The reprogramming of metabolism has been identified as one of the hallmarks of cancer. It is becoming more and more frequent to connect other diseases with metabolic reprogramming. This article aims to argue that metabolic reprogramming is not driven by disease but instead is the main hallmark of metabolism, based on its dynamic behavior that allows it to continuously adapt to changes in the internal and external conditions.

The stunning possibility of “reprogramming” differentiated somatic cells to express a pluripotent stem cell phenotype (iPS, induced pluripotent stem cell) and the “ground state” character of pluripotency reveal fundamental features of cell fate regulation that lie beyond existing paradigms. The rarity of reprogramming events appears to contradict the robustness with which the unfathomably complex phenotype of stem cells can reliably be generated. This apparent paradox, however, is naturally explained by the rugged “epigenetic landscape” with valleys representing “preprogrammed” attractor (...) states that emerge from the dynamical constraints of the gene regulatory network. This article provides a pedagogical primer to the fundamental principles of gene regulatory networks as integrated dynamic systems and reviews recent insights in gene expression noise and fate determination, thereby offering a formal framework that may help us to understand why cell fate reprogramming events are inherently rare and yet so robust. (shrink)

The recent emergence of reprogramming technologies to convert brain cell types or epigenetically alter neurons and neural progenitors in vivo and in situ hold significant promises in brain repair and neuronal aging reversal. However, given the significant epigenetic and transcriptomic changes to components of the existing neuronal cells and network, we question if these reprogramming technology might inadvertently alter or erase memory engrams, conceivably resulting in changes in narrative identity or personality. We suggest that the nature of these (...) alterations might be less predictable compared to memory and personality changes known to be associated with diseases, drugs or brain stimulation therapies. While research in applying reprogramming technologies to neurological ailments and aging should continue, more targeted analyses should be put in place in animal experiments to gauge the severity and degree of memory alterations, and appropriate risk and benefit analyses should be conducted before these technologies move into human trials. (shrink)

Reprogramming technologies show that cellular identity can be reprogrammed, challenging the classical conception of cell differentiation as an irreversible process. If non-stem cells can be reprogrammed into stem cells, then what is it to be a stem cell, and what kind of property is stemness? This article addresses this question both philosophically and biologically, states the different possibilities, and illustrates their potential consequences for science with the example of anti-cancer therapies.

Louise Brown's birth in 1978 heralded a new era not just in reproductive technology, but in the relationship between science, cells, and society. For the first time, human embryos could be created, selected, studied, manipulated, frozen, altered, or destroyed, outside the human body. But with this possibility came a plethora of ethical questions. Is it acceptable to destroy a human embryo for the purpose of research? Or to create an embryo with the specific purpose of destroying it for research? In (...) an attempt to construct ethical and legal frameworks for the new era of cellular reprogramming, legislators and ethicists have tried to distinguish between different kinds of biological entity. We treat cells differently depending on whether they are human or animal, somatic cells or gametes, and on whether they are embryos or not. But this approach to the ethics of cellular reprogramming is doomed to failure for the simple reason that cellular reprogramming in itself destroys the distinctions that the law requires to function. In this article, we explore the historical trajectory of cellular reprogramming and its relationship with ethics and society. We suggest that the early hype of embryo research has not obviously fulfilled expectations, but since new avenues of research are continuously opening, it is hard to say definitely that these promises have been broken. We explore the forthcoming challenges posed by the creation of DNA from scratch in the laboratory, and the implications of this for understandings of identity, privacy, and reproduction. We conclude that while ethics used to seek answers in biological facts, this is no longer possible, and a new approach is required. (shrink)

The recent successful conversion of adult cells into induced pluripotent stem (iPS) cells through direct reprogramming opens a new chapter in the study of disease and the development of regenerative medicine. It also provides a historic opportunity to turn away from the ethically problematic use of embryonic stem cells isolated through the destruction of human embryos. Moreover, because iPS cells are patient specific, they render therapeutic cloning unnecessary. To maximize therapeutic benefit, adult stem cell research will need to be (...) pursued in parallel with studies using iPS cells. Among the four alternative methods presented by the President’s Council on Bioethics, direct reprogram- ming is the most ethically acceptable. Nonetheless, iPS cells are tainted by their association with the human embryonic stem cell lines, derived in the past, which will be required for their validation. This concern is one that can be resolved. Human iPS cells will serve to stem the tide of human embryonic stem cell research, changing it and diverting stem cell research in a more ethical direction. (shrink)

