Synthetic biology, which involves modifying existing organisms by applying IT and engineering techniques, is opening up huge opportunities in industrial biotechnology and medicine. It is still early days, but researchers are able to programme cells to function as ‘factories’ to produce desired medicines or biofuels, and are looking into programming cells to sense and destroy tumours. “One obstacle however is that genetic elements are not always as modular as one could wish,” explains RNA ORIGAMI project coordinator Ebbe Sloth Andersen, associate professor at Aarhus University, Denmark. “Biological systems are very complex. Pulling genetic elements out of their context doesn’t always work.”
Starting from scratch
Andersen believes that a solution to this challenge could be to redesign genetic elements from scratch. And a key enabling technology in this endeavour could be something called RNA origami. “The RNA origami method is inspired by the Japanese art of paper-folding,” says Andersen. “Instead of folding paper, we fold a single strand of RNA. This method allows us to genetically encode the RNA nanostructures, and express them in cells.” Andersen is a pioneer of this technique. Inspired by his collaboration with Paul Rothemund – a pioneer of the DNA origami technique – at California Institute of Technology, he set about applying this to RNA molecules in his own lab. Success led to the European Research Council funded RNA ORIGAMI project. In this project, Andersen sought to apply his fundamental research to synthetic biology applications in the real world. This involved developing computer-aided design tools to make it easy to create RNA nanostructures. “The project required expertise in several research areas,” notes Andersen. “So the starting point was to hire researchers with expertise in bioinformatics, biophysical characterisation techniques, RNA biochemistry and synthetic biology. Working together, we developed a coherent pipeline from computer design to synthesis and characterisation, through to applications in synthetic biology.”
The team succeeded in developing software tools capable of designing RNA origami structures of larger sizes and complexity. This software is open-source and available to the research community. “We hope this will inspire researchers to use this technology,” says Andersen. “This project enabled me to realise my goals of making this RNA technology more mature, advancing the software, and establishing new directions for RNA nanotechnology.” The results have underlined the potential of using rationally designed RNA molecules as tools for synthetic biology. A main strength of RNA origami structures, explains Andersen, is that they can serve as scaffolds to attach and organise molecular components of the cell. For example, genetically encoded sensors that report concentrations of metabolites in cells were developed. RNA origami scaffolds were placed inside cells, to control metabolic pathways. Andersen identifies medicine as a key area for further exploitation. “The emergence of RNA-based vaccines during the COVID-19 pandemic has brought RNA medicine under the spotlight,” he adds. “This technology has huge potential. For example, we can express RNA in cells in order to manipulate cell properties, or use RNA as particles to be delivered in the body as medicine.” Andersen is also keen to follow up on the theoretical side of things, to further advance the technology and to make it more functional. “My key interest is still trying to fundamentally understand RNA folding and to push RNA origami technology, to see what we can do,” he says.
RNA ORIGAMI, RNA, biological, cells, biotechnology, medicine, nanostructures, synthetic