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The memory of eating an apple: the sensation of a round object resting on three fingers of the left hand, smooth and cool; the visual recognition of the object’s green and red coloring; the sound “crunch” as the crisp object contacts the teeth; the perception of sweetness, with a slight hint of sour, registered by the tip of the tongue. The defining factor of this memory is the recognition of the object’s succulent taste, the result of its unique scent. It is as if this precise memory is stored and defined by innumerable dimensions registered by the senses: the shape, texture, color, temperature, smell, taste, time, location, name, and emotional mood: each independent coordinate is required to specify uniquely the point in space. While the metaphor of dimensions seems applicable to the description of memory storage in an organism’s brain, the specific mechanisms behind an organism’s perception of these dimensions remain elusive. In 1991, however, unprecedented progress in the understanding of an organisms’ ability to recognize and process external stimuli was articulated in Linda Buck’s and Richard Axel’s publication of A Novel Multigene Family May Encode Odorant Receptors: A Molecular Basis for Odor Reception, the paper that ultimately earned Linda Buck and Richard Axel the 2004 Nobel Prize in Physiology/Medicine for their “discoveries of odorant receptors and the organization of the olfactory system.” Possibly the most evocative sensory system in mammals is the sense of smell. Although humans may have the ability to perceive about 10,000 scents, many mammals have an even more potent olfactory system.(The molecular logic of smell 154) While human culture tends to cleanse each individual’s scent by frequent bathing, most animals depend on scent to “identify food, predators, and mates.”(The molecular logic of smell 154) Odors’ lack of significance in human culture is reflected in human’s limited vocabulary for describing different aromas, but humans do rely on olfaction for the sensation of both smell and taste: taste buds only distinguish between sweet, salty, sour, and bitter; all other flavors come from the sense of smell.(Pines 47) Almost all odors are chemicals or odorant molecules of different shapes and sizes in an animal’s environment. Over time, most organisms have evolved a mechanism to recognize these specific odors and relay the chemical stimuli to the brain to make “an internal representation of the external world.”(The molecular logic of smell 157) Not only can the brain identify and distinguish thousands of odors, but these odors can trigger emotion, cognitive, and behavioral responses. (The molecular logic of smell 154) Before Buck and Axel’s research, almost all of what was concretely defined about the olfactory system was the basic anatomy of the nose. (The molecular logic of smell 155) In mammals, the perception of airborne chemicals, or scents, was known to begin in a region in the posterior of the nose called the olfactory epithelium. When an animal inhales, the odorant molecules bind to specialized receptor proteins [See Figure1]. These proteins extend from cilia, hair-like sensors on one end of neurons. The axons of these neurons extend into the brain, “provid[ing] a direct physical connection between the external world and the brain.” (The molecular logic of smell 155) The binding of odorants to the receptor proteins triggers action potentials or electrical signals along the axons of the neurons that converge in the olfactory bulb. More neurons connect the olfactory bulb to the olfactory cortex, and then to the cerebral cortex, the brain center responsible for animal thoughts and behaviors where the signal is ultimately decoded. (The molecular logic of smell 155) Buck and Axel set out to research how an organism can respond to thousands of odorants in its environment, and in doing so they discovered a family of over 1,000 genes in mice that code for the specific receptor proteins in the olfactory epithelium. The gene family is the largest family yet identified in mammals, and indicates that perhaps one percent of all human genes are responsible for odor detection. (Pines 49) Figure 1 Buck and Axel’s research is so remarkable because it uses genetics to define the ultimate organization of the olfactory system. Buck and Axel began their investigation of the detection of smell where the “odor is first physically perceived—at the odor receptor proteins.”(The molecular logic of smell 155) Instead of studying the receptors, they decided to look for the genes, the actual DNA sequences, that code for these receptor proteins. Not only are the genes “much simpler and faster” to study than the receptors themselves, but the template of the receptors could then be artificially manipulated to modify the receptors to discern the precise mechanism behind their ability to relay the information in the chemical odorants to the brain.(The molecular logic of smell 155) The brilliance behind their discovery was how Buck was able to isolate and identify this specific gene family in the mammoth mouse genome. To narrow the enormous field of genes, Buck made three basic assumptions [see Table 1] that enabled her to locate what should be the DNA coding for the odorant receptor proteins. Her first assumption was that “the odorant receptors are likely to belong to the superfamily of receptor proteins that transduce intracellular signals by coupling to GTP-binding proteins;” that the protein receptors are part of a previously identified group of receptors that pass through cell membranes a characteristic seven times and activate the signaling proteins known as G-proteins to initiate the transmission of electrical impulses along axons.(Buck and Axel 176) Her second postulate was that “the large number of structurally distinct odorous molecules suggest that the odorant receptors themselves should exhibit significant diversity and are therefore likely to be encoded by a multigene family;” that because there are so many different variations of odorants, there should be a large range of odorant receptors, and therefore a large range of genes to code for these receptors; the genes would be strikingly similar, but not identical.(Buck and Axel 176) Her final assumption was the “expression of the odorant receptors should be restricted to the olfactory epithelium;” meaning that although the genes encoding for these receptors are carried by almost all cells in the body, they should only be active in olfactory neurons.(Buck and Axel 176) Table
1. Buck’s
