Nobel season is here once more. Has it really been a year?
Last year, The Nobel Prize in Physiology or Medicine was shared by Sir John Gurdon at Cambridge, and Shinya Yamanaka, a Japanese researcher with labs in Kyoto and San Francisco, for their work on cell reprogramming.
This year, The Karolinska Institute in Stockholm announced the winners: James E. Rothman,; Randy W. Schekman, and Dr. Thomas C. Südhof, on 07 October 2013 "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells". Their basic research solved the mystery of how cells, which are factories producing molecules, organize a system to transport the molecules within cells and export them outside.
In laymans term, each cell is a factory that produces and exports molecules. Cells move molecules around using tiny membrane-enclosed packages called vesicles. In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are crucial. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. For instance, insulin is manufactured and released into the blood and signaling molecules called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. How do these vesicles know where and when to deliver their cargo?
This year’s Nobel Laureates, who will share the $1.2 million prize, discovered how cells get those vesicles to their intended destination at the intended time.
Randy Schekman, Cell biologist at the University of California, Berkeley was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast Saccharomyces cerevisiae cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman developed a genetic screen of the yeast to determine the genes that regulate vesicle trafficking. With this information, he identified 23 key genes, which can be divided into three classes that control vesicles at the Golgi complex, the endoplasmic reticulum, or the cell surface.
Last year, The Nobel Prize in Physiology or Medicine was shared by Sir John Gurdon at Cambridge, and Shinya Yamanaka, a Japanese researcher with labs in Kyoto and San Francisco, for their work on cell reprogramming.
This year, The Karolinska Institute in Stockholm announced the winners: James E. Rothman,; Randy W. Schekman, and Dr. Thomas C. Südhof, on 07 October 2013 "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells". Their basic research solved the mystery of how cells, which are factories producing molecules, organize a system to transport the molecules within cells and export them outside.
In laymans term, each cell is a factory that produces and exports molecules. Cells move molecules around using tiny membrane-enclosed packages called vesicles. In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are crucial. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. For instance, insulin is manufactured and released into the blood and signaling molecules called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. How do these vesicles know where and when to deliver their cargo?
This year’s Nobel Laureates, who will share the $1.2 million prize, discovered how cells get those vesicles to their intended destination at the intended time.
Randy Schekman, Cell biologist at the University of California, Berkeley was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast Saccharomyces cerevisiae cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman developed a genetic screen of the yeast to determine the genes that regulate vesicle trafficking. With this information, he identified 23 key genes, which can be divided into three classes that control vesicles at the Golgi complex, the endoplasmic reticulum, or the cell surface.
James Rothman a cell biologist at Yale University was also intrigued by the nature of the cell´s transport system. When studying vesicle transport in mammalian cells in the 1980s and 1990s, Rothman discovered that a protein complex known as SNARE (soluble N-ethylmaleimide-sensitive factor-activating protein receptor) enables vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. These proteins had already been discovered by others, but their function was unknown. Rothman determined that these proteins interact with high specificity: The SNARE protein on a particular target membrane is able to interact with only one or a few vesicle SNARE proteins. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell´s outer membrane to release its contents. Thus, Rothman unravelled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo.
It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery
It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery
Dr. Thomas Südhof, a biochemist at Stanford University, was interested in how nerve cells communicate with one another in the brain. The signalling molecules, neurotransmitters, are released from vesicles that fuse with the outer membrane of nerve cells by using the machinery discovered by Rothman and Schekman. But these vesicles are only allowed to release their contents when the nerve cell signals to its neighbours. How is this release controlled in such a precise manner? Calcium ions were known to be involved in this process and in the 1990s, Südhof searched for calcium sensitive proteins in nerve cells. He identified molecular machinery that responds to an influx of calcium ions and directs neighbour proteins rapidly to bind vesicles to the outer membrane of the nerve cell. He discovered how calcium regulates neurotransmitter release and that two proteins—complexin and synaptotagmin-1—are key players in calcium-mediated vesicle fusion. Synaptotagmin-1 acts as a calcium sensor during synaptic fusion. Complexin acts as a clamp during synaptic fusion to make sure that regulated exocytosis occurs instead of the vesicle simply being incorporated into the cell membrane. The zipper opens up and signal substances are released. Südhof´s discovery explained how temporal precision is achieved and how vesicles´ contents can be released on command. Südhof also identified the genes that are responsible for controlling the timing of vesicle fusion, particularly those involved in the release of neurotransmitters
The three Nobel Laureates have discovered a fundamental process in cell physiology. Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Glitches in vesicle transport occur in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. . Mutations in genes associated with the protein machinery are involved in specific diseases. For example, mutations in one of the genes are involved in certain forms of epilepsy. Thus, they have revolutionised understanding of how cells are organised which is fundamental to huge number of diseases. Without this wonderfully precise organization, the cell would lapse into chaos.
The three Nobel Laureates have discovered a fundamental process in cell physiology. Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Glitches in vesicle transport occur in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. . Mutations in genes associated with the protein machinery are involved in specific diseases. For example, mutations in one of the genes are involved in certain forms of epilepsy. Thus, they have revolutionised understanding of how cells are organised which is fundamental to huge number of diseases. Without this wonderfully precise organization, the cell would lapse into chaos.
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