Synthetic biology seeks to engineer biological processes. “Xenobiology” challenges us to go further, to construct and manipulate biological processes using artificial chemistries beyond those used by nature.
Nucleic acids (DNA and RNA) are well known as genetic material, but are capable of much more than just information storage; oligonucleotides can be used to design self-assembling nanoscale objects, but can also be evolved into an almost limitless variety of 3D structures, including catalysts and chemical antibodies or “aptamers” – short oligonucleotides that fold into ligands that tightly and precisely bind to target molecules.
Functional oligos have huge potential for precision medicine – they can be made to recognise, for example, membrane-bound proteins and sugars, targeting tumours or pathogens with remarkable specificity, and simply prepared on a desktop oligo synthesiser as you would a primer for PCR.
Unfortunately, natural chemistries present some serious hurdles: nucleases severely limit their stability in vivo, and their chemical uniformity impacts the type of interactions or mechanisms they can participate in.
Taking the learned lessons in medicinal chemistry during the development of antisense therapeutics, artificial oligo chemistries – or “xeno nucleic acids” (XNAs) – offer properties beyond those of DNA and RNA, such as reduced immunogenicity and nuclease-resistance in serum.
However, the inability of natural polymerase enzymes to use synthetic XNA building blocks has been a major barrier. By engineering polymerases to read and write using artificial chemistries, “synthetic genetics” has now become possible, enabling directed evolution of functional fully-modified XNA molecules.
We have established methods and proof-of-concept that biostable XNAs can be evolved into high affinity aptamers for specific targets, into a variety of catalysts or “XNAzymes”, and that XNAs can be designed to self-assemble into nanoscale polyhedra.
Xenobiology allows us to explore the fundamental requirements of life and how alternative biology might operate, but also has the potential to provide a wealth of new tools and technologies for research, industry and medicine. In my lab we are combining directed evolution, synthetic biology and bioengineering approaches to develop biomedical applications of XNAs.
Arangundy-Franklin S … Taylor AI … Holliger P; A synthetic genetic polymer with an uncharged backbone chemistry based on alkyl-phosphonate nucleic acids; Nature Chemistry 2019; 10.1038/s41557-019-0255-4
Taylor AI, Houlihan, G. and Holliger P; Beyond DNA and RNA: the expanding toolbox of synthetic genetics , Cold Spring Harbour Perspectives in Biology 2019 (in RNA Worlds, eds. Cech TR, Steitz JA, Atkins FG, CSH Press); DOI: 10.1101/cshperspect.a032490
Taylor AI … Holliger P; Nanostructures from synthetic genetic polymers; ChemBioChem 2016; DOI: 10.7554/eLife.43022
Taylor AI … Holliger P; Catalysts from synthetic genetic polymers. Nature 2015; DOI: 10.1038/nature13982
Pinheiro VB, Taylor AI … Holliger P; Synthetic genetic polymers capable of heredity and evolution. Science 2012; DOI: 10.1126/science.1217622