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[
Harvey Lect,
1988]
Animal development involves a complex pattern of cell divisions ultimately leading to the generation of a highly diverse complement of cell types. What are the molecular mechanisms responsible for controlling patterns of cell division and for causing cells to become different from one another? To address the problem, my colleagues and I have been examining how genes control cell lineage and cell fate in the nematode Caenorhabditis elegans. The study of C. elegans was pioneered by Sydney Brenner (1973, 1974), who selected this organism because it is highly tractable genetically (e.g., see Herman, 1988)and because it is simple and essentially invariant in its cellular anatomy (the adult hermaphrodite is now known to contain a total of 959 somatic cell nuclei; Sulston and Horvitz, 1977; Kimble and Hirsh, 1979; Sulston et al., 1983). The invariance in C. elegans anatomy reflects a similar invariance in development. For example, the cell lineage of C. elegans is essentially the same in all individuals (Sulston and Horvitz, 1977; Kimble and Hirsh, 1979; Sulston et al., 1983). This cell lineage was determined by direct observation of living nematodes: individual nuclei were watched with the aid of Nomarski optics as they migrated,
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[
1983]
In 1974, Sydney Brenner published an elegant paper that described the genetic system of Caenorhabditis elegans and led to its use in research on a wide variety of topics, including aging (Brenner, 1974). Its small size (1mm as an adult) and determinate cell lineage has allowed a description of the entire somatic cell lineage from the one-cell stage to the adult (Sulston and Horvitz, 1977; Deppe et al., 1978; Kimble and Hirsh, 1979; Suslton et al., personal communication). Its ease of culture makes it an organism of choice for studies of various aspects of anatomy and physiology, including muscle formation and function (Zengel and Epstein, 1980; Mackenzie and Epstein, 1980), cuticle formation (Cox et al, 1981), neuroanatomy (Ward et al, 1975; Ware et al, 1975; Sulston et al, 1975), and behavior (Dusenbery, 1980). Several genes have been cloned by recombinant DNA techniques ablation (Kimble, 1981; Laufer and von Ehrenstin, 1981) procedures, as well as most of the modern molecular techniques, are in use.
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[
Human Genome News,
1999]
For the first time, scientists have the nearly complete genetic instructions for an animal that, like humans, has a nervous system, digests food, and reproduces sexually. The 97-million-base genome of the tiny roundworm Caenorhabditis elegans was deciphered by an international team led by Robert Waterston and John Sulston. The work was reported in a special issue of the journal Science (December 11, 1998) that featured six articles describing the history and significance of the accomplishment and some early sequence-analysis results.
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[
Genetics,
1990]
It has been ten years since we published in Genetics a paper describing the isolation and genetic characterization of cell lineage mutants of the nematode Caenorhabditis elegans (Horvitz and Sulston 1980). We have reviewed elsewhere what has been learned from the study of these and other mutants abnormal in the pattern of cell divisions and cell fates that characterizes C. elegans development (Horvitz 1988, 1990). Here we wish to reflect upon the days of our initial experiments, and to recall our excitement, our visions and our qualms as we elucidated the nematode cell lineage and began exploring methods for its
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[
Cell Death and Differentiation,
2004]
The award of the 2002 Nobel Prize to Brenner, Sulston, and Horvitz was one of the most satisfying I can recall, recognizing as it did the long sought meaningful conjunction of developmental biology with cancer research. Cancer is the ultimate derangement of growth and differentiation, affecting as it does the placenta, the embryo, the fetus, the infant, the child, the adolescent, and the adult of any age. Little wonder then that developmental biologists (embryologists in bygone days) have contributed so much to our understanding of cancer's origin. Indeed, the first coherent view of cancer was painted by the great embryologist Theodor Boveri in his heuristic volume of 1914 on the origin of cancer. Having observed the developmental aberrations of sea urchin embryos that can follow upon abnormalities of centrosome number and of the segregation of chromosomes, he associated causally the already known phenomenon of centrosome abnormalities of cancer with the latter's histopathology. He further posited that such pathology could be attributed to a single chromosomally aberrant cell.
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[
Science,
2004]
I'm one of the 2000 or so worm people who study the tiny nematode Caenorhabditis elegans. When we are asked by an outsider why we play with worms, our much-practiced answer goes something like this: In the
mid-1960s, Sydney Brenner chose C. elegans as a model organism for elucidating animal development and behavior because of the roundworm's cellular simplicity and advantages for genetic studies. The analysis of mutants helps us learn what the nonmutant versions of genes do. We know the location and lineage of every cell in an adult C. elegans as well as the wiring of all the worm's 302 neurons, down to the last synapse. C. elegans was the first multicellular organism to have its DNA completely sequenced (1), and many of its genes resemble those of humans and do similar jobs. The importance of such research was highlighted when Brenner, John Sulston, and Bob Horvitz were awarded the 2002 Nobel Prize in physiology or medicine for their worm work.
