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Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network


The evolution of life from the prebiotic environment required a gradual process of chemical evolution towards greater molecular complexity. Elaborate prebiotically relevant synthetic routes to the building blocks of life have been established. However, it is still unclear how functional chemical systems evolved with direction using only the interaction between inherent molecular chemical reactivity and the abiotic environment. Here we demonstrate how complex systems of chemical reactions exhibit well-defined self-organization in response to varying environmental conditions. This self-organization allows the compositional complexity of the reaction products to be controlled as a function of factors such as feedstock and catalyst availability. We observe how Breslow’s cycle contributes to the reaction composition by feeding C2 building blocks into the network, alongside reaction pathways dominated by formaldehyde-driven chain growth. The emergence of organized systems of chemical reactions in response to changes in the environment offers a potential mechanism for a chemical evolution process that bridges the gap between prebiotic chemical building blocks and the origin of life.

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Fig. 1: Background to this work.
Fig. 2: Description of the reaction composition dataset collected in this work.
Fig. 3: Elucidation of how the formose reaction network reorganizes in response to varying conditions.
Fig. 4: A summary of key reaction pathways governing the behaviour of the formose reaction.

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Data availability

All data supporting the findings of this study are available within the paper and Supplementary Data and Supplementary Information. Source data are provided with this paper.

Code availability

All programs used to analyse and plot the data are available on GitHub (


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This work was supported by funding from the Simons Collaboration on the Origins of Life (SCOL; award 477123, W.T.S.H., W.E.R.) and the Dutch Ministry of Education, Culture and Science (Functional Molecular Systems Gravity programme 024.001.035, W.T.S.H., W.E.R., E.D., P.D.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank P van Galen, R de Graaf and J del Pozo Mellado for support with GC–MS analysis.

Author information

Authors and Affiliations



W.E.R. and W.T.S.H. conceived the research and acquired funding. W.E.R. and E.D. developed the experimental methodology. W.T.S.H. administered the project and resources. All authors contributed to the design of experiments. W.E.R., E.D., P.v.D. and T.d.J. performed the experiments. W.E.R. curated and analysed the data. W.E.R. wrote the data analysis software and developed data visualizations. W.T.S.H. supervised the investigation. W.E.R. and W.T.S.H. wrote the original draft and all authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Wilhelm T. S. Huck.

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The authors declare no competing interests.

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Nature Chemistry thanks Subhabrata Maiti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Reaction types of the formose reaction.

Detailed reaction types which describe the transformations shown in Fig. 1a (main text).

Extended Data Fig. 2 A detailed schematic of the continuous stirred-tank reactor used in this work.

a Side schematic of the reactor depicting how inputs and the outlet were connected to the reactor and how the temperature was controlled. b Bottom view of the reactor showing the geometry of the inlet holes into the reactor.

Extended Data Fig. 3

The structures of compounds assigned in this work and their corresponding numbering scheme.

Extended Data Fig. 4 Mappings of key conditionals variations across data sets to the leaves of the dendrogram.

a Formaldehyde, b dihydroxyacetone, c CaCl2, d NaOH, e the ratio of CaCl2:NaOH, f The location of glycolaldehyde (2), erythrulose (9) and ribose (19) initiated reactions. The colour bars below each dendrogram indicate mapping of the colour to the value of each condition.

Extended Data Fig. 5 Variation of the composition of the formose reaction with temperature.

Conditions: formaldehyde (200 mM), dihydroxyacetone (25 mM amplitude, 50 mM offset, period 6 min.), CaCl2 (15 mM), NaOH (30 mM).

Extended Data Fig. 6 Variation of the formose reaction’s composition with residence time.

The data were determined from flow reactions at 21 °C, with inputs of dihydroxyacetone (25 mM amplitude, 50 mM offset, period three times the residence time), formaldehyde (200 mM), CaCl2 (15 mM), and NaOH (30 mM). Input concentrations are quoted as the initial concentration of compounds upon entering the continuous stirred-tank reactor.

Extended Data Fig. 7 A proposed mechanism for the selectivity between 14 and 20.

a The C2-C3 reaction to create 14 via a six-membered ring transition state in which α-hydroxymethyl groups adopt lower energy equatorial positions. b A similar reaction and transition state as show in panel a from which compound 20 is formed. Dashed bonds indicate those formed and broken over the course of the reaction.

Extended Data Fig. 8 A proposed mechanism for the selectivity between 12 and 13.

a The open-chain structure of 12. b The open-chain structure of 13. The likely conformation of the six-membered ring formed via coordination of Ca2+ to 12 (c) and 13 (d). Charges (Ca2+, O) are omitted for clarity.

Supplementary information

Supplementary Information

Supplementary Figs. 1–11.

Source data

Source Data Fig. 2

Data used to create the bar charts in Fig. 2a. Data used to create the traces in Fig. 2c. Data used to create the traces in Fig. 2e.

Source Data Fig. 3

Data used to create the traces in Fig. 3a. Data used to create the heatmap in Fig. 3d.

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Robinson, W.E., Daines, E., van Duppen, P. et al. Environmental conditions drive self-organization of reaction pathways in a prebiotic reaction network. Nat. Chem. 14, 623–631 (2022).

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