This essay considers how scholarly approaches to the development of molecular biology have too often narrowed the historical aperture to genes, overlooking the ways in which other objects and processes contributed to the molecularization of life. From structural and dynamic studies of biomolecules to cellular membranes and organelles to metabolism and nutrition, new work by historians, philosophers, and STS scholars of the life sciences has revitalized older issues, such as the relationship of life to matter, or of physicochemical inquiries (...) to biology. This scholarship points to a novel molecular vista that opens up a pluralist view of molecularizations in the twentieth century and considers their relevance to current science. (shrink)

The unit of selection is the concept of that ‘something’ to which biologists refer when they speak of an adaptation as being ‘for the good of’ something. Darwin identified the organism as the unit of selection because for him the ‘struggle for existence’ was an issue among individuals. Later on it was suggested that, in order to understand the evolution of social behavior, it is necessary to argue that groups, and not individuals, are the units of selection. The last addition (...) to this debate was the formulation by Dawkins, in 1976, that the genes themselves are the units of selection while the organisms are merely the temporary receptacles and vehicles for such genes. Thus, the preposterous dissolution of the organism into genes and the proteins coded by such genes has been introduced in the evolutionary discourse by neglecting that the explanations for biological phenomena can be either synchronic or diachronic, depending on the phenomenon to be explained. Therefore explanations in molecular biology are synchronic while evolutionary biology needs diachronic explanations. Nevertheless, for ultra-Darwinians such as Dawkins, efficient replication is all that biology is about. Here I develop an argument in order to show that there is nothing in molecular and cell biology that might support such a contention and that the idea of the gene as the unit of selection is incompatible with the evident evolution of biological complexity. (shrink)

The unit of selection is the concept of that ‘something’ to which biologists refer when they speak of an adaptation as being ‘for the good of’ something. Darwin identified the organism as the unit of selection because for him the ‘struggle for existence’ was an issue among individuals. Later on it was suggested that, in order to understand the evolution of social behavior, it is necessary to argue that groups, and not individuals, are the units of selection. The last addition (...) to this debate was the formulation by Dawkins, in 1976, that the genes themselves are the units of selection while organisms are merely the temporary receptacles and vehicles for such genes. Thus, the preposterous dissolution of the organism into genes and the proteins coded by such genes has been introduced in the evolutionary discourse by neglecting that the explanations for biological phenomena can be either synchronic or diachronic, depending on the phenomenon to be explained. Therefore explanations in molecular biology are synchronic while evolutionary biology needs diachronic explanations. Nevertheless, for ultra-Darwinians such as Dawkins, efficient replication is all that biology is about. Here I develop an argument in order to show that there is nothing in molecular and cell biology that might support such a contention and that the idea of the gene as the unit of selection is incompatible with the evident evolution of biological complexity. (shrink)

The Gene Ontology is an important tool for the representation and processing of information about gene products and functions. It provides controlled vocabularies for the designations of cellular components, molecular functions, and biological processes used in the annotation of genes and gene products. These constitute three separate ontologies, of cellular components), molecular functions and biological processes, respectively. The question we address here is: how are the terms in these three separate ontologies related to each other? (...) We use statistical methods and formal ontological principles as a first step towards finding answers to this question. (shrink)

In 1926, Haldane published an essay titled 'On Being the Right Size' in which he argued that the structure, function, and behavior of an organism are strongly conditioned by the physical forces that exert the greatest impact at the scale at which it exists. This chapter puts Haldane’s insight to work in the context of contemporary cell and molecular biology. Owing to their minuscule size, cells and molecules are subject to very different forces than macroscopic organisms. In a sense, (...) macroscopic and microscopic entities inhabit different “worlds”: the former is ruled by gravity and inertia, whereas the latter is governed by Brownian motion. One implication is that we should be extremely skeptical of models and analogies that seek to explain properties of microscopic entities by appealing to properties of macroscopic ones. Unfortunately, this is precisely what the appeal to engineering metaphors in molecular biology attempts to do. Molecular biologists routinely resort to such metaphors because they are familiar and intuitively intelligible. But if our machines were the size of molecules it would be impossible for them to function the way they do. It follows that we should avoid distorting biological reality by construing it in engineering terms. In this chapter I examine four key metaphors in molecular biology – “genetic program,” “cellular circuitry,” “molecular machine,” and “molecular motor” – and I argue that their deficiencies derive from their neglect of scale. I also try to explain why many biologists today appear to have forgotten the importance of scale that Haldane drew attention to in his essay. I suggest that the reason has to do with the influence of Schrödinger’s argument in 'What is Life?' regarding the stability of the gene. (shrink)

1900 was a remarkable year for science. Several ground-breaking events took place, in physics, biology and psychology. Planck introduced the quantum concept, the work of Mendel was rediscovered, and Sigmund Freud published The Interpretation of Dreams . These events heralded the emergence of completely new areas of inquiry, all of which greatly affected the intellectual landscape of the 20 th century, namely quantum physics, genetics and psychoanalysis. What do these developments have in common? Can we discern a family likeness, a (...) basic affinity between them, so that we can use the one to deepen our understanding of the other? One common denominator is that they open up realms of inquiry that are significantly different from the world of everyday experience, namely the realm of elementary particles, of genes and genomes, and of the unconscious. But to what extent can we meaningfully argue, for instance, that the genome is the biological unconscious, and the unconscious the psychic genome? To address these questions, I will build on the work of two key intellectual figures who have explored the affinities of these developments in depth, namely Erwin Schrödinger (a quantum physicist and avid reader of Schopenhauer who initiated molecular biology) and Jacques Lacan (who reframed the specificity of psychoanalysis with the help of 20 th century science: the era of structural linguistics, but also of quantum physics, molecular biology, bioinformatics and DNA). (shrink)

Surface water sources in the oil producing Niger Delta region of Nigeria are highly susceptible to pollution by petroleum hydrocarbons and so it is important to understand the microbial diversity of such ecosystems. Water and sediment samples were collected between April-August, 2013 from Bodo creeks and taken to Environmental Microbiology laboratory of University of Portharcourt for analysis. A total of thirty aerobic heterotrophic bacterial strains isolated ranged from 3.0 - 7.0 × 104 cfu for surface water and 1.6 - 5.6 (...) × 104 cfu for sediment samples of Bodo creek using serial dilution and spread plate technique. Pure cultures of bacteria were obtained on the basis of their morphological characteristics and subjected to biochemical tests and further classified on the basis of 16S rRNA gene sequence analysis. The DNA was isolated from size fractionated samples and the diversity of bacteria in each fraction was studied using PCR amplification of partial 16S rRNA. The sequences were submitted to NCBIGen bank for identification and assigning of accession numbers. The isolated aerobic heterotrophic bacteria belong to the families of Enterobacteriaceae, Bacilliceae, Alcaligenaceae, Pseudomonadaceae, Flavobactericeae and Planococcaceae. (shrink)

One of the defining features of the classical gene was its position. In molecular genetics, positions are defined instead as nucleotide numbers and there is no clear correspondence with its classical counterpart. However, the classical gene position did not simply disappear with the development of the molecular approach, but survived in the lab associated to different genetic practices. The survival of classical gene position would illustrate Waters’ view about the practical persistence of the genetic approach (...) beyond reductionism and anti-reductionist claims. We show instead that at the level of laboratory practices there are also reductive processes, operating through the rise and fall of different techniques. Molecular markers made the concept of classical gene position practically dispensable, leading us to rethink whether it had any causal role or was just a mere heuristic. (shrink)

Never was dogmatic reductionism helpful in conceiving the phenomenon of life. The post-genomic era has made it clear that genes alone cannot explain the functioning of whole organisms. Already each cell represents a unique, non-recurring individual. Recent progress in developmental biology has conveyed new perspectives both on the makings of individual organisms (ontogeny), as on evolutionary change (Evo-Devo). The genome (the entirety of all genes) of an animal remains constant from fertilization onwards in each cell. The realization of genes requires (...) molecular environments, in particular pertinent to the cytoplasm of the unfertilized egg. Individuality of an organism therefore is not only determined by its genome, but is shaped through developmental processes (it needs time!). Organisms can only exist through mutual interplays with their respective (molecular and cellular) environments at all levels of organization. Thus, life can be conceived of as endless networks of communication, e.g. as a mutual continuum, connecting all individuals, all species and all generations within their given environments. Evolutionarily, nature does not select fitting genes, but rather viable traits. The presented concepts render it unlikely that it was genes that founded our living world, but rather that distinct environments shaped “genes” (of whatever chemical nature) which proved to be “life-suitable”. (shrink)

