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Dunn, L.C.
590
D un n , L . C .
Both interactions could be studied in vitro, using cultured animal cells. These discoveries set the stage for molecular characterization of DNA tumor virus genes and the role of viral genes in cell transformation. In 1963 Dulbecco moved to the newly established Salk Institute for Biological Studies in San Diego. Over the next 10 years his laboratory used the small DNA tumor viruses, polyoma and SV40, to explore mechanisms of neoplastic cell transformation, producing a series of fundamental insights into the process. He and his collaborators demonstrated that viral DNA persisted in transformed cells, and was integrated into cellular DNA. They showed that there were two classes of viral genes, `early' and `late,' which were transcribed from opposite strands of the viral DNA. Both classes of genes were expressed during productive infection, but only the early genes were expressed in transformed cells. They provided evidence that the activity of viral genes led to transcription of cellular genes. Using viral mutants, they showed that viral genes could influence the growth properties of transformed cells. In recognition of this work, Dulbecco was awarded the Nobel Prize for Physiology or Medicine in 1975, together with his former associates, David Baltimore and Howard Temin, who were honored for their discovery of reverse transcriptase. From 1972 to 1977 Dulbecco served as Deputy Director of Research at the Imperial Cancer Research Fund Laboratories in London, where he and his colleagues used antisera directed against polyoma tumor antigens to characterize virus-specific proteins in the plasma membrane of infected and transformed cells. These experiments led to the identification of the polyoma middle T antigen, the viral protein that is primarily responsible for cell transformation by polyoma. Dulbecco returned to the Salk Institute in 1977 to pursue a new interest in mammary cell biology and breast cancer. At the same time, he continued to reflect on the implications of genetic discoveries for understanding cancer. These thoughts led him to propose an international undertaking to sequence the human genome, described in an article published in Science, in 1986. He interrupted his laboratory research to assume the presidency of the Salk Institute in 1988, serving with distinction in that post until 1993. Thereafter he joined the Istituto di Tecnologie Biomediche Avanzate in Milan, where he directed the Italian Genome Project while continuing to study genes involved in mammary cell differentiation. At present he divides his time between the institute in Milan and the Salk Institute, where he is Distinguished Research Professor and President Emeritus. See also: DelbruÈck, Max; Luria, Salvador
Dunn, L.C. K Artzt Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0386
L.C. Dunn (1893±1974) was a naturalist interested in development and evolution at the organismal level. He embarked on his formal studies of biology at Dartmouth College less than 10 years after the rediscovery of Mendel's principles. Later, as a graduate student he found himself in the laboratory of W.E. Castle who was one of the very `roots' of the tree of genetics in the United States, being the first to devote himself entirely to this new field. While Dunn was grappling with applying these new principles, he was interrupted by World War I breaking out. After serving in France, he returned to finish his PhD and took up his first position in 1919 as a geneticist at the Storrs Agricultural Station in Connecticut. There, he cut his teeth on the analysis of single gene mutations in chickens and mice. Later, he was inspired to return to a more academic environment as well as make a fresh start on what he was by then calling `developmental genetics.' In 1928, he was offered what he considered to be a prestigious full professorship at Columbia University, where he had the awesome task of helping to fill the vacancies left by the retirement of E.B. Wilson and the departures of Morgan, Bridges, and Sturtevant to form a new laboratory at the California Institute of Technology. ``Dunny,'' as he came to be called by generations of students, was only 35 at the time. The system he was lucky enough to come to study eventually challenged several of Mendel's principles and their later additions. It was a phenotypic reporter system that until `knockout' technology became available, defined most of the known mammalian embryonic lethals. The T locus, as it was once called, was a region of the mouse genome defined by the dominant mutation T (Brachyury) causing a short tail; however, when homozygous, it was an embryonic lethal. Thus was described one of the first deviations from Mendel's 1:2:1 rule, because when Brachyury heterozygotes were mated together, one quarter of the progeny were lost and a 2:1 ratio resulted. T had been given to Dunn by its discoverer DobrovolskaiaZavadskaia along with two wild trapped mutations (t), which caused him to struggle with the concept of multiple alleles. The recessive mutations were also embryonic lethals that he later dubbed `pseudoalleles.' This was because even though they acted like alleles of T by interacting with it to cause tailless animals,
