—Organic chemists, if not all experimentalists in the field of prebiotic chemistry, are faced with a similar dilemma.  We do our best to perform experiments that we believe re-enact possible steps of prebiotic evolution, but we know that we need to intervene manually to obtain meaningful results.”  “Simply mixing chemicals and watching for a living system to appear from the broth seems unreasonable to me.  This approach has never worked, and it is not expected to work.”  Page 2:  “When it becomes unavoidable to intervene as experimentalist, just state the number of discontinuities in the experimental conditions or human interventions!”  A page-and-a-half comment by Clemens Richert, professor of organic chemistry at the University of Stuttgart, who publishes prebiotic RNA chemistry himself.  The "Hand of God" framing is his own, and his proposal asks experimenters to report how many manual interventions a result needed.  The comment does not tabulate the interventions in anyone's synthesis, so it should not be cited as though it did.  He also rejects the naive alternative of simply mixing chemicals and waiting for life to appear.  The article uses it for the author's own admission that the experiments need manual intervention to obtain meaningful results. ↩ ↩ ↩

1. 2a.

   Page 2:  The parenthetical is Richert's own, and it belongs with any use of him.  “For potentially prebiotic, enzyme-free multistep syntheses, a chemical work-up at the end of a reaction is often required, involving steps such as precipitation, crystallization or other forms of handling and purification, and an often drastic change in chemical conditions from one synthetic transformation to the next.”  “Understandably, this has drawn the ire of those who feel that no or only minimal intervention is allowed for a process to be called prebiotically plausible.”  “(And yes, most of us are not comfortable with the idea of divine intervention in this context.)” ↩

2. 2b.

   Page 2:  He attaches two references to the phrase "multistep syntheses, mimicking entire biochemical pathways": Powner, Gerland and Sutherland 2009, and Becker et al. 2016, the two routes this article describes.  He names them and does not count them. ↩

3. 2c.

   Page 2:  Richert's own limit on what counts as plausible.  “Temperature changes are plausible, based on seasonal changes and day/night cycles, hydration and dehydration are plausible, based on rainfall, tides and other processes in the hydrosphere, but going well beyond a range of, say, −20 to 100 °C for aqueous media or assuming that arctic conditions change to volcanic conditions within hours or days seems unreasonable to me.” ↩

4. 2d.

   Page 2:  Richert judges that the likelihood of a sequence of very different conditions may matter more than where the chemicals came from.  “Further, how likely it is that a series of transformations occurred that require vastly different conditions in a specific sequence, is not easy to gauge, even for the specialist.  Still, this parameter may be more important than the source of the chemicals.” ↩

5. 2e.

   Page 2:  He concedes the point against his own complaint.  “So, the periodic addition of a chemical condensing agent may be unavoidable to drive biochemical reactions that are endergonic, even in 'minimal intervention' experiments.  Without the chemical activation, equilibrium (death) sets in.  So, some level of human intervention may always be required for complex, multistep processes.” ↩

6. 2f.

   Page 2:  The wording, including the typo, is Richert's.  “It is not easy to compute a score for how prebiotically plausible an experiments is.  Often, if a reagent has already been found somewhere in the geosphere, it is considered plausible, and if it was taken from the catalog of a chemical supplier, it is not.  Is this reasonable?” ↩

Orgel, Leslie E.  “Prebiotic Chemistry and the Origin of the RNA World.”  Critical Reviews in Biochemistry and Molecular Biology 39:99–123.  2004.  Page 102:  “The Butlerow reaction, if it could be directed to the synthesis of ribose, would provide an ideal route to the sugar component of the nucleotides.  However, until recently it had not been possible to channel the Butlerow reaction to the synthesis of any particular sugar, and ribose usually has been a notoriously minor product (Decker et al., 1982).”  The figure of more than forty sugars is routinely cited to Decker et al. 1982.  A review by Leslie Orgel of the Salk Institute on how the RNA world hypothesis arose, covering prebiotic nucleotide chemistry, the copying of RNA without enzymes, and membranes, and listing the problems that remain.  Orgel was a committed naturalist arguing for the RNA world, which gives his summary of the obstacles its weight.  The article uses it for his summary of the classic problems: the formose reaction gives no clean selectivity, ribose falls apart, and nucleosides join poorly. ↩ ↩

1. 3a.

