It is becoming increasingly evident that the driving forces of evolutionary novelty are not randomly derived chance mutations of the genetic text, but a precise genome editing by omnipresent viral agents. These competences integrate the whole toolbox of natural genetic engineering, replication, transcription, translation, genomic imprinting, genomic creativity, enzymatic inventions and all types of genetic repair patterns. Even the non-coding, repetitive DNA sequences which were interpreted as being ancient remnants of former evolutionary stages are now recognized as being of viral (...) descent and crucial for higher-order regulatory and constitutional functions of protein structural vocabulary. In this article I argue that non-randomly derived natural genome editing can be envisioned as (a) combinatorial (syntactic), (b) context-specific (pragmatic) and (c) content-sensitive (semantic) competences of viral agents. These three-leveled biosemiotic competences could explain the emergence of complex new phenotypes in single evolutionary events. After short descriptions of the non-coding regulatory networks, major viral life strategies and pre-cellular viral life three of the major steps in evolution serve as examples: There is growing evidence that natural genome-editing competences of viruses are essential (1) for the evolution of the eukaryotic nucleus, (2) the adaptive immune system and (3) the placental mammals. (shrink)

Post-translational histone modifications and their biological effects have been described as a ‘histone code’. Independently, Barbieri used the term ‘organic code’ to describe biological codes in addition to the genetic code. He also provided the defining criteria for an organic code, but to date the histone code has not been tested against these criteria. This paper therefore investigates whether the histone code is a bona fide organic code. After introducing the use of the term ‘code’ in biology, the criteria a (...) putative organic code such as the histone code must conform to in order to be recognised as an organic code are described. Our current knowledge of histones and their major post-translational modifications, and the specific protein binding domains that recognise and translate these into specific biological effects, is then reviewed in detail. The histone modification system is then placed in the context of an organic code and it is concluded that it fulfils all the requirements of an organic code. The marks produced on histones by processes such as acetylation and methylation act as organic signs that are translated into unique biological effects, their biological meanings. These translations are accomplished by effector proteins that consist of a binding domain that recognises a specific histone mark and a regulatory domain that mediates the biological effect. Crucially, these domains can be experimentally interchanged between different effector proteins, thus altering the rules that specify the relationships between sign and meaning. The effector proteins therefore fulfil the role of adaptor molecules. (shrink)

Biosemiotics is the synthesis of biology and semiotics, and its main purpose is to show that semiosis is a fundamental component of life, i.e., that signs and meaning exist in all living systems. This idea started circulating in the 1960s and was proposed independently from enquires taking place at both ends of the Scala Naturae. At the molecular end it was expressed by Howard Pattee’s analysis of the genetic code, whereas at the human end it took the form of Thomas (...) Sebeok’s investigation into the biological roots of culture. Other proposals appeared in the years that followed and gave origin to different theoretical frameworks, or different schools, of biosemiotics. They are: (1) the physical biosemiotics of Howard Pattee and its extension in Darwinian biosemiotics by Howard Pattee and by Terrence Deacon, (2) the zoosemiotics proposed by Thomas Sebeok and its extension in sign biosemiotics developed by Thomas Sebeok and by Jesper Hoffmeyer, (3) the code biosemiotics of Marcello Barbieri and (4) the hermeneutic biosemiotics of Anton Markoš. The differences that exist between the schools are a consequence of their different models of semiosis, but that is only the tip of the iceberg. In reality they go much deeper and concern the very nature of the new discipline. Is biosemiotics only a new way of looking at the known facts of biology or does it predict new facts? Does biosemiotics consist of testable hypotheses? Does it add anything to the history of life and to our understanding of evolution? These are the major issues of the young discipline, and the purpose of the present paper is to illustrate them by describing the origin and the historical development of its main schools. (shrink)

It is increasingly clear that chromatin is not just a device for packing DNA within the nucleus but also a dynamic material that changes as cellular environments alter. The precise control of chromatin modification in response to developmental and environmental cues determines the correct spatial and temporal expression of genes. Here, we review exciting discoveries that reveal chromatin participation in many facets of plant development. These include: chromatin modification from embryonic and meristematic development to flowering and seed formation, the involvement (...) of DNA methylation and chromatin in controlling invasive DNA and in maintenance of epigenetic states, and the function of chromatin modifying and remodeling complexes such as SWI/SNF and histone acetylases and deacetylases in gene control. Given the role chromatin structure plays in every facet of plant development, chromatin research will undoubtedly be integral in both basic and applied plant biology. BioEssays 24:234–243, 2002. © 2002 Wiley Periodicals, Inc.; DOI 10.1002/bies.10055. (shrink)

Epigenetic information is encoded by DNA methylation and by covalent modifications of histone tails. While defined epigenetic modification patterns have been frequently correlated with particular states of gene activity, very little is known about the integration level of epigenetic signals. Recent experiments have resulted in the characterization of several epigenetic adaptors that mediate interactions between distinct modifications. These adaptors include methyl‐DNA binding proteins, chromatin remodelling enzymes and siRNAs. Complex interactions between epigenetic modifiers and adaptors provide the foundation for the stability (...) of epigenetic inheritance. In addition, they also provide an explanation for the long‐range effects of epigenetic mechanisms. We propose that a major aspect of epigenetic regulation lies in the modification of chromosome architecture and that local changes in gene expression would be secondary consequences. This view is consistent with many results from recent genomic analyses. BioEssays 25:792–797, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

We focus here on the intercalary heterochromatin (IH) of Drosophila melanogaster and, in particular, its molecular properties. In the polytene chromosomes of Drosophila, IH is represented by a reproducible set of dense bands scattered along the euchromatic arms. IH contains mainly unique DNA sequences, and shares certain features with other heterochromatin types such as pericentric, telomeric, and PEV‐induced heterochromatin, the inactive mammalian X‐chromosome and the heterochromatized male chromosome set in coccids. These features are transcriptional silencing, chromatin compactness, late DNA replication, (...) underrreplication or elimination in somatic cells, and formation of the heterochromatin state in early embryogenesis. Post‐translational modification of histones and the specific nonhistone protein complexes are shown to participate in the establishment and maintenance of silencing for all heterochromatin types. Many IH regions contain binding sites for HP1 and/or Pc‐G proteins and all the regions are sites of heterochromatin‐associated SuUR protein. Some IH regions are known to contain homeotic genes. Summarizing these data, we suggest that IH regions comprise stable inactivated genes, whose silencing is developmentally programmed. BioEssays 25:1040–1051, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Systems Biology and the Modern Synthesis are recent versions of two classical biological paradigms that are known as structuralism and functionalism, or internalism and externalism. According to functionalism (or externalism), living matter is a fundamentally passive entity that owes its organization to external forces (functions that shape organs) or to an external organizing agent (natural selection). Structuralism (or internalism), is the view that living matter is an intrinsically active entity that is capable of organizing itself from within, with purely internal (...) processes that are based on mathematical principles and physical laws. At the molecular level, the basic mechanism of the Modern Synthesis is molecular copying, the process that leads in the short run to heredity and in the long run to natural selection. The basic mechanism of Systems Biology, instead, is self-assembly, the process by which many supramolecular structures are formed by the spontaneous aggregation of their components. In addition to molecular copying and self-assembly, however, molecular biology has uncovered also a third great mechanism at the heart of life. The existence of the genetic code and of many other organic codes in Nature tells us that molecular coding is a biological reality and we need therefore a framework that accounts for it. This framework is Code biology, the study of the codes of life, a new field of research that brings to light an entirely new dimension of the living world and gives us a completely new understanding of the origin and the evolution of life. (shrink)

The classical theories of the genetic code claimed that its coding rules were determined by chemistry—either by stereochemical affinities or by metabolic reactions—but the experimental evidence has revealed a totally different reality: it has shown that any codon can be associated with any amino acid, thus proving that there is no necessary link between them. The rules of the genetic code, in other words, obey the laws of physics and chemistry but are not determined by them. They are arbitrary, or (...) conventional, rules. The result is that the genetic code is not a metaphorical entity, as implied by the classical theories, but a real code, because it is precisely the presence of arbitrary rules that divides a code from all other natural processes. In the past 20 years, furthermore, various independent discoveries have shown that many other organic codes exist in living systems, which means that the genetic code has not been an isolated case in the history of life. These experimental facts have one outstanding theoretical implication: they imply that in addition to the concept of information we must introduce in biology the concept of meaning, because we cannot have codes without meaning or meaning without codes. The problem is that at present we have two different theoretical frameworks for that purpose: one is Code Biology, where meaning is the result of coding, and the other is Peircean biosemiotics, where meaning is the result of interpretation. Recently, however, a third party has entered the scene, and it has been proposed that Robert Rosen’s relational biology can provide a bridge between Code Biology and Peircean biosemiotics. (shrink)

Lysine acetylation has been shown to occur in many protein targets, including core histones, about 40 transcription factors and over 30 other proteins. This modification is reversible in vivo, with its specificity and level being largely controlled by signal‐dependent association of substrates with acetyltransferases and deacetylases. Like other covalent modifications, lysine acetylation exerts its effects through “loss‐of‐function” and “gain‐of‐function” mechanisms. Among the latter, lysine acetylation generates specific docking sites for bromodomain proteins. For example, bromodomains of Gcn5, PCAF, TAF1 and CBP (...) are able to recognize acetyllysine residues in histones, HIV Tat, p53, c‐Myb or MyoD. In addition to the acetyllysine moiety, the flanking sequences also contribute to efficient recognition. The relationship between acetyllysine and bromodomains is reminiscent of the specific recognition of phosphorylated residues by phospho‐specific binding modules such as SH2 domains and 14‐3‐3 proteins. Therefore, lysine acetylation forges a novel signaling partnership with bromodomains to govern the temporal and spatial regulation of protein functions in vivo. BioEssays 26:1076–1087, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Modern biology has not yet come to terms with the presence of many organic codes in Nature, despite the fact that we can prove their existence. As a result, it has not yet accepted the idea that the great events of macroevolution were associated with the origin of new organic codes, despite the fact that this is the most parsimonious and logical explanation of those events. This is probably due to the fact that the existence of organic codes in all (...) fundamental processes of life, and in all major transitions in the history of life, has enormous theoretical implications. It requires nothing less than a new theoretical framework, and that kind of change is inevitably slow. There are too many facts to reconsider, too many bits of history to weave together in a new mosaic. But this is what science is about, and the purpose of the present paper is to show that it can be done. More precisely, it is shown that the whole natural history of the brain can be revisited in the light of the organic codes. What is described here is only a bird’s-eye view of brain macroevolution, but it is hoped that the extraordinary potential of the organic codes can nevertheless come through. The paper contains also another message. The organic codes prove that life is based on semiosis, and are in fact the components of organic semiosis, the first and the most diffused form of semiosis on Earth, but not the only one. It will be shown that the evolution of the brain was accompanied by the development of two new types of sign processes. More precisely, it gave origin first to interpretive semiosis, mostly in vertebrates, and then to cultural semiosis, in our species. (shrink)

The themes, problems and challenges of developmental systems theory as described in Cycles of Contingency are discussed. We argue in favor of a robust approach to philosophical and scientific problems of extended heredity and the integration of behavior, development, inheritance, and evolution. Problems with Sterelny's proposal to evaluate inheritance systems using his `Hoyle criteria' are discussed and critically evaluated. Additional support for a developmental systems perspective is sought in evolutionary studies of performance and behavior modulation of fitness.

Expression of sexually dimorphic behaviors critical for reproduction depends on the organizational actions of steroid hormones on the developing brain. We offer the new hypothesis that transcriptional activities in brain regions executing these sexually dimorphic behaviors are modulated by estrogen‐induced modifications of histone proteins. Specifically, in preoptic nerve cells responsible for facilitating male sexual behavior in rodents, gene expression is fostered by increased histone acetylation and reduced methylation (Me), and, that the opposite set of histone modifications will be found in (...) females. Conversely, in ventromedial hypothalamic neurons that are responsible for coordinating female sexual behavior, transcriptional activities in genetic females are fostered by increased histone acetylation and reduced Me, and, further, that the opposite set of histone modifications will be found in males. Thus, these epigenetic events will guarantee that effects of sex hormone exposure during the neonatal critical period will be translated into lasting sex differences in adult reproductive behaviors. (shrink)

