The Scent of Success

Winner of the 2004 Nobel Prize, Linda Buck has expanded our knowledge of the human body and made landmark contributions to biomedical science

The reawakening of a long-forgotten memory by the scent of a warm summer day or a whiff of 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 was awarded the 2004 Nobel Prize in physiology or medicine. She shared the prize with Dr. Richard Axel of Columbia University.

Buck joins Fred Hutchinson’s two other Nobel Laureates, Dr. E. Donnall Thomas, who won the 1990 prize for his pioneering work in bone-marrow transplantation, and Dr. Lee Hartwell, who received the 2001 prize for his discoveries of the mechanisms that control cell division.

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 combination 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 2:30 a.m. on Oct. 4, when she was awakened by a call from Dr. Mark Groudine, Fred Hutchinson’s deputy director, 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 the phone rang, but in the dark, she missed the call — 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.”

“Fred Hutchinson 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.”

Buck’s discoveries are 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,” Groudine 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.

Unlocking the olfactory mystery

The basic principles for recognizing and remembering about 10,000 different odors had long been a mystery. In a series of pioneering studies with Axel, Buck discovered a large gene family in mice, made up of some 1,000 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 lining of the nose and detect odorant molecules.

Working independently of each other from 1991 on, the two researchers continued to probe the mysteries of the sense of smell. Buck showed that each olfactory-receptor cell produces only one of the odorant-receptor genes. 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 some 10,000 different odors.

All living organisms can detect and identify chemical substances in their environment. For example, smell is essential for a newborn mammalian pup to begin nursing — without it, the pup does not survive unaided. Olfaction is also key for many adult animals, since they 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, which have about 350 different odorant receptors.

The general principles that Buck and Axel discovered for the olfactory system appear also to apply to other sensory systems. Pheromones are molecules that can influence different social behaviors. Buck and Axel, independent of each other, discovered that pheromones are detected by two other families of receptors in a different part of the nasal lining. The taste buds of the tongue have yet other families of receptors.

Sensory basis for fear, appetite

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 on the faculty of Harvard Medical School. She is a member of the National Academy of Sciences, a Howard Hughes Medical Institute investigator and winner of the Gairdner International Award, the Lewis S. Rosenstiel Award for basic medical research and many other awards.

Barbara Berg, Ph.D., is senior science writer for Fred Hutchinson Cancer Research Center.

Three Nobel laureates probe the mysteries of life and disease from different angles

Three Nobel laureates: Drs. Don Thomas, left, Lee Hartwell and Linda Buck.

Fred Hutchinson Cancer Research Center is something of a scientific prodigy. A relatively young institution, it quickly has developed a world-renowned reputation far beyond its years.

Since its doors opened in 1975, Fred Hutchinson has attracted and nutured some of the brightest minds in biomedical research, including three Nobel Prize winners. The most prestigious award in all of biology, the Nobel Prize in physiology or medicine goes to scientists whose work has changed the way we think about life itself.

In addition to Dr. Linda Buck’s 2004 award, Fred Hutchinson researchers won the Nobel in 1990 and 2001.

Dr. E. Donnall (Don) Thomas, director emeritus of the center’s Clinical Research Division, received the Nobel in 1990 for his pioneering work in bone-marrow transplantation to treat leukemia and other cancers of the blood. This procedure remains one of the most important cancer-treatment breakthroughs of the last several decades.

Dr. Lee Hartwell, president and director of the center, received the award in 2001 for his discoveries regarding the mechanisms that control cell division. His findings have had a profound impact on our understanding of human cancer, a disease that arises from uncontrolled cell growth.

While the character of their work is very different, Buck, Thomas and Hartwell and the rest of their colleagues at Fred Hutchinson share the common goal of advancing scientific knowledge that will save lives in the fight against cancer, HIV and other life-threatening diseases.