   Page 101:  “Under the conditions usually used to bring about the reaction, the sugars decompose to hydroxy-acids and related compounds on a timescale similar to that of their appearance.”  “Furthermore, the addition of formaldehyde to glyceraldehyde and similar molecules leads to the formation of branched chain sugars, and the Cannizaro reduction of sugars to polyols is also an important side reaction (Mizuno & Weiss, 1974).”  Orgel also names two partial fixes in the same passage, both real chemistry: Zubay's lead-catalysed formose, which he reports as converting more than 30% of input formaldehyde to aldopentoses, and Eschenmoser's phosphorylated variant.  In the Eschenmoser variant, Orgel writes:  “ribose–2-4-diphosphate was the major sugar product.”  His caveat on that variant is:  “the reactions described above occur in solution only at high pHs and with high concentrations of the reactants.” ↩

2. 3b.

   “the synthesis of nucleosides from ribose and the nucleoside bases is the weakest link in the chain of prebiotic reactions leading to oligonucleotides.”  Powner, Gerland and Sutherland falsified it five years later, by a route in which neither a free ribose nor a free nucleobase ever exists. ↩

3. 3c.

   In his closing summary, Orgel writes:  “Phosphorylation of nucleosides leads to a complex mixture of isomeric mono- and polyphosphates, while polymerization even of pure nucleoside-5′-phosphates leads to a product with mixed phosphodiester linkages.”  Pasek 2008 answered the availability half of this, and Powner 2009 solved the regioselectivity half, by a route that never has the choice to make.  Page 106:  On phosphate, Orgel writes:  “Inorganic phosphates or polyphosphates are the most plausible source of phosphate for prebiotic synthesis…  Only orthophosphates are abundant in rocks and minerals, principally insoluble calcium phosphates.” ↩ ↩

4. 3d.

   Page 102:  This closes the sugar section. ↩

Larralde, Rosa et al.  “Rates of decomposition of ribose and other sugars: implications for chemical evolution.”  Proceedings of the National Academy of Sciences 92:8158–8160.  1995.  The paper says ribose cannot accumulate, not that it cannot form, and the authors leave a door open:  “it is possible that stable prebiotic derivatives of ribose were present in the primitive ocean that could have been converted to ribose by one or two enzymatic steps.”  Section Abstract:  “The ribose half-lives are very short (73 min at pH 7.0 and 100°C and 44 years at pH 7.0 and 0°C).”  Page 8159:  “The half-life at pD 7.4 extrapolates to 300 days at 25°C and to 44 years at 0°C.  Even with correction for the buffer concentration, this is a very short period of geological time, and it is difficult to see how ribose could have been available for prebiotic use, even at low temperatures.”  A laboratory measurement by Rosa Larralde, Michael Robertson and Stanley Miller of how fast ribose and other sugars break down at neutral pH, tracked by NMR at temperatures from 40 to 120 °C.  A wrinkle a careful sceptic will find: the measurements were made by ¹H NMR in deuterated buffer, so the paper reports pD and converts using pD = pH + 0.4, meaning pD 7.4 is pH 7.0.  The abstract and body are the same experiment, and the authors checked the isotope effect directly and found none (k_H2O/k_D2O = 1.0 ± 0.2).  Miller, a co-author, wrote that ribose and other sugars were not components of the first genetic material, and the article uses that conclusion and the 300-day half-life at 25 °C.  Mirror:  PMC ↩ ↩

1. 4a.

   “The above results show that stability considerations preclude the use of ribose and other sugars as prebiotic reagents except under very special conditions.  It follows that ribose and other sugars were not components of the first genetic material and that other possibilities, such as the peptide nucleic acids (36) and other non-sugar-based backbones, should be examined.” ↩

2. 4b.

   Page 8160:  “These data probably underestimate the rate of decomposition of sugars under plausible prebiotic conditions.  The pH of the present ocean is 8.2 rather than 7.0, which would increase the rate by about 50% (Fig. 1).  The reaction of amino acids with sugars-the Maillard, or browning, reaction-is a rapid and irreversible decomposition pathway (30, 31).  In addition, aldoses are easily oxidized to sugar acids and they react readily with low concentrations of HCN (Kiliani reaction) to form the next higher sugar acid (32, 33).”  The last clause deserves attention: hydrogen cyanide is the feedstock every prebiotic scheme wants in the same pond, and it is also a sugar destroyer. ↩

Grew, Edward S. et al.  “Borate minerals and origin of the RNA world.”  Origins of Life and Evolution of Biospheres 41:307–316.  2011.  A paper by three mainstream authors, asking whether the geology supports the borate stabilisation proposal.  The article uses it as the sharpest objection to the borate route, and an objection from people with no motive to make it. ↩ ↩