Dwarfism, in Mice 591 they suppressed normal recombination between T and nearby markers. He went on to describe over 100 such chromosomes that were ultimately found to contain six different lethals. Starting in 1935, along with a colleague Salome Glueckshon-Waelsch, he described the embryology of many different t lethal syndromes. The most blatant defiance of Mendel's rule of independent assortment was the fact that t haplotypes, as they later came to be called, suffered from transmission ratio distortion through males, so that over 90% of their progeny, instead of the expected 50%, carried the t. This phenomenon, which is still poorly understood, explains the maintenance of these mutations in wild populations of mice. During his Emeritus days and well into his retirement at the Nevis Biological Station of Columbia, Dunny worked actively in his mouse room and wrote extensively. As a young graduate student of his longtime colleague D. Bennett, I first encountered him in 1968 on his knees on the Nevis barn floor chasing an escapee wild mouse from Novosibirsk. He labored with love in that mouse room until he died there in 1974 at the age of 80. Dunn's perspective in the history of biology was a unique one. He spanned the age of the rediscovery of Mendel to the birth of molecular biology. Without understanding the significance at the time, he married the precise study of genetics to developmental biology. In that sense he debunked an intellectual dichotomy that in some corners was debated seriously until the advent of modern molecular biology, which unequivocally united the areas of developmental biology and genetics. As if a prophet, he commented on the progress of genetics in a presidential address presented at the 1961 meeting of the American Society of Human Genetics: What we may be witnessing now is only the beginning of a kind of renaissance . . . What seems to be most important, especially in its implications for the future, is the growing recognition of the logical unity of genetics . . . being concerned with a system of elements having similar attributes in all forms of life, can be seen to transcend the special problems of different categories of organisms.
Dunn thought and wrote broadly about scientific history, philosophy, and the human condition. He was indeed the renaissance geneticist.
Further Reading
Bennett D (1977) L.C. Dunn and his contribution to T-locus genetics. Annual Review of Genetics 11: 1±12.
See also: Brachyury Locus
Dwarfism K M Beckingham Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0389
Mutations that stunt growth and produce individuals with markedly reduced height, or dwarfism, are known in many species. One of the seven genetic traits originally analyzed by Mendel in his formulation of the laws of inheritance was dwarfism in the garden pea. Recently, Mendel's dwarf mutation has been shown to affect production of the hormone gibberellin, which is essential for internode elongation. In humans, mutations in at least 320 genes can cause short stature often in conjunction with other abnormalities. The most common form of human genetic dwarfism, achondroplasia, causes disrupted development of the long bone growth plates, producing disproportionate shortness of the limbs. In dogs, this defect is responsible for the distinctive body form of the dachshund and the basset hound. Human achondroplasia mutations are dominant mutations to the gene for fibroblast growth factor receptor 3 (FGFR3). Many of these human mutations appear to be spontaneously generated in a parental germline cell. See also: Achondroplasia
Dwarfism, in Mice K Douglas and S A Camper Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0388
Many spontaneous mouse mutants with growth insufficiency, or dwarfism, phenotypes exist. The genes mutated in these mice are important for normal growth regulation in mice and other mammals (Watkins-Chow and Camper, 1998). Several tissues are critical for normal growth. The hypothalamus secretes releasing factors that act directly on the adjacent pituitary gland. The pituitary, in response to hypothalamic signals, secretes hormones into the peripheral bloodstream. Finally, target organs act in response to the presence of pituitary hormones in the bloodstream. Target organs may also secrete factors that feed back to the hypothalamus and pituitary gland in order to regulate secretion of hormones.
