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Linda Buck receives Nobel Prize in "Medicine or Physiology" on December 10, 2004.

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On December 10, 2004, in Stockholm, Linda Buck (b. 1947), of Seattle's Fred Hutchinson Cancer Research Center, is presented the Nobel Prize for Medicine or Physiology. Buck shares the award with Richard Axel, director of the laboratory at Columbia University where the winning research was conducted. The prize is awarded for Buck's and Axel's unraveling of many of the mysteries of the sense of smell, first set forth in a 1991 paper published in the journal Cell. In 2002, Buck, a Seattle native, will return to the city of her birth to continue her investigations at the Fred Hutchinson Cancer Research Center. Both at Columbia and in Seattle, her research is funded in large part by the Howard Hughes Medical Institute.

Seattle-Born

Linda Brown Buck was born in Seattle on January 29, 1947, daughter of a homemaker mother and a father who was an electrical engineer. Buck credits her parents with instilling in her the curiosity and work ethic that would propel her career in the sciences:

"My father was an electrical engineer who, at home, spent much of his time inventing things and building them in our basement. It may be that my parents' interest in puzzles and inventions planted the seeds for my future affinity for science, but I never imagined as a child that I would someday be a scientist ... .

"I learned to appreciate music and beauty from my mother and my father taught me how to use power tools and build things ... .

"I was fortunate to have wonderfully supportive parents who told me that I had the ability to do anything I wanted with my life. They taught me to think independently and to be critical of my own ideas, and they urged me to do something worthwhile with my life ..." ("Autobiography").

Buck attended the University of Washington, where she earned a joint bachelor's degree in psychology and microbiology, graduating in 1975. She considered a career as a psychotherapist, but spent the next several years living on an island near Seattle, traveling, and taking a variety of college courses while trying to map her future course. One of these, a class in immunology, grabbed her interest, and Buck decided to pursue a career in biology. In 1975 she entered the graduate program in microbiology at the University of Texas Southwest Medical Center in Dallas, which shortly before had expanded its research program in immunology.

A Life in Science

Buck's research and thesis at UT studied B lymphocytes, a component of the human body's immune system. She focused her research on the function of molecules in the immune response at the cellular level and was awarded her Ph.D. in immunology in 1980. She then moved on to a position in post-doctoral research at the Howard Hughes Medical Institute at Columbia University, New York, working with Dr. Benvenuto Pernis (1923-2011). Pernis, born in Florence, Italy, was one of the first scientists to conduct fundamental research in the biology of immune-system lymphocytes and was a key player in the founding of the famed Basel Institute for Immunology in Switzerland. Buck's research focused on a class of proteins found on the surface of B lymphocytes. Put in the most basic terms, the significance of her research was the finding that, contrary to expectations, the class of proteins under study were being taken into the interior of a cell and then -- probably -- recycled back to the cell's surface.

Buck worked under Pernis until 1984. Then, realizing that the path her interests were taking her required a deeper knowledge than she possessed of the techniques used to study molecular biology, she moved to another lab at Columbia. Here, she worked as a postdoctoral fellow with Richard Axel, M.D., a researcher and professor at the Columbia University College of Physicians and Surgeons. It was the research they did together that would lead, many years later, to the Nobel Prize.

The Sense of Smell

Buck began her research in Axel's laboratory trying to develop a technique for cloning genes expressed by specific neurons (nerve cells) in Aplysia, a genus of sea slug. This was to be valuable groundwork for her later accomplishments. As Buck notes:

"During this period, I learned a lot of molecular biology from Richard and other members of his lab ... . I was grateful that Richard was tolerant of my high-risk endeavors. He was an unusual mentor in that he gave people in his lab extensive independence in charting their own course once they had established themselves" ("Autobiography").

While nearing the end of her sea-slug studies, Buck came upon a 1985 research publication that, in her words, "changed my life" ("Autobiography"). In it, prominent neuroscientist Sol Snyder (b. 1938) of Johns Hopkins, discussed possible mechanisms underlying the ability to detect odors. As Buck explains:

"This was the first time I had ever thought about olfaction and I was fascinated. How could humans and other mammals detect 10,000 or more odorous chemicals, and how could nearly identical chemicals generate different odor perceptions? In my mind, this was a monumental puzzle and an unparalleled diversity problem. It was obvious to me that the first step to solving the puzzle was to determine how odorants are initially detected in the nose. This meant finding odorant receptors, a class of molecules that had been proposed to exist, but had not been found. I decided that this is what I had to do ..." ("Autobiography").

