Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Emergence of light-driven protometabolism on recruitment of a photocatalytic cofactor by a self-replicator


Establishing how life can emerge from inanimate matter is among the grand challenges of contemporary science. Chemical systems that capture life’s essential characteristics—replication, metabolism and compartmentalization—offer a route to understanding this momentous process. The synthesis of life, whether based on canonical biomolecules or fully synthetic molecules, requires the functional integration of these three characteristics. Here we show how a system of fully synthetic self-replicating molecules, on recruiting a cofactor, acquires the ability to transform thiols in its environment into disulfide precursors from which the molecules can replicate. The binding of replicator and cofactor enhances the activity of the latter in oxidizing thiols into disulfides through photoredox catalysis and thereby accelerates replication by increasing the availability of the disulfide precursors. This positive feedback marks the emergence of light-driven protometabolism in a system that bears no resemblance to canonical biochemistry and constitutes a major step towards the highly challenging aim of creating a new and completely synthetic form of life.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Mechanism of light-driven protometabolic self-replication.
Fig. 2: Optical properties of 2 and 3 on binding to macrocycles derived from 1.
Fig. 3: Replicator 16 enhances photocatalytic oxidation of 1 mediated by 2 and 3.
Fig. 4: Emergence of replicator 16 promotes photocatalytic production of precursors 13/14, which promotes replication.

Data availability

The UPLC data generated and analysed in this Article is included in its Supplementary Information in the form of integrated peak areas and exported traces of representative chromatograms. All other chromatograms are stored locally on their native format and are available on request. All other data generated or analysed during this study are included in this published Article and its Supplementary Information. Source data are provided with this paper.


  1. Sutherland, J. D. Opinion: studies on the origin of life—the end of the beginning. Nat. Rev. Chem. 1, 1–8 (2017).

    Article  Google Scholar 

  2. Szostak, J. W., Bartel, D. P. & Luisi, P. L. Synthesizing life. Nature 409, 387–390 (2001).

    CAS  Article  Google Scholar 

  3. Benner, S. A., Ricardo, A. & Carrigan, M. A. Is there a common chemical model for life in the universe? Curr. Opin. Chem. Biol. 8, 672–689 (2004).

    CAS  Article  Google Scholar 

  4. Gayon, J., Malaterre, C., Morange, M., Raulin-Cerceau, F. & Tirard, S. Defining life: conference proceedings. Orig. Life Evol. Biosph. 40, 119–120 (2010).

    Article  Google Scholar 

  5. Ruiz-Mirazo, K., Briones, C. & De La Escosura, A. Prebiotic systems chemistry: new perspectives for the origins of life. Chem. Rev. 114, 285–366 (2014).

    CAS  Article  Google Scholar 

  6. Ganti, T. in The Principles of Life 78–83 (Oxford Univ. Press, 2003).

  7. Pascal, R., Pross, A. & Sutherland, J. D. Towards an evolutionary theory of the origin of life based on kinetics and thermodynamics. Open Biol. 3, 1–9 (2013).

    Article  Google Scholar 

  8. Pross, A. The driving force for life’s emergence: kinetic and thermodynamic considerations. J. Theor. Biol. 220, 393–406 (2003).

    Article  Google Scholar 

  9. Wagner, N., Pross, A. & Tannenbaum, E. Selection advantage of metabolic over non-metabolic replicators: a kinetic analysis. BioSystems 99, 126–129 (2010).

    CAS  Article  Google Scholar 

  10. Pross, A. How can a chemical system act purposefully? Bridging between life and non-life. J. Phys. Org. Chem. 21, 724–730 (2008).

    CAS  Article  Google Scholar 

  11. Hardy, M. D. et al. Self-reproducing catalyst drives repeated phospholipid synthesis and membrane growth. Proc. Natl Acad. Sci. USA 112, 8187–8192 (2015).

    CAS  Article  Google Scholar 

  12. Gardner, P. M., Winzer, K. & Davis, B. G. Sugar synthesis in a protocellular model leads to a cell signalling response in bacteria. Nat. Chem. 1, 377–383 (2009).

    CAS  Article  Google Scholar 

  13. Adamala, K. P. & Szostak, J. W. Nonenzymatic template-directed RNA synthesis inside model protocells. Science 1593, 283–289 (2003).

