Phil Holliger, Program Leader at the MRC Laboratory of Molecular Biology, Cambridge

Synthetic genetics: beyond DNA and RNA (and back to RNA)

Synthetic biology seeks to probe biological form and function by construction (i.e. resynthesis) rather than deconstruction (analysis). Synthesis thus complements analytic studies allowing novel approaches towards fundamental biological questions.

We have exploited the synthesis paradigm to explore the chemical etiology of the genetic apparatus shared by all life on earth, specifically the synthesis, reverse transcription and replication of novel synthetic genetic polymers (xeno nucleic acids: XNAs) based on nucleic acid architectures not found in nature showing that these too can mediate genetic information storage and propagation [1, 2]. Beyond heredity, we demonstrate a capacity for Darwinian evolution by the in vitro evolution of ligands (XNA aptamers) and catalysts (XNAzymes) [2] including XNAs with uncharged P-alkyl-phosphonate backbones [3], which challenge the polyelectrolyte paradigm for genetic polymers. Thus, heredity and evolution, two central hallmarks of living systems, are not limited to DNA and RNA, but can be implemented in synthetic polymers.

These strategies have also enabled the elaboration of XNA nanotechnology objects [4] and the discovery of RNA polymerase ribozymes with the potential for future (self-) replicating RNA nanostructures [5].

References

[1] Pinheiro VB, Taylor AI, Cozens C, Abramov M, Renders M, Zhang S, Chaput JC, Wengel J, Peak-Chew S-Y, McLaughlin SH, Herdewijn P & Holliger P (2012) Synthetic Genetic Polymers Capable of Heredity and Evolution. Science, 336: 341-44
[2] Taylor AI, Pinheiro VB, Smola MJ, Morgunov AS, Peak-Chew SY, Cozens C, Weeks KM, Herdewijn P & Holliger P. (2015) Catalysts from synthetic genetic polymers. Nature, 518: 427-30
[3] Arangundy-Franklin S, Taylor AI, Porebski BT, Genna V, Peak-Chew SY, Vaisman A, Woodgate R, Orozco M & Holliger P. (2019) A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl phosphonate nucleic acids. Nature Chemistry, 11: 533-42
[4] Taylor AI, Beuron F, Peak-Chew SY, Morris EP, Herdewijn P & Holliger P (2016) Nanostructures from Synthetic Genetic Polymers. Chembiochem, 17: 1107-10
[5] Attwater J, Raguram A, Morgunov AS, Gianni E & Holliger P (2018) Ribozyme-catalysed RNA synthesis using triplet building blocks. eLife, 7: e35255