This article considers the distinctive features of epigenetics and discusses whether, as a matter of ethics and law, epigenetics should be considered separate from genetics.

Emerging fields of science often create new challenges for ethics and law. In assessing the broader societal implications of scientific discoveries, a reasonable analytical starting point is determining how the discoveries compare with existing science. If the new field is substantially similar to an established one, then the ethical and legal analyses are likely to be comparable. On the other hand, if the new scientific developments are extraordinary in kind or degree, then a new analytical framework and new approaches to (...) ethics and law may be necessary. (shrink)

The conventional view of vitamins reflects a diverse group of small molecules that facilitate critical aspects of metabolism and prevent potentially fatal deficiency syndromes. However, vitamins also contribute to the shaping and maintenance of the human phenome over lifecycle and evolutionary timescales, enabling a degree of phenotypic plasticity that operates to allow adaptive responses that are appropriate to key periods of sensitivity (i.e., epigenetic response during prenatal development within the lifecycle or as an evolved response to environmental challenge over (...) a great many lifecycles). Individually, vitamins are important, but their effect is often based on nutrient‐nutrient (vitamin‐vitamin), nutrient‐gene (vitamin‐gene), and gene‐gene interactions, and the environmental influence of shifting geophysical cycles, as well as evolving cultural practices. These ideas will be explored within what I refer to as the “adaptive vitome (vitomics)” paradigm. (shrink)

That there is a heritable or familial component of susceptibility to chronic non‐communicable diseases such as type 2 diabetes, obesity and cardiovascular disease is well established, but there is increasing evidence that some elements of such heritability are transmitted non‐genomically and that the processes whereby environmental influences act during early development to shape disease risk in later life can have effects beyond a single generation. Such heritability may operate through epigenetic mechanisms involving regulation of either imprinted or non‐imprinted genes (...) but also through broader mechanisms related to parental physiology or behaviour. We review evidence and potential mechanisms for non‐genomic transgenerational inheritance of ‘lifestyle’ disease and propose that the ‘developmental origins of disease’ phenomenon is a maladaptive consequence of an ancestral mechanism of developmental plasticity that may have had adaptive value in the evolution of generalist species such as Homo sapiens. BioEssays 29: 145–154, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

There is increasing evidence that dynamic changes to chromatin, chromosomes and nuclear architecture are regulated by RNA signalling. Although the precise molecular mechanisms are not well understood, they appear to involve the differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. A significant fraction of the genome-wide transcription of non-protein coding RNAs may be involved in this process, comprising a previously hidden layer of intermediary genetic information that (...) underpins developmental ontogeny and the differences between species, ecotypes and individuals. It is also evident that RNA editing is a primary means by which hardwired genetic information in animals can be altered by environmental signals, especially in the brain, indicating a dynamic RNA-mediated interplay between the transcriptome, the environment and the epigenome. Moreover, RNA-directed regulatory processes may also transfer epigenetic information not only within cells but also between cells and organ systems, as well as across generations. (shrink)

Many models of evolution are implicitly causal processes. Features such as causal feedback between evolutionary variables and evolutionary processes acting at multiple levels, though, mean that conventional causal models miss important phenomena. We develop here a general theoretical framework for analyzing evolutionary processes drawing on recent approaches to causal modeling developed in the machine-learning literature, which have extended Pearls do-calculus to incorporate cyclic causal interactions and multilevel causation. We also develop information-theoretic notions necessary to analyze causal information dynamics in our (...) framework, introducing a causal generalization of the Partial Information Decomposition framework. We show how our causal framework helps to clarify conceptual issues in the contexts of complex trait analysis and cancer genetics, including assigning variation in an observed trait to genetic, epigenetic and environmental sources in the presence of epigenetic and environmental feedback processes, and variation in fitness to mutation processes in cancer using a multilevel causal model respectively, as well as relating causally-induced to observed variation in these variables via information theoretic bounds. In the process, we introduce a general class of multilevel causal evolutionary processes which connect evolutionary processes at multiple levels via coarse-graining relationships. Further, we show how a range of fitness models can be formulated in our framework, as well as a causal analog of Prices equation, clarifying the relationships between realized/probabilistic fitness and direct/indirect selection. Finally, we consider the potential relevance of our framework to foundational issues in biology and evolution, including supervenience, multilevel selection and individuality. Particularly, we argue that our class of multilevel causal evolutionary processes, in conjunction with a minimum description length principle, provides a conceptual framework in which identification of multiple levels of selection may be reduced to a model selection problem. (shrink)