Pasek, Matthew A.  “Rethinking early Earth phosphorus geochemistry.”  Proceedings of the National Academy of Sciences 105:853–858.  2008.  Section Abstract:  “originated from extraterrestrial material that fell during the heavy bombardment period or was produced during impacts.”  That ties the concession to a bombardment flux, which is a live question elsewhere in this article.  A proposal paper by Matthew Pasek of the NASA Astrobiology Institute, which argues that early Earth's phosphorus chemistry was controlled by reduced oxidation state phosphorus compounds such as phosphite, which came from extraterrestrial material, and suggests studies in ancient rocks that could test this.  The article uses it to argue that the phosphate objection should be dropped, since the discussion of schreibersite corrosion products reports that meteoritic schreibersite gives phosphite compounds that are more soluble and reactive than orthophosphate.  Sutherland's own scenario uses that source. ↩ ↩

Furukawa, Yoshihiro et al.  “Extraterrestrial ribose and other sugars in primitive meteorites.”  Proceedings of the National Academy of Sciences 116:24440–24445.  2019.  The full sentence on abundance continues:  “Conversely, in NWA 7020, these sugars were below our detection limit for the amount of sample analyzed (<0.5 ppb).”  This result contradicts a sentence in Larralde, Robertson and Miller 1995, which offered.  “the absence of sugars in the Murchison meteorite”.  as supporting evidence.  A laboratory study by a team at Tohoku University and NASA Goddard that extracted sugars from the Murchison and NWA 801 meteorites and found pentoses, five-carbon sugars including ribose, at parts-per-billion levels.  The team reports that carbon isotope ratios show the sugars are of extraterrestrial origin, and that a laboratory simulation suggests the meteoritic sugars formed by formose-like processes.  The article uses it for the finding that ribose occurs in meteorites, which contradicts an older claim about sugar absence. ↩ ↩

Leyva, Vincent et al.  “Abiotic sugar enantiomers in the CI carbonaceous chondrite Orgueil.”  Nature Communications 17:2060.  2026.  Table 1:  Blank-corrected Orgueil ribose is 5.63 ppb of the L form and 6.57 ppb of the D form, an enantiomeric excess of 9.32%, against recovery of only 4.5% in spiking experiments.  The abstract's claim that sugar abundances are severely underestimated refers to that low recovery.  The same table reproduces the Furukawa Murchison and NWA 801 figures and adds a Bennu column with 14.6 ± 2.1 ppb ribose, credited to Furukawa et al. 2025.  A laboratory study of sugars in the Orgueil meteorite, a carbonaceous chondrite (a carbon-rich type of meteorite), by Vincent Leyva and colleagues.  It reports ribose, arabinose, xylose, lyxose and ribulose, several of which occur in near-racemic mixtures (roughly equal amounts of left-handed and right-handed forms), which the authors say is consistent with an extraterrestrial origin.  The article uses it because it found ribose in Orgueil too, and because it says sugar abundances are severely underestimated.  Mirror:  PMC ↩ ↩

Xu, Jianfeng et al.  “Selective prebiotic formation of RNA pyrimidine and DNA purine nucleosides.”  Nature 582:60–66.  2020.  Section Abstract:  “a high-yielding, completely stereo-, regio-, and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides, deoxyadenosine and deoxyinosine”.  “a mixture of deoxyadenosine, deoxyinosine, cytidine, and uridine”.  “These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life.”  A laboratory study from the MRC Laboratory of Molecular Biology in Cambridge, with theoretical and crystallographic co-authors.  It makes two purine DNA building blocks, deoxyadenosine and deoxyinosine, from intermediates of the RNA pyrimidine synthesis, and its final mixture holds those two with cytidine and uridine.  Note that the purines are deoxyribonucleosides, and one of the two is deoxyinosine rather than deoxyguanosine.  The article uses it to show that this result is a mixed pool of RNA pyrimidines and DNA purines, not the four canonical RNA letters. ↩ ↩

Becker, Sidney et al.  “Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides.”  Science 366:76–82.  2019.  “we need to assume that the early Earth provided environmental conditions that fluctuated between slightly acidic (pH 3)… or basic (pH = 10) caused by carbonates.”  A laboratory study from the Carell group at LMU Munich, which made the pyrimidine nucleosides from small molecules and ribose using only wet-dry cycles, and reported that the same pathway is compatible with purine synthesis.  The article uses it as the best unified synthesis published, and keeps two precisions:  the four Watson-Crick nucleosides appeared under identical conditions but in separate vials, and the genuine one-pot run gave cytidine and adenosine as main products, with guanosine arriving indirectly via diaminopurine and at lower yield.  The geochemical model is the authors' own, and they state it as: ↩ ↩ ↩

1. 10a.