In 1988 Buck, working directly with Axel, turned her attention to the sense of smell, trying to answer a basic question that had defied resolution: "How does the brain know what the nose is smelling?" ("Richard Axel, M.D."). Studying both fruit flies (the workhorses of genetic research) and mammals, the two discovered that at least 100, and probably many more, separate genes are responsible for encoding development of the odor receptors found in the lining of nasal cavities. What was even more surprising was the similarity of the olfactory mechanism in two such disparate classes of life -- insects and mammals. This indicated to Buck and Axel that, genetically speaking, the mechanisms of smell were extremely ancient, and that "the basic principles of odor discrimination ... have been conserved over 500 million years" ("Richard Axel, M.D.").

The odor receptors in nasal cavities are responsible for detecting odorants (chemical compounds having an odor). Buck and Axel mapped the biological pathway for the sense of smell, and established that the large family of genes responsible for coding the receptors created a sense of smell that could detect and discriminate among as many as 10,000 different odors. In 1991, Buck and Axel published their research results in Cell magazine in an article entitled "A Novel Multigene Family May Encode Odorant Receptors: A Molecular Basis For Odor Recognition." This was the work for which the Nobel Prize was awarded 13 years later. The award citation stated that the two were honored "for their discoveries of odorant receptors and the organization of the olfactory system"

The research article by Buck and Axel created a stir in scientific circles almost immediately. A 1991 article in The Seattle Times sought to explain why the discovery was deemed important:

"Strong-smelling substances called pheromones play a role in insect behavior and reproduction. Learning how those substances are detected could lead to new means of inhibiting insect reproduction.

"Before this study, researchers had disagreed about whether smell was governed by a few genes or a large number. The study suggests that 100 to 200 genes may be involved, Buck and Axel said.

"'The number of genes, if it holds up to be true, is phenomenal,'" said [Charles ] Wysocki, an authority on the biology and psychology of smell.

'''It makes it now one of the largest related families of genes that's been identified.'

"He said the research is 'literally going to open up whole new fields. It's going to draw people who never even thought of doing work with the sense of smell'

"Odors are detected by tiny tubular extensions on nerve cells high in the nasal cavity, Buck said. The extensions, called cilia, are believed to be the location of molecules called receptors. Odor molecules are believed to slip into receptors as a key slips into a lock" ("Nose Knows Smells Thanks To Gene Group, Research Finds").

Subsequent research determined that each odor-sensing cell in the nose possesses only one type of odorant receptor, which can detect a limited range of specific odors. From here, Buck and her fellow researchers were able to learn how different odors are perceived by the brain, and they discovered a "sensory map" for the sense of smell that is virtually identical in all humans, located in an area of the brain called the olfactory bulb.

Moving On, Moving Back    

After completing the research with Axel, but long before winning the Nobel, Buck stayed in academia. From 1991 to 1996 she was an assistant professor in the Department of Neurobiology at Harvard Medical School in Boston, becoming an associate professor in 1996 and a full professor in 2001. Contemporaneous with her professorships, Buck continued her association with the Howard Hughes Medical Institute, first as an assistant investigator and, after 2001, as a full investigator. She continued her research on the sense of smell, while also tackling other subjects, including the sense of taste.

In 2001, Buck moved back to Seattle, becoming a member of the basic sciences division at Fred Hutchinson Cancer Research Center and an affiliate professor of physiology and biophysics at her alma mater, the University of Washington. In 2003, the year before receiving the Nobel, she was elected to the National Academy of Sciences, and in that same year was awarded, together with Axel and others, the prestigious Canada Gairdner International Award. This was followed in 2006 by her induction into the Institute of Medicine, considered one of the highest honors in the field.

A Scientist's Worst Nightmare

Buck's professional reputation seemed under threat in 2008 when she and her coauthors withdrew a paper on the sense of smell that was published in 2001 in the prestigious scientific journal, Nature, reporting that they had discovered problems in the data and were unable to duplicate their findings. The paper in question was written a decade after the work that had won the Nobel Prize, and Buck and her colleagues were straightforward on the matter:

"In the retraction, published by Nature on Thursday, the researchers said, 'Moreover, we have found inconsistencies between some of the figures and data published in the paper and the original data. We have therefore lost confidence in the reported conclusions.'

"'It’s disappointing,' Dr. Buck, who is now at the Fred Hutchinson Cancer Research Center in Seattle, told the journal Nature in a news article about the retraction. 'The important thing is to correct the literature'" ("Nobel Winner Retracts Research Paper").

The lead author on the withdrawn study was a postdoctoral researcher from China, Zhihua Zou, described as "the source for the paper's data and figures" ("Nobel Winner Retracts Research Paper"). Zou, while expressing disappointment, did not object to the withdrawal of the study and signed the notice of retraction. But the discovery led Buck and her colleagues to review other work involving Zou, and more problems were found.