Epigenetic modifications, such as DNA methylation and post‐translation modifications of histones, have been shown to play an important role in chromatin structure, promoter activity, and cellular reprogramming. Large protein complexes, such as Polycomb and trithorax, often harbor multiple activities which affect histone tail modification. Nevertheless, the mechanisms underlying the deposition of these marks, their propagation during cell replication, and the alteration on their distribution during transformation still require further study. Here we review recent data on those processes in both (...) normal and cancer cells, and we propose that the unscheduled expression of oncogenic transcription factors causes reprogramming of normal cells into cancer stem cells. (shrink)

Gene regulation involves various cis-regulatory elements that can act at a distance. They may physically interact each other or with their target genes to exert their effects. Such interactions are beginning to be uncovered in the imprinted Igf2/H19 domain.1 The differentially methylated regions (DMRs), containing insulators, silencers and activators, were shown to have physical contacts between them. The interactions were changeable depending on their epigenetic state, presumably enabling Igf2 to move between an active and a silent chromatin domain. The (...) study gives us a novel view on how regulatory elements influence gene expression and how epigenetic modifications modulate their long-range effects. (shrink)

N6‐methyladenine (6mA) is one of the most abundant types of DNA methylation, and plays an important role in bacteria; however, its roles in higher eukaryotes, such as plants, insects, and mammals, have been considered less important. Recent studies highlight that 6mA does indeed occur, and that it plays an important role in eukaryotes, such as worm, fly, and green algae, and thus the regulation of 6mA has emerged as a novel epigenetic mechanism in higher eukaryotes. Despite this intriguing development, (...) a number of important issues regarding its biological roles are yet to be addressed. In this review, we focus on the 5mC and 6mA modifications in terms of their production, distribution, and the erasure of 6mA in higher eukaryotes including mammals. We perform an analysis of the potential functions of 6mA, hence widening understanding of this new epigenetic mark in higher eukaryotes, and suggesting future studies in this field. (shrink)

Silencing of tumor suppressor genes (TSGs), by DNA methylation, is well known in adult cancers. However, based on the “stem cell” theory of tumorigenesis, the early epigenetic events arising in malignant precursors remain unknown. A recent report1 demonstrates that, while pluripotent embryonic stem cells lack DNA methylation and possess a “bivalent” pattern of activating and repressive histone marks in numerous TSGs, analogous multipotent malignant cells derived from germ cell tumors (embryonic carcinoma cells) gain additional silencing modifications to those same (...) genes. These results suggest a possible mechanism by which aberrant differentiation, mediated by histone and DNA methylation, instigates tumor progression. BioEssays 29:842–845, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The idea that development is the expression of information accumulated during evolution and that heredity is the transmission of this information is surprisingly hard to cash out in strict, scientific terms. This paper seeks to do so using the sense of information introduced by Francis Crick in his sequence hypothesis and central dogma of molecular biology. It focuses on Crick's idea of precise determination. This is analysed using an information-theoretic measure of causal specificity. This allows us to reconstruct some of (...) Crick's claims about information in transcription and translation. Crick's approach to information has natural extensions to non-coding regions of DNA, to epigenetic marks, and to the genetic or environmental upstream causes of those epigenetic marks. Epigenetic information cannot be reduced to genetic information. The existence of biological information in epigenetic and exogenetic factors is relevant to evolution as well as to development. (shrink)

All animals have evolved solutions to manage their genomes, enabling the efficient organization of meters of DNA strands in the nucleus and allowing for nuanced regulation of gene expression while keeping transposable elements suppressed. Epigenetic modifications are central to accomplishing all these. Recent advances in sequencing technologies and the development of techniques that profile epigenetic marks and chromatin accessibility using reagents that can be used in any species has catapulted epigenomic studies in diverse animal species, shedding light on (...) the multitude of epigenomic mechanisms utilized across the evolutionary tree. Now, comparative epigenomics is a rapidly growing field that is uncovering mechanistic aspects of epigenetic modifications and chromatin organization in non‐model invertebrates, ranging from octopus to sponges. This review puts recent discoveries in the epigenetics of non‐model invertebrates in historical context, and describes new insight into the patterning and functions of DNA methylation and other highly conserved epigenetic modifications. (shrink)

I argue that too much attention has been paid to the Baldwin effect. George Gaylord Simpson was probably right when he said that the effect is theoretically possible and may have actually occurred but that this has no major implications for evolutionary theory. The Baldwin effect is not even central to Baldwin's own account of social heredity and biology-culture co-evolution, an account that in important respects resembles the modern ideas of epigenetic inheritance and niche-construction.