Plant MADS‐box genes encode transcriptional regulators that are critical for a number of developmental processes. In the angiosperms (the flowering plants), these include the specification of floral organ identities, flowering time and fruit development. It appears that the MADS box gene family has undergone considerable gene duplication and sequence divergence within the angiosperms. Here I discuss the possibility that these events have allowed the recruitment of these genes to new developmental pathways in particular angiosperm lineages. Recent analyses of sequence changes, (...) expression patterns and, in a few cases, gene function are beginning to provide tantalizing evidence for deciphering when and how such genetic diversification has led to particular morphological innovations. In the future, comparative studies of large numbers of species will be required to assess the extent of such variation as well as to fully understand the mechanisms by which evolution of these developmental regulators has played a role in shaping new morphologies. BioEssays 25:637–646, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Thomas Sebeok and Noam Chomsky are the acknowledged founding fathers of two research fields which are known respectively as Biosemiotics and Biolinguistics and which have been developed in parallel during the past 50 years. Both fields claim that language has biological roots and must be studied as a natural phenomenon, thus bringing to an end the old divide between nature and culture. In addition to this common goal, there are many other important similarities between them. Their definitions of language, for (...) example, have much in common, despite the use of different terminologies. They both regard language as a faculty, or a modelling system, that appeared rapidly in the history of life and probably evolved as an exaptation from previous animal systems. Both accept that the fundamental characteristic of language is recursion, the ability to generate an unlimited number of structures from a finite set of elements (the property of ‘discrete infinity’). Both accept that human beings are born with a predisposition to acquire language in a few years and without apparent efforts (the innate component of language). In addition to similarities, however, there are also substantial differences between the two fields, and it is an historical fact that Sebeok and Chomsky made no attempt at resolving them. Biosemiotics and Biolinguistics have become two separate disciplines, and yet in the case of language they are studying the same phenomenon, so it should be possible to bring them together. Here it is shown that this is indeed the case. A convergence of the two fields does require a few basic readjustments in each of them, but leads to a unified framework that keeps the best of both disciplines and is in agreement with the experimental evidence. What is particularly important is that such a framework suggests immediately a new approach to the origin of language. More precisely, it suggests that the brain wiring processes that take place in all phases of human ontogenesis (embryonic, foetal, infant and child development) are based on organic codes, and it is the step-by-step appearance of these brain-wiring codes, in a condition that is referred to as cerebra bifida, that holds the key to the origin of language. (shrink)

The New World of the Organic CodesThe genetic code appeared on Earth at the origin of life, and the codes of culture arrived almost 4 billion years later, at the end of life’s history. Today it is widely assumed that these are the only codes that exist in Nature, and if this were true we would have to conclude that codes are extraordinary exceptions because they appeared only at the beginning and at the end of evolution. In reality, various other (...) organic codes have been discovered in the past few decades.In 1975, the American biochemist Gordon Tomkins published a paper entitled The Metabolic Code. Biological symbolism and the origin of intercellular communication . That was the very first announcement of a new organic code after the discovery of the genetic code, but tragically Tomkins died that very year and his new world of organic symbolism remained unexplored. Some 10 years later, Edward Trifonov started a life-long campaign in favour .. (shrink)

Molecular codes can be considered a special type of mapping among molecular species in biochemical systems. The formalization of molecular codes allows to identify these in network models of real world systems. Analyzing algorithmically identified codes leads to the observation that codes does not necessarily stand alone, but that we can identify certain relations among codes. In this paper I will define two types of relations that can occur among codes, code linkage and code nesting, and will discuss implications of (...) this finding. (shrink)

Over the past few years several drugs that target epigenetic modifications have shown clinical benefits, thus seemingly validating epigenetic cancer therapy. More recently, however, it has become clear that these drugs are either characterized by low specificity or that their target enzymes have low substrate specificity. As such, clinical proof‐of‐concept for epigenetic cancer therapies remains to be established. Human cancers are characterized by widespread changes in their genomic DNA methylation and histone modification patterns. Epigenetic cancer therapy aims to restore normal (...) epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. In this review, we provide an overview about the known functional roles of DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases in cancer development. The available data identify several examples that warrant further consideration as drug targets. Future research should be directed toward targeted enzyme inhibition and toward exploring interactions between epigenetic pathways to maximize cancer specificity. (shrink)

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