User talk:Emilfer

UNIVERSITY OF CARABOBO EDUCATION SCIENCES FACULTY MODERN LANGUAGES DEPARTMENT MODULE:COMMUNICATIVE COMPETENCES II               PROFESSOR IN CHARGE OF THE SUBJECT: MARY IRENE ALBERS DE URRIOLA

LINDA B BUCK THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 2004 DISCOVERIES OF OLFACTORY RECEPTORS AND THE            ORGANIZATION OF THE OLFACTORY SYSTEM

Seattle Linda B Buck was born in 1947 in Seattle city, Washington state, a city surrounded by mountains, forests, and the sea. Her mother was the daughter of Swedish immigrants who had come to the US in the late nineteenth century while her father's family had Irish roots on one side and ancestors extending back to the American Revolution on the other. Linda was the second of three children, all girls. Linda's mother was a homemaker who was exceptionally kind and witty and loved word puzzles. Her father was an electrical engineer who, at home, spent much of his time inventing things and building them in our basement. Linda says that it may be that her parents' interest in puzzles and inventions planted the seeds for her future affinity for science, but she never imagined as a child that she would someday be a scientist.

During her childhood, Linda did the things that girls often do, such as playing with dolls. she was also curious and easily bored though, so she frequently embarked on what were to her new adventures. Aside from school and music lessons, Linda's life was relatively unstructured and she was given considerable independence. She learned to appreciate music and beauty from her mother and her father, taught her how to use power tools and build things. This girl spent a lot of time with her maternal grandmother, who told her magical stories about her girlhood in Sweden and, to her delight, her grandmother taught her how to sew clothes for her dolls. Linda was fortunate to have wonderfully supportive parents who told her that she had the ability to do anything she wanted with her life. Moreover,they taught her to think independently and to be critical of her own ideas, and they urged her to do something worthwhile with her life. In her mother's words, to "not settle for something mediocre". This wonderful woman realized and  internalized those lessons and she said that they have influenced her work as a scientist.

Miss Linda received her undergraduate education at the University of Washington, which was only a few miles from her parents' home. Linda had always wanted to have a career in which she would help others, so she initially decided to major in psychology, thinking that she would become a psychotherapist. Over time, her interests expanded and she entertained a variety of different career possibilities. However, none seemed ideal and she was reluctant to embark on something that might prove to be inappropriate. Over the next several years, she intermittently traveled, lived on a nearby island, and took more classes in Seattle. She finally found her direction when she took a course in immunology, which she found fascinating. Buck would be a biologist.

Dallas In 1975, she began graduate school in the Microbiology Department at the University of Texas Medical Center in Dallas. The department had recently undergone an expansion in the area of immunology, making it a major center in this still young area and a stimulating place to learn. Linda had done a small amount of research at the University of Washington, first in psychology with Walter Makous and then in immunology with Ursula Storb, but it was in Texas that she truly learned to be a scientist. She had a wonderful thesis advisor, Ellen Vitetta, who demanded excellence and precision in research, habits that she believes are important to learn as a student. For her thesis, I compared the functional properties of subsets of B lymphocytes that differed in the class of cell surface immunoglobulin that they used as antigen receptors. In this work and much of her subsequent work, she thought in terms of molecules and the molecular mechanisms underlying biological systems, and sought to gain insight into those mechanisms in her experiments.

New York In 1980, Linda Buck moved to Columbia University in New York City to do postdoctoral work in immunology with Benvenuto Pernis. As a graduate student, Linda had become fascinated with the unexplained requirement for major histocompatibility complex (MHC) proteins in immune responses, a mystery that was later solved. She decided to explore this puzzle, focusing on class II MHC proteins found on the surface of B lymphocytes. She found that, contrary to expectation, the MHC proteins rapidly accumulated inside these cells when they were activated. Her further experiments indicated that they were being internalized from the cell surface and were probably being recycled to it. It was known that antigen is endocytosed with antigen receptors and then degraded. One possibility raised by the internalization and apparent recycling of MHC molecules was that, following internalization, they might be targeted to a specialized microenvironment where they could interact with degraded antigen. The MHC-antigen complexes might then be exported to the cell surface for corecognition by T helper cells.

By this time, it had become clear to her that to study molecular mechanisms underlying biological systems, which is what interested me, Linda needed to learn the recently developed techniques of molecular biology. To this end, she moved to the laboratory of Richard Axel at Columbia University. Richard had begun to work in the area of neuroscience several years earlier through collaboration with Eric Kandel, who was also at Columbia. Their collaboration had focused on molecular studies of the nervous system of Aplysia, a sea snail. This was the model organism that Eric had used in many of his studies of learning and memory, for which he received a Nobel Prize in 2000. She was interested in searching for genes encoding neuronal cell surface receptors. However, at that time, Richard wanted to continue studying Aplysia, so she agreed to a project in which she would try to develop a technique for cloning genes expressed in one Aplysia neuron, but not another. After spending a short time learning molecular techniques from Jim Roberts, a student in the lab, she started her Aplysia project. Eric Kandel's group showed her how to isolate giant Aplysia neurons that had been assigned names and could be identified by their locations and, within a relatively short time, she began to uncover genes that were differentially expressed among Aplysia neurons.