The Aristotelian axiom that function follows form was beautifully instantiated in molecular biology by the discovery of DNA’s structure that immediately suggested how DNA might work as depository and vehicle for genetic information. However, later on molecular biology became infatuated with the gene that became the center of the universe. This gene-centered viewpoint is an obstacle for the emerging field of evo-devo aiming at finding the causal connections between evolution and biological development. Here it is argued (...) that molecular biology must reject the narrow-minded causality associated with the gene-centered view and so it must recover to the spirit of Aristotelian natural history and its four types of causation in order to foster the evo-devo field of research. (shrink)

The philosophical debate around the impact of machine learning in science is often framed in terms of a choice between AI and classical methods as mutually exclusive alternatives involving difficult epistemological trade-offs. A common worry regarding machine learning methods specifically is that they lead to opaque models that make predictions but do not lead to explanation or understanding. Focusing on the field of molecular biology, I argue that in practice machine learning is often used with explanatory aims. More specifically, (...) I argue that machine learning can be tightly integrated with other, more traditional, research methods and in a clear sense can contribute to insight into the causal processes underlying phenomena of interest to biologists. One could even say that machine learning is not the end of theory in important areas of biology, as has been argued, but rather a new beginning. I support these claims with a detailed discussion of a case study involving gene regulation by microRNAs. (shrink)

Griffiths and Stotz’s Genetics and Philosophy: An Introduction offers a very good overview of scientific and philosophical issues raised by present-day genetics. Examining, in particular, the questions of how a “gene” should be defined and what a gene does from a causal point of view, the authors explore the different domains of the life sciences in which genetics has come to play a decisive role, from Mendelian genetics to molecular genetics, behavioural genetics, and evolution. In this review, (...) I highlight what I consider as the two main theses of the book, namely: genes are better conceived as tools; genes become causes only in a context. I situate these two theses in the wider perspective of developmental systems theory. This leads me to emphasize that Griffiths and Stotz reflect very well an on going process in genetics, which I call the “epigenetization” of genetics, i.e., the growing interest in the complex processes by which gene activation is regulated. I then make a factual objection, which is that Griffiths and Stotz have almost entirely neglected the perspective of ecological developmental biology, and more precisely recent work on developmental symbioses, and I suggest that this omission is unfortunate in so far as an examination of developmental symbioses would have considerably strengthened Griffiths and Stotz’s own conclusions. (shrink)

Gene clustering is a useful exploratory technique to group together genes with similar expression levels under distinct cell cycle phases or distinct conditions. It helps the biologist to identify potentially meaningful relationships between genes. In this study, we propose a clustering method based on multivariate normal mixture models, where the number of clusters is predicted via sequential hypothesis tests: at each step, the method considers a mixture model of m components (m = 2 in the first step) and tests (...) if in fact it should be m - 1. If the hypothesis is rejected, m is increased and a new test is carried out. The method continues (increasing m) until the hypothesis is accepted. The theoretical core of the method is the full Bayesian significance test, an intuitive Bayesian approach, which needs no model complexity penalization nor positive probabilities for sharp hypotheses. Numerical experiments were based on a cDNA microarray dataset consisting of expression levels of 205 genes belonging to four functional categories, for 10 distinct strains of Saccharomyces cerevisiae. To analyze the method’s sensitivity to data dimension, we performed principal components analysis on the original dataset and predicted the number of classes using 2 to 10 principal components. Compared to Mclust (model-based clustering), our method shows more consistent results. (shrink)

The chemical characterization of the substance responsible for the phenomenon of “transformation” of pneumococci was presented in the now famous 1944 paper by Avery, MacLeod, and McCarty. Reception of this work was mixed. Although interpreting their results as evidence that deoxyribonucleic acid (DNA) is the molecule responsible for genetic changes was, at the time, controversial, this paper has been retrospectively celebrated as providing such evidence. The mixed and changing assessment of the evidence presented in the paper was due to the (...) work’s interpretive flexibility – the evidence was interpreted in various ways, and such interpretations were justified given the neophytic state of molecular biology and methodological limitations of Avery’s transformation studies. I argue that the changing context in which the evidence presented by Avery’s group was interpreted partly explains the vicissitudes of the assessments of the evidence. Two less compelling explanations of the reception are a myth-making account and an appeal to the wartime historical context of its publication. (shrink)

The problem Plato sounds from the first lines of LAWS, his final dialogue, might be put in Jean-François Lyotard's term: it is the problem of the differend. Lyotard's position is briefly explained, shown to be applicable to the discussion in several ways (not the least of which is the three different gods appealed to as sources of the laws). We then see how Plato makes a chorus of the differend, resolving Lyotard's modern problem.

Discussion of partial grounds that aren't parts of full grounds; definition of full grounding in terms of partial grounding.

In recent years, sequencing technologies have enabled the identification of a wide range of non-coding RNAs (ncRNAs). Unfortunately, annotation and integration of ncRNA data has lagged behind their identification. Given the large quantity of information being obtained in this area, there emerges an urgent need to integrate what is being discovered by a broad range of relevant communities. To this end, the Non-Coding RNA Ontology (NCRO) is being developed to provide a systematically structured and precisely defined controlled vocabulary for the (...) domain of ncRNAs, thereby facilitating the discovery, curation, analysis, exchange, and reasoning of data about structures of ncRNAs, their molecular and cellular functions, and their impacts upon phenotypes. The goal of NCRO is to serve as a common resource for annotations of diverse research in a way that will significantly enhance integrative and comparative analysis of the myriad resources currently housed in disparate sources. It is our belief that the NCRO ontology can perform an important role in the comprehensive unification of ncRNA biology and, indeed, fill a critical gap in both the Open Biological and Biomedical Ontologies (OBO) Library and the National Center for Biomedical Ontology (NCBO) BioPortal. Our initial focus is on the ontological representation of small regulatory ncRNAs, which we see as the first step in providing a resource for the annotation of data about all forms of ncRNAs. (shrink)

Peter Winch famously critiqued Michael Oakeshott's view of human conduct. He argued that Oakeshott had missed the fact that truly human conduct is conduct that 'follows a rule.' This paper argues that, as is sometimes the case with Oakeshott, what seems, on the surface, to be a disagreement with another, somewhat compatible thinker about a matter of detail in some social theory in fact turns out to point to a deeper philosophical divide. In particular, I contend, Winch, as typical of (...) those who only picked up on Oakeshott's work in the 1940s and 1950s, when Oakeshott became known for his critique of rationalism, failed to understand the idealist metaphysics underlying that critique. (shrink)

A number of social theorists have contended that the essence of historical analysis is the employment of ideal types to comprehend past goings-on. But, while acknowledging that the study of history through ideal types can yield genuine insight, we may still ask if it represents the full emancipation of historical understanding from other modes of conceiving the past. This paper follows Michael Oakeshott's work on the philosophy of history in arguing that explaining the historical past by means of ideal types, (...) even though offering a coherent and fruitful enterprise, nevertheless falls short of fully embodying the characteristics that differentiate historical understanding. -/- This dispute involves fundamental issues regarding the nature of the social sciences. Furthermore, I suggest that it is of more than purely theoretical interest, in that social theorists who have accepted the Weberian view of historical inquiry will tend to be unaware of the defects inherent in all attempts to capture the nature of past events in a net of generalizations, and thus may be lead to ignore the inherent partiality of the understanding of historical happenings provided by ideal typification. (shrink)

The paper aims to explore what it means for something to be a social cycle, for a theory to be a social cycle theory, and to offer a suggestion for a simple, yet, we believe, fundamentally grounded schema for categorizing them. We show that a broad range of cycle theories can be described within the concept of disruption and adjustments. Further, many important cycle theories are true endogenous social cycle theories in which the theory provides a reason why the cycle (...) should recur. We find that many social cycle theories fit with a two-population disruption and adjustment model similar to the well-known predator-prey model. This implies that a general modeling framework could be established for creating agent-based models of many social cycle theories. (shrink)

This reading of Plato's Ion shows that the philosophic action mimed and engendered by the dialogue thoroughly reverses its (and Plato's) often supposed philosophical point, revealing that poetry is just as defensible as philosophy, and only in the same way. It is by Plato's indirections we find true directions out: the war between philosophy and poetry is a hoax on Plato's part, and a mistake on the part of his literalist readers. The dilemma around which the dialogue moves is false, (...) and would have been recognized as such by Plato's contemporaries. Further, it is intrinsically related to a false, but popular, view of language. So the way out of the false dilemma of the dialogue is the way out of the war between philosophy and poetry, and also makes one see what is false about the view of language which makes such war plausible. (shrink)

The purpose of this paper is to show the agreement of Camus and Aristotle on the cultural function of the art community, in particular their criticism of what should be called barbarian or nihilistic practices of art. Camus' art and criticism have been frequent targets of modern critics, but his point is and would be that such critics have the wrong idea of the purpose of art. His answer to such critics and the parallelism of his ideas with Aristotle's criticism (...) of barbarian culture, show that the real issue between Camus and his critics is cultural. (shrink)

As Shakespeare is closer in time and spirit to medieval psychology than to popular modern explanations of psyche, this article presents a fourfold analysis of ecstasy from Aquinas' Summa Theologiae to examine the characters of the play. I also suggest performance choices which make a variety of these ecstasies of soul more visible.