D un n , L . C .
Both interactions could be studied in vitro, using cultured animal cells. These discoveries set the stage for molecular characterization of DNA tumor virus genes and the role of viral genes in cell transformation. In 1963 Dulbecco moved to the newly established Salk Institute for Biological Studies in San Diego. Over the next 10 years his laboratory used the small DNA tumor viruses, polyoma and SV40, to explore mechanisms of neoplastic cell transformation, producing a series of fundamental insights into the process. He and his collaborators demonstrated that viral DNA persisted in transformed cells, and was integrated into cellular DNA. They showed that there were two classes of viral genes, `early' and `late,' which were transcribed from opposite strands of the viral DNA. Both classes of genes were expressed during productive infection, but only the early genes were expressed in transformed cells. They provided evidence that the activity of viral genes led to transcription of cellular genes. Using viral mutants, they showed that viral genes could influence the growth properties of transformed cells. In recognition of this work, Dulbecco was awarded the Nobel Prize for Physiology or Medicine in 1975, together with his former associates, David Baltimore and Howard Temin, who were honored for their discovery of reverse transcriptase. From 1972 to 1977 Dulbecco served as Deputy Director of Research at the Imperial Cancer Research Fund Laboratories in London, where he and his colleagues used antisera directed against polyoma tumor antigens to characterize virus-specific proteins in the plasma membrane of infected and transformed cells. These experiments led to the identification of the polyoma middle T antigen, the viral protein that is primarily responsible for cell transformation by polyoma. Dulbecco returned to the Salk Institute in 1977 to pursue a new interest in mammary cell biology and breast cancer. At the same time, he continued to reflect on the implications of genetic discoveries for understanding cancer. These thoughts led him to propose an international undertaking to sequence the human genome, described in an article published in Science, in 1986. He interrupted his laboratory research to assume the presidency of the Salk Institute in 1988, serving with distinction in that post until 1993. Thereafter he joined the Istituto di Tecnologie Biomediche Avanzate in Milan, where he directed the Italian Genome Project while continuing to study genes involved in mammary cell differentiation. At present he divides his time between the institute in Milan and the Salk Institute, where he is Distinguished Research Professor and President Emeritus. See also: DelbruÈck, Max; Luria, Salvador
Dunn, L.C. K Artzt Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0386
L.C. Dunn (1893±1974) was a naturalist interested in development and evolution at the organismal level. He embarked on his formal studies of biology at Dartmouth College less than 10 years after the rediscovery of Mendel's principles. Later, as a graduate student he found himself in the laboratory of W.E. Castle who was one of the very `roots' of the tree of genetics in the United States, being the first to devote himself entirely to this new field. While Dunn was grappling with applying these new principles, he was interrupted by World War I breaking out. After serving in France, he returned to finish his PhD and took up his first position in 1919 as a geneticist at the Storrs Agricultural Station in Connecticut. There, he cut his teeth on the analysis of single gene mutations in chickens and mice. Later, he was inspired to return to a more academic environment as well as make a fresh start on what he was by then calling `developmental genetics.' In 1928, he was offered what he considered to be a prestigious full professorship at Columbia University, where he had the awesome task of helping to fill the vacancies left by the retirement of E.B. Wilson and the departures of Morgan, Bridges, and Sturtevant to form a new laboratory at the California Institute of Technology. ``Dunny,'' as he came to be called by generations of students, was only 35 at the time. The system he was lucky enough to come to study eventually challenged several of Mendel's principles and their later additions. It was a phenotypic reporter system that until `knockout' technology became available, defined most of the known mammalian embryonic lethals. The T locus, as it was once called, was a region of the mouse genome defined by the dominant mutation T (Brachyury) causing a short tail; however, when homozygous, it was an embryonic lethal. Thus was described one of the first deviations from Mendel's 1:2:1 rule, because when Brachyury heterozygotes were mated together, one quarter of the progeny were lost and a 2:1 ratio resulted. T had been given to Dunn by its discoverer DobrovolskaiaZavadskaia along with two wild trapped mutations (t), which caused him to struggle with the concept of multiple alleles. The recessive mutations were also embryonic lethals that he later dubbed `pseudoalleles.' This was because even though they acted like alleles of T by interacting with it to cause tailless animals,