Three Assumptions Using these three assumptions, Buck set out to identify the specific genes. Her first step was create primers for a technique called polymerase chain reaction or PCR [see Figure 2].(The molecular logic of smell 156) In this procedure, specific sections of DNA are amplified in vitro by incubating them with specific primers for the beginnings of the sequences, nucleotides, and DNA polymerase. Knowing that the odorant receptors should have sections of sequences identical to the receptors that cross the membrane a characteristic seven times, the primers used for the PCR were made according to sequences found in a variety of those receptors. Sections of the olfactory epithelium DNA were then amplified using several primers, hopefully one of those coding for the odorant receptor proteins. The next question was whether any of the PCR products were multiple DNA sequences, reflecting the amplification of a large family of genes. Buck was not merely looking for one receptor, but a family of over 1,000 similar, but unique, receptors. If there was a family of receptors all with the characteristic sections of the other receptor proteins, then they all could be amplified with the same pair of primers: what Buck deduced was that if the various PCR products were digested and cut at specific intervals, then the sum of the molecular weight of the fragments should be greater than the molecular weight of the original PCR product if a whole family of receptors had been amplified.(The molecular logic of smell 156) [See figure 2] Although almost all of the PCR products when digested resulted in a set of fragments with a total molecular weight equal to that of the original DNA, there was one product whose total molecular weight was significantly greater: the family of odorant receptors. To confirm that these sequences indeed coded for the protein receptors in the nose, tests were then performed to confirm that this gene family is only expressed in olfactory epithelium neurons. Using a technique known as Northern Blot, or RNA hybridization, to locate a particular sequence of RNA in a complex mixture, nine tissues in mice were tested for the presence of the RNA complementary to the series of DNA thought to code for the receptors [See figure 2]. Because RNA is the intermediary molecule between DNA and the actual protein, the only place these RNA sequences should be expressed is where the proteins are actually being produced, the olfactory epithelium. And it was. After the PCR and Northern Blot procedures, Buck and Axel concluded, “the properties of the gene family we have identified suggest that this family is likely to encode a large number of distinct odorant receptors:” they had discovered the precise genetic sequences of the protein receptors responsible for the perception of smell.(Buck and Axel 183) Figure 2 Between the discovery in 1991 and the present, Buck, Axel, and others have continued to explore the organization of the olfactory system. The next big question facing Buck and Axel was, and still is, how the brain processes the information from the activated receptors. There are roughly 1,000 different receptors, but mammals can detect at least 10,000 odors. It has since been deduced that each of these odors must bind to several receptors, and it is the combination of receptors activated that indicate a particular odor.(The molecular logic of smell 157) “How does the brain identify which of the receptors have been turned on?” (The molecular logic of smell 158) Axel asked. In all other sensory systems, it is the specific pattern of the neurons that defines the sensation. Numerous experiments now suggest that the olfactory bulb provides a type of “map” identifying which of the receptors have been activated.(Scents and Sensibility: Towards a Molecular Logic of Perception 8) The challenge that remains for scientists is to demonstrate how the olfactory cortex interprets the map provided by the olfactory bulb, and from there, to determine how the cortex initiates the emotional and behavioral responses scents are known to invoke. Axel and Buck’s current research continues to focus on how the brain perceives different sensory information. Like a rose bud just before blooming, Buck and Axel’s research continues to peel away more and more petals, reaching closer and closer to the central truth behind the brain’s ability to interpret external stimuli and translate them into memories and feelings. Although the Nobel Assembly has said that the medical and scientific implications of Buck and Axel’s discovery remain unclear, their research discovery appears to have countless applications in both medicine and society.(Ritter 2) Their work could have implications for the study of psychology, appetite regulation, and cancer therapies. It may begin to explain why scents are often reminiscent of previous experiences and how scents can trigger instinctive behaviors.(The Scent of Success Fred Hutchinson Cancer Research Center) It may be helpful in determining what triggers overeating as scent and taste are intertwined.(Ritter 2) It may even help to solve the problem of dreadful tasting medicine endured by cancer patients worldwide.(The scent of Success Fred Hutchinson Cancer Research Center) It is clear that their hallmark discovery marks a major advance in the understanding of the nervous system, and that the general principles they have revealed about the olfactory system and signaling proteins may well apply to other sensory systems. Possibly what is most important about their work is that it defines one of the fundamental functions of every organism. “Research on the basic properties of cells and organisms turns out to be a remarkably powerful strategy for making breakthroughs in the understanding, treatment and prevention of cancer and other serious diseases.”(Nobel Prize Research: Understanding how the body functions often leads to medical breakthroughs Fred Hutchinson Cancer Research Center) Scientists cannot detect, prevent, or treat diseases without knowing how the cells function when they are healthy, and these fundamental breakthroughs will eventually lead to the most significant advancements. Buck and Axel’s studies confirm that there is much left to learn about the fundamental mechanisms of living organisms. To understand what seems to be the simple sensation of the scent of a rose or the taste of an apple is actually an area of research worthy of the greatest minds of the century. Buck and Axel’s work is even more noteworthy because of its revolutionary application of the study of genetics. Applying basic logic to the complex techniques of modern molecular and cellular biology, their work joined the study of anatomy with DNA sequencing. The sense of smell can no longer be thought of as simply the irresistible taste and scent of an apple, but instead as a complex a series of adenines, guanines, thymines, and cytosines. Welcome to scents in the 21st Century. Works Cited |
Physiology
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