    Google Scholar 

  14. Ichihashi, N. et al. Darwinian evolution in a translation-coupled RNA replication system within a cell-like compartment. Nat. Commun. 4, 1–7 (2013).

    Article  Google Scholar 

  15. Könnyu, B. & Czárán, T. The evolution of enzyme specificity in the metabolic replicator model of prebiotic evolution. PLoS One (2011).

  16. Czárán, T., Könnyu, B. & Szathmáry, E. Metabolically coupled replicator systems: overview of an RNA-world model concept of prebiotic evolution on mineral surfaces. J. Theor. Biol. 381, 39–54 (2015).

    Article  Google Scholar 

  17. Arsène, S., Ameta, S., Lehman, N., Griffiths, A. D. & Nghe, P. Coupled catabolism and anabolism in autocatalytic RNA sets. Nucleic Acids Res. 46, 9660–9666 (2018).

    Article  Google Scholar 

  18. Kamioka, S., Ajami, D. & Rebek, J. Autocatalysis and organocatalysis with synthetic structures. Proc. Natl Acad. Sci. USA 107, 541–544 (2010).

    CAS  Article  Google Scholar 

  19. Colomb-Delsuc, M., Mattia, E., Sadownik, J. W. & Otto, S. Exponential self-replication enabled through a fibre elongation/breakage mechanism. Nat. Commun. 6, 1–7 (2015).

    Article  Google Scholar 

  20. Carnall, J. M. A. et al. Mechanosensitive self-replication driven by self-organization. Science 327, 1502–1507 (2010).

    CAS  Article  Google Scholar 

  21. Caetano-Anollés, G., Kim, K. M. & Caetano-Anollés, D. The phylogenomic roots of modern biochemistry: origins of proteins, cofactors and protein biosynthesis. J. Mol. Evol. 74, 1–34 (2012).

    Article  Google Scholar 

  22. Wachtershauser, G. Evolution of the first metabolic cycles. Proc. Natl Acad. Sci. USA 87, 200–204 (1990).

    CAS  Article  Google Scholar 

  23. Croce, R. & Van Amerongen, H. Natural strategies for photosynthetic light harvesting. Nat. Chem. Biol. 10, 492–501 (2014).

    CAS  Article  Google Scholar 

  24. Tankam, T., Poochampa, K., Vilaivan, T., Sukwattanasinitt, M. & Wacharasindhu, S. Organocatalytic visible light induced S–S bond formation for oxidative coupling of thiols to disulfides. Tetrahedron 72, 788–793 (2016).

    CAS  Article  Google Scholar 

  25. Frederix, P. W. J. M. et al. Structural and spectroscopic properties of assemblies of self-replicating peptide macrocycles. ACS Nano 11, 7858–7868 (2017).

    CAS  Article  Google Scholar 

  26. Würthner, F., Kaiser, T. E. & Saha-Möller, C. R. J-Aggregates: from serendipitous discovery to supramolecular engineering of functional dye materials. Angew. Chem. Int. Ed. 50, 3376–3410 (2011).

    Article  Google Scholar 

  27. Bilski, P., Holt, R. N. & Chignell, C. F. Premicellar aggregates of Rose Bengal with cationic and zwitterionic surfactants. J. Photochem. Photobiol. A Chem 110, 67–74 (1997).

    CAS  Article  Google Scholar 

  28. Krasnovsky, A. A. Photoluminescence of singlet oxygen in pigment solutions. Photochem. Photobiol. 29, 29–36 (1979).

    CAS  Article  Google Scholar 

  29. Redmond, R. W. & Gamlin, J. N. A compilation of singlet oxygen yields from biologically relevant molecules. Photochem. Photobiol. 70, 391–475 (1999).

    CAS  Article  Google Scholar 

  30. Komatsu, T., Wang, R. M., Zunszain, P. A., Curry, S. & Tsuchida, E. Photosensitized reduction of water to hydrogen using human serum albumin complexed with zinc-protoporphyrin IX. J. Am. Chem. Soc. 128, 16297–16301 (2006).

    CAS  Article  Google Scholar 

  31. Lindig, B. A., Rodgers, M. A. J. & Schaaplc, A. P. Determination of the lifetime of singlet oxygen in D2O using 9,10-anthracenedipropionic acid, a water-soluble probe. J. Am. Chem. Soc. 102, 5590–5593 (1980).

