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Nature Jan 2012Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The... (Review)
Review
Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control.
Topics: Animals; Clonal Evolution; Clone Cells; Genomics; Humans; Mutation; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 22258609
DOI: 10.1038/nature10762 -
Proceedings of the National Academy of... Jul 2015There are, in mankind, two kinds of heredity: biological and cultural. Cultural inheritance makes possible for humans what no other organism can accomplish: the... (Review)
Review
There are, in mankind, two kinds of heredity: biological and cultural. Cultural inheritance makes possible for humans what no other organism can accomplish: the cumulative transmission of experience from generation to generation. In turn, cultural inheritance leads to cultural evolution, the prevailing mode of human adaptation. For the last few millennia, humans have been adapting the environments to their genes more often than their genes to the environments. Nevertheless, natural selection persists in modern humans, both as differential mortality and as differential fertility, although its intensity may decrease in the future. More than 2,000 human diseases and abnormalities have a genetic causation. Health care and the increasing feasibility of genetic therapy will, although slowly, augment the future incidence of hereditary ailments. Germ-line gene therapy could halt this increase, but at present, it is not technically feasible. The proposal to enhance the human genetic endowment by genetic cloning of eminent individuals is not warranted. Genomes can be cloned; individuals cannot. In the future, therapeutic cloning will bring enhanced possibilities for organ transplantation, nerve cells and tissue healing, and other health benefits.
Topics: Animals; Cloning, Organism; Genetic Diseases, Inborn; Genetic Therapy; Genotype; Humans; Phylogeny; Social Values
PubMed: 26195738
DOI: 10.1073/pnas.1501798112 -
Nature Nov 2020Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk...
Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.
Topics: Cell Separation; Clone Cells; DNA Mutational Analysis; Humans; Immunophenotyping; Mutation; Myeloproliferative Disorders; Single-Cell Analysis
PubMed: 33116311
DOI: 10.1038/s41586-020-2864-x -
International Journal of Molecular... Mar 2020Somatic cell nuclear transfer (SCNT) has been an area of interest in the field of stem cell research and regenerative medicine for the past 20 years. The main biological... (Review)
Review
Somatic cell nuclear transfer (SCNT) has been an area of interest in the field of stem cell research and regenerative medicine for the past 20 years. The main biological goal of SCNT is to reverse the differentiated state of a somatic cell, for the purpose of creating blastocysts from which embryonic stem cells (ESCs) can be derived for therapeutic cloning, or for the purpose of reproductive cloning. However, the consensus is that the low efficiency in creating normal viable offspring in animals by SCNT (1-5%) and the high number of abnormalities seen in these cloned animals is due to epigenetic reprogramming failure. In this review we provide an overview of the current literature on SCNT, focusing on protocol development, which includes early SCNT protocol deficiencies and optimizations along with donor cell type and cell cycle synchrony; epigenetic reprogramming in SCNT; current protocol optimizations such as nuclear reprogramming strategies that can be applied to improve epigenetic reprogramming by SCNT; applications of SCNT; the ethical and legal implications of SCNT in humans; and specific lessons learned for establishing an optimized SCNT protocol using a mouse model.
Topics: Animals; Blastocyst; Cell Differentiation; Cellular Reprogramming; Cloning, Organism; Embryo, Mammalian; Embryonic Development; Embryonic Stem Cells; Epigenomics; Eye Enucleation; Humans; Nuclear Transfer Techniques; Oocytes
PubMed: 32230814
DOI: 10.3390/ijms21072314 -
Molecular Therapy : the Journal of the... May 2003
Topics: Animals; Animals, Genetically Modified; Biotechnology; Cloning, Organism; Sheep
PubMed: 12755157
DOI: 10.1016/s1525-0016(03)00109-6 -
Journal of Assisted Reproduction and... Aug 2001
Topics: Cloning, Organism; Embryo, Mammalian; Ethics; Humans; Research; Stem Cells
PubMed: 11599469
DOI: 10.1023/a:1016699024033 -
La Clinica Terapeutica 2023This scholarly article delves into the multifaceted domains of human cloning, encompassing its biological underpinnings, ethical dimensions, and broader societal... (Review)
Review
This scholarly article delves into the multifaceted domains of human cloning, encompassing its biological underpinnings, ethical dimensions, and broader societal implications. The exposition commences with a succinct historical and contextual overview of human cloning, segueing into an in-depth exploration of its biological intri-cacies. Central to this biological scrutiny is a comprehensive analysis of somatic cell nuclear transfer (SCNT) and its assorted iterations. The accomplishments and discoveries in cloning technology, such as successful animal cloning operations and advances in the efficiency and viability of cloned embryos, are reviewed. Future improvements, such as reprogramming procedures and gene editing technology, are also discussed. The discourse extends to ethical quandaries intrinsic to human cloning, entailing an extensive contemplation of values such as human dignity, autonomy, and safety. Furthermore, the ramifications of human cloning on a societal plane are subjected to scrutiny, with a dedicated emphasis on ramifications encompassing personal identity, kinship connections, and the fundamental notion of maternity. Culminating the analysis is a reiteration of the imperative to develop and govern human cloning technology judiciously and conscientiously. Finally, it discusses several ethical and practical issues, such as safety concerns, the possibility of exploitation, and the erosion of human dignity, and emphasizes the significance of carefully considering these issues.
