The ovarian reserve defines female reproductive lifespan, which in humans spans decades. The ovarian reserve consists of oocytes residing in primordial follicles arrested in meiotic prophase I and is maintained independent of DNA replication and cell proliferation, thereby lacking stem cell‐based maintenance. Largely unknown is how cellular states of the ovarian reserve are established and maintained for decades. Our recent study revealed that a distinct chromatin state is established during ovarian reserve formation in mice, uncovering a novel window of (...) class='Hi'>epigenetic programming in female germline development. We showed that an epigenetic regulator, Polycomb Repressive Complex 1 (PRC1), establishes a repressive chromatin state in perinatal mouse oocytes that is essential for prophase I‐arrested oocytes to form the ovarian reserve. Here we discuss the biological roles and mechanisms underlying epigenetic programming in ovarian reserve formation, highlighting current knowledge gaps and emerging research areas in female reproductive biology. (shrink)

Gestational factors play a role in the development of several neuropsychiatric disorders including schizophrenia and autism. In utero conditions influence future mental health through epigenetic mechanisms, which alter gene expression without affecting DNA coding sequence. Environmental factors account for at least 60% of the risk for developing major depression, and earlier onset of depressive illness has been observed over the past decades. I speculate that gestational factors may play a greater role in programing depression than previously recognized. Here, I (...) examine recent evidence for a role for gestational factors in programing mood disorders, and how epigenetic mechanisms mediate this effect. (shrink)

The environment can have a long‐lasting influence on an individual's physiology and behavior. While some environmental conditions can be beneficial and result in adaptive responses, others can lead to pathological behaviors. Many studies have demonstrated that changes induced by the environment are expressed not only by the individuals directly exposed, but also by the offspring sometimes across multiple generations. Epigenetic alterations have been proposed as underlying mechanisms for such transmissible effects. Here, we review the most relevant literature on these (...) changes and the developmental stages they affect the most. We discuss current evidence for transgenerational effects of prenatal and postnatal factors on bodily functions and behavioral responses, and the potential epigenetic mechanisms involved. We also discuss the need for a careful evaluation of the evolutionary importance with respect to health and disease, and possible directions for future research in the field. (shrink)

Recent evidence of intergenerational epigenetic programming of disease risk broadens the scope of public health preventive interventions to future generations, i.e. non existing people. Due to the transmission of epigenetic predispositions, lifestyles such as smoking or unhealthy diet might affect the health of populations across several generations. While public policy for the health of future generations can be justified through impersonal considerations, such as maximizing aggregate well-being, in this article we explore whether there are rights-based obligations supervening (...) on intergenerational epigenetic programming despite the non-identity argument, which challenges this rationale in case of policies that affect the number and identity of future people. We propose that rights based obligations grounded in the interests of non-existing people might fall upon existing people when generations overlap. In particular, if environmental exposure in F0 will affect the health of F2 through epigenetic programming, then F1 might face increased costs to address F2's condition in the future: this might generate obligations upon F0 from various distributive principles, such as the principle of equal opportunity for well being. (shrink)

Recent epidemiological reports of associations between socioeconomic status and epigenetic markers that predict vulnerability to diseases are bringing to light substantial biological effects of social inequalities. Here, we start the discussion of the moral consequences of these findings. We firstly highlight their explanatory importance in the context of the research program on the Developmental Origins of Health and Disease (DOHaD) and the social determinants of health. In the second section, we review some theories of the moral status of health (...) inequalities. Rather than a complete outline of the debate, we single out those theories that rest on the principle of equality of opportunity and analyze the consequences of DOHaD and epigenetics for these particular conceptions of justice. We argue that DOHaD and epigenetics reshape the conceptual distinction between natural and acquired traits on which these theories rely and might provide important policy tools to tackle unjust distributions of health. (shrink)

How epigenetic mechanisms regulate genome output and response to stimuli is a fundamental question in development and disease. Past decades have made tremendous progress in deciphering the regulatory relationships involved by correlating aggregated (epi)genomics profiles with global perturbations. However, the recent development of epigenetic editing technologies now enables researchers to move beyond inferred conclusions, towards explicit causal reasoning, through 'programing’ precise chromatin perturbations in single cells. Here, we first discuss the major unresolved questions in the epigenetics field that (...) can be addressed by programable epigenome editing, including the context‐dependent function and memory of chromatin states. We then describe the epigenetic editing toolkit focusing on CRISPR‐based technologies, and highlight its achievements, drawbacks and promise. Finally, we consider the potential future application of epigenetic editing to the study and treatment of specific disease conditions. (shrink)