The usual interpretation of Republic 10 takes it as Socrates’ multilevel philosophical demonstration of the untruth and dangerousness of mimesis and its required excision from a well ordered polity. Such readings miss the play of the Platonic mimesis which has within it precisely ordered antistrophes which turn its oft remarked strophes perfectly around. First, this argument, famously concluding to the unreliability of image-makers for producing knowledge begins with two images—the mirror (596e) and the painter. I will show both undercut the (...) argument they introduce. Secondly, Socrates repeats the “three removes” argument three times. Each has its own object and philosophical axis. The “bed” argument (596a-598d) concerns the ontological status of images vis-à-vis human makers and the divine idea. The bit and bridle,” 601b-601d) emphasizes the epistemological status of image-making as beneath the human maker of bridles (having correct opinion) and the human user, who knows. This second takes away the ontological distinction which was the point of the first. Thus, any human being could be in any of the three positions—user, maker, imitator. This dance might bring one to doubt the conclusion that the imitator has “neither knowledge nor right opinion” (602a). Plato leads into his concluding psychological and moral argument (602c-605c) after a third variation of the 3 removes. This last gives us the image of the flute player (601d-602) as the one who knows and so can order the flute maker. We will conclude by considering what it is this flutist could know, and given that his art is itself a mimesis, who the imitator of this imitative artist could be. Thus attention to the differences among these examples opens a defense of the arts, which reverses many of the claims made against the arts within the ostensible “Platonic” argument. (shrink)

In a very literarily complicated setting, Frater Taciturnus sets a remark about Hamlet not being a Christian tragedy. After unpeeling that literary setting and noting that Taciturnus' remark aims more at Jacob Börne than at Shakespeare, the paper shows how Frater Taciturnus' remark calls into question the religious project of a certain danish author. For, Taciturnus' primary concern is to show that religious drama is not possible, or at least "ought not be." This general law applies to Hamlet as well, (...) and if Shakespeare was attempting a religious drama he a) shouldn't have because such a thing is essentially undramatizable, and b) failed because he did not begin (which would be possible) by showing the hero's religious presuppositions. Frater Taciturnus himself has given considerable thought to the extent and the manner in which the religious can be represented; in fact the letter to the reader is his proof of how perfectly his own narrative, "Guilty/Not Guilty," was constructed with precisely these problems in mind. The play is not the thing that Taciturnus is really interested in, nor is he interested in the playwright's intentions, he considers that the play's the thing that catches out Börne's misunderstanding of the religious, and it is this field—in particular, that area where the religious life and literary art intersect, that is the brother's interest and forte. But if Taciturnus is correct in his criticism of Börne, it should be impossible for S. Kierkegaard to produce a religious authorship as well. (shrink)

This paper aims at interpreting (primarily) the first six chapters of Aristotle’s Poetics in a way that dissolves many of the scholarly arguments conceming them. It shows that Aristotle frequently identifies the object of his inquiry by opposing it to what is other than it (in several different ways). As a result aporiai arise where there is only supposed to be illuminating exclusion of one sort or another. Two exemplary cases of this in chapters 1-6 are Aristotle’s account of mimesis (...) as other than enunciative speech (speech that makes truth claims, or representation) and his account of the final cause of tragedy in itself as plot, vis a vis its final cause as regards the audience, which is katharsis. Confusions arising from failure to see the otherness of representation and katharsis leads to an overly intellectualist understanding of the purpose of tragedy. (shrink)

ABSTRACT Clinicians, researchers and the informed public have come to view addiction as a brain disease. However, in nature even extreme events often reflect normal processes, for instance the principles of plate tectonics explain earthquakes as well as the gradual changes in the face of the earth. In the same way, excessive drug use is predicted by general principles of choice. One of the implications of this result is that drugs do not turn addicts into compulsive drug users; they retain (...) the capacity to say ?no?. In support of the logical implications of the choice theory approach to addiction, research reveals that most addicts quit using drugs by about age 30, that most quit without professional help, that the correlates of quitting are the correlates of decision making, and, according to the most recent epidemiological evidence, the probability of quitting remains constant over time and independent of the onset of dependence. This last result implies that, after an initial period of heavy drug use, remission is independent of any further exposure to drugs. In short, there is much empirical support for the claim that addiction emerges as a function of the rules of everyday choice. (shrink)

Kant admits that there are two kinds of human works that have something sublime about them, the work of the poet, e.g., tragedy, and the work of the politician, i.e., war. This paper will explore Kant's reasoning about the sublime element in these two human works.

In this book, author Gene Fendt shows how Plato's Republic provides a liturgical purification for the political and psychic delusions of democratic readers, even as Socrates provides the same for his interlocutors at the festival of Bendis. Each of the several characters is analyzed in accord with Book Eight's 6 geometrically possible kinds of character showing how their answers and failures in the dialogue exhibit the particular kind of movement and blindness predictable for the type.

Defense of an account of intrinsic properties in terms of (what is now called) grounding rather than naturalness.

The present thesis explores some metaphysical issues concerning biochemical kinds and the relations between chemical and biological properties and phenomena. The main result of this thesis is that there is something sui generis about biochemical kinds. This result is motivated by two theoretical steps. The first is characterising biochemical functions as weakly emergent from the chemical structure [Chapter 3, Chapter 6]. The second is via an account for which biochemical kinds are natural categories [Chapter 4, Chapter 7]. The thesis comprises (...) four parts. Part I [Chapter 1, Chapter 2] aims to offer the methodological and conceptual tools that underpin this research. Chapter 1 presents the debate on the unity of science and the motivation of the research. Chapter 2 presents the account of natural kinds that will be used throughout the thesis. Part II [Chapter 3, Chapter 4] offers a detailed metaphysical analysis of the molecular gene. Chapter 3 argues that molecular genes are weakly emergent from nucleic acids. Chapter 4 argues that the category "molecular gene" can be deemed a natural kind, following the account presented in Chapter 2. Part III [Chapter 5, Chapter 6, Chapter 7] explores some of the themes related to biochemical kinds and generalises some of the results from Part II. Chapter 5 considers biochemical functions and how functional attribution should be interpreted for biochemical molecules. Chapter 6 considers the relation between biochemical functions and structure, spelt in terms of weak emergence and explores unity in biochemistry. Chapter 7 considers the topic of biochemical kinds per se and argues that biochemical kinds are natural categories. Part IV [Chapter 8] elucidates the main outcome and the implications that this research can have for future discussion in the philosophy and metaphysics of biochemistry and the unity of science. (shrink)

Where humans can manipulate and integrate the information they receive in subtle and ever-changing ways from context to context, computers need structured and context-free background information of a sort which ontologies can help to provide. A domain ontology captures the stable, highly general and commonly accepted core knowledge for an application domain. The domain at issue here is that of the life sciences, in particular molecular biology and bioinformatics. Contemporary life science research includes components drawn from physics, chemistry, mathematics, (...) medicine and many other areas, and all of these dimensions, as well as fundamental philosophical issues, must be taken into account in the construction of a domain ontology. Here we describe the basic features of domain ontologies in the life sciences and show how they can be used. (shrink)

The rise of molecular epigenetics over the last few years promises to bring the discourse about the sociality and susceptibility to environmental influences of the brain to an entirely new level. Epigenetics deals with molecular mechanisms such as gene expression, which may embed in the organism “memories” of social experiences and environmental exposures. These changes in gene expression may be transmitted across generations without changes in the DNA sequence. Epigenetics is the most advanced example of the (...) new postgenomic and context-dependent view of the gene that is making its way into contemporary biology. In my article I will use the current emergence of epigenetics and its link with neuroscience research as an example of the new, and in a way unprecedented sociality of contemporary biology. After a review of the most important developments of epigenetic research, and some of its links with neuroscience, in the second part I reflect on the novel challenges that epigenetics presents for the social sciences for a re-conceptualization of the link between the biological and the social in a postgenomic age. Although epigenetics remains a contested, hyped, and often uncritical terrain, I claim that especially when conceptualized in broader non-genecentric frameworks,. (shrink)