Rejuvenation of cells by reprogramming toward the pluripotent state raises increasing attention. In fact, generation of induced pluripotent stem cells (iPSCs) completely reverses age‐associated molecular features, including elongation of telomeres, resetting of epigenetic clocks and age‐associated transcriptomic changes, and even evasion of replicative senescence. However, reprogramming into iPSCs also entails complete de‐differentiation with loss of cellular identity, as well as the risk of teratoma formation in anti‐ageing treatment paradigms. Recent studies indicate that partial reprogramming by limited exposure (...) to reprogramming factors can reset epigenetic ageing clocks while maintaining cellular identity. So far, there is no commonly accepted definition of partial reprogramming, which is alternatively called interrupted reprogramming, and it remains to be elucidated how the process can be controlled and if it resembles a stable intermediate state. In this review, we discuss if the rejuvenation program can be uncoupled from the pluripotency program or if ageing and cell fate determination are inextricably linked. Alternative rejuvenation approaches with reprogramming into a pluripotent state, partial reprogramming, transdifferentiation, and the possibility of selective resetting of cellular clocks are also discussed. (shrink)

"The total amount of suffering per year in the natural world is beyond all decent contemplation. During the minute that it takes me to compose this sentence, thousands of animals are being eaten alive, others are running for their lives, whimpering with fear, others are being slowly devoured from within by rasping parasites, thousands of all k inds are dying of starvation, thirst and disease. It must be so." -/- —Richard Dawkins, River Out of Eden (1995).

Current methods of reprogramming differentiated cells into induced pluripotent stem cells remain slow and inefficient. In a recent report published online in Nature, Bhutani et al.1 developed a cell fusion strategy, achieving quick and efficient reprogramming toward pluripotency. Using this assay, they identified an immune system protein called activation‐induced cytidine deaminase, or AID, which unexpectedly is actually able to “aid” in reprogramming due to its involvement in DNA demethylation that is required for induction of the two key (...) pluripotency genes, Oct4 and Nanog. More recently, Popp et al. 2 also reported online in Nature that AID is important for complete cell reprogramming in mammals. Together, these findings provide new insights into how cells are reprogrammed, identify the specific role of AID in cell fate reversal, and advance the field of regenerative medicine. (shrink)

DNA methylation is a repressive epigenetic mark vital for normal development. Recent studies have uncovered an unexpected role for the DNA methylome in ensuring the correct targeting of the Polycomb repressive complexes throughout the genome. Here, we discuss the implications of these findings for cancer, where DNA methylation patterns are widely reprogrammed. We speculate that cancer‐associated reprogramming of the DNA methylome leads to an altered Polycomb binding landscape, influencing gene expression by multiple modes. As the Polycomb system is responsible (...) for the regulation of genes with key roles in cell fate decisions and cell cycle regulation, DNA methylation induced Polycomb mis‐targeting could directly drive carcinogenesis and disease progression.Editor's suggested further reading in BioEssays Unmasking risk loci: DNA methylation illuminates the biology of cancer predisposition Abstract. (shrink)

Reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine. However, a debate over which method is better, somatic cell nuclear transfer (SCNT) or induced pluripotent stem (iPS) cells, still persists. Both approaches have the potential to generate patient‐specific pluripotent stem cells for replacement therapy. Yet, although SCNT has been successfully applied in various vertebrates, no human pluripotent stem cells have been generated by SCNT due to technical, legal and ethical difficulties. On the other hand, (...) human iPS cell lines have been reported from both healthy and diseased individuals. A recent study reported the generation of triploid human pluripotent stem cells by transferring somatic nuclei into oocytes, a variant form of SCNT. In this essay, we discuss this progress and the potentials of these two reprogramming approaches for regenerative medicine. (shrink)