Dwarfism, in Mice 591 they suppressed normal recombination between T and nearby markers. He went on to describe over 100 such chromosomes that were ultimately found to contain six different lethals. Starting in 1935, along with a colleague Salome Glueckshon-Waelsch, he described the embryology of many different t lethal syndromes. The most blatant defiance of Mendel's rule of independent assortment was the fact that t haplotypes, as they later came to be called, suffered from transmission ratio distortion through males, so that over 90% of their progeny, instead of the expected 50%, carried the t. This phenomenon, which is still poorly understood, explains the maintenance of these mutations in wild populations of mice. During his Emeritus days and well into his retirement at the Nevis Biological Station of Columbia, Dunny worked actively in his mouse room and wrote extensively. As a young graduate student of his longtime colleague D. Bennett, I first encountered him in 1968 on his knees on the Nevis barn floor chasing an escapee wild mouse from Novosibirsk. He labored with love in that mouse room until he died there in 1974 at the age of 80. Dunn's perspective in the history of biology was a unique one. He spanned the age of the rediscovery of Mendel to the birth of molecular biology. Without understanding the significance at the time, he married the precise study of genetics to developmental biology. In that sense he debunked an intellectual dichotomy that in some corners was debated seriously until the advent of modern molecular biology, which unequivocally united the areas of developmental biology and genetics. As if a prophet, he commented on the progress of genetics in a presidential address presented at the 1961 meeting of the American Society of Human Genetics: What we may be witnessing now is only the beginning of a kind of renaissance . . . What seems to be most important, especially in its implications for the future, is the growing recognition of the logical unity of genetics . . . being concerned with a system of elements having similar attributes in all forms of life, can be seen to transcend the special problems of different categories of organisms.
Dunn thought and wrote broadly about scientific history, philosophy, and the human condition. He was indeed the renaissance geneticist.
Further Reading
Bennett D (1977) L.C. Dunn and his contribution to T-locus genetics. Annual Review of Genetics 11: 1±12.
See also: Brachyury Locus
Dwarfism K M Beckingham Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0389
Mutations that stunt growth and produce individuals with markedly reduced height, or dwarfism, are known in many species. One of the seven genetic traits originally analyzed by Mendel in his formulation of the laws of inheritance was dwarfism in the garden pea. Recently, Mendel's dwarf mutation has been shown to affect production of the hormone gibberellin, which is essential for internode elongation. In humans, mutations in at least 320 genes can cause short stature often in conjunction with other abnormalities. The most common form of human genetic dwarfism, achondroplasia, causes disrupted development of the long bone growth plates, producing disproportionate shortness of the limbs. In dogs, this defect is responsible for the distinctive body form of the dachshund and the basset hound. Human achondroplasia mutations are dominant mutations to the gene for fibroblast growth factor receptor 3 (FGFR3). Many of these human mutations appear to be spontaneously generated in a parental germline cell. See also: Achondroplasia
Dwarfism, in Mice K Douglas and S A Camper Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0388
Many spontaneous mouse mutants with growth insufficiency, or dwarfism, phenotypes exist. The genes mutated in these mice are important for normal growth regulation in mice and other mammals (Watkins-Chow and Camper, 1998). Several tissues are critical for normal growth. The hypothalamus secretes releasing factors that act directly on the adjacent pituitary gland. The pituitary, in response to hypothalamic signals, secretes hormones into the peripheral bloodstream. Finally, target organs act in response to the presence of pituitary hormones in the bloodstream. Target organs may also secrete factors that feed back to the hypothalamus and pituitary gland in order to regulate secretion of hormones.