The neutral theory often is presented as a theory of "noise" or silent changes at an isolated "molecular level", relevant to marking the steady pace of divergence, but not to the origin of biological structure, function, or complexity. Nevertheless, precisely these issues can be addressed in neutral models, such as those elaborated here in regard to scrambled ciliate genes, gRNA-mediated RNA editing, the transition from self-splicing to spliceosomal splicing, and the retention of duplicate genes. All of these are instances (...) of a more general scheme of "constructive neutral evolution" that invokes biased variation, epistatic interactions, and excess capacities to account for a complex series of steps giving rise to novel structures or operations. The directional and constructive outcomes of these models are not due to neutral allele fixations per se, but to these other factors. Neutral models of this type may help to clarify the poorly understood role of non-selective factors in evolutionary innovation and directionality. (shrink)

DESENVOLVIMENTO EMBRIONÁRIO E DIFERENCIAÇÃO SEXUAL -/- E. I. C. da Silva Departamento de Agropecuária – IFPE Campus Belo Jardim Departamento de Zootecnia – UFRPE sede -/- 1.1 INTRODUÇÃO O sexo foi definido como a soma das diferenças morfológicas, fisiológicas e psicológicas que distinguem o macho da fêmea permitindo a reprodução sexual e assegurando a continuidade das espécies. Os processos de diferenciação sexual são realizados durante o desenvolvimento embrionário, onde ocorre a proliferação, diferenciação e maturação das células germinativas e primordiais, precursoras (...) de ovócitos e espermatozoides em fêmeas e machos, respectivamente. Assim, os embriões machos e fêmeas iniciam o seu desenvolvimento de forma semelhante, de modo que em ambos os sexos se estabelecem em estruturas idênticas a partir das quais se formarão os órgãos reprodutores correspondentes a cada sexo. O conhecimento da origem e do desenvolvimento do aparelho genital é indispensável para entender sua função e as alterações que produzem infertilidade ou esterilidade. 1.2 DETERMINAÇÃO DO SEXO CROMOSSÔMICO Nos mamíferos, o sexo cromossômico é determinado no momento da fertilização, quando um óvulo, que contém um cromossomo X, é fecundado por um espermatozoide portador de um cromossomo X ou um cromossomo Y. No primeiro caso, o complemento cromossômico seria XX, o que originaria uma fêmea (sexo homogamético), e no segundo daria como resultado um macho com a fórmula cromossômica XY (sexo heterogâmico). 1.3 A GÔNADA INDIFERENCIADA A primeira manifestação das gônadas se aprecia no embrião em forma de um par de eminências longitudinais chamadas cristas ou dobras gonodais, situadas em ambos os lados da linha média entre os mesonefros (rins em desenvolvimento) e do mesentério dorsal. Nos embriões dos mamíferos, as células germinativas primordiais (CGP) manifestam-se em estágios precoces do desenvolvimento, podendo ser detectadas pela primeira vez na metade da gastrulação. As CGP são células grandes, de citoplasma claro e núcleo grande e redondo, localizadas na parede do saco vitelino, perto do alantoide. Essas células possuem grande capacidade de proliferação e vão migrar desde o endoderma do intestino e o epitélio do saco vitelino, através do mesentério, até as cristas gonodais. Isso ocorre por volta do 26° dia da gestação no bovino. Sua migração realiza-se graças aos movimentos de translocação passiva e deslocamento ameboide ativo. Desconhece-se o mecanismo pelo qual estas células são dirigidas para as cristas gonodais, porém foram estudadas algumas moléculas que se expressam durante sua migração e que poderiam desempenhar um papel importante na diferenciação deste tipo celular. A fosfatase alcalina é uma enzima que tem sido usada como marcador de CGP para determinar a sua origem e migração. Num estudo recente, foi inserido um marcador fluorescente que se exprime unicamente nas células germinativas primordiais de embriões transgênicos, e utilizando este marcador e a fosfatase alcalina determinou-se a origem e o padrão de migração destas células. O primeiro sinal de diferenciação das células germinativas primordiais é a expressão de fosfatase alcalina, e esta apareceu pela primeira vez na parte mais posterior da linha primitiva. No sétimo dia de desenvolvimento no embrião do camundongo, o endoderma visceral (AF+) é substituído pelo endoderma definitivo (AF-) originado na parte anterior da linha primitiva. O fator de transcrição Oct-4 é expresso nas CGP de ambos os sexos, pelo que acredita-se estar envolvido na mantença a totipotêncialidade das células. O receptor tirosina quinase, cujo ligante é o fator de Steel, é outra das moléculas que expressam as CGP. Tem sido demonstrado que este receptor possui um papel muito importante na sobrevivência deste tipo celular. Existem outros fatores que promovem a sobrevivência e/ou proliferação de CGP in vitro. Em experiências realizadas com o fator de transformação beta I (TGFβ-I), observou-se que este tem um efeito negativo sobre a proliferação das CGP. Outra atividade que tem sido postulada a este fator é o de um agente quimioatraente que possivelmente possa direcionar a migração destas células para a gônada. a) Um formado pelas células germinativas primordiais (precursoras dos gametas masculinos ou femininos), rodeadas de células somáticas das quais posteriormente se derivarão as células de Sertoli no macho e as células da granulosa na fêmea. b) O tecido que formará o estroma da gônada: tecido conjuntivo, vasos sanguíneos e as células intersticiais com atividade esteroidogênica (células de Leydig no testículo e a teca interna do ovário). As células somáticas do primórdio gonodal originam-se do mesoderma. Inicialmente são de três tipos: mesenquimáticas, mesoteliais e endoteliais. As células mesenquimáticas e mesoteliais iniciam grande atividade proliferativa ao chegar as CGP. Observa-se então uma condensação de células de origem mesotelial e mesenquimatoso que forma um agregado compacto denominado "blastema gonodal". A partir deste primórdio embrionário, diferenciam-se dois tecidos gonodais: os cordões sexuais e o estroma. Os cordões sexuais são arranjos epiteliais que se encontram delimitados por uma folha basal, e dentro deles encontramos as CGP. Por sua vez, no estroma encontram-se células do tipo mesenquimático e vasos sanguíneos. Neste momento, as gônadas são indiferenciadas e bipotencialmente sexuais, sendo impossível diferenciar, morfologicamente, uma gônada masculina de uma feminina, mas no caso dos machos genéticos já existe uma diferenciação da gônada a nível molecular. Nesta fase já se encontram presentes as estruturas das quais se desenvolvem os dutos mesonéfricos ou de Wolff precursores do aparelho genital masculino e os dutos paramesonéfricos ou de Müller que darão origem ao aparelho reprodutor feminino. Há uma série de fatores envolvidos no desenvolvimento precoce da gônada, entre os quais o fator esteroidogênico I (SFI: Steroidogenic fator l), que é um membro da subfamília de receptores nucleares, receptores órfãos. Este fator de transcrição tem um local de ligação ao DNA composto por dois dedos-de-Zinc. O SFI foi identificado como um ativador de genes envolvidos na biossíntese de esteroides em diferentes células. O SFI está presente durante o desenvolvimento embrionário em regiões associadas com funções endócrinas como gônadas, adrenais, pituitárias e hipotálamos. Os animais homozigotos para o gene SFI defeituoso, necessitam de gônadas e adrenais e têm a função gonadotrófica alterada. Os ratos sem SFI carecem de gonadotrofos e têm um desenvolvimento anormal do núcleo ventro-medial do hipotálamo; em particular as gônadas deixam de se desenvolver entre os dias 11 a 15 e degeneram-se por apoptose. No entanto, a crista genital forma-se e é colonizada pelas células germinativas, o que indica que estas continuam a receber o sinal adequado para a sua migração. Portanto, o SFI não está envolvido no desenvolvimento precoce da gônada e do sistema urogenital, mas parece estar envolvido na manutenção do crescimento das células somáticas presentes na gônada indiferenciada. O gene associado ao tumor de Wilms (WTI: Wilm's tumor Associated) está envolvido no desenvolvimento da gônada e do rim. Durante o desenvolvimento embrionário, WTI se expressa em todo o mesoderma intermediário e posteriormente na gônada indiferenciada, bem como no rim em formação. WTI regula o sinal indutivo do mesênquima para o epitélio celômico dos mesonefros. Se este for o caso, então WTI é responsável pelo crescimento da crista genital ao dirigir a entrada do epitélio celômico. Dado que estas células darão origem às células de Sertoli, a carência de WTI pode causar o desenvolvimento de embriões XY como fêmeas simplesmente porque não se formam as células de Sertoli. Em geral, todos os genes importantes na diferenciação do mesoderma intermediário e do sistema urogenital intervêm no desenvolvimento da gônada precoce. 