Fifteen Eighty Four

The actions of genes are fundamental to life as we know it. But how is your genome’s prodigious output controlled? What checks and balances ensure the right ‘amount’ of gene activity in each of your trillions of cells? What is conducting the molecular orchestra of life?

Researchers have been unpicking the pathway from gene to protein for decades, inching ever closer to a complete understanding. The basics are familiar. A signal from within the cell or outside causes a stretch of DNA – a gene – to be ‘read’ producing a messenger RNA (mRNA) copy. The mRNA is itself decoded to assemble a chain of amino acids. When finished, we have a new protein, ready to act: an enzyme that powers our cells, construction materials to support growth or a receptor to draw in nutrients. The gene-to-protein pathway is elegant, remarkable and understood in staggering detail. But this is not the whole story and this system doesn’t work as smoothly as we once thought. Fluctuations in the biochemistry of the gene pathway generates unwanted molecular ‘noise’. Life must battle this randomness and needs a way to sharpen the signal of our genome’s flow from DNA to protein.

Evolution found a fix. An entirely different type of gene, hidden from science until 30 years ago, was discovered by researchers who were studying how worms develop. They had found a conductor of cells’ molecular orchestra. These new genes would soon have a name: MicroRNA. Compared to mRNAs they are a mere snip of RNA, part of the wider world of noncoding RNAs, but nonetheless powerful. MicroRNAs would transform what we know about the biochemistry of life. Master controllers, microRNAs lock onto mRNA and bring precision to the molecular noise in our cells by fine-tuning protein levels. They confer robustness on the programmes that run our cells making them resilient to external and internal disruptors. MicroRNAs expanded our genome’s capabilities – sculpting existing gene sets to create ever richer diversity of cell types. 

I have been fascinated by microRNA for more than 15 years, as part of my own research into the brain disease epilepsy. Fine-tuning Life is the story of microRNA – what we know and how we came to know it. The book is written to be understood by a broad audience. Undergraduate or postgraduate students of biochemistry, cell biology, neuroscience and medicine or the interested general reader, curious about how genomes work. Readers interested in developments in the fields of gene therapy and drug development, synthetic biology, epigenetics and all things RNA will find plenty to interest them. The book includes descriptions of key experiments that yielded important advances, to give the reader a sense of how we know what we know. This should capture more of the life of the bench scientist: their toolkit of microscopes, enzyme reactions, cells, model organisms and algorithms.

The early chapters of the book cover the discovery of microRNA, tracing their evolution back to the earliest moments in the history of life on Earth, and looking at how microRNAs helped complex life evolve. The pace of discovery is captured, from a relatively slow start to a momentous burst of scientific endeavour, with teams around the world competing to make the next big discovery; a scientific arms race.

The book describes the mechanics of how microRNAs are produced in cells and how they perform their jobs, exploring the processes they control (and the ones they don’t) and how microRNAs shape the gene programmes directing human development. Here, the book takes a special look at the developing brain and, later, how microRNAs serve two competing demands – creating the fixed neural circuits that execute and re-execute myriad functions without error over the long course of our lives with, on the other hand, flexibility to be reshaped from one moment to the next as we learn.

A theme that runs through the book is what happens when microRNAs fail to do their job. When a body produces too much or too little microRNA. Like removing the brakes of the genome (or stamping too hard on the pedal), the effects range from a failure to mature, to extra or missing organs, accelerated aging and cancers. This leads to a discussion about how problems with microRNAs impact on human health, in particular conditions affecting the brain including epilepsy, motoneuron disease (amyotrophic lateral sclerosis) and psychosis.

The book concludes with a discussion about the applications of these discoveries in medicine and technology. The remarkable ability of microRNAs to convert cells from one type into another, with applications in regenerative medicine, and how microRNAs in the circulation can help diagnose disease. How the science of microRNAs has driven remarkable developments in technology and instrumentation change in the laboratory, and on to the discovery of how to ‘drug’ microRNAs. Here, I include the story of the first microRNA medicine to reach patients and my own team’s journey to develop a microRNA drug for epilepsy. Finally, what is next? The book finishes with questions researchers are asking now, and hope to answer in the future.

Fine-tuning Life will take you on a journey through the discovery of these remarkable molecules and their impact on human health, disease and biology as we know it.

Title: Fine-Tuning Life

ISBN: 9781009466424

Author: David C. Henshall