Graphical AbstractA recent study reported that longevity in Caenorhabditits elegans can be inherited over several generations. This is probably achieved through the following epigenetic mechanism: inherited demethylated histones at some central loci, such as miRNA, transcription factors or signaling regulators affect the expression of certain genes leading to the longevity phenotype.

We generally agree with Burt's thesis. However, we note that the author did not discuss epigenetics, the study of how the environment can alter gene structure and function. Given epigenetic mechanisms, the utility of polygenic risk scores (PRS) is limited in studies of development and mental illness. Finally, in this commentary we expand upon the risks of reliance upon PRSs.

As well as having the remarkable ability to differentiate into all of the cell types in the embryo, embryonic stem (ES) cells also have the capacity to divide and self‐renew. Maintenance of pluripotency through repeated cell divisions indicates that the developmental plasticity of ES cells has a specific epigenetic basis. We propose that tightly localised regions of histone modification are formed in ES cells by binding of sequence‐specific transcription factors at genes that are destined for expression at later stages (...) of differentiation. These ‘early transcription competence marks’ would help to maintain pluripotency by preventing the spread of repressive chromatin modifications. We further propose that the presence of discrete histone modification marks in pluripotent cells facilitates the binding of lineage‐specific and general transcription factors to the marked regions as ES cells commit to different fates. By helping to organise the precisely timed responses of genes to the signals that determine lineage choice, the gene‐specific localised epigenetic marks would play a key role in the establishment of complex gene expression programmes in differentiating cells. BioEssays 27:1286–1293, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Looking at the new and often disputed science of epigenetics, we examined the challenges faced by scientists when they communicate scientific research to the public. We focused on the use of metaphors to illustrate notions of epigenetics and genetics. We studied the “encoding” by epigeneticists and “decoding” in focus groups with diverse backgrounds. We observed considerable overlap in the dominant metaphors favored by both researchers and the lay public. However, the groups differed markedly in their interpretations of which metaphors aided (...) understanding or not. We conclude by discussing the role of metaphors and their interpretations in the context of a shift from pre-deterministic genomic metaphors to more active, dynamic and nuanced epigenetic metaphors. These reflections on the choice of metaphors and differences in encoding/decoding are important for science communication and scientific boundary-maintenance. (shrink)

DNA methylation constitutes one of the pillars of epigenetics, relying on covalent bonds for addition and/or removal of chemically distinct marks within the major groove of the double helix. DNA methyltransferases, enzymes which introduce methyl marks, initially evolved in prokaryotes as components of restriction‐modification systems protecting host genomes from bacteriophages and other invading foreign DNA. In early eukaryotic evolution, DNA methyltransferases were horizontally transferred from bacteria into eukaryotes several times and independently co‐opted into epigenetic regulatory systems, primarily via establishing (...) connections with the chromatin environment. While C5‐methylcytosine is the cornerstone of plant and animal epigenetics and has been investigated in much detail, the epigenetic role of other methylated bases is less clear. The recent addition of N4‐methylcytosine of bacterial origin as a metazoan DNA modification highlights the prerequisites for foreign gene co‐option into the host regulatory networks, and challenges the existing paradigms concerning the origin and evolution of eukaryotic regulatory systems. (shrink)

Genetic studies have revealed that the antagonistic interplay between PcG and TrxG/MLL complexes is essential for the proper maintenance of vertebrate Hox gene expression in time and space. Hox genes must be silenced in totipotent embryonic stem cells and, in contrast, rapidly activated during embryogenesis. Here we discuss some recently published articles1-4 that propose a novel mechanism for the induction of Hox gene transcription. These studies report a new family of histone demethylases that remove H3K27me3/me2 repressive marks at Hox promoters (...) during differentiation of stem cells. Though the overall importance of these enzymes for proper embryogenesis was demonstrated, their precise role in Hox gene epigenetic regulation during development still remains to be firmly established. BioEssays 30:199–202, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Four sequential, sub-processes are identified as the fundamental steps in the processing of signals by big-brained animals. These are, Detection of the signal, its Representation in correlated sensory brain structure, the Interpretation of the signal in another part of the brain and the Expression of the receiver’s response. We label this four-step spatiotemporal process DRIE. We support the view that when the context within which such signals are produced and received is relatively constant, the DRIE process can be ultimately assimilated (...) into the genome, with the Interpretation sub-phase is markedly decreased in duration as speed and efficiency are maximized. With frequent repetition and learning, an analogous result can be attained epigenetically as exemplified in human word and text recognition, allowing tasks critical to primate social function to be accomplished with rapidity and accuracy. (shrink)