    CAS  Article  Google Scholar 

  32. Malakoutikhah, M. et al. Uncovering the selection criteria for the emergence of multi-building-block replicators from dynamic combinatorial libraries. J. Am. Chem. Soc. 135, 18406–18417 (2013).

    CAS  Article  Google Scholar 

  33. Ottelé, J., Hussain, A. S., Mayer, C. & Otto, S. Chance emergence of catalytic activity and promiscuity in a self-replicator. Nat. Catal. (2020).

  34. Stuart, M. C. A., van de Pas, J. C. & Engberts, J. B. F. N. The use of nile red to monitor the aggregation behavior in ternary surfactant-water-organic solvent systems. J. Phys. Org. Chem. 18, 929–934 (2005).

    CAS  Article  Google Scholar 

Download references


We thank B. M. Matysiak for performing mass spectrometry measurements. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement (no. 642192) and was supported by the ERC (AdG 741774), NWO (VICI grant) and the Dutch Ministry of Education, Culture and Science (Gravitation programme 024.001.035). K. L. acknowledges support from Simons Foundation (award no. 553330) and Marie Skłodowska-Curie grant (no. 786350).

Author information

Authors and Affiliations



S.O., G.M.S. and K.L. conceived the experiments. G.M.S. performed the experiments related to rose bengal. K.L. performed the experiments related to porphyrins. W.R.B. performed the experiments related to IR luminescence of singlet oxygen. G.M.S, K.L. and S.O. wrote the manuscript.

Corresponding author

Correspondence to Sijbren Otto.

Ethics declarations

Competing interests

Authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Absorption spectra of 3 recorded in reduced scattering conditions.

Visible absorption spectra of 3 (10 μM) in buffer (black), and in the presence of 13/14 (1.0 mM in 1; blue) and 16 (1.0 mM in 1; red). In order to show that the increased absorbance of 3 in presence of 16 is not related to scattering, this effect was minimized by recording these spectra in a different spectrophotometer (see Materials), using a wider slit (4 nm), a shorter light path (4.5 mm), and placing the cuvette immediately in front of the detector.

Source data

Extended Data Fig. 2 Non-irradiated controls for the emergence of 16 in presence of 2 and 3.

Evolution over time of the concentrations of 1 and 16 in non-irradiated libraries made from 1 and 2 (a) or 1 and 3 (b). The top halves of the graphs show the concentration of 1 (black squares) and 16 (red squares, in units of 1). The bottom halves of the graphs represent the oxidation (black circles) and replication (red circles) rates in the system, calculated by numerical differentiation of the curves in the top halves. Both libraries were prepared exactly as their equivalents in Fig. 4a,b, but they were kept in the dark.

Source data

Extended Data Fig. 3 Non-irradiated controls for the emergence of 16 in absence of photosensitizers.

Evolution over time of the concentrations of 1 and 16 in non-irradiated libraries prepared from 1, with no dyes added, in the same conditions as in Fig. 4a (left panel) or Fig. 4b (right panel). The top halves of the graphs show the concentration of 1 (black squares) and 16 (red squares, in units of 1). The bottom halves of the graphs represent the oxidation (black circles) and replication (red circles) rates in the system, calculated by numerical differentiation of the curves in the top halves.

Source data

Supplementary information

Supplementary Information

Supplementary Figs. 1–17, Tables 1 and 2.

Supplementary Data

Source Data for Supplementary Figs. 1–11,13–15 and Supplementary Table 2.

Source data

Source Data Fig. 2

Raw spectral data.

Source Data Fig. 3

Integrated peak areas of 1 in chromatograms, and calculation of oxidation rates from them.

Source Data Fig. 4

Integrated peak areas of 1 and 16, and calculation of concentrations and rates from them.

Source Data Extended Data Fig. 1

Raw spectral data.

Source Data Extended Data Fig. 2

Integrated peak areas of 1 and 16, and calculation of concentrations and rates from them.

Source Data Extended Data Fig. 3

Integrated peak areas of 1 and 16, and calculation of concentrations and rates from them.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Monreal Santiago, G., Liu, K., Browne, W.R. et al. Emergence of light-driven protometabolism on recruitment of a photocatalytic cofactor by a self-replicator. Nat. Chem. 12, 603–607 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing