Love at First Smell — The 2004 Nobel Prize in Physiology or Medicine
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《新英格兰医药杂志》
I should think we might fairly gauge the future of biological science, centuries ahead, by estimating the time it will take to reach a complete, comprehensive understanding of odor. It may not seem a profound enough problem to dominate all the life sciences, but it contains, piece by piece, all the mysteries.
— Lewis Thomas,
New England Journal of Medicine, 1980
In the spring of 1991, Linda Buck and Richard Axel reported a large family of rat genes that, they hypothesized, encoded odorant receptors.1 I was a graduate student at the time, and it was love at first sight for me. I read the title and abstract of the paper and decided then and there to study this extraordinary family of genes for my postdoctoral work, which I did with Axel. More important for the authors, their discovery also captured the attention of the scientific community, including the Nobel Committee at the Karolinska Institute. This fall, Buck and Axel were awarded the 2004 Nobel Prize in Physiology or Medicine "for their discoveries of odorant receptors and the organization of the olfactory system." Buck is only the seventh woman ever to receive the prize.
The chemical senses, smell and taste, are ancient sensory modalities. Even primitive unicellular organisms possess the means to sample the chemical composition of their external environment. Animals must locate and evaluate sources of food and avoid becoming food for predators. They must identify mating partners so that they can pass on their genes. Evolutionary pressure has thus produced elaborate olfactory systems that contribute to the survival of both the individual and the species.
In the late 1980s, evidence mounted that olfactory transduction makes use of a G protein–coupled pathway, but the literature also contained suggestions of other mechanisms. By 1988, several genes encoding G protein–coupled receptors had been cloned, and it had become clear that these receptors have common motifs in their amino acid sequences. Around the same time, the technique of polymerase chain reaction (PCR) was invented, allowing for the specific amplification of DNA sequences. There had been a few cases of the application of "degenerate" PCR for the amplification of distantly related DNA sequences. This variant of PCR facilitates the discovery of unknown genes that are related to known genes.
Enter Linda Buck, a sixth-year postdoctoral fellow in the laboratory of Richard Axel at Columbia University in New York. In 1988, during the pregenomic dark ages, she designed a clever strategy based on degenerate PCR to identify a large family of genes encoding G protein–coupled receptors that are expressed specifically in the rat olfactory epithelium.2 It took three years from the origin of the idea to the submission of the manuscript; submission to acceptance took six days. Functional proof that these genes encode odorant receptors was delivered seven years after publication.
The 1991 article has become the classic paper of the field of olfaction; it has been cited 1177 times. It sparked a molecular exploration of the sense of smell in vertebrates (mostly mice), followed in the late 1990s — in the wake of genome-sequencing projects — by rapid progress in the biology of receptors for vertebrate taste and invertebrate olfaction. In my view, olfaction research can be divided into two eras: before and after the publication of this paper. Although the term "breakthrough" is used all too often these days, the identification of odorant receptor genes is an excellent example of a landmark finding.
After the initial report, Buck and Axel went their separate ways. Buck established her own laboratory at Harvard Medical School in 1992 and moved in 2002 to the Fred Hutchinson Cancer Research Center in her native Seattle. In parallel and complementary articles, Buck and Axel described the expression patterns of odorant receptor genes in the olfactory epithelium and showed that axons of neurons expressing the same odorant receptor converge in the olfactory bulb on the same loci, termed glomeruli (see diagram). It turns out that the receptor is involved in the process of axonal convergence. Buck provided evidence in support of a combinatorial model for odor coding: an odorant can activate multiple receptors, and a receptor can be activated by multiple odorants. She also visualized the projections of second-order neurons from the olfactory bulb to the olfactory cortex.
Sorting out the Sense of Smell.
Three types of olfactory sensory neurons are shown, each expressing a different odorant receptor. Axons of neurons expressing the same receptor project to the same glomeruli in the olfactory bulb.
Genome sequencing has been used to identify about 1400 intact odorant receptor genes in rats, 1000 in mice, 350 in humans, and 400 in chimpanzees (there are also many defective odorant receptor genes, particularly in humans and chimpanzees). These genes thus constitute the largest gene repertoires known to date. Meanwhile, the tally of the total number of genes in mice and humans has dropped to roughly 25,000. This means that 4 percent of all genes in mice and 1.4 percent in humans encode odorant receptors.
The story of Buck and Axel is a prime example of the clarity that molecular biology can bring to mysteries — such as how the brain processes sensory information. Neither Buck nor Axel is a physiologist, but they worked out the basics of olfaction by applying the incisive logic of molecular biology. Their lasting achievement is to have elevated research in olfaction to a sophisticated molecular discipline.
Source Information
From the Rockefeller University, New York.