Recent investigations with non‐model species and whole‐genome approaches have challenged several paradigms in animal epigenetics. They revealed that epigenetic variation in populations is not the mere consequence of genetic variation, but is a semi‐independent or independent source of phenotypic variation, depending on mode of reproduction. DNA methylation is not positively correlated with genome size and phylogenetic position as earlier believed, but has evolved differently between and within higher taxa. Epigenetic marks are usually not completely erased in the zygote (...) and germ cells as generalized from mouse, but often persist and can be transgenerationally inherited, making them evolutionarily relevant. Gene body methylation and promoter methylation are similar in vertebrates and invertebrates with well methylated genomes but transposon silencing through methylation is variable. The new data also suggest that animals use epigenetic mechanisms to cope with rapid environmental changes and to adapt to new environments. The main benefiters are asexual populations, invaders, sessile taxa and long‐lived species. (shrink)

We recently synthesized and reinterpreted published studies to advance an epigenetic model for the development of homosexuality (HS). The model is based on epigenetic marks laid down in response to the XX vs. XY karyotype in embryonic stem cells. These marks boost sensitivity to testosterone in XY fetuses and lower it in XX fetuses, thereby canalizing sexual development. Our model predicts that a subset of these canalizing epigenetic marks stochastically carry over across generations and lead to mosaicism (...) for sexual development in opposite‐sex offspring – the homosexual phenotype being one such outcome. Here, we begin by outlining why HS has been under‐appreciated as a commonplace phenomenon in nature, and how this trend is currently being reversed in the field of neurobiology. We next briefly describe our epigenetic model of HS, develop a set of predictions, and describe how epigenetic profiles of human stem cells can provide for a strong test of the model. (shrink)

In the history of biology, knowledge about human differences often has been produced through an interaction with politics and values assumed to be external to science. Two recent books—Jonathan Marks’ Is Science Racist? and Maurizio Meloni’s Political Biology—shed new light on this interplay. While Marks looks into the field of anthropology, Meloni offers a historiographical view on the soft-hard heredity debate. Based on these new contributions, this essay addresses a number of current ways in which society and science conceptualize human (...) differences through categories like race, gender, and class. Especially, this refers to the separation of what is taken as natural and purportedly fixed, from what is cultural and changeable. (shrink)

It is generally assumed that the developmental program of embryogenesis relies on epigenetic mechanisms. However, a mechanistic link between epigenetic marks and cell fate decisions had not been established so far. In a recent article, Torres‐Padilla and colleagues1 show that epigenetic information and, more precisely, histone arginine methylation mediated by CARM1 could contribute to cell fate decisions in the mouse 4‐cell‐stage embryo. It provides the first indications that global epigenetic information influences allocation of pluripotent cells toward (...) the first cell lineages. BioEssays 29:520–524, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

This paper builds upon historico-epistemological analyses of plasticity across the nineteenth and twentieth centuries to distinguish among uses of this notion in contemporary epigenetics. By digging into this diachronic phase of plasticity thinking, we highlight a series of historically situated understandings and pragmatic dimensions of this notion. Specifically, our analysis describes four distinct phases in plasticity thinking across the nineteenth and twentieth centuries: plasticity as chemical modification of the body by its milieu; plasticity as explanandum for the modifications of life’s (...) ontogenetic and phylogenetic substrates; plasticity as mechanistic process in need of distinct explanations in ontogeny and phylogeny; and plasticity as responsive potential to perturbations of a complex genetic system of development. These four versions of plasticity provide, in turn, the opportunity to discern synchronically the uses of this notion in epigenetic biosciences. Fleshing out these historical ramifications animating the present, we argue, highlights a fundamental epistemological disagreement at the basis of the controversies around the definition, scope, and epistemic priorities of epigenetics: how to reconcile the contemporary epistemologies of plasticity that hold epigenetic marks capable of bearing the material impression of the environment with those grounded on a strong view of plasticity as operating under genetic control? Parallel to this analysis of the epistemic space of plasticity from the nineteenth century onward, we show how these distinct modes of understanding body–environment relationships also constituted conceptual, representational, and experimental resources for understanding the entanglement between life as a biological and socially situated phenomenon. These different traces of biosocial thinking ante litteram, we conclude, provide a blueprint to interrogate today’s assumptions, values, ontologies, and political leanings behind similar attempts to interpret the biosocial nexus that links our biology with its material, social, and cultural environments. (shrink)