During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid‐blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic memory (...) suppressing replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non‐permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development. (shrink)

Here, the emerging data on DNA G‐quadruplexes (G4s) as epigenetic modulators are reviewed and integrated. This concept has appeared and evolved substantially in recent years. First, persistent G4s (e.g., those stabilized by exogenous ligands) were linked to the loss of the histone code. More recently, transient G4s (i.e., those formed upon replication or transcription and unfolded rapidly by helicases) were implicated in CpG island methylation maintenance and de novo CpG methylation control. The most recent data indicate that there are (...) direct interactions between G4s and chromatin remodeling factors. Finally, multiple findings support the indirect participation of G4s in chromatin reshaping via interactions with remodeling‐related transcription factors (TFs) or damage responders. Here, the links between the above processes are analyzed; also, how further elucidation of these processes may stimulate the progress of epigenetic therapy is discussed, and the remaining open questions are highlighted. (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)

In this article, I argue that genomic programs are not substitutes for multi-causal molecular mechanistic explanations of inheritance, but abstract representations of the same sort as mechanism schemas already described in the philosophical literature. On this account, the program analogy is not reductionistic and does not ignore or underestimate the active contribution of epigenetic elements to phenotypes and development. Rather, genomic program representations specifically highlight the genomic determinants of inheritance and their organizational features at work in the wider context (...) of the mechanisms of genome expression. (shrink)

The nature of children's early environment has profound long-term consequences. We are beginning to understand the underlying molecular programming of the stress-response system, which may mediate the destructive long-term effects of cruelty to children, explain the evolutionary stability of cruelty, and provide opportunities for its reversal of early trauma.

The contribution of inherited non‐genetic factors to complex diseases is of great current interest. The ways in which mothers and fathers can affect their offspring's health clearly differ as a result of the intimate interactions between mother and offspring during pre‐ and postnatal life. There is, however, potential for some overlap in mechanisms, particularly epigenetic mechanisms. A small number of epidemiological studies and animal models have investigated the non‐genetic contribution of the parents to offspring health. Discovering new mechanisms of (...) disease inheritance is technically difficult, especially in genetically, socially and environmentally heterogeneous human populations. Therefore, rigorous experimental design, appropriate sample numbers and the use of high‐throughput technologies are necessary to provide convincing evidence. Based on recent examples from the literature, here we propose several ways to improve human studies that aim to identify the underlying mechanisms of transgenerational inheritance of metabolic disease. (shrink)

Since the early days of embryology, a central puzzle for biologists has been how a fertilized egg can execute a clearly defined and reproducible program that leads ultimately to a complex organism. It was clear that all of the information necessary to create the adult must already reside in the zygote, but how that information was translated into a complex organism was obscure. Even as recently as the late 1940s, the molecular mechanisms associated with early development were unknown and, in (...) a sense, unknowable, given the available knowledge and technology. In the preceding centuries, embryologists had described in detail the progression of events during embryonic development, in both vertebrates and .. (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)

In 1853, the young Thomas Henry Huxley published a long review of German cell theory in which he roundly criticized the basic tenets of the Schleiden-Schwann model of the cell. Although historians of cytology have dismissed Huxley's criticism as based on an erroneous interpretation of cell physiology, the review is better understood as a contribution to embryology. "The Cell-theory" presents Huxley's "epigenetic" interpretation of histological organization emerging from changes in the protoplasm to replace the "preformationist" cell theory of Schleiden (...) and Schwann (as modified by Albert von Kölliker), which posited the nucleus as the seat of organic vitality. Huxley's views influenced a number of British biologists, who continued to oppose German cell theory well into the twentieth century. Yet Huxley was pivotal in introducing the new German program of "scientific zoology" to Britain in the early 1850s, championing its empiricist methodology as a means to enact broad disciplinary and institutional reforms in British natural history. (shrink)

