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A simple physical mechanism enables homeostasis in primitive cells

Nature Chemistry volume 8, pages 448–453 (2016)Cite this article

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Abstract

The emergence of homeostatic mechanisms that enable maintenance of an intracellular steady state during growth was critical to the advent of cellular life. Here, we show that concentration-dependent reversible binding of short oligonucleotides, of both specific and random sequence, can modulate ribozyme activity. In both cases, catalysis is inhibited at high concentrations, and dilution activates the ribozyme via inhibitor dissociation, thus maintaining near-constant ribozyme specific activity throughout protocell growth. To mimic the result of RNA synthesis within non-growing protocells, we co-encapsulated high concentrations of ribozyme and oligonucleotides within fatty acid vesicles, and ribozyme activity was inhibited. Following vesicle growth, the resulting internal dilution produced ribozyme activation. This simple physical system enables a primitive homeostatic behaviour: the maintenance of constant ribozyme activity per unit volume during protocell volume changes. We suggest that such systems, wherein short oligonucleotides reversibly inhibit functional RNAs, could have preceded sophisticated modern RNA regulatory mechanisms, such as those involving miRNAs.

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Figure 1: Regulation of enzyme activity in model protocells by dissociation of short complementary oligonucleotides.
Figure 2: A small ribozyme exhibits diminished activity upon dilution, while the same ribozyme, in the presence of short oligonucleotide inhibitors, exhibits enhanced activity upon dilution.
Figure 3: Competition-driven growth relieves inhibition of ribozyme activity in vesicles.

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Acknowledgements

The authors thank K.A. Björkbom, T. Walton, N. Kamat, C. Hentrich, L. Jin and other Szostak laboratory members for discussions. This work was supported in part by NASA Exobiology grant NNX11AD56G to J.W.S. and a grant (290363) from the Simons Foundation to J.W.S. A.E.E. was supported by an appointment to the NASA Postdoctoral Program, administered by Oak Ridge Associated Universities through a contract with NASA, and by a Tosteson Fellowship from the Massachusetts General Hospital Executive Committee on Research. J.W.S. is an Investigator of the Howard Hughes Medical Institute.

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  1. Aaron E. Engelhart and Katarzyna P. Adamala: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Molecular Biology, and Center for Computational and Integrative Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Aaron E. Engelhart, Katarzyna P. Adamala & Jack W. Szostak

  2. MIT Media Lab, 77 Massachusetts Avenue, E14/E15, Cambridge, 02139-4307, Massachusetts, USA

    Katarzyna P. Adamala

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  1. Aaron E. Engelhart
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Contributions

A.E.E., K.P.A. and J.W.S. designed experiments, analysed data and wrote the manuscript. A.E.E. and K.P.A. performed experiments. A.E.E. and K.P.A. contributed equally to this work.

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Correspondence to Jack W. Szostak.

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The authors declare no competing financial interests.

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Engelhart, A., Adamala, K. & Szostak, J. A simple physical mechanism enables homeostasis in primitive cells. Nature Chem 8, 448–453 (2016). https://doi.org/10.1038/nchem.2475

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