In humans, the sense of smell can elicit vivid memories. But for most animals, smell is the primal sense that enables them to find food, detect predators, and locate mates. From fruit flies to humans, one question has long puzzled researchers: How does the brain know what the nose is smelling?

A series of pioneering studies by Richard Axel has answered that question, clarifying in exquisite detail how the sense of smell works. It is for this work that Axel and fellow HHMI investigator Linda B. Buck won the 2004 Nobel Prize in Physiology or Medicine. Today, Axel's research continues to focus on olfactory perception, in particular, how the sense of smell is established during development, how it may change over time, and ultimately how certain smells can elicit appropriate thoughts and behaviors.

By studying olfactory recognition in both fruit flies and mammals, Axel has discovered an amazing similarity among species. "There is a remarkable conservation of much of the logic of olfactory perception between insects and mammals, such that the basic principles of odor discrimination, we believe, have been conserved over 500 million years," he said.

In 1991, Axel, working with Buck—who was then a postdoctoral fellow in Axel's lab—discovered a family of roughly 1,000 genes that encode odor receptors lining the nasal cavity. These receptors in the olfactory epithelium contain neurons that send messages directly to the olfactory bulb of the brain. When a particular odor excites a neuron, the signal travels along the nerve cell's axon and is transferred to the neurons in the olfactory bulb. This structure, located in the very front of the brain, is the clearinghouse for the sense of smell. From the olfactory bulb, odor signals are relayed to both the brain's higher cortex, which handles conscious thought processes, and to the limbic system, which generates emotional feelings.

In experiments designed to probe the molecular logic behind the olfactory system, Axel and Buck then asked how many kinds of receptor proteins are made in a single olfactory neuron. In independent studies, both groups concluded that a given olfactory neuron can make only one type of odorant receptor. In another set of studies, Axel's and Buck's groups found that neurons that make a given odorant receptor are not clustered together, but are instead randomly distributed within regions of the olfactory epithelium. Furthermore, the teams found that axons from neurons expressing the same type of odorant receptor converge on the same place in the olfactory bulb. The result is a highly organized spatial map of information derived from different receptors.

Before focusing on olfactory research, Axel helped to develop gene transfer techniques that permit virtually any gene to be introduced into any cell. This early work has allowed biologists to analyze the function of numerous genes in vivo and allowed the large-scale production of drugs, such as human growth hormone, by inserting human or mammalian genes into bacteria. He has also been involved in research investigating how the AIDS virus infects healthy cells.