Fishing for Genes: How the Largest Gene Family in the Mammalian Genome was Found (and Why Idiosyncrasy in Exploration Matters)

In 1991, Linda Buck and Richard Axel identified the multigene family expressing odor receptors. Their discovery transformed research on olfaction overnight, and Buck and Axel were awarded the 2004 Nobel Prize in Physiology or Medicine. Behind this success lies another, less visible study about the methodological ingenuity of Buck. This hidden tale holds the key to answering a fundamental question in discovery analysis: What makes specific discovery tools fit their tasks? Why do some strategies turn out to be more fruitful than others? The fit of a method with an experimental system often establishes the success of a discovery. However, the underlying reasoning of discovery is hard to codify. These difficulties point toward an element of discovery analysis routinely sidelined as a mere biographical element in the philosophical analysis of science: the individual discoverer’s role. I argue that the individual researcher is not a replaceable epistemic element in discovery analysis. This article draws on contemporary oral history, including interviews with Buck and other actors key to developments in late 1980s olfaction.

A First Glimpse of the Mexican Fruit Fly Anastrepha ludens (Diptera: Tephritidae) Antenna Morphology and Proteome in Response to a Proteinaceous Attractant

Anastrepha ludens is a key pest of mangoes and citrus from Texas to Costa Rica but the mechanisms of odorant perception in this species are poorly understood. Detection of volatiles in insects occurs mainly in the antenna, where molecules penetrate sensillum pores and link to soluble proteins in the hemolymph until reaching specific odor receptors that trigger signal transduction and lead to behavioral responses. Scrutinizing the molecular foundation of odorant perception in A. ludens is necessary to improve biorational management strategies against this pest. After exposing adults of three maturity stages to a proteinaceous attractant, we studied antennal morphology and comparative proteomic profiles using nano-LC-MS/MS with tandem mass tags combined with synchronous precursor selection (SPS)-MS3. Antennas from newly emerged flies exhibited dense agglomerations of olfactory sensory neurons. We discovered 4618 unique proteins in the antennas of A. ludens and identified some associated with odor signaling, including odorant-binding and calcium signaling related proteins, the odorant receptor co-receptor (Orco), and putative odorant-degrading enzymes. Antennas of sexually immature flies exhibited the most upregulation of odor perception proteins compared to mature flies exposed to the attractant. This is the first report where critical molecular players are linked to the odor perception mechanism of A. ludens.

Robust olfactory responses in the absence of odorant binding proteins

Odorant binding proteins (Obps) are expressed at extremely high levels in the antennae of insects, and have long been believed essential for carrying hydrophobic odorants to odor receptors. Previously we found that when one functional type of olfactory sensillum in Drosophila was depleted of its sole abundant Obp, it retained a robust olfactory response (Larter et al., 2016). Here we have deleted all the Obp genes that are abundantly expressed in the antennal basiconic sensilla. All of six tested sensillum types responded robustly to odors of widely diverse chemical or temporal structure. One mutant gave a greater physiological and behavioral response to an odorant that affects oviposition. Our results support a model in which many sensilla can respond to odorants in the absence of Obps, and many Obps are not essential for olfactory response, but that some Obps can modulate olfactory physiology and the behavior that it drives.

Learning with naturalistic odor representations in a dynamic model of the Drosophila olfactory system

Many odor receptors in the insect olfactory system are broadly tuned, yet insects can form associative memories that are odor-specific. The key site of associative olfactory learning in insects, the mushroom body, contains a population of Kenyon Cells (KCs) that form sparse representations of odor identity and enable associative learning of odors by mushroom body output neurons (MBONs). This architecture is well suited to odor-specific associative learning if KC responses to odors are uncorrelated with each other, however it is unclear whether this hold for actual KC representations of natural odors. We introduce a dynamic model of the Drosophila olfactory system that predicts the responses of KCs to a panel of 110 natural and monomolecular odors, and examine the generalization properties of associative learning in model MBONs. While model KC representations of odors are often quite correlated, we identify mechanisms by which odor-specific associative learning is still possible.

Odor Code Sensor and Odor Reproduction

In biological olfactory systems, odor receptors receive odor molecules by recognizing the molecular information. Humans can sense the odor by the signal from these activated receptors. The combination of the activated receptors is called “odor code,” and the odor codes are expressed as an “odor cluster map” of glomeruli on the olfactory bulb surface. The odor code is essential information for qualitative and quantitative analyses of odor sensation. In this chapter, development of odor sensors based on the odor code concept and an attempt to extract the parameters for odor coding from molecular informatics are described. Application of the obtained odor code for odor reproduction is also presented.