References
Buck L, Axel R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 1991;65:175-187.
Buck LB. The search for odorant receptors. Cell 2004;116:Suppl:S117-S119.(Peter Mombaerts, M.D., Ph)
— Lewis Thomas,
New England Journal of Medicine, 1980
In the spring of 1991, Linda Buck and Richard Axel reported a large family of rat genes that, they hypothesized, encoded odorant receptors.1 I was a graduate student at the time, and it was love at first sight for me. I read the title and abstract of the paper and decided then and there to study this extraordinary family of genes for my postdoctoral work, which I did with Axel. More important for the authors, their discovery also captured the attention of the scientific community, including the Nobel Committee at the Karolinska Institute. This fall, Buck and Axel were awarded the 2004 Nobel Prize in Physiology or Medicine "for their discoveries of odorant receptors and the organization of the olfactory system." Buck is only the seventh woman ever to receive the prize.
The chemical senses, smell and taste, are ancient sensory modalities. Even primitive unicellular organisms possess the means to sample the chemical composition of their external environment. Animals must locate and evaluate sources of food and avoid becoming food for predators. They must identify mating partners so that they can pass on their genes. Evolutionary pressure has thus produced elaborate olfactory systems that contribute to the survival of both the individual and the species.
In the late 1980s, evidence mounted that olfactory transduction makes use of a G protein–coupled pathway, but the literature also contained suggestions of other mechanisms. By 1988, several genes encoding G protein–coupled receptors had been cloned, and it had become clear that these receptors have common motifs in their amino acid sequences. Around the same time, the technique of polymerase chain reaction (PCR) was invented, allowing for the specific amplification of DNA sequences. There had been a few cases of the application of "degenerate" PCR for the amplification of distantly related DNA sequences. This variant of PCR facilitates the discovery of unknown genes that are related to known genes.
Enter Linda Buck, a sixth-year postdoctoral fellow in the laboratory of Richard Axel at Columbia University in New York. In 1988, during the pregenomic dark ages, she designed a clever strategy based on degenerate PCR to identify a large family of genes encoding G protein–coupled receptors that are expressed specifically in the rat olfactory epithelium.2 It took three years from the origin of the idea to the submission of the manuscript; submission to acceptance took six days. Functional proof that these genes encode odorant receptors was delivered seven years after publication.
The 1991 article has become the classic paper of the field of olfaction; it has been cited 1177 times. It sparked a molecular exploration of the sense of smell in vertebrates (mostly mice), followed in the late 1990s — in the wake of genome-sequencing projects — by rapid progress in the biology of receptors for vertebrate taste and invertebrate olfaction. In my view, olfaction research can be divided into two eras: before and after the publication of this paper. Although the term "breakthrough" is used all too often these days, the identification of odorant receptor genes is an excellent example of a landmark finding.
After the initial report, Buck and Axel went their separate ways. Buck established her own laboratory at Harvard Medical School in 1992 and moved in 2002 to the Fred Hutchinson Cancer Research Center in her native Seattle. In parallel and complementary articles, Buck and Axel described the expression patterns of odorant receptor genes in the olfactory epithelium and showed that axons of neurons expressing the same odorant receptor converge in the olfactory bulb on the same loci, termed glomeruli (see diagram). It turns out that the receptor is involved in the process of axonal convergence. Buck provided evidence in support of a combinatorial model for odor coding: an odorant can activate multiple receptors, and a receptor can be activated by multiple odorants. She also visualized the projections of second-order neurons from the olfactory bulb to the olfactory cortex.
Sorting out the Sense of Smell.
Three types of olfactory sensory neurons are shown, each expressing a different odorant receptor. Axons of neurons expressing the same receptor project to the same glomeruli in the olfactory bulb.
Genome sequencing has been used to identify about 1400 intact odorant receptor genes in rats, 1000 in mice, 350 in humans, and 400 in chimpanzees (there are also many defective odorant receptor genes, particularly in humans and chimpanzees). These genes thus constitute the largest gene repertoires known to date. Meanwhile, the tally of the total number of genes in mice and humans has dropped to roughly 25,000. This means that 4 percent of all genes in mice and 1.4 percent in humans encode odorant receptors.
The story of Buck and Axel is a prime example of the clarity that molecular biology can bring to mysteries — such as how the brain processes sensory information. Neither Buck nor Axel is a physiologist, but they worked out the basics of olfaction by applying the incisive logic of molecular biology. Their lasting achievement is to have elevated research in olfaction to a sophisticated molecular discipline.
Source Information
From the Rockefeller University, New York.
References
Buck L, Axel R. A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 1991;65:175-187.
Buck LB. The search for odorant receptors. Cell 2004;116:Suppl:S117-S119.(Peter Mombaerts, M.D., Ph)