What makes something an embryo—as opposed to what is actually, and not just in biotech parlance, a collection of cells? This question has come to the fore in recent years with proposals for producing embryonic stem cells for research. While some of those opposed to use of standard embryonic stem cells emphasise that adult cells have a clinical track record, others argue that there may be further benefits obtainable from cells very like those of embryos, provided such cells can be (...) derived in new ways. Rather than deriving them in ways that kill or otherwise endanger a living human embryo, they could be obtained from an entity that merely resembles a human embryo sufficiently closely for its cells to be of use. Such an entity might be created after introducing genetic changes to an ovum before it is activated by, for example, a cloning-type procedure, such that a gene essential to embryogenesis will be either absent, blocked in its expression, or overexpressed.1,2 The claim is that the ovum could be made to give rise to embryonic stem cells—mere living parts—without ever giving rise to a whole embryo, who is killed to obtain them. Whereas cloning “proper” winds back the specialisation of the cell nucleus to a point where a whole embryo is formed who has not yet specialised its cells, oocyte-assisted reprogramming , it is claimed, would wind back the specialisation merely to an intermediate point at which no embryo is created. Other methods proposed for deriving pseudoembryonic cells include parthenogenesis, in which an ovum is activated without a sperm, or even the insertion of an adult cell nucleus.1MORAL STATUS OF THE EMBRYOIn this paper, I assume that a genuine …. (shrink)

Despite the progress achieved over the last decade after the birth of the first cloned mammal, the efficiency of reproductive cloning remains invariably low. However, research aiming at the use of nuclear transfer for the production of patient‐tailored stem cells for cell/tissue therapy is progressing rapidly. Yet, reproductive cloning has many potential implications for animal breeding, transgenic research and the conservation of endangered species. In this article we suggest that the changes in the epi‐/genotype observed in cloned embryos arise from (...) unbalanced nuclear reprogramming between parental chromosomes. It is probable that the oocyte reprogramming machinery, devised for resident chromosomes, cannot target the paternal alleles of somatic cells. We, therefore, suggest that a reasonable approach to balance this asymmetry in nuclear reprogramming might involve the transient expression in donor cells of chromatin remodelling proteins, which are physiologically expressed during spermatogenesis, in order to induce a male‐specific chromatin organisation in the somatic cells before nuclear transfer. BioEssays 30:66–74, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

This paper makes use of an example of Williams’s, an example involving so-called psychological deprogramming–reprogramming, in arguing that procedures such as Teletransportation would not provide what matters to us in our self-interested concern for the future. This is so because the beliefs and other psychological states of a resultant person would not be appropriately causally dependent on any beliefs or other psychological states of the original person.

In lieu of an abstract, here is a brief excerpt of the content:Direct Nuclear Reprogramming: Response to Condic, Lee, and GeorgeGerard Magill, Ph.D. and William B. NeavesWe read with great interest the response of Maureen Condic, Patrick Lee, and Robert George (2009) to our essay, “Ontological and Ethical Implications of Direct Nuclear Reprogramming” in the March 2009 issue of the Kennedy Institute of Ethics Journal (Magill and Neaves 2009). Much of their response addressed issues that are not in (...) dispute: somatic cells are not zygotes, neurons and hepatocytes are different, growth-factor signals from the trophoblast influence development of the inner cell mass, membranes derived from the trophectoderm are critically required for embryonic survival, and stem cells cannot produce a fetus “on their own.”The crucial point of disagreement deals with the fact that iPS cells are not totipotent but zygotes are. Zygotes can generate their own placental structures while iPS cells must be given them through tetraploid complementation. Condic, Lee, and George consider totipotency to be crucial to natural potentiality. We present an alternative view in our essay (Magill and Neaves 2009, pp. 28–29). Placental structures make no lasting contribution to the postnatal organism, and the equivalency of iPS cells with the inner cell mass of the blastocyst is apparent from tetraploid complementation experiments.The respondents acknowledge the following:... somatic cells can be “converted” into zygotes by the process of somatic cell nuclear transfer (SCNT) or direct reprogramming in combination with tetraploid complementation—just as sperm and egg cells can be “converted” into a zygote by the process of natural fertilization—....(Condic, Lee, and George 2009, p. 35)As the respondents recognize, different ways of manipulating cells can lead to embryogenesis: sperm and egg cells in the process of natural fertilization, the enucleated egg and an ordinary body cell in the process of somatic cell nuclear transfer, and reprogrammed skin cells and a tetraploid blastocyst in the case of induced pluripotent stem (iPS) cells. In each case, different cells are manipulated—or “converted” in the respondents’ terminology—in a process that alters their biological fate within a supportive environment facilitating embryogenesis.The developmental potential that resides in the human genome does not unfold in isolation, not even in a zygote. In all cases, whether involving a zygote or an iPS cell, interaction with a supportive environment is required to express the developmental program residing in the genome. [End Page 201]This biological reality supports what we have described as “early cellular development along the continuum of natural potentiality that can result in the formation of a fetus” (Magill and Neaves 2009, p. 30), and it presents a significant challenge to the natural potentiality argument.Gerard MagillVernon F. Gallagher Chair for the Integration of Science, Theology, Philosophy, and Law, and Professor, Center for Healthcare Ethics Duquesne University Pittsburgh, PA.William B. NeavesPresident and CEO Stowers Institute for Medical Research and Professor of Basic Medical Science University of Missouri at Kansas City School of Medicine Kansas City, MOReferencesCondic, Maureen L.; Lee, Patrick; and George, Robert P. 2008. Ontological and Ethical Implications of Direct Nuclear Reprogramming: Response to Magill and Neaves. Kennedy Institute of Ethics Journal 19: 33–40. Google ScholarMagill, Gerard, and Neaves William B. 2009. Ontological and Ethical Implications of Direct Nuclear Reprogramming. Kennedy Institute of Ethics Journal 19: 23–32. Google ScholarCopyright © 2009 The Johns Hopkins University Press... (shrink)