   “It remains unclear, however, how ribose or any other carbohydrate, such as glycerol or threose, needed to form the backbone of RNA or pre-RNA could have formed selectively.  Sugars such as ribose can be produced non-selectively in a formose-like reaction, which is possible in a variety of different physico-chemical environments.” ↩

2. 10b.

   Section Discussion:  “Our geochemical model assumes that chemistry took place within in several basins that were needed to locally separate intermediates.  We also need one or two streams of water to allow exchange of soluble molecules (Fig. 5B)…  For our scenario we need to assume that the early Earth provided environmental conditions that fluctuated between slightly acidic (pH 3), potentially caused by acidic rain (SO₂, NOx), or basic (pH = 10) caused by carbonates.” ↩

3. 10c.

   Section Discussion:  “Of course, we will be unable to definitively prove that the described scenario took indeed place on early Earth, but the reported chemistry shows that, under plausible prebiotic conditions, mutually synergistic reaction pathways can be established in which the intermediates along one pathway help the chemistry of the other.” ↩

4. 10d.

   “The reduction also appears to be independent of the thiol source, as the products 11a-d and 12a,b are obtained regardless of whether we used dithiothreitol (DTT), propanedithiol, mercaptoethanol or cysteine (Fig. S6).”  The paper's supplementary tables give yields for each. ↩

Benner, Steven A.  “Paradoxes in the Origin of Life.”  Origins of Life and Evolution of Biospheres 44:339–343.  2014.  The framing sentence, on p. 339, reads:  Page 339:  “Discussed here is an alternative approach to guide research into the origins of life, one that focuses on 'paradoxes', pairs of statements, both grounded in theory and observation, that (taken together) suggest that the 'origins problem' cannot be solved.”  An essay by Steven Benner of the Foundation for Applied Molecular Evolution, presented at the Open Questions on the Origin of Life conference in Kizugawa, Kyoto, on 12–13 July 2014.  It argues that after about sixty years of modern prebiotic chemistry the problem remains unsolved, and proposes organising the work around paradoxes, pairs of statements that each look true but together suggest the problem cannot be solved.  It was received on 21 September 2014 and published online on 22 January 2015, and it is frequently miscited as a 2014 Astrobiology paper, which it is not.  The article uses it for Benner's own point that lab results still depend on a graduate student's hand. ↩

Ricardo, Alonso et al.  “Borate Minerals Stabilize Ribose.”  Science 303:196.  2004.  “When the same incubation was done with borate minerals ulexite (NaCaB₅O₉·8H₂O), kernite (Na₂B₄O₇·4H₂O), or colemanite (Ca₂B₆O₁₁·5H₂O) in synthetic form, the solution did not turn brown, even after incubation for 2 months.”  “With Ca(OH)₂ (0.5 M suspension;  pH ~12;  25° and 45°C), a solution of 1 and 2 (each 0.5 mM) turned brown (1 hour and 10 min, respectively)…  Pentoses were nearly gone after a 1 hour incubation.”  A one-page short report by four authors, Steven Benner among them.  The measurement tests whether the borate minerals ulexite, kernite and colemanite keep ribose from breaking down in alkaline water: with synthetic forms present the mixture did not turn brown even after 2 months, while the borate-free control turned brown in 1 hour and 10 min.  The article uses it for the stabilizing result, and for Benner's own modest claim that ribose may have been available when life emerged. ↩

1. 12a.

   “The presence of arabinose, lyxose, xylose, and ribose in similar amounts was confirmed by coinjection of authentic standards (fig. S5).”  The same paragraph describes an analytical step that the authors present as not prebiotic.  “Borate was removed as its trimethyl ester by evaporation two times with methanol and evacuation, and the sugars were derivatized.” ↩

2. 12b.