Consolidation of long-term memory is a highly and precisely regulated multistep process. The transcription regulator cAMP response element-binding protein (CREB) plays a key role in initiating memory consolidation. With time processing, first the cofactors are changed and, secondly, CREB gets dispensable. This ultimately changes the expressed gene program to genes required to maintain the memory. Regulation of memory consolidation also requires epigenetic mechanisms and control at the RNA level. At the neuronal circuit level, oscillation in the activity of CREB (...) and downstream factor define engram cells. Together the combination of all regulation mechanisms allows correct memory processing while keeping the process dynamic and flexible to adjust to different contexts. Also see the video abstract here https://youtu.be/BhSCSmorpEc. (shrink)

Information about the structure, function and regulation of the maize Suppressormutator (Spm) transposable element has emerged from the genetic and molecular characterization of both deletion mutations and an unconventional type of reversible genetic change (epimutation). The element is subject to an epigenetic mechanism that can either stably inactivate it or specify one of a variety of heritable programs of differential element expression in development. The essay explores the relationship between the Spm element's epigenetic developmental programming mechanism and (...) the determinative events central to plant development and differentiation. (shrink)

The Joint International Conference on Logic Programming, sponsored by the Association for Logic Programming, is a major forum for presentations of research, applications, and implementations in this important area of computer science. Logic programming is one of the most promising steps toward declarative programming and forms the theoretical basis of the programming language Prolog and its various extensions. Logic programming is also fundamental to work in artificial intelligence, where it has been used for nonmonotonic (...) and commonsense reasoning, expert systems implementation, deductive databases, and applications such as computer-aided manufacturing. Krzysztof R. Apt is project leader at the Centre for Mathematics and Computer Science in Amsterdam and part-time Professor in Computer Science at the University of Amsterdam. Topics covered: Theory Foundations. Programming Languages. Implementation. Programming Methodologies and Tools. Applications. Deductive Databases. Artificial Intelligence. Parallelism. (shrink)

Doctoral programs at U.S. universities play a critical role in the development of human resources both in the United States and abroad. This volume reports the results of an extensive study of U.S. research-doctorate programs in five broad fields: physical sciences and mathematics, engineering, social and behavioral sciences, biological sciences, and the humanities. Research-Doctorate Programs in the United States documents changes that have taken place in the size, structure, and quality of doctoral education since the widely used 1982 editions. This (...) update provides selected information on nearly 4,000 doctoral programs in 41 subdisciplines at 274 doctorate-granting institutions. This volume also reports the results of the National Survey of Graduate Faculty, which polled a sample of faculty for their views on the scholarly quality of program faculty and the effectiveness of doctoral programs in preparing research scholars/scientists. This much-anticipated update of such an essential reference will be useful to education administrators, university faculty, and students seeking authoritative information on doctoral programs. (shrink)

"An important contribution to contemporary jurisprudential debate and to legal thought more generally, Just Interpretations is far ahead of currently available work."--Peter Goodrich, author of Oedipus Lex "I was struck repeatedly by the clarity of expression throughout the book. Rosenfeld's description and criticism of the recent work of leading thinkers distinguishes his work within the legal theory genre. Furthermore, his own theory is quite original and provocative."--Aviam Soifer, author of Law and the Company We Keep.

The First International Workshop brings together researchers from the theoretical ends of the logic programming and artificial intelligence communities to discuss their mutual interests. Logic programming deals with the use of models of mathematical logic as a way of programming computers, where theoretical AI deals with abstract issues in modeling and representing human knowledge and beliefs. One common ground is nonmonotonic reasoning, a family of logics that includes room for the kinds of variations that can be found (...) in human reasoning. Topics covered: Stable Semantics. Default Logic. AutoEpistemic Logic. Truth Maintenance Systems. Implementation Issues. Diagnosis. Applications. Inheritance Reasoning. Logics of Belief. Inconsistency and Non-Monotonicity. (shrink)

This volume presents a collection of refereed papers reflecting the state of the art in the area of over-constrained systems. Besides 11 revised full papers, selected from the 24 submissions to the OCS workshop held in conjunction with the First International Conference on Principles and Practice of Constraint Programming, CP '95, held in Marseilles in September 1995, the book includes three comprehensive background papers of central importance for the workshop papers and the whole field. Also included is an introduction (...) by one of the volume editors together with a bibliography listing 243 entries. All in all this is a very useful reference book relevant for all researchers and practitioners interested in hierarchical, partial, and over-constrained systems. (shrink)

