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.

Template-directed synthesis of a genetic polymer in a model protocell


Contemporary phospholipid-based cell membranes are formidable barriers to the uptake of polar and charged molecules ranging from metal ions to complex nutrients. Modern cells therefore require sophisticated protein channels and pumps to mediate the exchange of molecules with their environment. The strong barrier function of membranes has made it difficult to understand the origin of cellular life and has been thought to preclude a heterotrophic lifestyle for primitive cells. Although nucleotides can cross dimyristoyl phosphatidylcholine membranes through defects formed at the gel-to-liquid transition temperature1,2, phospholipid membranes lack the dynamic properties required for membrane growth. Fatty acids and their corresponding alcohols and glycerol monoesters are attractive candidates for the components of protocell membranes because they are simple amphiphiles that form bilayer membrane vesicles3,4,5 that retain encapsulated oligonucleotides3,6 and are capable of growth and division7,8,9. Here we show that such membranes allow the passage of charged molecules such as nucleotides, so that activated nucleotides added to the outside of a model protocell spontaneously cross the membrane and take part in efficient template copying in the protocell interior. The permeability properties of prebiotically plausible membranes suggest that primitive protocells could have acquired complex nutrients from their environment in the absence of any macromolecular transport machinery; that is, they could have been obligate heterotrophs.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Conceptual model of a heterotrophic protocell.
Figure 2: Ribose permeability of fatty acid based membranes.
Figure 3: Time courses of nucleotide permeation through fatty acid based membranes.
Figure 4: Template-copying chemistry inside vesicles.


  1. Chakrabarti, A. C., Breaker, R. R., Joyce, G. F. & Deamer, D. W. Production of RNA by a polymerase protein encapsulated within phospholipid vesicles. J. Mol. Evol. 39, 555–559 (1994)

    Article  ADS  CAS  Google Scholar 

  2. Monnard, P. A., Luptak, A. & Deamer, D. W. Models of primitive cellular life: polymerases and templates in liposomes. Phil. Trans. R. Soc. Lond. B 362, 1741–1750 (2007)

    Article  CAS  Google Scholar 

  3. Apel, C. L., Deamer, D. W. & Mautner, M. N. Self-assembled vesicles of monocarboxylic acids and alcohols: conditions for stability and for the encapsulation of biopolymers. Biochim. Biophys. Acta 1559, 1–9 (2002)

    Article  CAS  Google Scholar 

  4. Blochliger, E., Blocher, M., Walde, P. & Luisi, P. L. Matrix effect in the size distribution of fatty acid vesicles. J. Phys. Chem. B 102, 10383–10390 (1998)

    Article  Google Scholar 

  5. Hargreaves, W. R. & Deamer, D. W. Liposomes from ionic, single-chain amphiphiles. Biochemistry 17, 3759–3768 (1978)

    Article  CAS  Google Scholar 

  6. Chen, I. A., Salehi-Ashtiani, K. & Szostak, J. W. RNA catalysis in model protocell vesicles. J. Am. Chem. Soc. 127, 13213–13219 (2005)

    Article  CAS  Google Scholar 

  7. Chen, I. A., Roberts, R. W. & Szostak, J. W. The emergence of competition between model protocells. Science 305, 1474–1476 (2004)

    Article  ADS  CAS  Google Scholar 

  8. Chen, I. A. & Szostak, J. W. A kinetic study of the growth of fatty acid vesicles. Biophys. J. 87, 988–998 (2004)

    Article  CAS  Google Scholar 

  9. Hanczyc, M. M., Fujikawa, S. M. & Szostak, J. W. Experimental models of primitive cellular compartments: encapsulation, growth, and division. Science 302, 618–622 (2003)

    Article  ADS  CAS  Google Scholar 

  10. Chen, P. Y., Pearce, D. & Verkman, A. S. Membrane water and solute permeability determined quantitatively by self-quenching of an entrapped fluorophore. Biochemistry 27, 5713–5718 (1988)

    Article  CAS  Google Scholar 

  11. Sacerdote, M. G. & Szostak, J. W. Semipermeable lipid bilayers exhibit diastereoselectivity favoring ribose. Proc. Natl Acad. Sci. USA 102, 6004–6008 (2005)

    Article  ADS  CAS  Google Scholar 

  12. Israelachvili, J. N. Intermolecular and Surface Forces (Academic, London, 1992)

    Google Scholar 

  13. Lande, M. B., Donovan, J. M. & Zeidel, M. L. The relationship between membrane fluidity and permeabilities to water, solutes, ammonia, and protons. J. Gen. Physiol. 106, 67–84 (1995)

    Article  CAS  Google Scholar 

  14. Rowat, A. C., Keller, D. & Ipsen, J. H. Effects of farnesol on the physical properties of DMPC membranes. Biochim. Biophys. Acta 1713, 29–39 (2005)

    Article  CAS  Google Scholar 

  15. Deamer, D. W. Boundary structures are formed by organic components of the Murchison carbonaceous chondrite. Nature 317, 792–794 (1985)

    Article  ADS  CAS  Google Scholar 

  16. Huang, Y. et al. Molecular and compound-specific isotopic characterization of monocarboxylic acids in carbonaceous meteorites. Geochim. Cosmochim. Acta 69, 1073–1084 (2005)