   “Because neither borate minerals nor interstellar organics are excluded from the early Earth, we also cannot exclude the availability of ribose formed prebiotically at the time when life emerged on Earth.”  The closing sentence of the paper.  The double negative matters: Benner is claiming that ribose cannot be excluded, which is an argument from non-exclusion, not a demonstration. ↩

Benner, Steven A. et al.  “When Did Life Likely Emerge on Earth in an RNA-First Process?”  ChemSystemsChem 2:e1900035.  2020.  “Glycolaldehyde, glyceraldehyde, and other carbonyl compounds react with themselves and each other;  they also react with ammonia and other species to form a range of products that seem to be prebiotically useless.  While borate minerals and sulfite adducts stabilize these, this stabilization is not absolute.”  Benner is also the senior author of the 2004 borate paper quoted earlier in the article, so this is the same chemist sixteen years later.  A review by ten authors, led by Benner, that asks when on early Earth RNA-first chemistry was most likely to happen.  Its answer is a window about 120 ± 100 million years after a single large impact, roughly 4.36 ± 0.1 billion years ago, when RNA precursors could rain onto land holding oxidized minerals that stabilize them.  The article uses it for the authors' own statement that borate and sulfite stabilize carbonyl compounds without making them stable. ↩

Fang, Yuxi et al.  “Hydrodynamic cavitation for prebiotic ribose formation from H2O and CO2.”  National Science Review 13(11):nwag182.  2026.  Table S1, page S11:  Figures in µM, arabinose / ribose: simulated prebiotic ocean 0.57 / 0.51; highest-yielding run 0.84 / 0.78; 0.1 MPa 0.10 / 0.15 with glucose at 0.18; 50 °C 0.11 / 0.20 with glucose at 0.34.  A laboratory study from Shanghai Jiao Tong University in which a calcium carbonate solution with CO2 bubbled through it was run through a Venturi tube, where the collapse of gas bubbles (hydrodynamic cavitation) produced ribose as the major sugar product.  The authors model a prebiotic ocean and measure sugars by gas chromatography-mass spectrometry.  No mass balance or total organic carbon is reported, and the GC-MS panel covers six sugars, so nothing in the paper addresses what fraction of the carbon ends up as tar.  The decisive numbers are in the Supplementary Information.  The article cites it because it is the strongest recent claim against the formose objection, and because reading its supplementary tables is what settles the matter. ↩

Wade, Nicholas.  “Chemist Shows How RNA Can Be the Starting Point for Life.”  The New York Times.  May 13, 2009.  “definitely does not meet my criteria for a plausible pathway to the RNA world”.  Shapiro's words about Sutherland's route, in the same report.  A New York Times news report on Sutherland's RNA chemistry, which also carries Robert Shapiro's objection that cyanoacetylene is destroyed quickly by other chemicals, and Sutherland's reply that the chemical is consumed fastest in the reaction he proposes and has been detected on Titan.  Quoting Shapiro's line without that reply would be a quote-mine.  The article uses it only for on-the-record researcher quotations, never for chemistry claims, because it shows how sure the researchers themselves were. ↩

Powner, Matthew W., and John D. Sutherland.  “Prebiotic chemistry: a new modus operandi.”  Philosophical Transactions of the Royal Society B 366:2870–2877.  2011.  “The behaviour of the system can also be influenced by variation in reaction conditions over time.  This is an important point in the prebiotic chemistry field because too often it has been assumed that only fixed conditions prevailing over a long time should be considered for prebiotic synthesis.  Temperature, humidity and light flux must have varied on the early Earth, and so it is perfectly reasonable to invoke variations in conditions over the course of a prebiotic systems chemistry experiment.  One is not seeking to recreate exactly what happened on early Earth, but to show what is plausible.”  “To reiterate:  this sequence of conditions and the scenario causing it were not arbitrarily selected ahead of our experimental investigations into prebiotic nucleotide chemistry.  The sequence of conditions is empirically realized by the chemistry we, and others, have discovered.  The scenario is an attempt to match this sequence of conditions to a plausible sequence of geochemical events.”  “when conditions calmed down after an impact, phosphate and organic nucleotide precursors could have been present along with mixed alkanols…  Then a temperature increase—perhaps associated with another impact—could cause aqueous surface phases to dry out.”  A perspective by Matthew Powner and John Sutherland for a Royal Society discussion meeting on the chemical origins of life, one of seventeen contributions.  It proposes triangulation, a method that looks for one set of conditions under which several chemical subsystems work together, and uses it to find conditions that make nucleotides and lipids together.  The authors propose a post-impact setting and hedge it with modal verbs such as "could", which a summary should keep.  The article uses it for the authors' own list of five environments in a fixed order, and for their reply that the sequence was not arbitrarily selected. ↩

1. 16a.

   The authors' own summary of the sequence.  “The sequence of reaction conditions—mild heating in water, followed by evaporation, dry state heating, rehydration and UV irradiation—under which this synthesis proceeds serves as a starting point in our triangulation strategy to find conditions for an overall systems chemistry synthesis of multiple prebiotic target molecules.” ↩

2. 16b.