The metabolic requirements of differentiated neurons are significantly different from that of neuronal precursor and neural stem cells. While a re‐programming of metabolism is tightly coupled to the neuronal differentiation process, whether shifts in mitochondrial mass, glycolysis, and oxidative phosphorylation are required (or merely consequential) in differentiation is not yet certain. In addition to providing more energy, enhanced metabolism facilitates differentiation by supporting increased neurotransmitter signaling and underpinning epigenetic regulation of gene expression. Both epidemiological and animal studies demonstrate (...) that micronutrients (MNs) significantly influence many aspects of neonatal brain development, particularly neural migration and survival, neurite outgrowth, and process maturation. Here we review recent insights into the importance of metabolic reprogramming in neuronal differentiation, before considering evidence that micronutrient signaling may be key to regulating these processes. (shrink)

Stress is one of the most powerful experiences to influence health and disease. Through epigenetic mechanisms, stress may generate a footprint that propagates to subsequent generations. Programming by prenatal stress or adverse experience in parents, grandparents, or earlier generations may thus be a critical determinant of lifetime health trajectories. Changes in regulation of microRNAs (miRNAs) by stress may enhance the vulnerability to certain pathogenic factors. This review explores the hypothesis that miRNAs represent stress‐responsive elements in epigenetic regulation (...) that are potentially heritable. Recent findings suggest that miRNAs are key players linking adverse early environments or ancestral stress with disease risk, thus they represent useful predictive disease biomarkers. Since miRNA signatures of disease are potentially heritable, big data management platforms will be vital to harness multi‐generational information and capture succinct yet potent biomarkers capable of directing preventative treatments. This feature would offer a unique window of opportunity to advance personalized medicine. (shrink)

Cell cycle dynamics has emerged as a key regulator of stem cell fate decisions. In particular, differentiation decisions are associated with the G1 phase, and recent evidence suggests that self‐renewal is actively regulated outside of G1. The mechanisms underlying these phenomena are largely unknown, but direct control of gene regulatory programs by the cell cycle machinery is heavily implicated. A recent study sheds important mechanistic insight by demonstrating that in human embryonic stem cells (hESCs) the Cyclin‐dependent kinase CDK2 controls a (...) wide‐spread epigenetic program that drives transcription at differentiation‐related gene promoters specifically in G1. Here, we discuss this finding and explore whether similar mechanisms are likely to function in multipotent stem cells. The implications of this discovery toward our understanding of stem cell‐related disease are discussed, and we postulate novel mechanisms that position the cell cycle as a regulator of cell fate gene networks at epigenetic, transcriptional and post‐transcriptional levels. (shrink)

Methylation of cytosine DNA residues is a well‐studied epigenetic modification with important roles in formation of heterochromatic regions of the genome, and also in tissue‐specific repression of transcription. However, we recently found that the ciliate Oxytricha uses methylcytosine in a novel DNA elimination pathway important for programmed genome restructuring. Remarkably, mounting evidence suggests that methylcytosine can play a dual role in ciliates, repressing gene expression during some life‐stages and directing DNA elimination in others. In this essay, I describe these (...) recent advances in the DNA methylation field and discuss whether this unexpected novel role for methylcytosine in DNA elimination might be more widely conserved in eukaryotic biology, particularly in apoptotic pathways. (shrink)

Cells and tissues are continuously exposed to a changing microenvironment, hence the necessity of a flexible modulation of gene expression that in complex organism have been achieved through specialized chromatin mechanisms. Chromatin-based cell memory enables cells to maintain their identity by fixing lineage specific transcriptional programs, ensuring their faithful transmission through cell division; in particular PcG-based memory system evolved to maintain the silenced state of developmental and cell cycle genes. In evolution the complexity of this system have increased, particularly in (...) vertebrates, indicating combinatorial and dynamic properties of Polycomb proteins, in some cases even overflowing outside the cell nucleus. Therefore, their function may not be limited to the imposition of rigid states of genetic programs, but on the ability to recognize signals and allow plastic transcriptional changes in response to different stimuli. Here, we discuss the most novel PcG mediated memory functions in facing and responding to the challenges posed by a fluctuating environment. Cellular microenvironment can regularly change, hence the need for a dynamic modulation of transcriptional programs by the epigenome. In the current review, we highlight novel emerging aspects of epigenetic memory controlled by PcG proteins and the evolution of specialized functions to convey plasticity and adaptability to environmental changes. (shrink)

