Major problems in cancer chemotherapy are toxicity, resistance, and cancer heterogeneity. A new theranostic paradigm has been proposed by the authors. Many million small molecules (SM) are bound to the proteins extracted from a patient's cancer. SM that also bind proteins extracted from normal human tissues are subtracted from the cancer protein bound SM leaving a large array of SM targeting many sites on each of the cancer biomarkers. Targeting many more than the conventional 1 – 4 cancer (...) biomarkers will reduce development of tumor resistance. After several cycles of selection and counter selection, DNA codes appended to the SM will be PCR amplified to provide templates for restricted libraries of the SM to improve selectivity and sensitivity. The large array of selected and counter selected SM assures that many of the compounds in the array will penetrate the cell membrane and bind to intracellular targets, low tumor resistance, low background for imaging, low therapeutic toxicity, and targeting of the diverse biomarkers present in the heterogeneous mixture of cells in primary and metastatic cancer. Theranostic use of radiolabeled SM binding many sites on many, not necessarily critical, biomarkers provides high cancer cell killing. Experiments to provide proof of principle of this novel concept suggested by the authors. -/- . (shrink)

There is growing evidence of evolutionary genome plasticity. The evolution of repetitive DNA elements, the major components of most eukaryotic genomes, involves the amplification of various classes of mobile genetic elements, the expansion of satellite DNA, the transfer of fragments or entire organellar genomes and may have connections with viruses. In addition to various repetitive DNA elements, a plethora of large and small RNAs migrate within and between cells during individual development as well as during evolution and contribute to (...) changes of genome structure and function. Such migration of DNA and RNA molecules often results in horizontal gene transfer, thus shaping the whole genomic network of interconnected species. Here, we propose that a high evolutionary dynamism of repetitive genome components is often related to the migration/movement of DNA or RNA molecules. We speculate that the cytoplasm is probably an ideal compartment for such evolutionary experiments. (shrink)

This article is concerned with the problem of the relation between the genetic information contained in the DNA and the emergence of visible structure in multicellular animals. The answer is sought in a reappraisal of the data of experimental embryology, considering molecular, cellular and organismal aspects. The presence of specific molecules only confers a tissue identity on the cells when their concentration exceeds the threshold of differentiation. When this condition is not fulfilled the activity of the genes that code (...) for the specific molecules in question only confers on them a histogenetic potency, i.e. the capacity to form the corresponding tissue in further development (or to transdifferentiate to that tissue). The progressive restriction of histogenetic potencies during development reflects the irreversible repression of more and more genes. The establishment of a given tissue identity under the influence of an inducing tissue (or a morphogenetic hormone) is only possible when the cells have acquired the competence to respond. Tissue differentiation proceeds progressively during development thanks to the cytoplasmic memory that cells retain collectively (or sometimes individually) of the items of information successively registered by their ancestors cells. The increasing complexity of visible structure emerging during development results only from the progression of tissue differentiation. This involves continual exchange of information among the cells and leads to (1) cell displacements and rearrangements, particularly during organogenesis and (2) extreme diversification of cell individualities within tissues, particularly during postembryonic growth. A mutation (just as a teratogenic factor) evokes an anomaly that is localized in both space and time because it alters a certain aspect of cell behaviour (particularly cell surface adhesiveness or mitotic activity) at the time when this is involved in the establishment of a particular structural trait. Neither the organization of the adult nor the modalities of development are encoded in the DNA. The automatic concatenation of cell interactions in the embryo and the structural amplification it entails is conditioned by the specific biochemical composition of the cytoplasm of the egg and by the heterogeneous distribution of its inclusions. (shrink)