1.4 DIFERENCIAÇÃO GONODAL O desenvolvimento das gônadas e ductos genitais descritos até o momento, é o mesmo para ambos os sexos. Igualmente, os genes descritos, que estão envolvidos no desenvolvimento das gônadas, ductos genitais e migração das células germinativas, afetam igualmente os embriões com genótipo XX ou XY. A gônada primitiva consiste anatomicamente de uma medula (interna) e uma crosta (externa), e de acordo com o local onde ocorre a colonização das células germinativas, diferenciara em testículo ou um ovário, respectivamente. Nos mamíferos, a primeira manifestação estrutural de diferenciação sexual é detectada na gônada dos machos, onde as células germinativas estão localizadas na medula. A diferenciação do testículo inicia-se quando os cordões sexuais se separam do epitélio celômico como consequência dos arranjos produzidos por uma invasão do mesênquima e vasos sanguíneos que provoca a compactação dos cordões, agora denominados cordões testiculares. As células que rodeiam os cordões se achatam e formam as células mioides, que são responsáveis pela formação das membranas basais. As células do epitélio interno, ou seja, as células de Sertoli, têm duas funções principais: o suporte das CGP e a síntese da hormona antimulleriana, responsável pela regressão dos ductos de Müller e secretada durante o período de diferenciação sexual. As células do estroma que rodeiam os cordões testiculares diferenciam-se para formar vários tipos de células: células mioides, fibroblastos, endotélio e células de Leydig, que são as mais importantes pela sua atividade endócrina. Posteriormente, os cordões testiculares dão origem aos túbulos seminíferos, que contêm o epitélio que produzirá os espermatozoides ao chegar à puberdade. Na fêmea, durante os estágios iniciais de diferenciação gonodal, não se observam mudanças em relação à gônada indiferenciada, só pode-se observar um certo crescimento devido à proliferação de células somáticas e germinativas. As células germinativas iniciam um período de proliferação, que termina com o início da meiose. Iniciada a meiose, dá-se o processo de foliculogênese; neste momento os cordões epiteliais se fragmentam, de tal maneira que cada ovócito fica rodeado de células epiteliais cobertas por uma folha basal fina (figura 1). Para que a gônada primitiva se desenvolva em testículo é indispensável a presença do cromossoma Y, independentemente do número de cromossomas X que contenha o genoma de um indivíduo. O gene determinante do testículo encontra-se localizado no cromossoma Y, denominado sry em ratos e SRY em humanos. O gene sry se expressa durante o desenvolvimento embrionário na crista genital de embriões de camundongos. A expressão é detectável no dia 10,5, pouco depois do aparecimento das cristas genitais, atinge o seu máximo durante o dia 11,5 e mantém-se até pouco depois de ocorrerem os primeiros sinais morfológicos de diferenciação testicular no dia 12,5. Este padrão de expressão é compatível com a teoria de que sry atua induzindo a ativação dos genes (figura 2) que conduzem ao desenvolvimento testicular, sem que exista a necessidade da expressão contínua de sry para manter a diferenciação do testículo após o dia 12,5. Como mencionado anteriormente, a gônada primitiva é composta por vários tipos de células. No entanto, as células germinativas primordiais não são o local de expressão do sry, já que os embriões que necessitam de células germinativas mantêm a expressão de sry e desenvolvem o sexo gonodal normalmente. As células somáticas na gônada em desenvolvimento incluem também as células de suporte. Sabe-se que é nestas células que o sry é expresso para que se diferenciem em células de Sertoli, e a expressão transitória de sry indica que deve ativar a outros genes para a manutenção das células de Sertoli. Uma vez diferenciadas as células de Sertoli, elas se encarregarão da diferenciação do resto das células na gônada. -/- Figura 1: Representação da diferenciação dos órgãos genitais internos. Adaptado de BRONSON, 1989. Figura 2: Cascada de genes envolvidos na diferenciação sexual, adaptado de KOOPMAN, 1999. O fator sry é necessário para a diferenciação do testículo. Embora não se conheçam os genes que provavelmente regulam esse gene, estudos realizados em camundongos demonstram que este gene parece coordenar-se com certos genes autossômicos. Entre estes genes autossômicos, o sox9, que é produzido pelas células de Sertoli uma vez que são estimuladas por sry, de modo que sox9 é um dos genes relacionados estruturalmente com sry. O Sox9 funciona como um fator de transcrição, mas não se sabe se a proteína tem qualquer outra função estrutural; este gene exprime-se abundantemente nos condrócitos e está relacionado com defeitos do aparelho ósseo chamados displasia campomélica. Curiosamente, os pacientes XY com esta condição sofrem frequentemente de reversão do sexo. O Sox9 é um dos poucos genes, além do SRY, do qual as mutações demonstraram interferir com a determinação sexual masculina. No entanto, apenas 75% dos pacientes com anomalias esqueléticas de tipo displasia campomélica têm reversão sexual e não foram encontrados casos de reversão sexual devido a um defeito de Sox9 que não seja acompanhado de defeitos esqueléticos. Isso indica que o Sox9 é apenas um membro da rede de genes que são ativados para determinar a diferenciação sexual, enquanto a rota que rege a condrogênese é mais sensível a perturbações deste. O momento em que se detecta a expressão do gene Sox9 (11dpc em ratos) coincide com a máxima expressão de sry, o que poderia indicar a possibilidade de que sry regule positivamente a Sox9. De fato, na região do promotor de Sox9 há um local de união ao que potencialmente se pode unir o sry. A expressão de Sox9 durante a diferenciação sexual sugere um papel abaixo de sry na diferenciação das células de Sertoli. O cromossoma X também é importante na diferenciação gonodal. O gene DAX-I foi isolado do lócus DSS (Dosage sensitive sex reversal) do cromossoma X. DAX-I é parte da cascata de determinação sexual, mas não é necessário para a formação do testículo. DAX-I é um membro dos receptores nucleares conhecidos como receptores órfãos. Este gene demonstrou ser um poderoso repressor da transcrição de SFI e de vários genes. Os padrões de expressão de DAX-I são complementares daqueles de SFI, ambos expressos nas cristas genitais. Em resumo, dada a evidência exposta, desenvolveu-se a hipótese de que DAX-I é um antagonista de sry; esse antagonismo é dependente dos níveis relativos de DAX-I e sry e de um limiar que varia de espécie para espécie. A DAX-I foi classificada como o gene antitestículo. Na fêmea (cariótipo XX) é importante que ocorra a inativação de um dos cromossomas sexuais X para que se mantenha o equilíbrio genético ao igualar o conteúdo de DNA dos cromossomas. Esse cromossoma inativado constitui o chamado corpúsculo de Barr. No entanto, para que a meiose se realize, é necessário dos dois cromossomas X ativos nos ovócitos para assegurar a diferenciação ovárica e a fertilidade. 