Many natural and biological phenomena can be depicted as networks. Theoretical and empirical analyses of networks have become prevalent. I discuss theoretical biases involved in the delineation of biological networks. The network perspective is shown to dissolve the distinction between regulatory architecture and regulatory state, consistent with the theoretical impossibility of distinguishing a priori between “program” and “data”. The evolutionary significance of the dynamics of trans-generational and inter-organism regulatory networks is explored and implications are presented for understanding the evolution of (...) the biological categories development-heredity; plasticity-evolvability; and epigenetic-genetic. (shrink)

This presentation discusses a notion encountered across disciplines, and in different facets of human activity: autonomous activity. We engage it in an interdisciplinary way. We start by considering the reactions and behaviors of biological entities to biotechnological intervention. An attempt is made to characterize the degree of freedom of embryos & clones, which show openness to different outcomes when the epigenetic developmental landscape is factored in. We then consider the claim made in programming and artificial intelligence that automata (...) could show self-directed behavior as to the determination of their step-wise decisions on courses of action. This question remains largely open and calls for some important qualifications. We try to make sense of the presence of claims of freedom in agency, first in common sense, then by ascribing developmental plasticity in biology and biotechnology, and in the mapping of programmed systems in the presence of environmental cues and self-referenced circuits as well as environmental coupling. This is the occasion to recall attempts at working out a logical and methodological approach to the openness of concepts that are still to be found, and assess whether they can operate the structuring intelligibility of a yet undeveloped or underdeveloped field of study, where a “bisociation" and a unification of knowledge might be possible. (shrink)

This dissertation is centered on problems within the history and philosophy of biology. The project identifies the philosophical roots of the current ecological movement and shows how a version of philosophical naturalism might be put to use within contemporary ethical issues in biology, and aid in the development of research programs. The approach is historically informed, but has application for current dilemmas. The traditions from which I primarily draw include classical American philosophy, particularly C.S. Peirce and John Dewey, as well (...) as thinkers associated with the German Naturphilosophie movement, such as Goethe and Schopenhauer. There are deep, but often overlooked, resonances between these seemingly disparate traditions and contemporary biology that are located in the conflict between the developing organism and the ever-fluctuating environment. The dissertation makes the case for a shared description of nature among these traditions and proposes applications to burgeoning contemporary ecological interpretations of issues such as hybridization and epigenetics. (shrink)

This paper serves as an introduction to the special issue on “Reconciling Nature and Nurture in Behavior and Cognition Research” and sets its agenda to resolve the 'interactionist' dichotomy of nature as the genetic, and stable, factors of development, and nurture as the environmental, and plastic influences. In contrast to this received view it promotes the idea that all traits, no matter how developmentally fixed or universal they seem, contingently develop out of a single-cell state through the interaction of a (...) multitude of developmental resources that defies any easy, dichotomous separation. It goes on to analyze the necessary ingredients for such a radical, epigenetic account of development, heredity and evolution: 1. A detailed understanding of the epigenetic nature of the regulatory mechanisms of gene expression; 2. The systematical questioning of preconceptions of 'explanatory' categories of behavior, such as 'innate' or 'programmed'; 3. Especially in psychological research the integration of the concepts of 'development' and 'learning', and a richer classification of the concept of 'environment' in the production of behavior; 4. A fuller understanding of the nature of inheritance that transcends the restriction to the genetic material as the sole hereditary unit, and the study of the process of developmental niche construction; and last 5. Taking serious the role of ecology in development and evolution. I hope that an accomplishment of the above task will then lead to a 'postgenomic' synthesis of nature and nurture that conceptualizes 'nature' as the natural phenotypic outcome 'nurtured' by the natural developmental process leading to it. (shrink)

The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein-coding RNA (ncRNA) transcription in the higher eukaryotes (...) and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of the structure of genetic regulatory systems in animals and plants may be incorrect. ncRNA dominates the genomic output of the higher organisms and has been shown to control chromosome architecture, mRNA turnover and the developmental timing of protein expression, and may also regulate transcription and alternative splicing. This paper re-examines the available evidence and suggests a new framework for considering and understanding the genomic programming of biological complexity, autopoletic development and phenotypic variation. BioEssays 25:930-939,2003. (C) 2003 Wiley Periodicals, Inc. (shrink)