While studying a neuropeptide gene expressed in neuron number R15, she discovered that the gene was also expressed in some other neurons, but that its primary transcript was alternatively spliced in different neurons to give different polyproteins. The two polyproteins could generate two different combinations of peptides in different neurons, suggesting a way to produce physiological or behavioral programs with partially overlapping components. While working on the neuropeptide gene, she encountered numerous technical challenges that increased her knowledge of molecular biology and honed her abilities. During that period, she learned a lot of molecular biology from Richard and other members of his lab. She also got to know Eric Kandel, who has continued to be a wonderful source of inspiration and encouragement for me over the years.

From her first introduction to neuroscience, she had been fascinated by the brain's cellular and connectional diversity. In parallel with her Aplysia experiments, she sporadically tried to find a way to scan the genome for genes that had undergone gene rearrangement or gene conversion in neurons, thinking that genes that showed this characteristic might be involved in the generation of neuronal diversity. One method that Linda devised showed promise in Drosophila, but was not sensitive enough for the much larger genome of a mammal, which is what interested her. Nonetheless, these efforts were a great source of creative enjoyment for me as I proceeded with the more mundane task of searching for minute alternative exons in the Aplysia genome.

Linda Buck was grateful that Richard was tolerant of her 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. During that time, she had many colleagues at Columbia with whom she enjoyed long discussions about science. Among these were George Gaitanaris, who has remained a close friend over the years, and Tom Jessell and Jane Dodd, neuroscientists from whom she learned a great deal about neural development.

As she was nearing the end of her Aplysia project, she read a paper that changed her life. It was a 1985 publication from Sol Snyder's group that discussed potential mechanisms underlying odor detection. This was the first time she had ever thought about olfaction and she 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 her mind, this was a monumental puzzle and an unparalleled diversity problem. It was obvious to her 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. Therefore, Linda B Buck decided that that was what she had to do as soon as her neuropeptide work was completed.

In 1988, This enterprising embarked on a search for odorant receptors, staying on in Richard's lab for that purpose. In a recent commentary in the journal Cell, she described what was known about odor detection at that time and the approaches that she tried in the quest to find the elusive odorant receptors. In short, it was known that odorants depolarize, and thereby they activate olfactory sensory neurons in the nose. Although there were varied proposals as to what kind of molecules might interact with odorants, there was compelling evidence that olfactory transduction involved G-protein induced increases in cAMP. After trying several different approaches, she could identify the odorant receptor family by designing experiments based on three assumptions. First, since odorants vary in structure and can be discriminated, there would be a family of varied, but related odorant receptors, which would be encoded by a multigene family. Second, odorant receptors would be at least distantly related to the relatively small set of G protein coupled receptors whose sequences were known at that time. And finally, odorant receptors would be selectively expressed in the olfactory epithelium, where olfactory sensory neurons are located. It took some time to devise and develop the methods she used in her search, but in the end they succeeded. Looking at the first sequences of odorant receptors obtained from rat, she was moved by Nature's marvelous invention. This work showed that the rat has a multigene family that codes for in excess of one hundred different odorant receptors, all related, but each one unique. The unprecedented size and diversity of this family explained the ability of mammals to detect a vast array of diverse chemicals as having distinct odors. In 1991, Richard Axel and she published the identification of odorant receptors.

The discovery of odorant receptors had explained how the olfactory system detects odorants. Her next goal was to learn how signals from those receptors are organized in the brain to generate diverse odor perceptions. Linda was joined in this endeavor by a series of excellent students and postdoctoral fellows. The discoveries on the organization of the olfactory system that were cited by the Nobel Foundation were made over a period of ten years, during which she was a faculty member at Harvard university.

