RNA molecules ruled ancient life by serving as primitive enzymes and chemical sensors long before proteins emerged in evolution. Some believe these natural RNA devices were lost billions of years ago, but groundbreaking research is revealing echoes of this ancient RNA World that still shape life today, including in our own brains. The Breaker Laboratory is leading this field through the discovery of specialized RNAs called riboswitches (pronounced ‘ribo-switches’) that detect chemical signals and control genes. Our past research proved that bacteria make extensive use of riboswitches to sense chemicals essential for life. We have recently found the first examples of these RNAs in humans and other vertebrates.
Some human riboswitches respond to lithium, sodium, or guanidine - chemicals that we now know are linked to neuron development, mental disorders, and neuromuscular function. For decades, lithium has been used to treat bipolar disorder, but scientists have long puzzled over how it works at the chemical level. The discovery of lithium-sensing riboswitches is the breakthrough needed to solve this mystery. Likewise, riboswitches for sodium are connected to genes involved in neural development and cognition, and riboswitches for guanidine – commonly used as an industrial chemical and explosives component – reveal that this molecule is key to signaling calcium-dependent muscle and nerve function.
We will establish the contributions made by lithium-sensing RNAs by mapping every human gene influenced by these RNA devices and by establishing the precise mechanisms for how they work. Using tools from genetics, biochemistry, and computational biology, we will uncover how ancient RNA structures regulate brain activity and how disruptions in these processes contribute to neurological diseases. By following clues left by ancient RNA biology, we will open new frontiers for understanding the molecular mechanisms of the human mind and how our thoughts translate into actions.