    Article  ADS  CAS  Google Scholar 

  17. McCollom, T. M., Ritter, G. & Simoneit, B. R. Lipid synthesis under hydrothermal conditions by Fischer–Tropsch-type reactions. Orig. Life Evol. Biosph. 29, 153–156 (1999)

    Article  ADS  CAS  Google Scholar 

  18. Khalil, M. M. Complexation equilibria and determination of stability constants of binary and ternary complexes with ribonucleotides (AMP, ADP, and ATP) and salicylhydroxamic acid as ligands. J. Chem. Eng. Data 45, 70–74 (2000)

    Article  CAS  Google Scholar 

  19. Westheimer, F. H. Why nature chose phosphates. Science 235, 1173–1178 (1987)

    Article  ADS  CAS  Google Scholar 

  20. Eschenmoser, A. The search for the chemistry of life’s orgin. Tetrahedron 63, 12821–12844 (2007)

    Article  CAS  Google Scholar 

  21. Ferris, J. P., Hill, A. R., Liu, R. & Orgel, L. E. Synthesis of long prebiotic oligomers on mineral surfaces. Nature 381, 59–61 (1996)

    Article  ADS  CAS  Google Scholar 

  22. Kozlov, I. A., Pitsch, S. & Orgel, L. E. Oligomerization of activated d- and l-guanosine mononucleotides on templates containing d- and l-deoxycytidylate residues. Proc. Natl Acad. Sci. USA 95, 13448–13452 (1998)

    Article  ADS  CAS  Google Scholar 

  23. Tohidi, M., Zielinski, W. S., Chen, C. H. & Orgel, L. E. Oligomerization of the 3′-amino-3′deoxyguanosine-5′phosphorimidazolidate on a d(CpCpCpCpC) template. J. Mol. Evol. 25, 97–99 (1987)

    Article  ADS  CAS  Google Scholar 

  24. Wilson, M. A. & Pohorille, A. Mechanism of unassisted ion transport across membrane bilayers. J. Am. Chem. Soc. 118, 6580–6587 (1996)

    Article  CAS  Google Scholar 

  25. Chen, I. A. & Szostak, J. W. Membrane growth can generate a transmembrane pH gradient in fatty acid vesicles. Proc. Natl Acad. Sci. USA 101, 7965–7970 (2004)

    Article  ADS  CAS  Google Scholar 

  26. Paula, S. G., Volkov, A. G., Van Hoek, A. N., Haines, T. H. & Deamer, D. W. Permeation of protons, potassium ions, and small polar molecules through phospholipid bilayers as a function of membrane thickness. Biophys. J. 70, 339–348 (1996)

    Article  CAS  Google Scholar 

  27. Hagenbuch, P., Kervio, E., Hochgesand, A., Plutowski, U. & Clemens, R. Chemical primer extension: efficiently determining single nucleotides in DNA. Angew. Chem. Int. Edn Engl. 44, 6588–6592 (2005)

    Article  CAS  Google Scholar 

  28. Chen, I. A., Hanczyc, M. M., Sazani, P. L. & Szostak, J. W. in The RNA World (eds Gesteland, R. F., Cech, T. R. & Atkins, J. F.) 57–88 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 2006)

    Google Scholar 

  29. Morowitz, H. J. Beginnings of Cellular Life: Metabolism Recapitulates Biogenesis (Yale Univ. Press, New Haven, 2004)

    Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  31. Danilov, L. L. & Chojnacki, T. A simple procedure for preparing dolichyl monophosphate by the use of POCl3 . FEBS Lett. 131, 310–312 (1981)

    Article  CAS  Google Scholar 

  32. Guernelli, S. et al. Supramolecular complex formation: a study of the interactions between β-cyclodextrin and some different classes of organic compounds by ESI-MS, surface tension measurements, and UV/Vis and 1H NMR spectroscopy. Eur. J. Org. Chem. 24, 4765–4776 (2003)

    Article  Google Scholar 

  33. Nelson, A. K. & Toy, A. D. F. The preparation of long-chain monoalkyl phosphates from pyrophosphoric acid and alcohols. Inorg. Chem. 2, 775–777 (1963)

    Article  CAS  Google Scholar 

  34. Kawana, M. & Kuzuhara, H. General method for the synthesis of 2′-azido-2′,3′-dideoxynucleosides by the use of [1,2]-hydride shift and β-elimination reactions. J. Chem. Soc. Perkin Trans. I 4, 469–478 (1992)

    Article  Google Scholar 

Download references


This work was supported by grants from the NASA Exobiology Program (EXB02-0031-0018) and the NSF (CHE-0434507) to J.W.S. J.W.S. is an Investigator of the Howard Hughes Medical Institute. S.S.M. was supported by the NIH (F32 GM07450601). We thank I. Chen, M. Hanczyc, R. Bruckner, T. Zhu and Q. Dufton for discussions, and J. Iwasa for Fig. 1 and Supplementary Fig. 5.

Author Contributions Permeability experiments were performed by S.S.M. J.P.S. performed primer-extension experiments. M.K. synthesized 2′-aminoguanosine. S.T. and D.A.T. contributed to the development of the encapsulated primer-extension system. All authors helped to design the experiments and discussed the results. S.S.M., J.P.S. and J.W.S. wrote the paper.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jack W. Szostak.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S7 with Legends and Supplementary Table S1. (PDF 1451 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mansy, S., Schrum, J., Krishnamurthy, M. et al. Template-directed synthesis of a genetic polymer in a model protocell. Nature 454, 122–125 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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