The first question they asked was how odorant receptors (ORs) are organized in the olfactory epithelium of the nose. This work was begun by Kerry Ressler, an M.D./Ph.D. student who came to the laboratory for a few months just as the equipment and supplies she had ordered began to arrive in January 1992. she had decided to switch from rat to mouse as a model organism because of the advantage of using isogenic inbred strains for dissecting a multigene family, and the possibility of generating transgenic mice. After cloning and sequencing a series of mouse OR genes, Kerry did their first in situ hybridization experiments to examine patterns of OR gene expression. By June, Kerry had returned as a full time student and Susan Sullivan had joined the lab as a postdoctoral fellow. At that point, they began to precisely analyze OR expression patterns and to compare them in different individuals. Prior to the present era of digital photographs that can be stored and analyzed on a computer, this was painstaking work that involved displaying photographic slides on a desktop viewer and recording, on transparencies, the locations of individual labeled cells in different animals. Their studies showed that each OR gene is expressed in about 1/1000 olfactory sensory neurons, that the olfactory epithelium has several spatial zones that express nonoverlapping sets of OR genes, and that neurons with the same OR are randomly scattered throughout one zone. This indicated that signals derived from different ORs are segregated in different sensory neurons and in the information they transmit to the brain. It further indicated that, in the olfactory epithelium, neurons that detect the same odorant are dispersed and those that detect different odorants are interspersed. Thus, there is a broad organization of sensory information into several zonal sets in the epithelium, but, overall, information is encoded in a highly distributed manner. They published these findings in 1993. Similar observations in rat by Richard Axel and his colleagues were also reported that year.

Having determined how inputs from different ORs are organized in the nose, They asked how they are arranged at the next structure in the olfactory pathway, the olfactory bulb. In the bulb, the axons of olfactory sensory neurons synapse in about 2,000 spherical structures, called glomeruli. Kerry began to use retroviral vectors to investigate how the axons of neurons expressing specific ORs are organized in the bulb, but then they inadvertently found another way to address the question. While using in situ hybridization to identify a number of OR genes expressed in each epithelial zone for chromosomal mapping studies, Susan found that, in one tissue section, an OR probe labeled a single spot in the bulb, which proved to be a glomerulus. Using probes that recognized single OR genes rather than subfamilies of related OR genes, they found that each probe labeled OR mRNAs in sensory axons that were confined to one or a few glomeruli at only two sites, one on either side of the bulb. Different OR probes labeled different glomeruli and those glomeruli had virtually identical locations in different individuals. Linda says that she still remembers a meeting with Kerry and Susan in her office in which she asked Kerry how many sections separated different labeled glomeruli in different bulbs. All of them were stunned by his answer, because it provided the first hint that the bulb might have a stereotyped map of OR inputs and they could not imagine how that could be generated given the organization of OR gene expression in the epithelium. That mystery still has not been solved. Those studies indicated that while thousands of neurons expressing the same OR are highly dispersed in the epithelium, their axons all converge in a few specific olfactory bulb glomeruli. The result is a stereotyped map of OR inputs in which signals derived from different ORs are segregated in different glomeruli and in the bulb projection neurons whose dendrites innervate those glomeruli. Remarkably, Bob Vassar in Richard Axel's lab had concurrently found that different OR probes labeled different glomeruli in the rat bulb. Their two groups published these findings in 1994.

Several years later, they began to investigate how the OR family and the patterning of OR inputs encode the identities of different odorants. Using single cell RT-PCR (reverse transcriptase-polymerase chain reaction), Bettina Malnic, a fellow in the lab, had been comparing gene expression in single olfactory sensory neurons. Her work demonstrated that each neuron expresses only a single OR gene, something that they had previously suspected, but that needed to be verified. Bettina was initially focused on the identification of genes that might be involved in OR gene choice or axon targeting in the bulb, but they decided to change course when Takaaki Sato visited their lab and told them about his calcium imaging studies of odor responses in the olfactory epithelium. That was the beginning of a highly successful collaboration in which Takaaki used calcium imaging to define the odor response profiles of individual neurons and Bettina then used RT-PCR to identify the OR expressed by each responsive neuron. These studies demonstrated that the OR family is used in a combinatorial manner. Different neurons are recognized, and thereby encoded, by different combinations of ORs, but each OR is used as one component of the combinatorial receptor codes for many different odorants. As discussed in her Nobel Lecture, these studies also provided explanations for several intriguing features of human odor perception, including how a slight change in the structure of an odorant can dramatically change its perceived odor quality.

As soon as they had determined how OR inputs are organized in the olfactory bulb, they began to explore how they are arranged at the next structure in the olfactory pathway, the olfactory cortex. Lisa Horowitz, an M.D./Ph.D. student in the lab, initially investigated connections between the bulb and cortex using classical anatomical techniques. By depositing different tracers in the dorsal and ventral bulb, she determined that these areas project axons to the same regions of the cortex. In agreement with previous findings, this indicated that there could not be a point-to-point patterning of connections between the bulb and cortex. They decided to abandon traditional approaches and to instead ask whether they could chart neural pathways genetically by expressing a gene encoding a transneuronal tracer in olfactory sensory neurons. Lisa found that this was indeed possible. When she made transgenic mice that expressed barley lectin in all olfactory sensory neurons, the lectin crossed two synapses, labeling second-order neurons in the bulb and then third-order neurons in the cortex. This work, which they published in 1999, opened the way to investigating a wide array of questions concerning neural circuits, including those that carry olfactory information.