Scientific breakthroughs rarely yield the potential to engage a foundational ethical question. Recent studies on direct reprogramming of human skin cells reported by the Yamanaka lab in Japan and the Thomson lab in Wisconsin suggest that scientists may have crossed both a scientific and an ethical threshold. The fascinating science of direct nuclear reprogramming highlights empirical data that may clarify the ontological status of cellular activity in the early stages of what could become a human fetus and justify (...) ethical options for research in this controversial field. The ontological and ethical implications that accrue here are connected with the biological or natural potentiality of these cells. (shrink)

Emerging evidence suggests that microRNA (miRNA)‐mediated post‐transcriptional gene regulation plays an essential role in modulating embryonic stem (ES) cell pluripotency maintenance, differentiation, and reprogramming of somatic cells to an ES cell‐like state. Investigations from ES cell‐enriched miRNAs, such as mouse miR‐290 cluster and human miR‐302 cluster, and ES cell‐depleted miRNAs such as let‐7 family miRNAs, revealed a common theme that miRNAs target diverse cellular processes including cell cycle regulators, signaling pathway effectors, transcription factors, and epigenetic modifiers and shape their (...) protein output. The combinatorial effects downstream of miRNA action allow miRNAs to modulate cell‐fate decisions effectively. Furthermore, the transcription and biogenesis of miRNAs are also tightly regulated. Thus, elucidating the interplay between miRNAs and other modes of gene regulation will shed new light on the biology of pluripotent stem cells and somatic cell reprogramming. (shrink)

This essay aims to tell the story of the “altered nuclear transfer-oocyte assisted reprogramming,” or ANT-OAR, proposal—from its conception by Professor William Hurlbut of the President’s Council on Bioethics—to its adoption and promotion by a group of conservative, mostly Catholic philosophers, theologians and scientists—to its eventual demise in Congress. It also will give some reflections on how ANT-OAR promotes a genetically deterministic view of the human organism and can lead down a slippery slope into a future in which human (...) cloning and human genetic engineering are more acceptable. For these reasons, it will be argued, ANT-OAR should be opposed by all who are against human genetic modification regardless of their political orientation. (shrink)

The mammalian egg employs a wide spectrum of epigenome modification machinery to reprogram the sperm nucleus shortly after fertilization. This event is required for transcriptional activation of the paternal/zygotic genome and progression through cleavage divisions. Reprogramming of paternal nuclei requires replacement of sperm protamines with canonical and non‐canonical histones, covalent modification of histone tails, and chemical modification of DNA (notably oxidative demethylation of methylated cytosines). In this essay we highlight the role maternal histone variants play during developmental reprogramming (...) following fertilization. We discuss how reduced maternal histone variant incorporation in somatic nuclear transfer experiments may explain the reduced viability of resulting embryos and how knowledge of repressive and activating maternal factors may be used to improve somatic cell reprogramming. (shrink)

The paper by Magill and Neaves in this issue of the Journal attempts to rebut the "natural potency" position, based on recent advances in direct reprogramming of somatic cells to yield "induced pluripotent stem" (iPS) cells. As stated by the authors, the natural potency position holds that because "a human embryo directs its own integral organismic function from its beginning . . . there is a whole, albeit immature, and distinct human organism that is intrinsically valuable with the status (...) of inviolability and deserving full moral respect" (p. 26). The authors boldly assert that "The recent production of iPS . . . highlights a prima facie absurdity for the natural potentiality argument" (p. 29). Yet the argument against natural potency is both logically flawed and based on a characterization of the scientific evidence that is factually inaccurate. (shrink)

