The process of how we get from gene to protein is one of the most intensely studied and best understood in biology. The reading of DNA, the generation of a messenger ribonucleic acid (mRNA) and the translation of that transcript into a protein through assembling chains of amino acids. But what we thought we knew about the gene pathway changed forever in 1993, when Gary Ruvkun and Victor Ambros discovered microRNAs. This chapter begins by explaining the basic biochemistry of genes and proteins before moving on to the seminal work of 30 years ago. The objective of those experiments was to understand which genes controlled the timing of animal development in a worm called Caenorhabditis elegans. That led to the realisation that a gene called lin−4, crucial for worms to transition from juvenile to adult stages, did not code for a protein; instead, its RNA acted by sticking to the mRNA of a protein-coding gene. Lin−4 was a gene silencer, working to lower the amounts of protein in cells. The finding of a new step on the journey from gene to protein would go on to transform our understanding of the biology of living organisms.

Seven years passed since the discovery of lin−4’s unique properties and then, around the turn of the millennium, the research floodgates opened. This chapter tracks the nascent field of microRNA research, the frenetic race to discover and catalogue new microRNAs and find the organisms in which they were made. MicroRNAs held a prominent position in evolution, their number and diversity expanding at key transitions to more complex life, including for our own species, Homo sapiens. MicroRNAs, it would become clear, are the genome’s solution to how to control the natural fluctuations, randomness and noise in gene expression. The chapter also covers the pivotal experiments that laid the ground rules for how microRNAs work and revealed their effects on gene expression. Along the way, a selection of the scientific toolkit gets special attention, including some of the models used to find microRNAs and the technologies that would prove that microRNAs, despite their small size and limited number in genomes, controlled the vast majority of gene activity in our cells.