Whenever the state of a biological system is not determined solely by present conditions but depends on its past history, we can say that the system has memory. Bacteria and bacteriophage use a variety of memory mechanisms, some of which seem to convey adaptive value. A genetic type of heritable memory is the programmed inversion of specific DNA sequences, which causes switching between alternative patterns of gene expression. Heritable memory can also be based on epigenetic circuits, in which a (...) system with two possible steady states is locked in one or the other state by a positive feedback loop. Epigenetic states have been observed in a variety of cellular processes, and are maintained by diverse mechanisms. Some of these involve alternative DNA methylation patterns that are stably transmitted to daughter molecules and can affect DNA–protein interactions (e.g., gene transcription). Other mechanisms exploit autocatalytic loops whereby proteins establish the proper conditions for their continued synthesis. Template polymers other than nucleic acids (e.g., components of the cell wall) may also propagate epigenetic states. Non‐heritable memory is exemplified by parasitic organisms that bear a signature of their previous host, such as host‐controlled modification of phage DNA or porin hitchhiking in predatory bacteria. The heterogeneous nature of the examples known may be indicative of widespread occurrence of memory mechanisms in bacteria and phage. However, the actual extent, variety and potential selective value of prokaryotic memory devices remain open questions, still to be addressed experimentally. BioEssays 24:512–518, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

The distinction between causal role and selected effect functions is typically framed in terms of their respective explanatory roles. However, much of the controversy over functions in genomics takes place in an investigative, not an explanatory context. Specifically, the process of component-driven functional investigation begins with the designation of some genetic or epigenetic element as functional —i.e. not junk— because it possesses properties that, arguably, suggest some biologically interesting organismal effect. The investigative process then proceeds, in a bottom-up fashion, (...) to search for those effects. I argue that this process encounters a problem reminiscent of one that Gould and Lewontin associated with the adaptationist program. Just as their stereotypical adaptationst became trapped in the myopic pursuit of one selectionist hypothesis after another, so can the investigation of CR functions in genomics lead to an unending series putative organism-level CR functions for junk DNA. This is an acute problem for genomics, because eukaryotic genomes are littered with transposable elements and their deactivated descendants which often masquerade as interesting CR-functional components and it is experimentally onerous to determine whether they lack such a function. I further argue that selectionist reasoning about TE-host coevolutionary dynamics can greatly streamline the investigative process. Importantly, selectionist hypotheses need not be well confirmed to be illuminating in this context. Informed selectionist reasoning about the strategic roles of TEs in the genome offers a corrective to the idea that most of our DNA is somehow CR functional for the organism. (shrink)

Cancers often express hundreds of genes otherwise specific to germ cells, the germline/cancer (GC) genes. Here, we present and discuss the hypothesis that activation of a “germline program” promotes cancer cell malignancy. We do so by proposing four hallmark processes of the germline: meiosis, epigenetic plasticity, migration, and metabolic plasticity. Together, these hallmarks enable replicative immortality of germ cells as well as cancer cells. Especially meiotic genes are frequently expressed in cancer, implying that genes unique to meiosis may play (...) a role in oncogenesis. Because GC genes are not expressed in healthy somatic tissues, they form an appealing source of specific treatment targets with limited side effects besides infertility. Although it is still unclear why germ cell specific genes are so abundantly expressed in cancer, from our hypothesis it follows that the germline's reproductive program is intrinsic to cancer development. (shrink)

This symposium of the Journal of Bioethical Inquiry illustrates structural competency: how clinical practitioners can intervene on social and institutional determinants of health. It will require training clinicians to see and act on structural barriers to health, to adapt imaginative structural approaches from fields outside of medicine, and to collaborate with disciplines and institutions outside of medicine. Case studies of effective work on all of these levels are presented in this volume. The contributors exemplify structural competency from many angles, from (...) the implications of epigenetics for environmental intervention in personalized medicine to the ways clinicians can act on fundamental causes of disease, address abuses of power in clinical training, racially desegregate cities to reduce health disparities, address the systemic causes of torture by police, and implement harm-reduction programs for addiction in the face of punitive drug laws. Together, these contributors demonstrate the unique roles that clinicians can play in breaking systemic barriers to health and the benefit to the U.S. healthcare system of adopting innovations from outside of the United States and outside of clinical medicine. (shrink)

