Linda Buck

Appointments and Affiliations

Fred Hutchinson Cancer Research Center
Basic Sciences
Member, Appointed: 2002
 
University of Washington
School of Medicine
Physiology and Biophysics
Affiliate Professor, Appointed: 2003
 
Howard Hughes Medical Institute
Investigator, Appointed: 1994
Professional Headshot of Linda Buck

Mailing Address

Fred Hutchinson Cancer Research Center
A3-020
P.O. Box 19024
Seattle, Washington 98109-1024
United States

Contact

Phone: (206) 667-6316
Fax: (206) 667-1031
lbuck@fredhutch.org
http://labs.fhcrc.org/buck/index.html

Degrees

Ph.D., University of Texas Southwestern Medical Center at Dallas, Immunology, 1980.
B.S., University of Washington, Psychology, 1975.
B.S., University of Washington, Microbiology, 1975.

Research Interests

ODOR AND PHEROMONE SENSING IN MAMMALS

The mammalian olfactory system detects a multitude of environmental chemicals. These include odorants perceived as odors and pheromones that elicit instinctive behaviors. We are interested in how the olfactory system detects myriad chemicals and how the brain translates those chemicals into diverse perceptions and behaviors.

Our initial studies showed that odor detection in the mouse nose is mediated by ~1000 different odorant receptors (ORs) on olfactory sensory neurons in the nasal olfactory epithelium. Each neuron expresses a single OR gene and those with the same OR are highly dispersed. However, their axons all converge in a few OR-specific glomeruli in the olfactory bulb, producing a precise map of OR inputs that is nearly identical among individuals. Our studies showed that ORs are used in a combinatorial fashion, with different odorants detected by different combinations of ORs. This explains how we can distinguish nearly identical odorants and perceive them as having different odors. The spatial code for an odorant in the nose is thus a dispersed ensemble of neurons expressing different components of its combinatorial receptor code while, in the olfactory bulb, it is a combination of glomeruli that receive input from those receptors and whose spatial arrangement is similar among individuals. How olfactory information is encoded at higher levels of the nervous system is still largely a mystery.

To investigate pheromone detection, we focused on the vomeronasal organ (VNO), an olfactory structure that detects pheromones and other molecules that elicit innate responses. Our lab and others identified three VNO receptor families, the V1R and V2R families, with over 100 members each, and a third family comprising five of seven members of the formyl peptide receptor (FPR) family. The other two FPRs are found on immune system cells, where they can recognize formylated bacterial peptides, raising intriguing questions about the function of VNO FPRs. Although little is known about the ligands of VNO receptors, our studies suggest that each pheromone might be detected by only one or a few dedicated receptors, a strategy that might help prevent the induction of innate responses to inappropriate stimuli.

To explore the neural circuits underlying pheromone effects on reproduction, we prepared mice that expressed a lectin transneuronal tracer in hypothalamic GnRH neurons. The 800 GnRH neurons in mice control reproductive hormones and are linked to sexual behaviors. Surprisingly, these studies suggested that GnRH neurons directly communicate with ~50,000 neurons in numerous brain areas, many upstream of GnRH neurons and many downstream. Furthermore, these and other studies suggested that pheromones are detected not only in the VNO, but also the nose.

In a subsequent search for additional receptor types that might recognize pheromones in the nose, we identified a second family of 14 chemosensory receptors in the nose, called trace amine-associated receptors (TAARs). Our studies indicated that some neurons use individual TAARs rather than ORs to detect olfactory stimuli. By testing TAARs with over 200 odorants, we identified ligands for four TAARs, each of which recognized a distinct set of volatile amines. One TAAR detected a compound elevated in the urine of stressed animals while two others detected compounds enriched in male versus female mouse urine. TAARs are evolutionarily conserved from fish to humans, suggesting that they serve a function distinct from ORs. One potential function suggested by these studies is the detection of social cues. We are now investigating the functions of TAARs and their associated neural circuits. We are also using viral tracers to explore the mechanisms and neural circuits by which olfactory stimuli elicit innate responses and impact basic drives.

AGING

In addition to our major focus on olfaction, we are interested in aging. One goal of aging research is to identify drugs that could delay the onset of age-associated disease. Studies of the short-lived nematode, Caenorhabditis elegans have identified numerous genes that affect aging. Moreover, at least some aging mechanisms appear to be evolutionarily conserved from nematodes to mice. This suggests that the identification of drugs that increase nematode longevity might point to drugs that could be tested for beneficial effects on aging in mammals.

In initial studies, we screened 88,000 diverse small molecules and identified over 100 that increased C. elegans lifespan. Further studies of one chemical led to the finding that nematode lifespan can be increased about 30% by a human antidepressant, mianserin. This effect requires SER-4, a serotonin receptor, and SER-3, an octopamine receptor. Similar to its antagonistic effect on human serotonin receptors, mianserin blocked both SER-3 and SER-4, but was a more potent antagonist of SER-4 than SER-3. Additional studies suggested that mianserin increases lifespan by mechanisms linked to dietary restriction, but without reducing food intake. In C. elegans, serotonin appears to signal food availability and octopamine starvation. One possible explanation for mianserin's effect on lifespan is that its greater inhibition of SER-4 than SER-3 mimics reduced food intake, thereby triggering mechanisms downstream of dietary restriction.

More recently, we have been testing drugs with known or suspected mammalian targets for the ability to extend C. elegans lifespan. The identification of such drugs could facilitate determination of their targets in nematodes and hasten the identification of candidates for testing in mice.