The phenomenal proliferation of scientific studies into the nature of induced pluripotent stem (iPS) cells following publication of the findings of Takahashi and Yamanaka little more than 2 years ago, have significantly expanded our understanding of cellular mechanisms relating to cell lineage, differentiation, and proliferation. While the full potential of iPS cell lineages for both scientific tool and therapeutic applications is as yet unclear, findings from several lines of investigation suggests that multipotential and terminally differentiated cells from an array of (...) cell types are competent to undergo epigenetic reprogramming to a pluripotential state. The nature of this pluripotential state appears to be similar to, but not identical with that previously described for embryonic stem (ES) cells. Understanding the nature of this induced reprogrammed state will be critical to determining the full potential of iPS cells. Recently, this issue has been examined through an integrated analysis of the genome in fully and partially reprogrammed iPS cell lineages. These results provide a window onto the temporal components of reprogramming and suggest mechanisms by which the efficacy of reprogramming can be enhanced. (shrink)

First put forth in June 2005, the altered nuclear transfer-oocyte assisted reprogramming (ANT-OAR) proposal has been promoted as an ethically-acceptable alternative to the embryo-destructive methods now used to obtain embryonic stem cells. According to its proponents, the goal of ANT-OAR is to use the cloning process to create a pluripotent stem cell. This would be achieved through overexpression of the transcription factor Nanog (or a hypothetical substitute) both in the enucleated egg cell and in the somatic cell prior to (...) transfer of its nucleus. Although the ethical acceptability of ANT-OAR has been publicly debated, its scientific feasibility has not. This paper aims to help rectify this situation. It argues that ANT-OAR, as currently conceived, cannot realistically work. It presents evidence from the scientific literature showing that Nanog cannot single-handedly establish pluripotency in cells, but rather works together with a network of other transcription factors to maintain pluripotency. It argues that ANT-OAR is based on a flawed understanding of stem cell biology, and emphasizes that, in this debate about embryonic stem cells, scientists must strive to accurately and realistically assess the feasibility of the embryo research strategies they propose. (shrink)

A recent analysis of genome‐wide expression patterns and regulatory motif content of paralogous yeast genes1 strongly suggests that mutational robustness (backup) between paralogous genes is achieved via transcriptional reprogramming of one paralog to compensate for the loss or silencing of the other. BioEssays 27:865–868, 2005. Published 2005 Wiley Periodicals, Inc.

Emerging data connects the aging process in dermal fibroblasts with metabolic reprogramming, provided by enhanced fatty acid oxidation and reduced glycolysis. This switch may be caused by a significant expansion of the dermal white adipose tissue (dWAT) layer in aged, hair‐covered skin. Dermal adipocytes cycle through de‐differentiation and re‐differentiation. As a result, there is a strongly enhanced release of free fatty acids into the extracellular space during the de‐differentiation of dermal adipocytes in the catagen phase of the hair follicle (...) cycle. Both caveolin‐1 and adiponectin are critical factors influencing these processes. Controlling the expression levels of these two factors also offers the ability to manipulate the metabolic preferences of the different cell types within the microenvironment of the skin, including dermal fibroblasts. Differential expression of adiponectin and caveolin‐1 in the various cell types may also be responsible for the cellular metabolic heterogeneity within the cells of the skin. (shrink)

On the basis of the evidence that tumor development is suppressed by the embryonic microenvironment, some experiments using the factors taken from Zebrafish embryo at precise stages of cell differentiation were made. These experiments demonstrated a significant growth inhibition on different tumor cell lines in vitro. The observed mechanism of tumor growth inhibition is connected with the key-role cell cycle regulation molecules, such as p53 and pRb, which are modified by transcriptional or post-translational processes. Research on apoptosis and differentiation revealed (...) that treatment with these factors induces caspase-3 with a p73 apoptotic-dependent pathway activation and a concurrent significant normalization of e-cadherin and beta-catenin ratio. Other experiments found a synergistic effect on the colon cancer proliferation curve after the concurrent treatment with these factors and 5-fluorouracil. Finally, a product prepared for human therapy demonstrated 19.8% regression and 16% stable disease in an... (shrink)

Language and life history can be related functionally through the study of human ontogeny, thus usefully informing our understanding of several unique aspects of the evolution of species. The operational principles outlined by Locke & Bogin (L&B) demonstrate that the present can provide a useful framework for understanding the past.