The inclusion of structural competency training in pre-health undergraduate programs may offer significant benefits to future healthcare professionals. This paper presents the results of a comparative study of an interdisciplinary pre-health curriculum based in structural competency with a traditional premedical curriculum. The authors describe a new evaluation tool, the Structural Foundations of Health Survey ©, developed to evaluate structural skills and sensibilities. The authors use the survey to evaluate two groups of graduating seniors at Vanderbilt University—majors in an interdisciplinary pre-health (...) curriculum titled Medicine, Health, and Society, and premed science majors—with particular attention to understanding how political, cultural, economic, and social factors shape health. Results suggest that MHS majors identified and analyzed relationships between structural factors and health outcomes at higher rates and in deeper ways than did premed science majors. MHS students also demonstrated higher understanding of structural and cultural competency in their approaches to race, intersectionality, and racial health disparities. The skills that MHS students exhibited represent proficiencies increasingly emphasized by the MCAT, the AAMC, and other educational bodies that, in an era of epigenetics and social determinants, emphasize how contextual factors shape expressions of health and illness. (shrink)

This is the introduction to a special issue of 'Science in Context' on vitalism that I edited. The contents are: 1. Guido Giglioni — “What Ever Happened to Francis Glisson? Albrecht Haller and the Fate of Eighteenth-Century Irritability” 2. Dominique Boury— “Irritability and Sensibility: Two Key Concepts in Assessing the Medical Doctrines of Haller and Bordeu” 3. Tobias Cheung — “Regulating Agents, Functional Interactions, and Stimulus-Reaction-Schemes: The Concept of “Organism” in the Organic System Theories of Stahl, Bordeu and Barthez” 4. (...) Charles T. Wolfe & Motoichi Terada — “The Animal Economy as Object and Program in Montpellier Vitalism” 5. Timo Kaitaro — “Can Matter Mark the Hours? – Eighteenth-Century Vitalist Materialism and Functional Properties” 6. Elizabeth Williams —“Of Two Lives One? Jean-Charles-Marguerite-Guillaume Grimaud and the Question of Holism in Vitalist Medicine” 7. Philippe Huneman — “Montpellier Vitalism and the Emergence of Alienism in France (1750-1800): The Case of the Passions” 8. Elke Witt —“Form – A Matter of Generation. The Relation of Generation, Form and Function in the Epigenetic Theory of C.F. Wolff” . (shrink)

CHARLES DUPRAS | : L’épigénétique est un champ d’études qui s’intéresse aux modifications biochimiques et aux changements dans la structure tridimensionnelle de l’ADN ayant pour effet de contraindre ou de faciliter la lecture et l’expression des gènes. Au cours des dix dernières années, l’épigénétique a attiré l’attention d’un nombre croissant de chercheurs en sciences sociales, puisqu’elle semble venir confirmer, cette fois sur le plan moléculaire, le rôle déterminant de l’environnement développemental des personnes dans la configuration de leur individualité biologique et (...) dans la programmation de leur santé future. Cet article se penche sur les implications épistémologiques potentielles de l’épigénétique. Nous distinguons et décrivons trois perspectives socio-anthropologiques complémentaires, adoptées par différents auteurs, sur le rapprochement des concepts de « nature » et de « culture » par l’épigénétique : la socialisation du biologique, la biologisation du social et la superposition nature-culture. | : Epigenetics is a field of study that focuses on biochemical modifications and changes in the tridimensional structure of DNA that have the effect of constraining or facilitating the reading and expression of genes. Over the last ten years, epigenetics has captured the attention of several social scientists since it appears to confirm, this time at the molecular level, the determining role of the developing environment of people in configurating their biological individuality and programming their future health. This article discusses the potential epistemological implications of epigenetics. It distinguishes and describes three complementary socio-anthropological perspectives, taken by different authors, on the rapprochement of the concepts “nature” and “nurture” by epigenetics: the socialization of the biological, the biologization of the social, and the superimposition nature-nurture. (shrink)

T‐bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells. Recent genome‐wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the (...) class='Hi'>epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion. We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T‐bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking. (shrink)