Two years later, in September 2010, Buck and her team announced the withdrawal of two additional papers, one published in the Proceedings of the National Academy of Sciences in 2005 and the other in Science in 2006. The reasons were the same -- Buck and her team couldn’t reproduce findings reported by Dr. Zou. This time, although he was the lead author on both papers, Zou did not sign the notice of retraction. He had been laid off from his position as an assistant professor at the University of Texas Medical Branch in Galveston after the facility was extensively damaged by Hurricane Ike in 2008. In 2010 a spokesman for UT indicated that Zou had returned to China, and that his "current whereabouts ... are unknown" ("Nobel Laureate Linda Buck Retracts Two Studies on Sense of Smell in Brain").

Throughout the ordeal, there were neither allegations made nor evidence produced that Buck, or any researchers other than Zou, bore responsibility for the withdrawn papers' questionable data or irreproducible results. By promptly and forthrightly acknowledging the problems and withdrawing the papers, Buck and her team fulfilled the ideal of good science being self-correcting. Although unfortunate, the incidents have had no lasting detrimental impact on Buck's reputation or her work.

Continuing Research

Over her career, Buck has received numerous awards and much recognition in addition to the Nobel Prize, including induction into the European Academy of Sciences (2009), the State of Washington Medal of Merit (2007), and the University of Washington's Distinguished Alumnus Award (2005). Today (2012) she continues her research at the Hutchinson center, heading the eponymous Linda Buck Lab.

Buck continues to receive funding from the Hughes institute, and she and her fellow researchers are still studying the intricacies of the sense of smell, while also branching out into other areas of scientific interest. In their own words:

"Our laboratory, led by Linda Buck, Ph.D., is investigating the mechanisms that underlie the sense of smell and pheromone sensing in mammals. One major question is how humans and other mammals detect as many as 10,000 or more chemicals in the external environment. Another is how the brain translates those chemicals into different smells, such as rose or garlic. A third is how pheromones and other social cues elicit hormonal changes and instinctive behaviors in animals ... . Our recent work has also touched on aging, particularly the identification of drugs that might delay the onset of age-associated disease" ("Laboratory of Linda Buck, Ph.D").

In an autobiographical sketch prepared for the Nobel Institute, Buck reflected on her life in science:

"Looking back over my life, I am struck by the good fortune I have had to be a scientist. Very few in this world have the opportunity to do everyday what they love to do, as I have. I have had wonderful mentors, colleagues, and students with whom to explore what fascinates me and have enjoyed both challenges and discoveries. I am grateful for all of these things and look forward to learning what Nature will next reveal to us.

"As a woman in science, I sincerely hope that my receiving a Nobel Prize will send a message to young women everywhere that the doors are open to them and that they should follow their dreams" ("Autobiography").

Sources:
"Autobiography," Nobel Prize website accessed November 23, 2012 (http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/buck.html); Giselle Weiss, "Closing of Basel Institute Scatters Immunologists," Science, Vol. 293, No. 5528 (July 13, 2001), pp. 238-239; "Benvenuto G. Pernis M.D.: Obituary,"  Boston Globe website accessed November 25, 2012 (http://www.legacy.com/obituaries/bostonglobe/obituary.aspx?pid=154279752#fbLoggedOut); "Richard Axel, M.D.," Howard Hughes Medical Institute website accessed November 25, 2012 (http://www.hhmi.org/research/investigators/axel_bio.html); "The Nobel Prize in Physiology or Medicine 2004: Richard Axel, Linda B. Buck," Nobel Prize website accessed November 25, 2012 (http://www.nobelprize.org/nobel_prizes/medicine/laureates/2004/); "Linda B. Buck PhD: Recipient of the Canada Gairdner International Award, 2003," Gairdner Foundation website accessed November 25, 2012 (http://www.gairdner.org/content/linda-b-buck); "Linda Buck," Howard Hughes Medical Institute website accessed November 24, 2012 (http://www.hhmi.org/research/nobel/buck.html);  "Nose Knows Smells Thanks To Gene Group, Research Finds," The Seattle Times, April 5, 1991, p. A-4; "On the Move," Ibid., May 19, 2003, p. C-4; "Nobel Winner Retracts Her Study,"  Science Digest," Ibid., March 7, 2008, p. A-8; Kenneth Chang, "Nobel Winner Retracts Research Paper," The New York Times, March 7, 2009 (http://www.nytimes.com/); Elizabeth Lopatto, " Nobel Laureate Linda Buck Retracts Two Studies on Sense of Smell in Brain," Bloomberg.com website accessed November 25, 2012 (http://www.bloomberg.com/news/2010-09-23/nobel-laureate-buck-retracts-two-papers-on-sense-of-smell-journals-say.html).

By John Caldbick, November 30, 2012

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