7/27/2016
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`The Nobel Prize in Physiology or Medicine for 2002
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`The Nobel Prize in Physiology or Medicine for 2002
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`7 October 2002
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`The Nobel Assembly at Karolinska Institutet has today decided to award
`The Nobel Prize in Physiology or Medicine for 2002 jointly to
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`Sydney Brenner, H. Robert Horvitz and John E. Sulston
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`for their discoveries concerning "genetic regulation of organ development and programmed cell death"
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`Summary
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`The human body consists of hundreds of cell types, all originating from the fertilized egg. During the embryonic
`and foetal periods, the number of cells increase dramatically. The cells mature and become specialized to form
`the various tissues and organs of the body. Large numbers of cells are formed also in the adult body. In parallel
`with this generation of new cells, cell death is a normal process, both in the foetus and adult, to maintain the
`appropriate number of cells in the tissues. This delicate, controlled elimination of cells is called programmed cell
`death.
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`This year's Nobel Laureates in Physiology or Medicine have made seminal discoveries concerning the genetic
`regulation of organ development and programmed cell death. By establishing and using the nematode
`Caenorhabditis elegans as an experimental model system, possibilities were opened to follow cell division and
`differentiation from the fertilized egg to the adult. The Laureates have identified key genes regulating organ
`development and programmed cell death and have shown that corresponding genes exist in higher species,
`including man. The discoveries are important for medical research and have shed new light on the
`pathogenesis of many diseases.
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`Sydney Brenner (b 1927), Berkeley, CA, USA, established C. elegans as a novel experimental model
`organism. This provided a unique opportunity to link genetic analysis to cell division, differentiation and organ
`development – and to follow these processes under the microscope. Brenner's discoveries, carried out in
`Cambridge, UK, laid the foundation for this year's Prize.
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`John Sulston (b 1942), Cambridge, England, mapped a cell lineage where every cell division and
`differentiation could be followed in the development of a tissue in C. elegans. He showed that specific cells
`undergo programmed cell death as an integral part of the normal differentiation process, and he identified the
`first mutation of a gene participating in the cell death process.
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`Robert Horvitz (b 1947), Cambridge, MA, USA, has discovered and characterized key genes controlling cell
`death in C. elegans. He has shown how these genes interact with each other in the cell death process and that
`corresponding genes exist in humans.
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`Cell lineage – from egg to adult
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`http://www.nobelprize.org/nobel_prizes/medicine/laureates/2002/press.html
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`The Nobel Prize in Physiology or Medicine for 2002
`All cells in our body are descendents from the fertilized egg cell. Their relationship can be referred to as a
`cellular pedigree or cell lineage. Cells differentiate and specialize to form various tissues and organs, for
`example muscle, blood, heart and the nervous system. The human body consists of several hundreds of cell
`types, and the cooperation between specialized cells makes the body function as an integrated unit. To
`maintain the appropriate number of cells in the tissues, a fine-tuned balance between cell division and cell
`death is required. Cells have to differentiate in a correct manner and at the right time during development in
`order to generate the correct cell type.
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`It is of considerable biological and medical importance to understand how these complicated processes are
`controlled. In unicellular model organisms, e.g. bacteria and yeast, organ development and the interplay
`between different cells cannot be studied. Mammals, on the other hand, are too complex for these basic
`studies, as they are composed of an enormous number of cells. The nematode C. elegans, being multi-cellular,
`yet relatively simple, was therefore chosen as the most appropriate model system, which has then led to
`characterization of these processes also in humans.
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`Programmed cell death
`
`Normal life requires cell division to generate new cells but also the presence of cell death, so that a balance is
`maintained in our organs. In an adult human being, more than a thousand billion cells are created every day. At
`the same time, an equal number of cells die through a controlled "suicide process", referred to as programmed
`cell death.
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`Developmental biologists first described programmed cell death. They noted that cell death was necessary for
`embryonic development, for example when tadpoles undergo metamorphosis to become adult frogs. In the
`human foetus, the interdigital mesoderm initially formed between fingers and toes is removed by programmed
`cell death. The vast excess of neuronal cells present during the early stages of brain development is also
`eliminated by the same mechanism.
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`The seminal breakthrough in our understanding of programmed cell death was made by this year's Nobel
`Laureates. They discovered that specific genes control the cellular death program in the nematode C. elegans.
`Detailed studies in this simple model organism demonstrated that 131 of totally 1090 cells die reproducibly
`during development, and that this natural cell death is controlled by a unique set of genes.
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`The model organism C. elegans
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`Sydney Brenner realized, in the early 1960s, that fundamental questions regarding cell differentiation and
`organ development were hard to tackle in higher animals. Therefore, a genetically amenable and multicellular
`model organism simpler than mammals, was required. The ideal solution proved to be the nematode
`Caenorhabditis elegans. This worm, approximately 1 mm long, has a short generation time and is transparent,
`which made it possible to follow cell division directly under the microscope.