Heritable traits are predominantly encoded within genomic DNA, but it is now appreciated that epigenetic information is also inherited through DNA methylation, histone modifications, and small RNAs. Several examples of transgenerational epigenetic inheritance of traits have been documented in plants and animals. These include even the inheritance of traits acquired through the soma during the life of an organism, implicating the transfer of epigenetic information via the germline to the next generation. Small RNAs appear to play a (...) significant role in carrying epigenetic information across generations. This review focuses on how epigenetic information in the form of small RNAs is transmitted from the germline to the embryos through the gametes. We also consider how inherited epigenetic information is maintained across generations in a small RNA‐dependent and independent manner. Finally, we discuss how epigenetic traits acquired from the soma can be inherited through small RNAs. (shrink)

The small, relatively constant size and conservative evolution of chloroplast DNA (cpDNA) make it an ideal molecule for tracing the evolutionary history of plant species. At lower taxonomic levels, cpDNA variation is easily and conveniently assayed by comparing restriction patterns and maps, while at higher taxonomic levels, DNA sequencing and inversion analysis are the methods of choice for comparing chloroplast genomes. The study of cpDNA variation has already yielded important new insights into the origin and evolution of many agriculturally (...) important crop plants, and promises to significantly enhance our phylogenetic understanding of the major lines of descent among land plants and algae. (shrink)

This paper examines a specific kind of part-whole relations that exist in the molecular genetic domain. The central question is under which conditions a particular molecule, such as a DNA sequence, is a biological part of the human genome. I address this question by analyzing how biologists in fact partition the human genome into parts. This paper thus presents a case study in the metaphysics of biological practice. I develop a metaphysical account of genomic parthood by analyzing the investigative and (...) reasoning practices in the ENCODE (ENCyclopedia Of DNA Elements) project. My account reveals two conditions that determine whether a molecule is a part of the human genome (i.e., a genomic part). First, genomic parts must possess a causal role function in the genome as a whole, that is, their functions must contribute to the genome directing the overall functioning of the cell. Second, genomic parts must have a specific chemical structure and be actual segments of the DNA sequence of the genome. (shrink)

Nucleosomes are the basic elements of chromatin structure. Polyamines, such as spermine and spermidine, are small ubiquitous molecules absolutely required for cell growth. Photoaffinity polyamines bind to specific locations in nucleosomes and can change the helical twist of DNA in nucleosomes. Acetylation of polyamines reduces their affinity for DNA and nucleosomes, thus the helical twist of DNA in nucleosomes could be regulated by cells through acetylation. I suggest that histone and polyamine acetylation act synergistically to modulate chromatin structure. (...) On naked DNA, the photoaffinity spermine bound preferentially to a specific ‘TATA’ sequence element, suggesting that polyamines may be involved in the unusual chromatin structure in this region. Further work is needed to test whether the specificities shown by photoaffinity polyamines are also shown by cellular polyamines; such experiments are now feasible. (shrink)

Interferon stimulated gene 15 (ISG15) encodes a ubiquitin‐like protein that is highly induced upon activation of interferon signaling and cytoplasmic DNA sensing pathways. As part of the innate immune system ISG15 acts to inhibit viral replication and particle release via the covalent conjugation to both viral and host proteins. Unlike ubiquitin, unconjugated ISG15 also functions as an intracellular and extra‐cellular signaling molecule to modulate the immune response. Several recent studies have shown ISG15 to also function in a diverse array of (...) cellular processes and pathways outside of the innate immune response. This review explores the role of ISG15 in maintaining genome stability, particularly during DNA replication, and how this relates to cancer biology. It puts forth the hypothesis that ISG15, along with DNA sensors, function within a DNA replication fork surveillance pathway to help maintain genome stability. (shrink)