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[
Cell Death Differ,
2004]
Awarding the 2002 Nobel Prize in Physiology or Medicine to Sydney Brenner, H Robert Horvitz, and John E Sulston for 'their discoveries concerning the genetic regulation of organ development and programmed cell death (PCD)' highlights the significant contribution that the study of experimental organisms, such as the nematode Caenorhabditis elegans, has made to our understanding of human physiology and pathophysiology. Their studies of lineage determination in worms established the 'central dogma' of apoptosis: The BH3-only protein EGL-1 is induced in cells destined to die, interacts with the BCL-2-like inhibitor CED-9, displacing the adaptor CED-4, which then promotes activation of the caspase CED-3. The vast majority of cells undergoing PCD during development in C. elegans, as in vertebrates, are neurons. Accordingly, the genetic regulation of apoptosis is strikingly similar in nematode and vertebrate neurons. This review summarizes these similarities - and the important differences - in the molecular mechanisms responsible for neuronal PCD in C. elegans and vertebrates, and examines the implications that our understanding of physiological neuronal apoptosis may have for the diagnosis and treatment of acute and chronic human neurodegenerative
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[
Parasitol Today,
1992]
Like particle physics, biology is now a big expensive business, and like CERN, the genome projects alternately provoke admiration and detraction. Some feel that it would be more valuable to go for specific genes of interest rather than fill databases with sequences of junk DNA. The detractors would also say that the costs entailed, the limited intellectual and practical payback, and the ethical worries are too big to justify. But like the mythological juggernaut, once started it won't stop and it is indisputable that exciting information will come out of these efforts. Like some of the best discoveries many will be unexpected and have repercussions of immense value. This is indisputable on statistical grounds alone; the Caenorhabditis elegans genome is estimated to contain tens of thousands of genes. However, genome projects cannot be justified by serendipity and they do have obvious immediate value for tracing the genes involved in cancer and other inheritable disorders, and indeed for the multiple technological spin-offs. The C. elegans genome project is already bearing luscious fruit, of the 34 genes reported so far some of which have sequence similarity with genes such as glutathione reductase, an immunogenic protein from Trichostrongylus colubriformis, acetyl-CoA acetyltransferase and various other enzymes, growth factors and signal transducing components. Up-to-date cDNA data will be published by John Sulston and his colleagues in the early issues of Nature Genetics, due out this month.
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[
1982]
The small soil nematode Caenorhabditis elegans is an attractive organism for the molecular study of muscle function and development because of its anatomical simplicity and suitability for genetic and biochemical analysis (Brenner 1974; Sulston and Horvitz 1977). The body-wall musculature of C. elegans is composed of 95 cell disposed in four quadrants, which run the length of the animal beneath the cuticle. The musculature is obliquely striated, and the sarcomeres are oriented parallel to the long axis of the animal. Since these cells represent a large reaction of the animal mass, isolation of contractile proteins is comparatively simple (Epstein et al. 1974; Waterston et al. 1974, 1977a; Harris and Epstein 1977; Mackenzie and Epstein 1980). Mutants affecting the characteristic pattern of motility of C. elegans can be easily identified, and microscopic examination of these "uncoordinated," or unc strains, in the living animal by polarized light microscopy or, more carefully, by electron microscopy has led to the identification of 22 genes that produce altered muscle phenotypes (Waterston et al. 1980; Zengel and Epstein 1980). Of these, two are known to code for major structural proteins of muscle: The
unc-54 gene codes for the major heavy chain of myosin (Epstein et al. 1974; MacLeod et al. 1977b), whereas the un-15 gene codes for paramyosin, the core protein of the thick filaments (Waterston et al. 1974; MacLeod et al. 1977a; Harris and Epstein 1977).
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[
Curr Top Dev Biol,
2007]
Recent, surprising, and controversial discoveries have challenged conventional concepts regarding the origins and plasticity of stem cells, and their contributions to tissue regeneration, and highlight just how little is known about mammalian development in comparison to simpler model organisms. In the case of the transparent worm, Caenorhabditis elegans, Sulston and colleagues used a microscope to record the birth and death of every cell during its life, and the compilation of this "fate map" represents a milestone achievement of developmental biology. Determining a fate map for mammals or other higher organisms is more complicated because they are opaque, take a long time to mature, and have a tremendous number of cells. Consequently, fate mapping experiments have relied on tagging a progenitor cell with a dye or genetic marker in order to later identify its descendants. This approach, however, extracts little information because it demonstrates that a population of cells, all having inherited the same label, shares a common ancestor, but it does not reveal how cells in that population are related to one another. To avoid that problem, as well as technical limitations of current methods for mapping cell fate, we, and others, have developed a new strategy for retrospectively deriving cell fate maps by using phylogenetics to infer the order in which somatic mutations have arisen in the genomes of individual cells during development in multicellular organisms. DNA replication inevitably introduces mutations, particularly at repetitive sequences, every time a cell divides. It is thus possible to deduce the history of cell divisions by cataloging somatic mutations and phylogenetically reconstructing cell lineage. This approach has the potential to produce a complete mammalian cell fate map that, in principle, could describe the developmental lineage of any cell and help resolve outstanding questions of stem cell biology, tissue repair and maintenance, and aging.