Evolution of Novel Biopolymers

Every organism’s blueprint is stored as genetic information encoded in DNA. Before a cell can divide, its genetic information needs to be copied and duplicated. This process is carried out by sophisticated enzymes called polymerases. The astonishing ability of polymerases to both “read” and “write” genetic information is vital to all life on earth and central to modern biology and medicine enabling genome sequencing and the polymerase chain reaction. Our work is aimed at the engineering of novel polymerases capable of activity in unfavourable conditions, and utilising unnatural building blocks. Such "designer" polymerases will be key enabling technologies for the generation of next-generation nucleic acid drugs, sensors and nanomaterials.

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

We have been exploiting the synthesis paradigm to explore the chemical etiology of the genetic apparatus shared by all life on earth. Specifically, we ask why information storage and propagation in biological systems is based on just two types of nucleic acids, DNA and RNA. Is the chemistry of life’s genetic system based on chance or necessity? Does it reflect a "frozen accident", imposed at the origin of life, or are DNA and RNA functionally superior to simple alternatives.

We have developed advanced generation selection and screening strategies that have enabled the discovery of efficient polymerases and reverse transcriptases for the enzymatic synthesis, replication and evolution of synthetic genetic polymers (xeno-nucleic acids, XNAs) enabling the de novo selection of specific ligands (XNA aptamers) and catalysts (XNAzymes) based on these entirely synthetic backbones. Thus, key hallmarks of living systems, including heredity and evolution are not limited to DNA and RNA but can be implemented in synthetic genetic polymers and are likely to be emergent properties of any polymer capable of information storage.

The further exploration of the informational, structural and catalytic potential of synthetic genetic polymers, should advance our understanding of the parameters of chemical information encoding, and will provide a source of novel ligands, catalysts and nanostructures with tailor-made chemistries for applications in biotechnology and medicine.

We have also leveraged our selection technologies to make progress in the engineering and evolution of RNA polymerase ribozymes towards a general polymerase and self-replication capacity We have discovered RNA polymerase ribozymes (RPRs) that are capable of the templated synthesis (i.e. transcription) of another simple ribozyme or RNA oligomers exceeding their own size, a key milestone on the road to self-replication. Finally, we have discovered RPRs that utilize trinucleotide triphosphates (triplets) as substrates and show an unprecedented ability to copy structured RNAs including parts of the RPR itself thereby resolving a fundamental incongruity of RNA-catalysed RNA replication.