They then went on to use the genetic tracer to examine how inputs from individual types of ORs are organized in the olfactory cortex. To do that, they used gene targeting to generate mice that coexpressed barley lectin with a single OR gene. Lisa, together with a fellow in the lab, Jean-Pierre Montmayeur, prepared the DNA constructs for gene targeting. Zhihua Zou, another fellow, then made and analyzed mice that coexpressed the tracer with different OR genes. The approach worked, but was difficult, with Zhihua investing almost a year in perfecting the conditions needed to detect minute amounts of the tracer in cortical neurons. These studies revealed that the olfactory cortex has a stereotyped map of OR inputs, but one that is radically different from that in the bulb. As linda discussed in my Nobel Lecture, the segregation of OR inputs in different glomeruli and neurons in the bulb gives way in the cortex to a complex array of OR inputs in which signals from different ORs partially overlap and single cortical neurons appear to receive signals from combinations of different ORs. That offers a means by which the individual components of an odorant's receptor code could be integrated at the level of single neurons. That could serve as an initial step in the reconstruction of an odor image from its deconstructed features, which are conveyed by the OR elements of the receptor code. They published their findings on the cortex in 2001.

During the ten year period at Harvard in which they did the work described above, Linda's laboratory also investigated a number of other questions. These included studies of the chromosomal organization of OR genes and the evolution of the OR gene family by Susan Sullivan, studies of the development of OR gene expression patterns by Susan and Staffan Bohm, and bioinformatic studies by Bettina Malnic and Paul Godfrey that defined and compared the OR gene repertoires of human and mouse. They also conducted a series of studies on the detection of pheromones in the vomeronasal organ, including studies by Emily Liman and Anna Berghard that revealed differences between transduction molecules involved in odor versus pheromone detection, the discovery of zonal patterns of transduction molecules likely to be involved in pheromone detection by Anna, analyses of vomeronasal responses to pheromones and odorants by Mehran Sam, and the discovery, by Hiroaki Matsunami, of a family of candidate pheromone receptors. During the latter part of this period, Hiroaki Matsunami, Jean-Pierre Montmayeur, and Stephen Liberles also began to explore the mechanisms underlying taste detection, in the process discovering candidate receptors for both bitter and sweet tastes, both of which were also found by other groups at about the same time.

Seattle In 2002, Linda B Buck returned to Seattle to be a member of the Division of Basic Sciences at Fred Hutchinson Cancer Research Center and Affiliate Professor of Physiology and Biophysics at the University of Washington. She had always intended to someday return to the West Coast and had already stayed longer in Boston than she had anticipated. When Mark Groudine, then Director of the Basic Sciences Division at Fred Hutchinson, offered her a faculty position there, she gladly accepted. The Hutchinson Center had a reputation for cutting edge science as well as a high level of collegiality, both of which were important to her. In addition, by moving to Seattle, she would be closer to her partner, Roger, who lived in Berkeley, and to her family and friends in Seattle.

In Seattle, They are continuing to explore the mechanisms underlying odor perception as well as the means by which pheromones elicit instinctive behaviors. They have also become interested in the neural circuits that underlie innate behaviors and basic drives, such as fear, appetite, and reproduction. They are currently developing molecular techniques to uncover those circuits and to define their composite neurons and the genes they express. In a different vein, they have developed a high throughput approach in which we are using chemical libraries to identify genes that control aging and lifespan, their chief interest being whether there might be a central mechanism that determines lifespan and regulates the aging of cells throughout the body.

Looking back Since Richard Axel and Linda published the discovery of odorant receptors in 1991, it has been immensely satisfying for her to see many laboratories using these receptors in a large scale effort to dissect the mechanisms that underlie the sense of smell and the developmental processes that shape the organization of the olfactory system. Molecular approaches to studying olfaction have extended to other vertebrates as well as to invertebrate species, with Cori Bargmann's group discovering a large variety of chemosensory receptors in the nematode worm, C. elegans, and several groups, including Richard Axel's, identifying families of odorant and taste receptors in the fruit fly, D. melanogaster.

Looking back over her life, she is struck by the good fortune she has had to be scientist. Very few in that world have the opportunity to do everyday what they love to do, as Linda has. Buck have had wonderful mentors, colleagues, and students with whom to explore what fascinates her and have enjoyed both challenges and discoveries. She is grateful for all of these things and look forward to learning what Nature will next reveal to them.

As a woman in science, she sincerely hopes that her 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.

If there is any mistake, ask for excuses for all those people that had read this Buck Linda's important theory.

This portal has been elaborated by: Emilio J Aguiar F. Education student who is majoring in English at Carabobo university, Valencia-Venezuela.