Topics: Animals; Female; Humans; Pregnancy; Cloning, Organism; Nuclear Transfer Techniques; Self Concept; Biology
PubMed: 37994769
DOI: 10.7417/CT.2023.2492 -
Proceedings of the National Academy of... Jul 2015Domestic animals can be cloned using techniques such as embryo splitting and nuclear transfer to produce genetically identical individuals. Although embryo splitting is... (Review)
Review
Domestic animals can be cloned using techniques such as embryo splitting and nuclear transfer to produce genetically identical individuals. Although embryo splitting is limited to the production of only a few identical individuals, nuclear transfer of donor nuclei into recipient oocytes, whose own nuclear DNA has been removed, can result in large numbers of identical individuals. Moreover, clones can be produced using donor cells from sterile animals, such as steers and geldings, and, unlike their genetic source, these clones are fertile. In reality, due to low efficiencies and the high costs of cloning domestic species, only a limited number of identical individuals are generally produced, and these clones are primarily used as breed stock. In addition to providing a means of rescuing and propagating valuable genetics, somatic cell nuclear transfer (SCNT) research has contributed knowledge that has led to the direct reprogramming of cells (e.g., to induce pluripotent stem cells) and a better understanding of epigenetic regulation during embryonic development. In this review, I provide a broad overview of the historical development of cloning in domestic animals, of its application to the propagation of livestock and transgenic animal production, and of its scientific promise for advancing basic research.
Topics: Animals; Animals, Domestic; Animals, Genetically Modified; Biological Evolution; Cloning, Organism; Nuclear Transfer Techniques
PubMed: 26195770
DOI: 10.1073/pnas.1501718112 -
Journal of Veterinary Science Sep 2018Dogs serve human society in various ways by working at tasks that are based on their superior olfactory sensitivity. However, it has been reported that only about half... (Review)
Review
Dogs serve human society in various ways by working at tasks that are based on their superior olfactory sensitivity. However, it has been reported that only about half of all trained dogs may qualify as working dogs through conventional breeding management because proper temperament and health are needed in addition to their innate scent detection ability. To overcome this low efficiency of breeding qualified working dogs, and to reduce the enormous costs of maintaining unqualified dogs, somatic cell nuclear transfer has been applied in the propagation of working dogs. Herein, we review the history of cloning working dogs and evaluate the health development, temperaments, and behavioral similarities among the cloned dogs. We also discuss concerns about dog cloning including those related to birth defects, lifespan, and cloning efficiency.
Topics: Animals; Behavior, Animal; Cloning, Organism; Dogs; Nuclear Transfer Techniques; Temperament
PubMed: 29929355
DOI: 10.4142/jvs.2018.19.5.585 -
Gerontology 2017The number of species for which somatic cell nuclear transfer (SCNT) protocols are established is still increasing. Due to the high number of cloned farm, companion, and... (Review)
Review
The number of species for which somatic cell nuclear transfer (SCNT) protocols are established is still increasing. Due to the high number of cloned farm, companion, and sport animals, the topic of animal cloning never ceases to be of public interest. Numerous studies cover the health status of SCNT-derived animals, but very few cover the effects of SCNT on aging. However, only cloned animals that reach the full extent of the species-specific lifespan, doing so with only the normal age-related afflictions and diseases, would prove that SCNT can produce completely healthy offspring. Here, we review the available literature and own data to answer the question whether the aging process of cloned animals is qualitatively different from normal animals. We focus on 4 main factors that were proposed to influence aging in these animals: epigenetic (dys)regulation, accumulation of damaged macromolecules, shortened telomeres, and (nuclear donor-derived) age-related DNA damage. We find that at least some cloned animals can reach the species-specific maximum age with a performance that matches that of normal animals. However, for most species, only anecdotal evidence of cloned animals reaching high age is available. We therefore encourage reports on the aging of cloned animals to make further analysis on the performance of SCNT possible.
Topics: Aging; Animals; Cloning, Organism; DNA Damage; Epigenesis, Genetic; Telomere Shortening
PubMed: 27820924
DOI: 10.1159/000452444