Kinetochores can form and be maintained on DNA sequences that are normally non‐centromeric. The existence of these so‐called neo‐centromeres has posed the problem as to the nature of the epigenetic mechanisms that maintain the centromere. Here we highlight results that indicate that the amount of CENP‐A at human centromeres is tightly regulated. It is also known that kinetochore assembly requires sister chromatid cohesion at mitosis. We therefore suggest that separation or stretching between the sister chromatids at metaphase reciprocally determines (...) the amount of centromere assembly in the subsequent interphase. This reciprocal relationship forms the basis of a negative feedback loop that could precisely control the amount of CENP‐A and faithfully maintain the presence of a kinetochore over many cell divisions. We describe how the feedback loop would work, propose how it could be tested experimentally and suggest possible components of its mechanism. (shrink)

Cancer cells accumulate widespread local and global chromatin changes and the source of this instability remains a key question. Here we hypothesize that chromatin alterations including unscheduled silencing can arise as a consequence of perturbed histone dynamics in response to replication stress. Chromatin organization is transiently disrupted during DNA replication and maintenance of epigenetic information thus relies on faithful restoration of chromatin on the new daughter strands. Acute replication stress challenges proper chromatin restoration by deregulating histone H3 lysine 9 (...) mono‐methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor‐promoting insults is recognized as a significant source of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis. (shrink)

While N6‐methyladenosine (m6A) is a well‐known epigenetic modification in bacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well‐studied 5‐methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction‐modification and counter‐restriction systems. On at least four to five instances, these methyltransferases were recruited as (...) RNA methylases. Thus, m6A marks in eukaryotic DNA and RNA might be more widespread and diversified than previously believed. Several m6A‐binding protein domains from prokaryotes were also acquired by eukaryotes, facilitating prediction of potential readers for these marks. Further, multiple lineages of the AlkB family of dioxygenases have been recruited as m6A demethylases. Although members of the TET/JBP family of dioxygenases have also been suggested to be m6A demethylases, this proposal needs more careful evaluation. (shrink)

Several metabolites serve as substrates for histone modifications and communicate changes in the metabolic environment to the epigenome. Technologies such as metabolomics and proteomics have allowed us to reconstruct the interactions between metabolic pathways and histones. These technologies have shed light on how nutrient availability can have a dramatic effect on various histone modifications. This metabolism–epigenome cross talk plays a fundamental role in development, immune function, and diseases like cancer. Yet, major challenges remain in understanding the interactions between cellular metabolism (...) and the epigenome. How the levels and fluxes of various metabolites impact epigenetic marks is still unclear. Discussed herein are recent applications and the potential of systems biology methods such as flux tracing and metabolic modeling to address these challenges and to uncover new metabolic–epigenetic interactions. These systems approaches can ultimately help elucidate how nutrients shape the epigenome of microbes and mammalian cells. (shrink)

Let us begin with the simple observation that applied mathematics can be very tough! It is a common occurrence that basic physical principle instructs us to construct some syntactically simple set of differential equations, but it then proves almost impossible to extract salient information from them. As Charles Peirce once remarked, you can’t get a set of such equations to divulge their secrets by simply tilting at them like Don Quixote. As a consequence, applied mathematicians are often forced to pursue (...) roundabout and shakily rationalized expedients if any useful progress is to be made. Often these provisional and quasi-empirical procedures within applied mathematics loom large in motivating the “anti-realist” or “anti-unificationist” conclusions of Nancy Cartwright and allied authors. (shrink)

Abstract6‐methyladenine (6mA) is fairly abundant in nuclear DNA of basal fungi, ciliates and green algae. In these organisms, 6mA is maintained near transcription start sites in ApT context by a parental‐strand instruction dependent maintenance methyltransferase and is positively associated with transcription. In animals and plants, 6mA levels are high only in organellar DNA. The 6mA levels in nuclear DNA are very low. They are attributable to nucleotide salvage and the activity of otherwise mitochondrial METTL4, and may be considered as a (...) price that cells pay for adenine methylation in RNA and/or organellar DNA. Cells minimize this price by sanitizing dNTP pools to limit 6mA incorporation, and by converting 6mA that has been incorporated into DNA back to adenine. Hence, 6mA in nuclear DNA should be described as an epigenetic mark only in basal fungi, ciliates and green algae, but not in animals and plants. (shrink)