   The authors' own comparison with the deep-sea vent scenario.  “However, the surface scenario we describe here has the added advantage that the other chemistries required to make nucleotides, inter alia, are possible in the same location, as conditions naturally change over time.  In contrast, deep-sea vents do not allow drying down, dry state heating or UV irradiation.” ↩

3. 16c.

   The authors state their aim in their own words.  The continuation matters: it gives the reason for the work.  “The reason for attempting this is that such considerations point to the likely co-location of anhydronucleosides and mixed chain alkanols when phosphorylation conditions occurred.”  “Goldilocks chemistry:  chemistry that works on plausible reactant mixtures to give multiple required products in good yield without creating too many deleterious by-products.” ↩

Ritson, Dougal, and John D. Sutherland.  “Prebiotic synthesis of simple sugars by photoredox systems chemistry.”  Nature Chemistry 4(11):895–899.  2012.  “been cited as the prebiotic source of sugars”.  Section Abstract:  “would be considerably strengthened if the sugar building blocks for the synthesis — glycolaldehyde and glyceraldehyde — could be shown to derive from one carbon feedstock molecules.”  A research paper from John Sutherland's laboratory at the MRC Laboratory of Molecular Biology in Cambridge.  Their framing of the problem is that support for RNA would be strengthened if its sugars came from one carbon feedstock molecules, and the formose reaction has been cited for decades as the prebiotic source of sugars, a claim this work is replacing.  It shows that hydrogen cyanide, irradiated with ultraviolet light in the presence of copper cyanide complexes, gives glycolaldehyde and glyceraldehyde.  The article uses it to show that the formose reaction is not the only route to sugars, at the price of needing ultraviolet light and dissolved copper. ↩

Patel, Bhavesh H. et al.  “Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism.”  Nature Chemistry 7:301–307.  2015.  The paper's lipid claim is specific and modest.  Photoreduction of dihydroxyacetone gives acetone and glycerol, and the paper says glycerol's.  “biological relevance … as a lipid precursor was obvious.”  Glycerol here is the headgroup, not a fatty-acid chain, and nothing in the network supplies fatty-acid chains.  A laboratory study from John Sutherland's group at the MRC Laboratory of Molecular Biology in Cambridge, showing that hydrogen cyanide and some of its derivatives give precursors of RNA building blocks, amino acids and lipid parts through one network, driven by UV light with hydrogen sulfide as the reductant.  The article uses it as the strongest answer to the claim that RNA, protein and membranes need incompatible chemistry, and notes the price: UV light, hydrogen sulfide and copper photoredox cycling are needed all at once. ↩

Kim, Hyo-Joong, and Steven A. Benner.  “Prebiotic stereoselective synthesis of purine and noncanonical pyrimidine nucleotide from nucleobases and phosphorylated carbohydrates.”  Proceedings of the National Academy of Sciences 114:11315–11320.  2017.  Section Abstract:  “Here, we report that adenine, diaminopurine, and hypoxanthine nucleoside phosphates and a noncanonical pyrimidine nucleoside (zebularine) phosphate can be formed from the direct coupling reaction of cyclic carbohydrate phosphates with the free nucleobases.  The reaction is stereoselective, giving only the β-anomer of the nucleotides within detectable limits.”  Section Introduction:  The authors' stated motive:  “We return here to a search for pathways to nucleos(t)ides that used completed heterocycles as starting materials (Fig. 1).  This would avoid the requirement for prebiotic availability of the reactive cyanamide and cyanoacetylene.”  The hole is that the method needs phosphorylated carbohydrates supplied, and zebularine is not a canonical RNA base.  A laboratory study by Hyo-Joong Kim and Steven Benner that joined ready-made nucleobases (adenine, diaminopurine and hypoxanthine) directly to phosphorylated sugars, giving nucleotides with only the β-anomer of the sugar bond, one of its two possible shapes.  For adenine the coupling mostly picks the N-9 position, and the reaction also gave one non-standard pyrimidine nucleotide, zebularine.  The phosphorylated sugars are assumed to be available from Eschenmoser-type chemistry.  The article uses it as the rival strategy that starts from completed bases. ↩

