For many years scientists wondered how specific molecules evoke specific smells. In 1991 Axel and Buck identified about 1,000 olfactory-receptor genes in the mouse genome and showed that these receptors are membrane proteins of the G-protein-coupled receptor family. They further demonstrated the “one neuron–one receptor” rule: each olfactory neuron expresses a single receptor gene, and neurons expressing the same receptor send their axons to the same glomerulus in the olfactory bulb. This finding revealed that odors are represented in the brain as a combinatorial code mapped onto discrete glomeruli, pushing forward our understanding of chemosensation and neural circuit formation. Their work now underpins the design of artificial fragrances and the search for therapies for smell disorders.

Olfactory receptors (ORs) are seven-transmembrane GPCRs that constitute the largest gene family in mammalian genomes. Using an elegant cloning strategy with degenerate primers and RT-PCR, Axel and Buck isolated OR genes and showed that each OR binds a limited subset of odorants, whereas a single odorant can activate multiple ORs. Subsequent work revealed that stochastic promoter/enhancer competition in the olfactory epithelium enforces the ‘one neuron–one receptor’ rule and that cAMP signaling downstream of OR activation modulates the expression of axon-guidance molecules, thereby establishing the topographic map in the olfactory bulb. Despite the large gene repertoire, the system achieves high-resolution odor discrimination through a redundant yet efficient combinatorial code, making it a paradigmatic model of sensory information encoding. The prize-winning work has influenced evolutionary biology, molecular cognition and the development of biosensors, illustrating its broad impact.

Through RT-PCR screening with degenerate primers, Axel and Buck catalogued the majority of the mouse OR gene repertoire (~1,100 genes, 7TM GPCR family) and demonstrated that ligand specificity is primarily dictated by residues in the third extracellular loop and the fifth/sixth transmembrane domains. Using in situ hybridization they delineated a mosaic, zone-specific expression pattern in the olfactory epithelium and showed that axons from neurons expressing the same OR converge onto two isofunctional glomeruli (SOP and DOP) in the ipsilateral olfactory bulb. A cAMP level-dependent Eph/Ephrin and Nrp/Sema guidance cascade was proposed and later validated by genetic ablation to underlie the topographic mapping. Monoallelic, monogenic OR expression relies on H-enhancer/LSH-mediated chromatin looping, and recent deep-mutational scanning of OR ligand-binding domains corroborates the initial specificity predictions made by the laureates. These findings have accelerated the integrated understanding of GPCR diversity, neural wiring and epigenetic noise control in the olfactory system, redefining paradigms across chemosensory research, including nausea signaling and pheromone detection.