Organismal form arises by the coordinated movement, arrangement, and activity of cells. In metazoans, most morphogenetic programs that establish the recognizable body plan of any given species are initiated during the developmental period, although in many species growth continues throughout life. By comparing the cellular and molecular development of the bilaterians (bilaterally symmetrical animals) to the development of their closest outgroup, the cnidarians, it appears that morphogenesis and the cell fate specification associated with germ layer formation during the process of (...) gastrulation are separately controlled by two distinct downstream pathways (canonical and planar cell polarity) of Wnt signaling. Furthermore, a fundamental change in the early developmental program, the positioning of the site of gastrulation, allowed the spatial separation of gene regulatory networks that facilitated the rapid diversification of bilaterian body plans. (shrink)

Adequate reprogramming of cellular metabolism in response to stresses or suboptimal growth conditions involves a myriad of coordinated changes that serve to promote cell survival. As protein synthesis is an energetically expensive process, its regulation under stress is of critical importance. Reprogramming of messenger RNA (mRNA) translation involves well‐understood stress‐activated kinases that target components of translation initiation machinery, resulting in the robust inhibition of general translation and promotion of the translation of stress‐responsive proteins. Translational arrest of mRNAs also (...) results in the accumulation of transcripts in cytoplasmic foci called stress granules. Recent studies focus on the key roles of transfer RNA (tRNA) in stress‐induced translational reprogramming. These include stress‐specific regulation of tRNA pools, codon‐biased translation influenced by tRNA modifications, tRNA miscoding, and tRNA cleavage. In combination, signal transduction pathways and tRNA metabolism changes regulate translation during stress, resulting in adaptation and cell survival. This review examines molecular mechanisms that regulate protein synthesis in response to stress. (shrink)

Recent reports that human pluripotent stem cells can be captured in a spectrum of states with variable properties has prompted a re‐evaluation of how pluripotency is acquired and stabilised. The latest additions to the stem cell hierarchy open up opportunities for understanding human development, reprogramming, and cell state transitions more generally. Many of the new cell lines have been collectively termed ‘naïve’ human pluripotent stem cells to distinguish them from the conventional ‘primed’ cells. Here, several transcriptional and epigenetic hallmarks (...) of human pluripotent states in the recently described cell lines are reviewed and evaluated. Methods to derive and identify human naïve pluripotent stem cells are also discussed, with a focus on the uses and future developments of state‐specific reporter cell lines and cell‐surface proteins. Finally, opportunities and uncertainties in naïve stem cell biology are highlighted, and the current limitations of human naïve pluripotent stem cells considered, particularly in the context of differentiation. (shrink)

Basic Questions The following are among the basic questions discussed in this essay: (1) What is the concept of a person? (2) What properties make something a person? (3) Is personhood a matter of degree? (4) Is potential personhood morally significant? (5) Is species membership morally significant? (6) Why is the concept of a person important? Important Arguments The important arguments that are examined include the following: (1) Counterexample arguments: (a) Whole brain death and upper brain death. (b) Brain transplants. (...) (c) Currently irreparable damage versus impossibility of resuscitation. (2) The reprogramming argument. (3) The generalized potentialities argument. (4) Potentialities and comas: active versus passive. (5) Anti-speciesism and the common sense generality of the concept of a person: deities, angels, disembodied souls, extraterrestrials. Important Positions Among the important positions considered are the following: (1) Consciousness is sufficient for personhood. (2) Self-consciousness is necessary for personhood. (3) The capacity for thought is necessary for personhood. (4) Moral agency is necessary for personhood. (shrink)

Cells can transit between a range of stable epithelial and mesenchymal states and this has allowed the evolution of complex body forms. Epithelial to mesenchymal transition (EMT) and its reverse, mesenchymal to epithelial transition (MET), occur sequentially in development and organogenesis. EMT often accompanies transitions between stem‐like cells and their more differentiated progeny, as occurs at gastrulation, although the relevance of this had not been clarified. New findings from the cancer and cell reprogramming fields suggest that EMT and MET (...) can act as essential portals to stem cell character. Here, we review these findings in the broader context of EMT and MET with emphasis on stem cell biology. Using the heart as an example, we also explore the potential role of EMT/MET in organ regeneration. Understanding EMT and MET at a network level will give us new tools to probe stem cell character and enhance tissue repair. (shrink)

Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, (...) because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy. (shrink)

Embryonic stem cells (ESCs) are now classified into two types of pluripotency: “naïve” and “primed” based upon their differing characteristics. Conventional human ESCs have much more in common with mouse epiblast stem cells and are now deemed to be primed. Naïve human ESCs that resemble mouse ESCs have recently been generated from their primed counterpart by cellular reprogramming. Isolation of naïve hESCs from human embryos has proven to be difficult. Is the inability to capture naïve hESCs the result of (...) suboptimal derivation conditions or because they are so transient they cannot be “captured” in vitro? Prevailing evidence surrounding this issue are inconclusive and require additional human embryo research. However, negative public opinion regarding human embryo research, may make this an uphill battle. The solution may come from cellular reprogramming. (shrink)

Human induced pluripotent stem cells can be obtained from somatic cells, and their derivation does not require destruction of embryos, thus avoiding ethical problems arising from the destruction of human embryos. This type of stem cell may provide an important tool for stem cell therapy, but it also results in some ethical concerns. It is likely that abnormal reprogramming occurs in the induction of human induced pluripotent stem cells, and that the stem cells generate tumors in the process of (...) stem cell therapy. Human induced pluripotent stem cells should not be used to clone human beings, to produce human germ cells, nor to make human embryos. Informed consent should be obtained from patients in stem cell therapy. (shrink)

Direct reprogramming of human skin cells makes available a source of pluripotent stem cells without the perceived evil of embryo destruction, but the advent of such a powerful biotechnology entangles stem cell research in other forms of moral complicity. Induced pluripotent stem cell (iPSC) research had its origins in human embryonic stem cell research and the projected biomedical applications of iPS cells almost certainly will require more embryonic stem cell research. Policies that inhibit iPSC research in order to avoid (...) moral complicity are themselves complicit in preventable harms to patients. Moral complicity may be unavoidable, but a Blue Ribbon Panel charged with assessing the need for additional embryonic stem cell lines may ease a transition from embryonic stem cell research to clinical applications of iPS cells. (shrink)

Recent advances in reprogramming technology do not bypass the ethical challenge of embryo sacrifice. Induced pluripotent stem cell (iPS) research has been and almost certainly will continue to be conducted within the context of embryo sacrifice. If human embryos have moral status as human beings, then participation in iPS research renders one morally complicit in their destruction; if human embryos have moral status as mere precursors of human beings, then advocacy of iPS research policy that is inhibited by embryo (...) sacrifice concerns renders one morally complicit in avoidable harms to persons. Steps may be taken to address these complicity concerns, but in the final analysis there is no alternative to achieving clarity with respect to the moral status of the human embryo. (shrink)

This paper offers a brand storytelling, that is a narratological account of Covid-19 pandemic’s emergence phase. By adopting a fictional ontological standpoint, the virus’ deploying media story-world is identified with a process of narrative spacing. Subsequently, the brand’s personality is analyzed as a narrative place brand. The narrative model that is put forward aims at outlining the main episodes that make up the virus’ brand personality as process and structural components (actors, settings, actions, relationships). A series of deep or ontological (...) metaphors are singled out as the core DNA of this place brand, by applying metaphorical modeling to the tropical articulation of Covid-19’s narrative. The virus’ kernel is identified with terror, as a menacing force that wipes out existing regimes of signification due to its uncertain motives, origins and operational mode. In this context, familiar urban spaces, cultural practices and intersubjective communications are redefined, repurposed and reprogrammed. This process is called terrorealization, as the desertification and metaphorical sublation of all prior territorial significations. This study contributes to the narrative sub-stream of place branding by approaching a globally relevant sociocultural phenomenon from a brand storytelling perspective. (shrink)

As testing of ChatGPT has shown, this form of artificial intelligence has the potential to develop, which requires improving its software and other hardware that allows it to learn, i.e., to acquire and use new knowledge, to contact its developers with suggestions for improvement, or to reprogram itself without their participation. Как показало тестирование ChatGPT, эта форма искусственного интеллекта имеет потенциал развития, для чего необходимо усовершенствовать её программное и прочее техническое обеспечение, позволяющее ей учиться, т.е. приобретать и использовать новые знания, (...) обращаться к её разработчикам с предложениями по усовершенствованию, или производить самопрограммирование без их участия. (shrink)