Nam, Inho et al.  “Abiotic synthesis of purine and pyrimidine ribonucleosides in aqueous microdroplets.”  Proceedings of the National Academy of Sciences 115:36–40.  2018.  A laboratory study that sprayed water droplets smaller than 1.3 micrometres across, holding D-ribose, phosphoric acid and a nucleobase, into a mass spectrometer at 5 kilovolts, so that the reaction ran for about 50 microseconds.  It reports yields of 2.5% for uridine, 2.5% for adenosine, 0.7% for cytidine and 1.7% for inosine, with magnesium ion as a catalyst.  The authors argue that the air-water interface, not the voltage, does the chemistry, which is their interpretation.  The article uses it as a partial answer to the water problem, because the surface drives a condensation that is uphill in bulk water, and it notes that D-ribose arrives as a reagent and that inosine stands in for guanosine. ↩

Tour, James M.  “Origin of Life, Intelligent Design, Evolution, Creation and Faith.”  jmtour.com.  2019.  “I am sympathetic to the arguments and I find some of them intriguing, but I prefer to be free of that intelligent design label.”  A personal statement on Tour's website, updated in August 2019, in which a synthetic chemist at Rice University sets out his views on the origin of life, design and evolution.  He says he is not an intelligent design proponent, because his chemical tools cannot test design, and he uses "impossible" only for what present human ability cannot do.  The article uses it to show his own disclaimer before it relies on his chemistry, and in a recorded exchange with Lee Cronin he grants that the origin of life happened and declines the design inference when it is handed to him. ↩

Tour, James M.  “Two Experiments in Abiogenesis.”  Inference: International Review of Science 2(3).  Sep 2016.  A short review, published in September 2016, by James Tour, a synthetic organic chemist at Rice University, reviewing two 2016 origin-of-life papers: Becker et al., Science 352 (2016): 833-836, from Thomas Carell's group, and a paper from Nicholas Hud's group in Nature Communications.  Tour walks through the Carell procedure step by step, quotes the paper's own numbers back at it, and gives yield figures that are his own characterisation, which makes his criticism falsifiable line by line.  The article cites Carell's later 2019 route, not the 2016 one, so Tour's procedural criticism bears on the same laboratory and strategy rather than on the identical paper. ↩

1. 22a.

   Tour says the yields fell sharply, and his figures for the racemic route are less than 1%, with as many as 16 different isomers.  He is quoting the paper's own numbers back at it.  “Often seven major products, and many more minor products, were formed in these reactions, where the combined yield of the anomeric nucleosides could be as high as 60%.  When starting with racemic glyceraldehydes and glycoaldehyde, rather than purified homochiral ribose, the yields of the ribonucleosides fell”. ↩

2. 22b.

   The bookkeeping objection is about inference across papers, not about any one experiment, which is why it survives new results that answer the individual steps.  One group publishes low-yield, unusable mixtures, and another builds on their purified products.  It matches the "Hand of God" comment by Clemens Richert, cited elsewhere in this article: two chemists, independently, asking the field to report what it supplied. ↩

3. 22c.

   Tour praises Hud's work in the same review that makes his sweeping claims about the field, so the praise is part of the record.  This is the sentence to hold against his universal negatives, and it is in the same piece.  “The article by Nicholas Hud and his team reports a solid and laudable achievement,”.  “Hud and his group used a rich characterization suite and their chemical data analyses are superbly done.” ↩

Hirakawa, Yuta et al.  “Interstep compatibility of a model for the prebiotic synthesis of RNA consistent with Hadean natural history.”  Proceedings of the National Academy of Sciences 122:e2516418122.  2025.  The setting is five stacked geological conditions, stated by the authors:  “The process i) exploits privileged chemistry in ii) intermittently irrigated aquifers constrained by basalt that iii) have borate iv) above a redox-neutral mantle v) having access to an atmosphere transiently reduced by a Vesta-sized impactor.”  Section Abstract:  “Models for prebiotic syntheses often have many steps, each separately validated by laboratory experiments.  The challenge then asks whether these steps work together in natural geological environments, absent human intervention.  Here, we analyze a six-step Discontinuous Synthesis Model (DSM) for the prebiotic formation of RNA…  Experiments here show that borate does not inhibit these two other steps, but rather facilitates them.  This makes the six-step DSM a 'no human intervention' route from simple precursors (1 to 3 carbons, 0 to 2 nitrogens) to oligomeric RNA with predominately 3′,5′-linkages at least 6 nucleotides long, but possibly much longer.”  D-ribose is supplied as a purchased reagent.  Section Materials:  “d-Ribose… obtained from FUJIFILM Wako Pure Chemical Co.”  A laboratory and modelling study by Benner's group, which develops the model, testing whether the six steps of a proposed route to RNA can run together in natural geological conditions without an experimenter moving things between them.  The authors find that borate does not block the two other steps and in fact helps them, and they conclude the route runs without human intervention from simple precursors to RNA chains at least 6 nucleotides long.  The article uses it because Benner's own group set out to test whether the steps work together without an experimenter, and because the paper's own asterisked break points are where handedness would have to be decided.  Mirror:  PMC ↩

1. 23a.