On the basis of careful textual exegesis and philosophical analysis, and contrary to the received view, Mark R. Wheeler demonstrates that Aristotle presents and systematically explicates his definition of the essence of the truth in the Metaphysics. Aristotle states the nominal definitions of the terms "truth" and "falsehood" as part of his arguments in defense of the logical axioms. These nominal definitions express conceptions of truth and falsehood his philosophical opponents would have recognized and accepted in the context of (...) dialectical argument. On the basis of these nominal definitions, Aristotle develops his definitions of the essences of truth and falsehood--his "real" definitions of truth and falsehood. Aristotle's methodical exposition of his essential definitions of truth and falsehood in the Metaphysics serves as a well-developed example of how his philosophical inquiry starts with nominal definitions and ends with real definitions. Wheeler also argues for the novel claim that Aristotle defines the most fundamental kind of truth in terms of accurate measurement. Aristotle's metrical conception of truth serves as the theoretical basis for specifying the truth conditions of various assertions, for identifying the sorts of beings implicated in these truth conditions, and for explaining the nature of approximate truth and falsehood. Far from offering us a minimal account of truth, Wheeler shows how Aristotle offers us a sophisticated and metrical theory of truth. (shrink)

The ability to engage in reflexive thought—in thought about thought or about other mental states more generally—is regarded as a complex intellectual achievement that is beyond the capacities of most nonhuman animals. To the extent that reflexive thought capacities are believed necessary for the possession of many other psychological states or capacities, including consciousness, belief, emotion, and empathy, the inability of animals to engage in reflexive thought calls into question their other psychological abilities. This chapter attacks the idea that reflexive (...) thought is required in this pervasive way and holds that supposing that it is derives from a tendency among philosophers and scientists toward overcomplication. Against this tendency, it recommends an aponoian framework, from apó, “away from” and noûs, “intelligence” or “thought,” arguing that seemingly complex psychological abilities are often not as complex as they seem, and do not require the ability to engage in reflexive thought. (shrink)

Philosophers have come to distinguish between ‘right’ and ‘wrong’ kinds of reasons for belief, intention, and other attitudes. Several theories about the nature of this distinction have been offered, by far the most prevalent of which is the idea that it is, at bottom, the distinction between what are known as ‘object-given’ and ‘state-given’ reasons. This paper argues that the object-given/state-given theory vastly overgeneralizes on a small set of data points, and in particular that any adequate account of the distinction (...) between the ‘right’ and ‘wrong’ kinds of reason must allow state-given reasons to be of the right kind. The paper has three main goals, corresponding to its three main parts. In part 1 I set up the problem by introducing the right-kind/wrong-kind distinction, the object-given/state-given distinction, and the object-given/state-given theory, according to which the former distinction simply amounts to the latter. Part 2 presents the main argument of the paper: I argue against the object-given/state-given theory by showing that all of the earmarks of the ‘right’ and ‘wrong’ kinds of reason apply to reasons not to intend and not to believe, but that these cases can’t be captured by the object-given/state-given theory. Finally, in part 3 I use these arguments to motivate and explore a more general hypothesis about the rightkind/wrong-kind distinction, and explore some of the consequences of rejecting the object-given/stategiven theory. (shrink)

Several authors have recently endorsed the thesis that there is what has been called pragmatic encroachment on knowledge—in other words, that two people who are in the same situation with respect to truth-related factors may differ in whether they know something, due to a difference in their practical circumstances. This paper aims not to defend this thesis, but to explore how it could be true. What I aim to do, is to show how practical factors could play a role in (...) defeating knowledge by defeating epistemic rationality—the very kind of rationality that is entailed by knowledge, and in which Pascalian considerations do not play any role—even though epistemic rationality consists in having adequate evidence. (shrink)

It is time to bring the rich resources of these traditions into the contemporary debate about the nature of self. This volume is the first of its kind.

Intentions matter. They have some kind of normative impact on our agency. Something goes wrong when an agent intends some end and fails to carry out the means she believes to be necessary for it, and something goes right when, intending the end, she adopts the means she thinks are required. This has even been claimed to be one of the only uncontroversial truths in ethical theory. But not only is there widespread disagreement about why this is so, there is (...) widespread disagreement about in what sense it is so. In this paper I explore an underdeveloped answer to the question of in what sense it is so, and argue that resolving an apparent difficulty with this view leads to an attractive picture about why it is so. (shrink)

This is one of those cases to which Dr. 8 oodhouse's remark applies with all its force, that a method which leads to true results must have its logic — H.S Smith (" On Some of the Methods at Present in Use in Pure Geometry," p. 6) A goodly amount of modern metaphysics has concerned itself, in one form or another, with the question: what attitude should we take in regard to a language whose semantic underpinnings seem less than certain? (...) Since much of standard English is surely of this type, many philosophers have felt driven to extreme and unpalatable resolutions — wholesale rejection of attractive logical rules, radical "antirealism", "minimalism" about truth, and so forth, Scientists, however, have long dealt with analogous foundational insecurities and, under the duress of practicality, have framed a set of shifting attitudes towards language and reasoning that seem far more commonsensical than the extreme positions to which pure philosophy has often been led. Following this lead, this essay will recommend a more nuanced approach to linguistic insecurity that is neither naively optimistic nor mired in the gloomy sloughs of antirealism. (shrink)

