ERASynBio: Establishment of a Fully Synthetic, Mirror-Image Biological System

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Synthetic Biology and Systems Biology have become key research areas in the quest for understanding living cells. What is missing is an experimental system in which the knowledge from system-wide analyses could be artificially reproduced and studied. The goal of this project is to create a mirror-image synthetic biology: that is, to mimic, entirely independent of nature, a biological system and to re-create it from artificial component parts. The project will influence -omics sciences, Systems Biology and Synthetic Biology and bring about a close contact of life sciences and chemistry. The artificial system will create new lines of science and may alter the way biology is done. At the same time, it will yield molecules of unique properties and characteristics for biotechnology and medicine. By using a biosynthesis from mirror components, a high-quality biosynthesis of larger mirror-image proteins might become a reality. Importantly, once the basic components are in place, the machinery itself can be used to create further components. This will eventually allow the high-quality synthesis of larger mirror image proteins. Such proteins should be non-immunogenic, and thus a potentially important source of new protein therapeutics and a new biomanufacturing platform. Technical Abstract: In this project, investigators will create a novel mirror-image synthetic biology platform from enantiomeric L-nucleotides and D-amino acids, which will be used to synthesize functional mirror-image biological system. Several basic DNA-DNA, DNA-protein and protein-protein interactions as well as the functions of few enzymes will be copied from nature into a totally synthetic artificial system based on L-DNA and D-proteins. This will require a few D-form enzymes (DNA-ligase, DNA- and RNA-polymerase) and L-DNA sequences plus co-factors that would form a basic enantiomeric system. In addition, particular binder molecules Designed Ankyrin Repeat Proteins (DARPins) and transcription factors, or DNA-binding domains thereof, will be generated and studied in comparison to their natural partners. Next to the establishment of components for artificial biology, there are immediate practical utilities that will be pursued within this project, such as the protection of therapeutic DARPins from degradation as they will not be substrates of natural proteases, permitting oral application for example, or the creation of a SELEX selection process for the isolation of specific L-DNA aptamers from a molecule library. In the long run, the aim is to set up a self-replicating system, eventually including D-protein production. While this is still way off and will not be achieved within this project, it would offer major advances in biomanufacturing, by creating a platform for the development of mirror image therapeutic proteins that are potentially non-immunogenic.