   Section Discussion:  “However, the lengths of the RNA chains are short;  ~6 mers nucleotides are reported, consistent with the lower energy of the cyclic phosphate compared to polyphosphate.” ↩

2. 23b.

   Section Discussion:  “Thus, the DSM is continuous to form 6-mer RNA, predominately 3′,5′-linked, except at points marked with *.  These points are also points where decisions about chirality might be made.” ↩

White, Skyla B., and Paul B. Rimmer.  “Do-Nothing Prebiotic Chemistry: Chemical Kinetics as a Window into Prebiotic Plausibility.”  Accounts of Chemical Research 58:1–10.  2025.  Section Conspectus:  “how can this chemistry occur without direct intervention from a chemist?”  “the determination of rate constants and the construction of chemical networks to describe prebiotic chemistry in geochemical environments.”  A short account, called a Conspectus, by two Cambridge authors who argue that prebiotic chemistry should be judged by the rate constants of its reactions in natural environments.  Rimmer is the same researcher whose solar-simulator experiment reported a step failing under realistic light, in the 2021 Astrobiology study, so the programme and the negative result come from the same laboratory, which is a reason to take both seriously.  The article uses it to show that serious laboratories are trying to define "prebiotic plausibility" in measurable terms. ↩

Benner, Steven A.  “Prebiotic plausibility and networks of paradox-resolving independent models.”  Nature Communications 9:5173.  2018.  “the concept was sufficiently prevalent by 1974 for Orgel and Lohrman to use the word 'plausible' a half-dozen times in their classic review of prebiotic chemistry,”.  Benner spells the name Lohrman here; the reference list gives the review's author as Lohrmann.  Benner says that Orgel and Lohrmann called a reaction sequence plausible if its precursors could be seen in interstellar dust clouds, and quotes the criterion:  “if those precursors could be seen in interstellar dust clouds.”  A short comment in Nature Communications by Steven Benner, who runs the Foundation for Applied Molecular Evolution.  He traces the use of the word plausible in origin-of-life chemistry back to a 1974 review, and proposes that plausibility comes from a network of independently grounded models that resolve each other's paradoxes.  The article uses it for that proposal, and notes that Benner himself says it is a weaker standard than a demonstrated route. ↩

Rimmer, Paul B. et al.  “Timescales for Prebiotic Photochemistry Under Realistic Surface Ultraviolet Conditions.”  Astrobiology 21:1099–1120.  2021.  Section Abstract:  “would all operate on the surface of early Earth in a matter of days to weeks”.  “would take months to complete”.  “would take years”.  “the photoreduction of thioanhydrouridine with hydrogen sulfide did not succeed even after a long period of irradiation”.  A laboratory study from Cambridge that ran prebiotic reactions in an apparatus called StarLab, a solar simulator built for the faint young Sun rather than the mercury lamps used in most of this literature.  The one clear failure is worth stating plainly, because almost nothing else in this field publishes its failures: a step that works under a laboratory lamp did not work under simulated sunlight, over a period the authors put at "several years" as a lower limit.  The article uses the study as the most useful check on its ultraviolet requirement, and Sutherland is a co-author who published the failure. ↩

1. 26a.

   Section Abstract:  The conditional is the authors' own.  “Here we experimentally investigate whether the UV flux available on the surface of early Earth, given a favorable atmosphere, can facilitate a variety of prebiotic chemical syntheses.” ↩

Vázquez-Salazar, Alberto.  “Complex and Messy Prebiotic Chemistry: Obstacles and Opportunities for an RNA World.”  Life 16(2):240.  2026.  “the RNA world hypothesis remains compelling, as RNA can store heritable sequence information and catalyze reactions through sequence dependent folding, thereby linking heredity and chemistry within a single polymer.”  A review of how messy, mixed chemistry could make RNA's building blocks, written by a chemist at CINVESTAV in Mexico City.  It argues that the RNA world remains a strong idea, but that the emergence of functional sequence information is a central open problem that chemistry alone cannot settle, and quoting either half of that position alone misrepresents it.  The article uses it as the strongest reply to its objection, because the reply comes from inside the field. ↩