In the 1960s, Peter Geach and John Searle independently posed an important objection to the wide class of 'noncognitivist' metaethical views that had at that time been dominant and widely defended for a quarter of a century. The problems raised by that objection have come to be known in the literature as the Frege-Geach Problem, because of Geach's attribution of the objection to Frege's distinction between content and assertoric force, and the problem has since occupied a great deal of the (...) attention both of defenders of broadly noncognitivist views, and of their critics. In this article I explain Geach and Searle's historical objections, and put the subsequent discussion into dialectical context, paying some attention to the developments along the way and how they have enhanced our overall understanding of the problem. The article covers a lot of territory, so we will only be able to see the highlights, along the way. For further reading, see the Works Cited. (shrink)

This paper is a survey of recent ‘hybrid’ approaches to metaethics, according to which moral sentences, in some sense or other, express both beliefs and desires. I try to show what kinds of theoretical issues come up at the different choice points we encounter in developing such a view, to raise some problems and explain where they come from, and to begin to get a sense for what the payoff of such views can be, and what they will need to (...) do in order to earn that payoff. (shrink)

Allow me to rehearse a familiar scenario. We all know that which ends you have has something to do with what you ought to do. If Ronnie is keen on dancing but Bradley can’t stand it, then the fact that there will be dancing at the party tonight affects what Ronnie and Bradley ought to do in different ways. In short, (HI) you ought, if you have the end, to take the means. But now trouble looms: what if you have (...) dreadful, murderous ends? Ought you to take the means to them? Seemingly not. But fortunately, an assumption made by deontic logics1 comes to the rescue. Since ‘‘ought’’, according to this assumption, is a sentential operator, HI must really be ambiguous. It could be read either as (Narrow) You have the end ! O(you take the means) or as (Wide) O(you have the end ! you take the means). Now if Narrow is true, then you really ought to take the means to your murderous ends. But this doesn’t follow from Wide. All that follows from Wide is that you ought to either take the means to these ends or else give them up. Conclusions: (1) Since HI is on some reading true, but Narrow isn’t, Wide is true. (2) Wide accounts for the relationship between your ends and what you ought to do. This elegant scenario repeats itself in many other domains in which it seems like something can have a bearing on what some particular agent ought to do. Does what you know affect what you ought to do? Do your beliefs about what you ought to do affect what you ought to do? Do your promises affect what you ought to do? Do your beliefs affect what you ought to believe? On each of these counts, the intuitive answer is ‘‘yes’’. And so each of these questions leaves something for the moral philosopher or the epistemologist to investigate. On each count, it seems that what we all know, is that (Account) you ought, if p, to do A. But on each count, the Narrow-scope reading of the ‘‘ought’’ in this claim yields unintuitive consequences. So since Account is true, it must be true on the Wide-scope reading.. (shrink)

It is now generally understood that constraints play an important role in commonsense moral thinking and generally accepted that they cannot be accommodated by ordinary, traditional consequentialism. Some have seen this as the most conclusive evidence that consequentialism is hopelessly wrong,1 while others have seen it as the most conclusive evidence that moral common sense is hopelessly paradoxical.2 Fortunately, or so it is widely thought, in the last twenty-five years a new research program, that of Agent-Relative Teleology, has come to (...) the rescue on all sides. While consequentialism says that every agent ought always to do that action that will bring about the most good, according to Agent- Relative Teleology. (shrink)

Particularists in ethics emphasize that the normative is holistic, and invite us to infer with them that it therefore defies generalization. This has been supposed to present an obstacle to traditional moral theorizing, to have striking implications for moral epistemology and moral deliberation, and to rule out reductive theories of the normative, making it a bold and important thesis across the areas of normative theory, moral epistemology, moral psychology, and normative metaphysics. Though particularists emphasize the importance of the holism of (...) the normative, however, it is not something that they have been able to explain. In this paper I’ll show how to use a small number of simple and, I’ll argue, independently compelling assumptions in order to both predict and explain the holistic features of the normative with respect to the non-normative. The basic idea of the paper is simple. It is that normative claims are holistic because they are general, rather than because they defy generalization. (shrink)