1.5 DIFERENCIAÇÃO DOS DUCTOS SEXUAIS O embrião possui, além das gônadas indiferenciadas, dois sistemas de ductos: os de potencialidade masculina denominam-se ductos de Wolff ou mesonéfricos, e os de potencialidade feminina se chamam ductos de Müller ou paramesonéfricos (figura 1). Se a diferenciação gonodal levou à formação de um testículo, a partir do ducto mesonéfrico ou de Wolff se desenvolverão os ductos eferentes, o epidídimo, os ductos deferentes e as vesículas seminais. As hormonas importantes no desenvolvimento do aparelho genital masculino são a testosterona, produzida pelas células de Leydig, e sua forma 5α reduzida, a 5α di-hidrotestosterona. Acredita-se que a testosterona é responsável pela virilização dos ductos de Wolff, e a di-hidrotestosterona dos órgãos genitais externos. No macho, os canais de Müller atrofiam-se devido à ação de uma hormona fetal de origem testicular denominada hormona inibidora das estruturas de Müller (HIM) ou hormona antimulleriana. Este processo começa assim que os cordões espermáticos se formam e se diferenciam as células de Sertoli. A existência de HIM foi proposta baseada em estudos realizados em bezerras freemartin, devido à existência de uma hormona responsável pela atresia dos ductos de Müller que na fêmea dá origem ao útero e aos ovidutos. Essa hormona provoca a involução do aparelho genital do bovino nas gestações gemelares nas quais os produtos de diferente sexo têm comunicação sanguínea por ter ocorrido a anastomose dos vasos de ambas as placentas (figura 3). A HIM é uma glicoproteína pertencente à subfamília de TGFβ, é expressa pelas células que darão origem às células de Sertoli e é um dos primeiros marcadores de diferenciação nestas células. A HIM é secretada na vida adulta pelas células de Sertoli no testículo e por células da granulosa no ovário. No rato a HIM é expressa-se no 12° dia em um teste padrão que segue muito de perto o aumento na expressão de sry. No macho, esta secreção de HIM continua durante a vida fetal e adulta, contudo os níveis de HIM declinam na puberdade devido a um aumento na secreção de testosterona. Vários fatores intervêm na regulação do gene de HIM, incluindo os acima descritos SFI e Sox9. O gene HIM contém segmentos de DNA que são conservados em várias espécies de vertebrados. Existe um nexo de ligação para SFI, que ativa a transcrição de HIM. A mutação no local de ligação de SFI resulta em reversão do sexo em indivíduos XY incluindo genitais femininos normais, presença de um útero formado enfatizando a importância de SFI na determinação sexual e na expressão de HIM. Embora SFI seja um bom candidato como regulador de HIM, é expresso em outras células, como as de Leydig e adrenais, que não expressam HIM. Em contrapartida, Sox9 é expresso unicamente nas células de Sertoli que são as produtoras de HIM. O gene HIM também tem um nexo de ligação para Sox9. Além disso, Sox9 pode atuar sinergicamente com SFI para promover a secreção de HIM. Ao contrário destes dois fatores de transcrição, DAX-I antagoniza a ação de Sox9 e provavelmente SFI sobre o promotor de HIM. Assim, para que as células de Sertoli secretem HIM, a transcrição de DAX-I deve diminuir. Figura 3: Representação da diferenciação dos órgãos genitais externos. Adaptado de BRONSON, 1989. Os ductos de Wolff tornam-se o sistema de ejaculação do macho. A porção mais próxima dos testículos dá origem ao epidídimo, a parte central ao ducto deferente e a porção mais distal às vesículas seminais. A próstata e a parte membranosa da uretra do macho desenvolvem-se a partir da porção pélvica do seio urogenital. A virilização e diferenciação dos ductos de Wolff dependem da produção de testosterona pelo testículo. Quanto aos órgãos genitais externos do macho, o tubérculo genital é ampliado e as dobras uretrais se fundem para formar a uretra peniana. A fusão das dobras uretrais aproxima os tubérculos genitais para formar o escroto (figura 4). Figura 4: Diferenciação do aparelho genital da fêmea e do macho. Adaptado de KOOPMAN, 1989. A diferenciação dos órgãos genitais da fêmea ocorre de forma passiva, já que a ausência de testículos e por isso da hormona inibidora dos ductos de Müller (HIM), assim como dos andrógenos virilizantes, favorece o desenvolvimento dos ductos de Müller, enquanto os de Wolff sofrem atrofia. A porção cefálica dos ductos de Müller dá origem aos ovidutos, que na sua terminação caudal se fundem com o útero. O contato dos ductos de Müller com o seio urogenital induz uma intensa proliferação celular que resulta na formação da área uterovaginal localizado entre o seio urogenital e os ductos de Müller. As células do prato uterovaginal proliferam e aumentam a distância entre as duas estruturas criando o espaço que formará a vagina quando o prato é canalizado e forma um lúmen. Em contraste com o que ocorre no macho, na fêmea a maior parte do seio urogenital se mantém exposta na superfície da abertura onde desembocam a vagina e a uretra. O tubérculo urogenital da fêmea tem um crescimento limitado e forma o clitóris. A sequência de passos da diferenciação sexual do aparelho genital é resumida na tabela 1. Tabela 1: Destino em desenvolvimento dos rudimentos sexuais dos fetos macho e fêmea dos mamíferos -/- Rudimento sexual Macho Fêmea Gônada Testículo Ovário Ductos de Müller (Paramesonéfricos) Vestígios Útero, parte da vagina, ovidutos Ductos de Wolff (Mesonéfricos) Ductos eferentes deferentes, epidídimo, vesículas seminais Vestígios Seio urogenital Uretra, próstata, glândulas bulbouretrais Parte da vagina, uretra, vestíbulo, glândulas vestibulares Tubérculo genital Pênis Clitóris Pregas vestibulares Escroto Lábios vulvares Fonte: HAFEZ, 2004. 1.6 DIFERENCIAÇÃO SEXUAL DO HIPOTÁLAMO Os processos de diferenciação sexual não se limitam apenas às células somáticas do organismo do feto, mas incluem também os centros nervosos superiores do cérebro. Assim, da mesma maneira que a gônada e os ductos sexuais se desenvolvem para o tipo feminino ou masculino, propôs-se que o cérebro pode ser "masculinizado" ou permanecer "Feminizado". A diferenciação do hipotálamo vai depender do ambiente esteroidal do neonato e ocorre na fase perinatal. Estes eventos serão de grande transcendência na vida reprodutiva do indivíduo. Tanto a fêmea como o macho nascem com a capacidade de secreção de gonadotropinas de acordo com um padrão cíclico; contudo, no macho, a exposição do hipotálamo à ação dos andrógenos testiculares durante os primeiros dias da vida extrauterina provoca a masculinização, com o qual o hipotálamo do macho é programado para que a secreção de gonadotropinas se realize a um ritmo relativamente constante por parte da hipófise (secreção tônica). Na fêmea, tanto a secreção tônica como a cíclica se conservam. No entanto, observou-se que a injeção de testosterona ou o transplante de testículo na rata fêmea durante os primeiros dias de vida, suprime a sua futura atividade estral (secreção cíclica). Por outro lado, se os ovários forem transplantados para o rato macho normal castrado na idade adulta, o animal não desenvolve qualquer atividade cíclica, mas se os machos transplantados forem castrados ao nascer, o ovário é capaz de efetuar mudanças cíclicas e ovulações. Isto foi demonstrado em roedores, mas não em animais domésticos ou na espécie humana. Portanto, o padrão de secreção de gonadotropinas, seja cíclico ou tônico, não depende da hipófise, mas do hipotálamo e sua correta diferenciação. 1.7 CONCLUSÕES A maioria dos conhecimentos no campo da biologia do desenvolvimento e, muito especificamente, dos processos de diferenciação sexual têm sido originados de estudos relacionados com desordens congênitas, que na sua maioria devem-se a defeitos de genes específicos. A análise detalhada destas desordens permitiu entender alguns mecanismos endócrinos, moleculares e genéticos envolvidos na diferenciação sexual. A identificação do gene sry como determinante do testículo foi uma contribuição crucial e abriu as portas à compreensão dos mecanismos moleculares e celulares relacionados com o desenvolvimento do testículo. Se este gene não estiver presente, é criado um programa genético alternativo para levar a cabo a diferenciação gonodal para o ovário. Finalmente, devemos ter presente que é necessária uma correlação entre mudanças morfológicas e expressão de genes durante o desenvolvimento para entender os mecanismos relacionados com a diferenciação. -/- Apoio -/- Realização -/- REFERÊNCIAS BIBLIOGRÁFICAS ANDERSON, Robert et al. The onset of germ cell migration in the mouse embryo. Mechanisms of development, v. 91, n. 1-2, p. 61-68, 2000. AUSTIN, Colin Russell; SHORT, R. V. Reproduction in Mammals: Volume 1, Germ Cells and Fertilization. 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A strong motivation for the human genome project was to relate biological features to the structure and function of small sets of genes, and ideally to individual genes. However, it is now increasingly realized that many problems require a "systems" approach emphasizing the interplay of large numbers of genes, and the involvement of complex networks of gene regulation. This implies a new emphasis on integrative, systems theoretical approaches. It may be called 'holistic' if the term is used without irrational (...) overtones, in the general sense of directing attention to integrated features of organs and organisms. In the history of biology, seemingly conflicting reductionist and holistic notions have alternated, with bottom-up as well as top-down approaches eventually contributing to the solutions of basic problems. By now, there is no doubt that biological features and phenomena are rooted in physico-chemical processes of the molecules involved; and yet, integrated systems aspects are becoming more and more relevant in developmental biology, brain and behavioural science, and socio-biology. -/- . (shrink)