In the postgenomic era, interactions between organism and environment are central in disciplines such as epigenetics, medical physiology, and immunology. Particularly in the more "applied" medical fields, an emphasis lies on interactions of the organism with other organisms, that is, other living things. There is, however, a growing amount of research investigating the impact of abiotic triggers on the immune system. While the distinction between biota and abiota features heavily in other contexts, its status is not explicit within immunology. Do (...) immunologists distinguish living from nonliving triggers? In this article, I will carve out whether and in which ways the biotic/abiotic distinction operates in immunology. I will look into responses to biotic and abiotic stressors in plant and invertebrate model species and ask how and why they are conceptually separated. I will trace the reasons by investigating the disciplinary situatedness of immune phenomena and the import of vertebrate immunology when conceptualizing immune responses in other model organisms. I will then investigate how the convergence of biotic and abiotic stress responses in plants and invertebrates adds to the recent philosophical programs advocating an ecological perspective on immune systems. (shrink)

Chromosomes are not randomly packed and positioned into the nucleus but folded in higher‐order chromatin structures with defined functions. However, the genome of a fertilized embryo undergoes a dramatic epigenetic reprogramming characterized by extensive chromatin relaxation and the lack of a defined three‐dimensional structure. This reprogramming is followed by a slow genome refolding that gradually strengthens the chromatin architecture during preimplantation development. Interestingly, genome refolding during early development coincides with a progressive loss of developmental potential suggesting a link between (...) chromatin organization and cell plasticity. In agreement, loss of chromatin architecture upon depletion of the insulator transcription factor CTCF in embryonic stem cells led to the upregulation of the transcriptional program found in totipotent cells of the embryo, those with the highest developmental potential. This essay will discuss the impact of genome folding in controlling the expression of transcriptional programs involved in early development and their plastic‐associated features. (shrink)

Evolution in Four Dimensions claims that epigenetic, behavioral, and symbolic inheritance systems should be considered equal partners to genetics in evolutionary biology. The evidence for, and applicable scope of, these additional inheritance systems is limited, particularly with regard to areas involving learning. It is unclear how including these extra dimensions in mainstream evolutionary thinking translates into testable hypotheses for a productive research program.

Normal fetal development is dependent upon an intricate exchange between mother and embryo. Several maternal and embryonic elements can influence this intimate interaction, including genetic, environmental or epigenetic factors, and have a significant impact on embryo development. The interaction of the genetic program of both mother and embryo, within the uterine environment, can shape the development of an individual. Accumulating data from animal models indicate that prenatal events may well initiate long‐term changes in the expression of the embryo genetic (...) program, which persist, or may only become apparent, much later in the individual's life. Also, environmental conditions during prenatal development may prompt the adoption of different developmental pathways, leading to alternative life histories. This review focuses on environmental factors, specifically maternally derived molecules, to illustrate how they can influence in utero embryonic development and, by extension, adult life. (shrink)

In Biodeconstruction (2018) I argued that Derrida, in the Life Death seminar (1975–76), would have anticipated the most recent developments in epigenetics, a field in which the dogma of genetic determinism is radically challenged by noting the influence of the environment in the production of mutations in the genetic program, particularly when a genetic population is faced with a radical change in its environmental conditions, which I propose to call an ‘ecological event’. I explore a comparison between the Derridean deconstruction (...) of genetic determinism and the theoretical elaborations of epigenesis, referring to the work of Eva Jablonka and Marion J. Lamb, Evolution in Four Dimensions (2005). Jablonka and Lamb propose a theory of genetic variation in which mutations would be the result of the interpretation of unpredictable environmental events by the individual whose survival would be in danger. Through this comparison, I show that the study of ‘interpretive Mutations’ as reactions to unpredictable environmental events can be helpful in understanding the Derridean theme of the ‘event’, rearticulating it in relation to the radical environmental changes that humanity will sooner or later face. (shrink)

Rose's attack on ultra-Darwinists' and evolutionary psychologists' accounts of human behavior fails, largely because he does not offer a viable alternative. His “lifelines” view of organismic development is essentially an epigenetic one that few sociobiologists would disagree with, Rose seeks to disempower genes where human behavior is concerned, despite contrary neurogenetic evidence and at odds with the implications of his own lifelines view. He attempts to discredit biological determinist accounts by suggesting that their research program is politically motivated, while (...) ignoring the scientific viability and novel insights such research has yielded. (shrink)