Expressivists have a problem with negation. The problem is that they have not, to date, been able to explain why ‘murdering is wrong’ and ‘murdering is not wrong’ are inconsistent sentences. In this paper, I explain the nature of the problem, and why the best efforts of Gibbard, Dreier, and Horgan and Timmons don’t solve it. Then I show how to diagnose where the problem comes from, and consequently how it is possible for expressivists to solve it. Expressivists should accept (...) this solution, I argue, because it is demonstrably the only way of avoiding the problem, and because it generalizes. Once we see how to solve the negation problem, I show, it becomes easy to state a constructive, compositional expressivist semantics for a purely normative language with the expressive power of propositional logic, in which we can for the first time give explanatory, formally adequate expressivist accounts of logical inconsistency, logical entailment, and logical validity. As a corollary, I give what I take to be the first real expressivist explanation of why Geach’s original moral modus ponens argument is genuinely logically valid. This proves that the problem with expressivism cannot be that it can’t account for the logical properties of complex normative sentences. But it does not show that the same solution can work for a language with both normative and descriptive predicates, let alone that expressivists are able to deal with more complex linguistic constructions like tense, modals, or even quantifiers. In the final section, I show what kind of constraints the solution offered here would place expressivists under, in answering these further questions. (shrink)

There is considerable likelihood that Gottlob Frege began writing his Foundations of Arithmetic with the expectation that he could introduce his numbers, not with sets, but through some algebraic techniques borrowed from earlier writers of the Gottingen school. These rewriting techniques, had they worked, would have required strong philosophical justification provided by Frege's celebrated "context principle," which otherwise serves little evident purpose in the published Foundations.

It doesn’t seem possible to be a realist about the traditional Christian God while claiming to be able to reduce God talk in naturalistically acceptable terms. Reduction, in this case, seems obviously eliminativist. Many philosophers seem to think that the same is true of the normative—that reductive “realists” about the normative are not really realists about the normative at all, or at least, only in some attenuated sense. This paper takes on the challenge of articulating what it is that makes (...) reductive theological realism look hopeless, with the aim of explaining why we should think that the normative is relevantly different. Although it follows from my diagnosis that reductivists have their work cut out for them, I find nothing which suggests that the prospects for a successful reductive realism about the normative are in any way diminished—particularly for reductive views about reasons. Even reductivists, I argue, can at least aspire to a realism that is robust. (shrink)

Expressivism’s central idea is that normative sentences bear the same relation to non-cognitive attitudes that ordinary descriptive sentences bear to beliefs: the expression relation. Allan Gibbard teIls us that “that words express judgments will be accepted by almost everyone” - the distinctive contribution of expressivism, his claim goes, is only a view about what kind of judgments words express. But not every account of the expression relation is equally suitable for the expressivist’s purposes. In fact, what I argue in this (...) paper, considering four possible accounts of expression, is that how suitable each account is for the expressivist’s purpose varies in proportion to how controversial it is. So Gibbard is wrong - if expression is to get expressivism off the ground, then it will be enormously controversial whether words do express judgments. And thus expressivism is committed to strong claims about the semantics of non-normative language. (shrink)

Socrates provides an argument at the end of the Apology that he believes gives hope that death is a blessing. This argument, grounded on the claim that death is one of two things, has been the subject of much derision and some recent defense. In this essay, I build on the work of other sympathetic commentators to show that Socrates' argument, when taken in context, not only makes good sense, but unifies Socrates' speech into a cohesive exhortation toward virtue.

This paper addresses the two extensional objections to the Humean Theory of Reasons—that it allows for too many reasons, and that it allows for too few. Although I won’t argue so here, manyof the other objections to the Humean Theoryof Reasons turn on assuming that it cannot successfully deal with these two objections.1 What I will argue, is that the force of the too many and the too few objections to the Humean Theorydepend on whether we assume that Humeans are (...) committed to a thesis about the weight of reasons—one I call Proportionalism. In particular, I’ll show how a version of the Humean Theorythat rejects Proportionalism can reasonablyhope to escape both the too many and the too few objections. This will constitute my defense of this version of the Humean Theory. But then, separately, I will argue that this defense of the Humean Theoryis not ad hoc. I’ll argue that Humeans have no reason to accept Proportionalism in the first place. Or at least, no weightyone. There are three parts to the paper. In Part 1 we introduce the Humean Theoryand the too few reasons objection. I’ll first layout the objection, and then layout the basis for a response on behalf of myfavored version of the Humean Theory. There will be an obvious objection to my defense— but it will turn out to depend on the assumption of Proportionalism. This will constitute myargument that the susceptibilityof the Humean Theoryto.. (shrink)