GoKawiilThe binding of a molecule to a riboswitch alters its control region (orange).Credit: Carlos Clarivan/SPL
For decades, RNA was the overlooked ‘middle child’ of cellular molecules. DNA was celebrated as the blueprint of life, proteins carried out the work of the cell, and RNA was cast in a supporting role as the messenger that relayed the genome’s instructions to the cell’s protein-production machinery.
This view has since shifted, with research, especially since the 1990s, showing that RNA behaves in far more active and unconventional ways than previously recognized. “It’s kind of like a dark horse of biology, it does so many things,” says Elisa Franco, a bioengineer at the University of California, Los Angeles.
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Biologists have identified RNAs with catalytic functions that resemble enzymes, for example, or that bind tightly to specific target molecules, an important consideration for the development of safe and effective drugs. Researchers are learning how to fold RNA into complex three-dimensional structures, enabling it to perform as a scaffold for molecular interactions or biological tasks. The versatility of RNA has energized the field, says Franco. “There’s a lot of RNA that nobody knows what it actually does.”
That versatility, together with the simplicity of its code — comprising just four nucleotides, adenine (A), uracil (U), cytosine (C) and guanine (G) — has made RNA remarkably adaptable as a biological tool. Its ability both to carry genetic information and to take on functions that are typically performed by proteins has made it especially appealing to researchers who are seeking to manipulate the behaviour of living cells for therapeutic or biotechnology applications, says Fei Zhang, a chemist at Rutgers University at Newark in New Jersey.
Supported by advances in nanotechnology, these properties are now being harnessed to build a new generation of molecular tools and technologies. From simple genetic ‘switches’ that let scientists tweak cell behaviour, to more elaborate structures that could underpin tiny production lines for the manufacture of drugs and other useful materials, there is a growing sense of what RNA-based nanodevices could be capable of.
But there are major knowledge gaps about how RNA behaves inside living cells that need to be resolved before RNA architects can reliably translate their designs into working technologies.
An unexpected switch
To understand the versatility of RNA, it helps to start with how it behaves at the molecular level. To make a protein, a cell first copies its DNA into messenger RNA (mRNA), which carries the genetic instructions to the protein-making machinery of the cell. Although mRNA is often depicted as a simple linear string of letters, its nucleotides can pair with each other in specific ways (A with U, or C with G, for example), which allows the RNA to fold over on itself as different sections stick together. This creates ‘secondary structures’ such as loops and stems, which can provide binding sites for proteins and influence how the cell reads the RNA to build a protein.
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