Photo by Clay Eals
A woman clearing out her grandmother's longtime home came across a cardboard box tucked away in a bedroom closet. Upon opening the carton, memories of her deceased grandfather washed over her with almost physical force.
"Inside was a maroon wool cap my grandfather wore all the time that still smelled like Old Spice and tobacco," she said. "Even 20 years after his death, I could recognize that scent as his. Breathing it in called up such powerful memories, it literally brought tears to my eyes."
Probably everyone has experienced such potent sensations after taking a deep breath of a long-forgotten smell. Odors have long been known to trigger primal responses like fear, feeding and mating in mice and other animals. In humans, too, odors elicit an array of behaviors, emotions and memories unlike any other sense.
Yet how a world of odorous chemicals activates responses by the brain has resembled a complete black box of mystery, said Dr. Linda Buck, an expert on sensory perception who recently joined the Basic Sciences Division.
Until now. With a combination of gene hunting and brain-visualization techniques, Buck's research illumines pathways that might begin with whiff of pizza, for example, and end with an uncontrollable response like salivation.
"We're interested not just in how animals detect chemicals, but how that sensing translates in the nervous system into perceptions and behaviors," said Buck, who moved her lab from the Department of Neurobiology at Harvard Medical School in February. "We look at olfactory (smell) perception as a way to study the brain."
Recently, her lab expanded its focus to include studies on the perception of taste and the detection of pheromones, chemical signals released by animals (their existence in humans is controversial) that elicit instinctive behaviors. And Buck holds insights into how her sensory work eventually may help cancer patients.
The nuts and bolts of all of these sensory systems are the receptors that make physical contact with the chemical world. These chemical catcher's mitts sit on the surfaces of cells that line the sensory organs. For olfaction, this area is a specialized patch high up inside the nose called the olfactory epithelium.
As a postdoctoral fellow more than a decade ago in Dr. Richard Axel's lab at Columbia University, Buck was the first to identify a genetic family with the blueprints for these olfactory receptors.
Dr. Mark Groudine, Basic Sciences Division director, said Buck's project had been considered unsolvable before her ingenuity and tenacity paid off.
"Linda has the wonderful talent of identifying important scientific problems and solving them, even when they appear intractable," he said. "A great example is her discovery of the olfactory-receptor genes. While many viewed this problem as too complex to approach, Linda developed new techniques and stuck to it until she got answers. She's an extremely gifted scientist, and we are fortunate to have her here."
The human olfactory system can sense 10,000 or more chemicals, with an extraordinary power to discriminate between molecules that are close in structure. For example, although quite similar chemically, the molecules for the distinct odors of pear or banana have unique fruity smells.
One of Buck's key discoveries was to learn that perception of smell relies on a combinatorial code that requires multiple receptors to sense a particular odor. Each nerve cell in the olfactory epithelium produces only one type of receptor, and each receptor can interact with a unique subset of odorant molecules. Likewise, a single odorant molecule can bind to multiple - though not all - receptors.
"Humans have only about 360 functional olfactory receptors, yet we can distinguish thousands of odors," she said. "This is because of the combinatorial coding scheme and a tremendous variability in the subsets of odorants recognized by different receptors.
"These two features of the system allow us not only to detect a large number of different odorants, but also to distinguish among them. You simply couldn't achieve that kind of discrimination if there were only one receptor for each odorant."
Buck, also an investigator of the Howard Hughes Medical Institute, found that the olfactory epithelium consists of four zones, yet there is little or no organization of olfactory receptors within them. Neurons that express a particular type of receptor on their surface are not clustered together but are scattered randomly throughout one zone.
"This argued against the idea that there might be spatial maps for odors in the nose," she said. "For example, there's no evidence of a 'banana spot.' But what we have found is that the axons of neurons expressing the same receptor all converge at two specific spots in the olfactory bulb, the part of the nervous system that receives input from the olfactory receptors."
Axons are long projections that extend from nerve cells and transmit electrical impulses to other nerve cells at contact sites called synapses after stimulation.