Previous Positions

2004-2007: Associate Director, Division of Basic Sciences, Fred Hutchinson Cancer Research Center
2001-2002: Professor, Department of Neurobiology, Harvard Medical School.
1996-2001: Associate Professor, Department of Neurobiology, Harvard Medical School.
1991-1996: Assistant Professor, Department of Neurobiology, Harvard Medical School.
1984-1991: Associate, Howard Hughes Medical Institute, Columbia University College of Physicians and Surgeons, Laboratory of Richard Axel.
1982-1984: Postdoctoral Fellow, Institute of Cancer Research, Columbia University College of Physicians and Surgeons, Laboratory of Richard Axel.
1980-1982: Postdoctoral Fellow, Microbiology Department, Columbia University College of Physicians and Surgeons, Laboratory of Benvenuto Pernis

Additional Experience

2011, Committee Member, Eric Kandel Young Neuroscientists Prize, The Hertie Foundation
2010-present, Committee Member, Shaw Prize in Life Science and Medicine
2009, Committee Member, The Royal Swedish Academy of Sciences Goran Gustafsson Prize
2008, Committee Member, Kavli Prize in Neuroscience
2007, Committee Member, Unilever Science Prize
2007, Member, Kavli Prize Committee in Neuroscience
2007-present, Board of Directors, International Flavors & Fragrances, Inc., New York
2007-present, Consultant, Omeros Corp., Seattle, WA
2006-present, Founding Board, Rosalind Franklin Society
2005-2009, Advisory Board, Peter Gruber Foundation Neuroscience Prize
2005-present, Editorial Advisory Council, HFSP Journal
2005-present, President's Council, New York Academy of Sciences
2005-present, Advisory Committee, March of Dimes Prize in Developmental Biology
2005-present, Medical Advisory Board, The Gairdner Foundation, Toronto, Canada
2004-present, Scientific Advisory Board, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden
2003-2006 Scientific Advisory Board, Nura Inc., Seattle, WA
2003-present, Editorial Board, Developmental Neurobiology
2002-present, Editorial Board, Molecular and Cellular Neuroscience
2000-2003 Scientific Advisor, Primal, Inc., Seattle, WA
1997- Editorial Board, Current Opinion in Neurobiology

Memberships

American Academy of Arts and Sciences
American Association for the Advancement of Science
European Academy of Sciences
Institute of Medicine of the National Academies
National Academy of Sciences

Honors and Awards

2011, Doctor of Science, honoris causa, Rockefeller University
2009, Member, European Academy of Sciences
2008, Member, American Academy of Arts & Sciences
2007, The Medal of Merit, State of Washington
2006, The International Hall of Fame, The International Women's Forum
2006, Alumna Summa Laude Dignata, University of Washington
2006, Member, Institute of Medicine of the National Academies
2005, The Golden Plate Award, The Academy of Achievement
2005, Distinguished Alumnus Award, University of Washington
2005, Brava Award, Women's University Club
2004, The Nobel Prize in Physiology or Medicine
2003, Member, National Academy of Sciences
2003, Gairdner Foundation International Award
2003, The Perl/UNC Neuroscience Prize
2002, Fellow, American Association for the Advancement of Science
2000, Senior Scholar Award in Aging, The Ellison Medical Foundation
1997, Lewis S. Rosenstiel Award for Distinguished Work in Basic Medical Research, Brandeis University
1996, The Unilever Science Award, Unilever
1996, The R.H. Wright Award in Olfactory Research, Simon Fraser University
1995, Distinguished Alumnus, University of Texas Southwestern Medical Center at Dallas
1993, John Merck Scholar in the Biology of Developmental Disabilities, The John Merck Fund
1992, The Sense of Smell Award, The Fragrance Foundation
1992, The Takasago Award for Research in Olfaction, Takasago
1992, Science for Art Prize, LVMH Moet Hennessy Louis Vuitton
1992, McKnight Scholar Award, The McKnight Endowment Fund for Neuroscience
1992, Sloan Research Fellowship Award, Alfred P. Sloan Foundation

Recent Publications

2016
2015
2014
2011
Nara K, Saraiva LR, Ye X, Buck LB.  2011.  A large-scale analysis of odor coding in the olfactory epithelium.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 31(25):9179-91. Abstract
2009
2007
2006
2005
2004
Buck LB.  2004.  The search for odorant receptors.. Cell. 116(2 Suppl):S117-9,1pfollowingS119.
Malnic B, Godfrey PA, Buck LB.  2004.  The human olfactory receptor gene family.. Proceedings of the National Academy of Sciences of the United States of America. 101(8):2584-9. Abstract
Godfrey PA, Malnic B, Buck LB.  2004.  The mouse olfactory receptor gene family.. Proceedings of the National Academy of Sciences of the United States of America. 101(7):2156-61. Abstract
2002
2001
2000
1999
Horowitz LF, Montmayeur JP, Echelard Y, Buck LB.  1999.  A genetic approach to trace neural circuits.. Proceedings of the National Academy of Sciences of the United States of America. 96(6):3194-9. Abstract
1997
1996
Berghard A, Buck LB, Liman ER.  1996.  Evidence for distinct signaling mechanisms in two mammalian olfactory sense organs.. Proceedings of the National Academy of Sciences of the United States of America. 93(6):2365-9. Abstract

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