Molecular developmental biology has expanded our conceptions of gene actions, underpinning that embryonic development is not only governed by a set of specific genes, but as much by space–time conditions of its developing modules. Typically, formation of cellular spheres, their transformation into planar epithelia, followed by tube formations and laminations are modular steps leading to the development of nervous tissues. Thereby, actions of organising centres, morphogenetic movements, inductive events between epithelia, tissue polarity reversal, widening of epithelia, and all (...) these occurring orderly in space and time, are driving forces of emergent laminar neural tissues, e.g. the vertebrate retina. Analyses of self-organisational formation of retina-like 3D structures from dispersed cells under defined cell culture conditions demonstrate that not only particular genetic networks, but—at least as important—the applied culture conditions define phenotypes of emergent tissues. Such in vitro approaches allow assigning emerging tissue formation to ground-laying genetic networks separately from contributions by conditional constraints. (shrink)

The Emotion Ontology is an ontology covering all aspects of emotional and affective mental functioning. It is being developed following the principles of the OBO Foundry and Ontological Realism. This means that in compiling the ontology, we emphasize the importance of the nature of the entities in reality that the ontology is describing. One of the ways in which realism-based ontologies are being successfully used within biomedical science is in the annotation of scientific research results in publicly available databases. Such (...) annotation enables several objectives, including searching, browsing and cross-database data integration. A key benefit conferred by realismbased ontology is that suitably annotated research results are able to be aggregated and compared in a fashion that is based on the underlying reality that the science is studying. This has the potential of increasing the power of statistical analysis and meta-analysis in data-driven science. This aspect has been fruitfully exploited in the investigation of the functions of genes in molecular biology. Cognitive neuroscience uses functional neuroimaging to investigate the brain correlates of areas of mental functioning such as memory, planning and emotion. The use of functional neuroimaging to study affective phenomena such as the emotions is called ‘affective neuroscience’. BrainMap is the largest curated database of coordinates and metadata for studies in cognitive neuroscience, including affective neuroscience (Laird et al., 2005). BrainMap data is already classified and indexed using a terminology for classification, called the ‘Cognitive Paradigm Ontology’ (CogPO), that has been developed to facilitate searching and browsing. However, CogPO has been developed specifically for the BrainMap database, and the data are thus far not annotated to a realism-based ontology which would allow the discovery of interrelationships between research results across different databases on the basis of what the research is about. In this contribution, we describe ongoing work that aims to annotate affective neuroscience data, starting with the BrainMap database, using the Emotion Ontology. We describe our objectives and technical approach to the annotation, and mention some of the challenges. (shrink)

Vaccine research, as well as the development, testing, clinical trials, and commercial uses of vaccines involve complex processes with various biological data that include gene and protein expression, analysis of molecular and cellular interactions, study of tissue and whole body responses, and extensive epidemiological modeling. Although many data resources are available to meet different aspects of vaccine needs, it remains a challenge how we are to standardize vaccine annotation, integrate data about varied vaccine types and resources, and support (...) advanced vaccine data analysis and inference. To address these problems, the community-based Vaccine Ontology (VO) has been developed through collaboration with vaccine researchers and many national and international centers and programs, including the National Center for Biomedical Ontology (NCBO), the Infectious Disease Ontology (IDO) Initiative, and the Ontology for Biomedical Investigations (OBI). VO utilizes the Basic Formal Ontology (BFO) as the top ontology and the Relation Ontology (RO) for definition of term relationships. VO is represented in the Web Ontology Language (OWL) and edited using the Protégé-OWL. Currently VO contains more than 2000 terms and relationships. VO emphasizes on classification of vaccines and vaccine components, vaccine quality and phenotypes, and host immune response to vaccines. These reflect different aspects of vaccine composition and biology and can thus be used to model individual vaccines. More than 200 licensed vaccines and many vaccine candidates in research or clinical trials have been modeled in VO. VO is being used for vaccine literature mining through collaboration with the National Center for Integrative Biomedical Informatics (NCIBI). Multiple VO applications will be presented. (shrink)

The scientific study of living organisms is permeated by machine and design metaphors. Genes are thought of as the ‘‘blueprint’’ of an organism, organisms are ‘‘reverse engineered’’ to discover their func- tionality, and living cells are compared to biochemical factories, complete with assembly lines, transport systems, messenger circuits, etc. Although the notion of design is indispensable to think about adapta- tions, and engineering analogies have considerable heuristic value (e.g., optimality assumptions), we argue they are limited in several important respects. In (...) particular, the analogy with human-made machines falters when we move down to the level of molecular biology and genetics. Living organisms are far more messy and less transparent than human-made machines. Notoriously, evolution is an oppor- tunistic tinkerer, blindly stumbling on ‘‘designs’’ that no sensible engineer would come up with. Despite impressive technological innovation, the prospect of artificially designing new life forms from scratch has proven more difficult than the superficial analogy with ‘‘programming’’ the right ‘‘software’’ would sug- gest. The idea of applying straightforward engineering approaches to living systems and their genomes— isolating functional components, designing new parts from scratch, recombining and assembling them into novel life forms—pushes the analogy with human artifacts beyond its limits. In the absence of a one-to-one correspondence between genotype and phenotype, there is no straightforward way to imple- ment novel biological functions and design new life forms. Both the developmental complexity of gene expression and the multifarious interactions of genes and environments are serious obstacles for ‘‘engi- neering’’ a particular phenotype. The problem of reverse-engineering a desired phenotype to its genetic ‘‘instructions’’ is probably intractable for any but the most simple phenotypes. Recent developments in the field of bio-engineering and synthetic biology reflect these limitations. Instead of genetically engi- neering a desired trait from scratch, as the machine/engineering metaphor promises, researchers are making greater strides by co-opting natural selection to ‘‘search’’ for a suitable genotype, or by borrowing and recombining genetic material from extant life forms. (shrink)

The scientific study of living organisms is permeated by machine and design metaphors. Genes are thought of as the ‘‘blueprint’’ of an organism, organisms are ‘‘reverse engineered’’ to discover their functionality, and living cells are compared to biochemical factories, complete with assembly lines, transport systems, messenger circuits, etc. Although the notion of design is indispensable to think about adaptations, and engineering analogies have considerable heuristic value (e.g., optimality assumptions), we argue they are limited in several important respects. In particular, the (...) analogy with human-made machines falters when we move down to the level of molecular biology and genetics. Living organisms are far more messy and less transparent than human-made machines. Notoriously, evolution is an opportunistic tinkerer, blindly stumbling on ‘‘designs’’ that no sensible engineer would come up with. Despite impressive technological innovation, the prospect of artificially designing new life forms from scratch has proven more difficult than the superficial analogy with ‘‘programming’’ the right ‘‘software’’ would suggest. The idea of applying straightforward engineering approaches to living systems and their genomes— isolating functional components, designing new parts from scratch, recombining and assembling them into novel life forms—pushes the analogy with human artifacts beyond its limits. In the absence of a one-to-one correspondence between genotype and phenotype, there is no straightforward way to implement novel biological functions and design new life forms. Both the developmental complexity of gene expression and the multifarious interactions of genes and environments are serious obstacles for ‘‘engineering’’ a particular phenotype. The problem of reverse-engineering a desired phenotype to its genetic ‘‘instructions’’ is probably intractable for any but the most simple phenotypes. Recent developments in the field of bio-engineering and synthetic biology reflect these limitations. Instead of genetically engineering a desired trait from scratch, as the machine/engineering metaphor promises, researchers are making greater strides by co-opting natural selection to ‘‘search’’ for a suitable genotype, or by borrowing and recombining genetic material from extant life forms. (shrink)

The Protein Ontology (PRO) is designed as a formal and principled Open Biomedical Ontologies (OBO) Foundry ontology for proteins. The components of PRO extend from a classification of proteins on the basis of evolutionary relationships at the homeomorphic level to the representation of the multiple protein forms of a gene, including those resulting from alternative splicing, cleavage and/or posttranslational modifications. Focusing specifically on the TGF-beta signaling proteins, we describe the building, curation, usage and dissemination of PRO. PRO provides a (...) framework for the formal representation of protein classes and protein forms in the OBO Foundry. It is designed to enable data retrieval and integration and machine reasoning at the molecular level of proteins, thereby facilitating cross-species comparisons, pathway analysis, disease modeling and the generation of new hypotheses. (shrink)