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`Brenner provided the basis in a publication from 1974, in which he broke new ground by demonstrating that
`specific gene mutations could be induced in the genome of C. elegans by the chemical compound EMS (ethyl
`methane sulphonate). Different mutations could be linked to specific genes and to specific effects on organ
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`development. This combination of genetic analysis and visualization of cell divisions observed under the
`microscope initiated the discoveries that are awarded by this year's Nobel Prize.
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`Mapping the cell lineage
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`John Sulston extended Brenner's work with C. elegans and developed techniques to study all cell divisions in
`the nematode, from the fertilized egg to the 959 cells in the adult organism. In a publication from 1976, Sulston
`described the cell lineage for a part of the developing nervous system. He showed that the cell lineage is
`invariant, i.e. every nematode underwent exactly the same program of cell division and differentiation.
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`As a result of these findings Sulston made the seminal discovery that specific cells in the cell lineage always die
`through programmed cell death and that this could be monitored in the living organism. He described the visible
`steps in the cellular death process and demonstrated the first mutations of genes participating in programmed
`cell death, including the nuc-1 gene. Sulston also showed that the protein encoded by the nuc-1 gene is
`required for degradation of the DNA of the dead cell.
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`Identification of "death genes"
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`Robert Horvitz continued Brenner's and Sulston's work on the genetics and cell lineage of C. elegans. In a
`series of elegant experiments that started during the 1970s, Horvitz used C. elegans to investigate whether
`there was a genetic program controlling cell death. In a pioneering publication from 1986, he identified the first
`two bona fide "death genes", ced-3 and ced-4. He showed that functional ced-3 and ced-4 genes were a
`prerequisite for cell death to be executed.
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`Later, Horvitz showed that another gene, ced-9, protects against cell death by interacting with ced-4 and ced-3.
`He also identified a number of genes that direct how the dead cell is eliminated. Horvitz showed that the human
`genome contains a ced-3-like gene. We now know that most genes that are involved in controlling cell death in
`C. elegans, have counterparts in humans.
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`Of importance for many research disciplines
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`The development of C. elegans as a novel experimental model system, the characterization of its invariant cell
`lineage, and the possibility to link this to genetic analysis have proven valuable for many research disciplines.
`For example, this is true for developmental biology and for analysis of the functions of various signaling
`pathways in a multicellular organism. The characterization of genes controlling programmed cell death in C.
`elegans soon made it possible to identify related genes with similar functions in humans. It is now clear that one
`of the signaling pathways in humans leading to cell death is evolutionarily well conserved. In this pathway ced-
`3-, ced-4- and ced-9-like molecules participate. Understanding perturbations in this and other signaling
`pathways controlling cell death are of prime importance for medicine.
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`Disease and programmed cell death
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`Knowledge of programmed cell death has helped us to understand the mechanisms by which some viruses and
`bacteria invade our cells. We also know that in AIDS, neurodegenerative diseases, stroke and myocardial
`infarction, cells are lost as a result of excessive cell death. Other diseases, like autoimmune conditions and
`cancer, are characterized by a reduction in cell death, leading to the survival of cells normally destined to die.
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`The Nobel Prize in Physiology or Medicine for 2002
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`Research on programmed cell death is intense, including in the field of cancer. Many treatment strategies are
`based on stimulation of the cellular "suicide program". This is, for the future, a most interesting and challenging
`task to further explore in order to reach a more refined manner to induce cell death in cancer cells.
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`Using the nematode C. elegans this year's Nobel Laureates have demonstrated how organ development and
`programmed cell death are genetically regulated. They have identified key genes regulating programmed cell
`death and demonstrated that corresponding genes exist also in higher animals, including man. The figure
`schematically illustrates the cell lineage (top left) and the programmed cell death (below) in C. elegans. The
`fertilized egg cell undergoes a series of cell divisions leading to cell differentiation and cell specialization,
`eventually producing the adult organism (top right). In C. elegans, all cell divisions and differentiations are
`invariant, i.e. identical from individual to individual, which made it possible to construct a cell lineage for all cell
`divisions. During development, 1090 cells are generated, but precisely 131 of these cells are eliminated by
`programmed cell death. This results in an adult nematode (the hermaphrodite), composed of 959 somatic cells.
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`MLA style: "The Nobel Prize in Physiology or Medicine for 2002 - Press Release". Nobelprize.org. Nobel Media
`AB 2014. Web. 27 Jul 2016. <http://www.nobelprize.org/nobel_prizes/medicine/laureates/2002/press.html>
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