Information sent to the olfactory bulb is then relayed to a region of the brain called the olfactory cortex, which somehow triggers the appropriate part of the brain to undertake a behavioral or instinctive response.
Buck's lab recently developed a genetic method for charting neural circuits, chains of connected neurons through which signals are transmitted. In their method, a plant protein is produced in a small population of neurons and then travels across synapses to label other neurons in the chain.
Using this method to trace inputs from different olfactory receptors, they found that sensory information is reorganized into a new kind of map in the cortex, one in which an odorant's combinatorial code may be initially integrated en route to perception.
Members of the Buck lab work on other techniques that they hope will allow them to essentially draw a road map of the brain to figure out which regions trigger the vast emotional, behavioral and instinctive responses elicited by odors.
But her lab's interest in sensory perception extends beyond smell. Buck and colleagues also have identified families of receptors that specify sweet and bitter taste.
Five human tastes
Humans can perceive only five tastes: bitter, sweet, salty, sour and "umami," the Japanese word for delicious that actually describes the taste of glutamate. Glutamate, an amino acid (a building block of protein), is used commonly as a flavor enhancer in many Asian cuisines. Flavor actually is a combination of taste and smell, which explains why a stuffy nose brought on by a cold diminishes the ability to discriminate flavors.
Taste receptors are located on specialized taste cells within taste buds on the tongue. In contrast to the olfactory neurons, taste cells can express multiple receptors of a given family. For example, a single taste cell can express multiple receptors that each sense different bitter chemicals.
Buck's group also identified a family of pheromone receptors. Animals have a small structure at the base of the nose called a vomeronasal organ, which is thought to be specialized for detecting pheromones. Humans lack this structure but may detect pheromones in the olfactory epithelium, although it is not clear that true human pheromones exist.
By identifying the receptors for pheromones that stimulate specific behaviors, such as aggression, it should be possible to trace pheromone signals into the deep recesses of the brain to begin to uncover the neural circuits underlying emotions, many of which are common to mice and humans.
Buck thinks these investigations of pheromone circuits may intersect with another of her interests: aging. Puberty, like life span, varies among animal species. Charting connections to a set of neurons in the brain that initiate puberty may provide information not only about how pheromones can halt or advance puberty, but also about how puberty is normally controlled.
In a more direct investigation of life-span control, the Buck group is initiating a large-scale screen for chemicals that can increase life span in the roundworm, Caenorhabditis elegans. They plan to use the chemicals they identify to pinpoint genes that can influence aging.
In addition to tackling the complex and fascinating biology of sensory perception, Buck has ideas about how her research might impact cancer patients.
"Taste can have important consequences for critically ill patients who must take medications orally," she said. "It might possible to develop chemicals that block the bitter taste of medicines, which would considerably increase the likelihood that patients would maintain their drug regimens. But you can't begin to develop such applications until you first sort out how the system works normally."
Positive clinical impact
Ultimately, an understanding of the neural circuits that control emotional responses, such as anxiety and stress, also is likely to have a positive clinical impact.
Born and raised in Seattle, Buck attended the University of Washington as an undergraduate, where she earned a dual degree in psychology and microbiology. She received her doctorate in immunology from the University of Texas Southwestern Medical Center in Dallas before moving to Columbia University for postdoctoral studies. She joined the Harvard faculty in 1991.
Buck's high regard for the center's research excellence was the major factor that drew her from a tenured position at Harvard Medical School. Seven laboratory members moved with her to Seattle.
"The Hutch has great scientists, an interactive, collaborative spirit and a diversity of research programs, making it a wonderful place to do research," she said. "At another level, I identify with the overarching mission of the Hutch as a cancer-research center."
What's in a Smell?
A molecule's characteristic smell depends on its chemical structure. Members of a similar chemical family often have related odors. For example, many acids have odors described as "rancid," "sweaty," "sour" or "goatlike," while alcohols are said to be "sweet" or "fruity."
Although related chemicals can have similar smells, molecules remarkably close in structure have distinguishable odors. For example (see above figure), molecules for the scents of pear and banana are almost identical, yet the human olfactory system can discriminate between them.