The genomics “revolution” is spreading. Originating in the molecular life sciences, it initially affected a number of biomedical research fields such as cancer genomics and clinical genetics. Now, however, a new “wave” of genomic bioinformation is transforming a widening array of disciplines, including those that address the social, historical and cultural dimensions of human life. Increasingly, bioinformation is affecting “human sciences” such as psychiatry, psychology, brain research, behavioural research (“behavioural genomics”), but also anthropology and archaeology (“bioarchaeology”). Thus, bioinformatics is (...) having an impact on how we define and understand ourselves, how identities are formed and constituted, and, finally, on how we (on the basis of these redefined identities) assess and address some of the more concrete societal issues involved in genomics governance in various settings. This article explores how genomics and bioinformation, by influencing research agendas in the human sciences and the humanities, are affecting our self-image, our identity, the way we see ourselves. The impact of bioinformation on self-understanding will be assessed on three levels: (1) the collective level (the impact of comparative genomics on our understanding of human beings as a species), (2) the individual level (the impact of behavioural genomics on our understanding of ourselves as individuals), and (3) the genealogical level (the impact of population genomics on our understanding of human history, notably early human history). This threefold impact will be assessed from two seemingly incompatible philosophical perspectives, namely a “humanistic” perspective (represented in this article by Francis Fukuyama) and a “post-humanistic” one (represented by Peter Sloterdijk). On the basis of this analysis it will be concluded that, rather than focussing on human “enhancement” by adding or deleting genes, genome-oriented practices of the Self will focus on using genomics information in the context of identity-formation. Genomic bioinformation will increasingly be built into our self-images and used in order to tailor and adapt our practices of Self to our “personalised” genome. We will keep working on ourselves, no doubt, not by modifying our genomes, but rather by fine-tuning our behaviour. What we are experiencing is a bioinformatisation of the life-world. Genomics-based technologies will increasingly pervade our daily lives, our autobiographies and narratives, as well as our anthropologies, rather than our genomes as such. (shrink)

In this paper I first offer a systematic outline of a series of conceptual novelties in the life-sciences that have favoured, over the last three decades, the emergence of a more social view of biology. I focus in particular on three areas of investigation: (1) technical changes in evolutionary literature that have provoked a rethinking of the possibility of altruism, morality and prosocial behaviours in evolution; (2) changes in neuroscience, from an understanding of the brain as an isolated data processor (...) to the ultrasocial and multiply connected social brain of contemporary neuroscience; and (3) changes in molecular biology, from the view of the gene as an autonomous master of development to the ‘reactive genome’ of the new emerging field of molecular epigenetics. In the second section I reflect on the possible implications for the social sciences of this novel biosocial terrain and argue that the postgenomic language of extended epigenetic inheritance and blurring of the nature/nurture boundaries will be as provocative for neo-Darwinism as it is for the social sciences as we have known them. Signs of a new biosocial language are emerging in several social-science disciplines and this may represent an exciting theoretical novelty for twenty-first social theory. (shrink)

In searching for life in extraterrestrial space, it is essential to act based on an unequivocal definition of life. In the twentieth century, life was defined as cells that self-replicate, metabolize, and are open for mutations, without which genetic information would remain unchangeable, and evolution would be impossible. Current definitions of life derive from statistical mechanics, physics, and chemistry of the twentieth century in which life is considered to function machine like, ignoring a central role of communication. Recent observations show (...) that context-dependent meaningful communication and network formation (and control) are central to all life forms. Evolutionary relevant new nucleotide sequences now appear to have originated from social agents such as viruses, their parasitic relatives, and related RNA networks, not from errors. By applying the known features of natural languages and communication, a new twenty-first century definition of life can be reached in which communicative interactions are central to all processes of life. A new definition of life must integrate the current empirical knowledge about interactions between cells, viruses, and RNA networks to provide a better explanatory power than the twentieth century narrative. (shrink)

Many researchers consider cancer to have molecular causes, namely mutated genes that result in abnormal cell proliferation (e.g. Weinberg 1998). For others, the causes of cancer are to be found not at the molecular level but at the tissue level where carcinogenesis consists of disrupted tissue organization with downward causation effects on cells and cellular components (e.g. Sonnenschein and Soto 2008). In this contribution, I ponder how to make sense of such downward causation claims. Adopting a manipulationist account (...) of causation (Woodward 2003), I propose a formal definition of downward causation and discuss further requirements (in light of Baumgartner 2009). I then show that such an account cannot be mobilized in support of non-reductive physicalism (contrary to Raatikainen 2010). However, I also argue that such downward causation claims might point at particularly interesting dynamic properties of causal relationships that might prove salient in characterizing causal relationships (following Woodward 2010). (shrink)

Many researchers consider cancer to have molecular causes, namely mutated genes that result in abnormal cell proliferation (e.g. Weinberg 1998); yet for others, the causes of cancer are to be found not at the molecular level but at the tissue level and carcinogenesis would consist in a disrupted tissue organization with downward causation effects on cells and cellular components (e.g. Sonnenschein & Soto 2008). In this contribution, I ponder how to make sense of such downward causation claims. Adopting (...) a manipulationist account of causation (Woodward 2003), I propose a formal definition of downward causation, and discuss further requirements (in light of Baumgartner 2009). I then show that such an account cannot be mobilized in support of non-reductive physicalism (contrary to Raatikainen 2010). However, I also argue that such downward causation claims might point at particularly interesting dynamic properties of causal relationships that might prove salient in characterizing causal relationships (following Woodward 2010). (shrink)

This essay moves along broad lines from molecular biology to evolutionary biology and ecology to theology. Its objectives are to: 1) present some recent scientific findings in the emerging field of epigenetics that indicate that it is “the genome in context,” not genes per se, that are important in biological development and evolution; 2) show that this weakens the gene-centric neo-Darwinist explanation of evolution which, in fact, shares a certain preformationist orientation with intelligent design theory; 3) argue that (...) the evidence against a gene-centric view in no way negates Darwin’s central idea of “descent with modification”; 4) argue that an embrace of the evolutionary story, with all of its contingency and apparent lack of directionality, is not only consistent with Christianity, but actually resonates with the notion of the self-emptying love of God in Jesus Christ; and finally 5) suggest that we are called through an ecological imperative to embrace our evolutionary story, to listen to our “genetic coding,” and to reclaim our grounding as a species in the natural world. Corrigendum (published in later issue of journal): There was an error in the paragraph describing the mode of action of the small temporally-expressed RNAs (stRNAs) lin-4 and let-7 from Caenorhabditis elegans. Instead of reading "These two stRNAs act by binding to the tails of their target messenger RNAs (mRNAs); this results in destruction of the target and an overall drop in the level of production of protein from agouti mRNA" [note that agouti mRNA is not a target of these stRNAs], the sentence should have read, "These two stRNAs act by binding to the tails of target messenger RNAs (mRNAs); this leads to inhibition of translation of the mRNAs into protein and a consequent drop in the levels of the corresponding target protein.". (shrink)

Since Aristotle the central question in biology was the origin of organic form; a question put in the backyard by neo-Darwinism that considers organic form as a side effect of the interactions between genes and their products. On the other hand, the fashionable notion of self-organization also fails to provide a true causal explanation for organic form. For Aristotle form is both a cause and the principle of intelligibility and this coupled to the classical concepts of potentiality and actuality provides (...) a rational framework,currently embodied in the contemporary concept of ‘attractor’, for understanding the origin of organic form. (shrink)

Ontologies are being developed throughout the biomedical sciences to address standardization, integration, classification and reasoning needs against the background of an increasingly data-driven research paradigm. In particular, ontologies facilitate the translation of basic research into benefits for the patient by making research results more discoverable and by facilitating knowledge transfer across disciplinary boundaries. Addressing and adequately treating mental illness is one of our most pressing public health challenges. Primary research across multiple disciplines such as psychology, psychiatry, biology, neuroscience and pharmacology (...) needs to be integrated in order to promote a more comprehensive understanding of underlying processes and mechanisms, and this need for integration only becomes more pressing with our increase in understanding of differences among individuals and populations at the molecular level concerning susceptibility to specific illnesses. Substance addiction is a particularly relevant public health challenge in the developed world, affecting a substantial percentage of the population, often co-morbid with other illnesses such as mood disorders. Currently, however, there is no straightforward automated method to combine data of relevance to the study of substance addiction across multiple disciplines and populations. In this contribution, we describe a framework of interlinked, interoperable bio-ontologies for the annotation of primary research data relating to substance addiction, and discuss how this framework enables easy integration of results across disciplinary boundaries. We describe entities and relationships relevant for the description of addiction within the Mental Functioning Ontology, Chemical Entities of Biological Interest Ontology, Protein Ontology, Gene Ontology and the Neuroscience Information Framework ontologies. (shrink)