Landmark discoveries of smell receptors answer key biological questions
The reawakening of a long-forgotten memory by the scent of a warm summer day or a whiff of a stranger's perfume is one of the most powerful human responses — and has long been one of the most mysterious. For solving many of the details of this fascinating neural system, Dr. Linda Buck, investigator in Fred Hutch's Basic Sciences Division, was awarded the 2004 Nobel Prize in physiology or medicine. She shared the prize with Dr. Richard Axel of Columbia University.
Buck's research provided the first key insights into the molecules that underlie the olfactory system — the complex network that governs our sense of smell. Her discovery of the family of olfactory receptor proteins and how they work in a combinatorial fashion to relay signals to the brain led to the understanding of how mammals can discriminate between a nearly infinite number of odors and how odors are perceived and remembered by the brain.
Buck received the news at about 2:30 a.m. on a Monday, when she was awakened by a call from Dr. Mark Groudine, director of the Basic Sciences Division, who had been called minutes earlier by a member of the Nobel committee.
"I called her because I wanted to make sure she was awake when the Nobel call came," Groudine said. "She said that someone had tried to call but she had accidentally hung up the phone — and I told her she had to answer the phone when they called back because it was the Nobel committee with some very important news."
Buck's first response to him was, "I can't believe it."
At a news conference later that day, Buck said she was "overjoyed and surprised to receive such a great honor, and to work at an institution that placed such value on basic research."
"The Hutch is a very unusual place to do science," she said. "There is a desire and a devotion to doing excellent science and a commitment to understanding basic biology. It's from the fundamental mechanisms of how life works that we make the greatest advances in treating disease — there is no doubt about it."
Groudine described Buck's discoveries as a landmark achievement with major implications for the understanding of the nervous system — and cancer.
"Linda's work is of fundamental importance to the understanding of the mechanisms that control the relay of sensory signals from the receptor to the central nervous system," he said. "What's more, the olfactory receptors are members of a much larger family of signaling proteins known as G-protein coupled receptors, which are often disrupted in cancer and other diseases and are the targets of a large number of drugs used clinically. Clearly, the understanding of how this family works is central to biomedical research in general."
Groudine also noted that the understanding of odor and taste perception, a field in which Buck also has made major contributions, could ultimately provide relief for patients undergoing chemotherapy who are unable to take bitter medications or whose sense of taste and smell are impaired by the potent drugs.
"As we learn more about how the brain functions in one system, we expect the principles may apply to other systems, which could lead to many clinical applications," Buck said.
The basic principles for recognizing and remembering about 10,000 different odors had long been a mystery. In a series of pioneering studies as a postdoctoral fellow with Axel, Buck discovered a large gene family in mice, made up of some 1,000 different genes that give rise to an equivalent number of olfactory receptor types. These receptors are located on the olfactory receptor cells, which occupy a small area in the upper part of the lining of the nose and detect the inhaled odorant molecules.
Buck and Axel showed that each olfactory receptor cell produces one and only one of the odorant receptor genes. Thus, there are as many types of olfactory receptor cells as there are odorant receptors. Most odors are composed of multiple odorant molecules, and each odorant molecule activates several odorant receptors. This leads to a combinatorial code forming an "odorant pattern" — somewhat like the colors in a patchwork quilt or in a mosaic. This is the basis for the ability to recognize and form memories of approximately 10,000 different odors.
The olfactory receptor cells send thin nerve projections directly to distinct domains in the olfactory bulb, the primary olfactory area of the brain. Receptor cells carrying the same type of receptor send their nerve processes to the same domain. From these domains in the olfactory bulb, the information is relayed further to other parts of the brain, where the information from several olfactory receptors is combined, forming a pattern. This is what makes it possible to experience the smell of a lilac flower in the spring and recall this olfactory memory at other times.
All living organisms can detect and identify chemical substances in their environment. Smell is absolutely essential for a newborn mammalian pup to begin nursing — without olfaction the pup does not survive unaided. Olfaction is also of paramount importance for many adult animals, since they observe and interpret their environment largely by sensing smell. For example, the area of the olfactory epithelium in dogs is some 40 times larger than in humans.
Whereas fish has a relatively small number of odorant receptors, about one hundred, mice — the species Axel and Buck studied — have about 1,000. Humans have about 350 different odorant receptors.
The general principles that Buck and Axel discovered for the olfactory system appears to apply also to other sensory systems. Pheromones are molecules that can influence different social behaviors, especially in animals. Buck and Axel, independent of each other, discovered that pheromones are detected by two other families of G-protein coupled receptors localized to a different part of the nasal lining. The taste buds of the tongue have yet another family of G-protein coupled receptors, which is associated with the sense of taste.
Buck's current research focuses on how the brain perceives different types of sensory information.
"We'd like to understand the basis of underlying instinctive behaviors, such as fear and appetite," she said. She also has begun to study aging and lifespan, exploring whether the brain has a "clock" that controls these phenomena.
Buck joined the center in 2002 after 11 years as a faculty member at Harvard Medical School. She is a member of the National Academy of Sciences, a Howard Hughes Medical Institute investigator and the recipient of the Gairdner Award, the Unilever Science Award, the Louis Vuitton-Moet Hennessy Science for Art Prize, the R. H. Wright Award in olfactory research and the Lewis S. Rosenstiel Award for work in basic medical research.