In this essay, I propose that DNA‐binding anti‐cancer drugs work more via chromatin disruption than DNA damage. Success of long‐awaited drugs targeting cancer‐specific drivers is limited by the heterogeneity of tumors. Therefore, chemotherapy acting via universal targets (e.g., DNA) is still the mainstream treatment for cancer. Nevertheless, the problem with targeting DNA is insufficient efficacy due to high toxicity. I propose that this problem stems from the presumption that DNA damage is critical for the anti‐cancer activity of these drugs. DNA (...) in cells exists as chromatin, and many DNA‐targeting drugs alter chromatin structure by destabilizing nucleosomes and inducing histone eviction from chromatin. This effect has been largely ignored because DNA damage is seen as the major reason for anti‐cancer activity. I discuss how DNA‐binding molecules destabilize chromatin, why this effect is more toxic to tumoral than normal cells, and why cells die as a result of chromatin destabilization. (shrink)

Genetic and early environmental factors are interwoven in the etiology of Borderline Personality Disorder (BPD). Epigenetic mechanisms offer the molecular machinery to adapt to environmental conditions. There are gaps in the knowledge about how epigenetic mechanisms are involved in the effects of early affective environment, development of BPD, and psychotherapy response. We reviewed the available evidence of the effects of psychotherapy on changes in DNA methylation and conducted a pilot study in a sample of 11 female adolescents diagnosed with BPD, (...) exploring for changes in peripheral DNA methylation of FKBP5 gene, which encodes for a stress response protein, in relation to psychotherapy, on symptomatology and underlying psychological processes. For this purpose, measures of early trauma, borderline and depressive symptoms, psychotherapy outcome, mentalization, and emotional regulation were studied. A reduction in the average FKBP5 methylation levels was observed over time. Additionally, the decrease in FKBP5 methylation observed occurred only in those individuals who had early trauma and responded to psychotherapy. The results suggest an effect of psychotherapy on epigenetic mechanisms associated with the stress response. The finding that epigenetic changes were only observed in patients with early trauma suggests a specific molecular mechanism of recovery. The results should be taken with caution given the small sample size. Also, further research is needed to adjust for confounding factors and include endocrinological markers and therapeutic process variables. (shrink)

Chlorarachniophytes are amoeboflagellate, marine protists that have acquired photosynthetic capacity by engulfing and retaining a green alga. These green algal endosymbionts are severely reduced, retaining only the chloroplast, nucleus, cytoplasm and plasma membrane. The vestigial nucleus of the endosymbiont, called the nucleomorph, contains only three small linear chromosomes and has a haploid genome size of just 380 kb ‐ the smallest eukaryotic genome known. Initial characterisation of nucleomorph DNA has revealed that all chromosomes are capped with inverted repeats comprising (...) a telomere and a single ribosomal RNA operon. The nucleomorph genome is the quintessence of compactness; average space between genes is a mere 65 bp, some genes overlap, others are cotranscribed. Intense reductive pressures upon nucleomorph genes have apparently squeezed their spliceosomal‐type introns down to only 18, 19 or 20 bases in length. Studies to date indicate the nucleomorph ‐ essentially a stripped‐down eukaryotic genome ‐ encodes principally genetic housekeeping functions such as translation, transcription and splicing. (shrink)

Forty years’ experience as a bacterial geneticist has taught me that bacteria possess many cognitive, computational and evolutionary capabilities unimaginable in the first six decades of the twentieth century. Analysis of cellular processes such as metabolism, regulation of protein synthesis, and DNA repair established that bacteria continually monitor their external and internal environments and compute functional outputs based on information provided by their sensory apparatus. Studies of genetic recombination, lysogeny, antibiotic resistance and my own work on transposable elements revealed multiple (...) widespread bacterial systems for mobilizing and engineering DNA molecules. Examination of colony development and organization led me to appreciate how extensive multicellular collaboration is among the majority of bacterial species. Contemporary research in many laboratories on cell–cell signaling, symbiosis and pathogenesis show that bacteria utilise sophisticated mechanisms for intercellular communication and even have the ability to commandeer the basic cell biology of ‘higher’ plants and animals to meet their own needs. This remarkable series of observations requires us to revise basic ideas about biological information processing and recognise that even the smallest cells are sentient beings. (shrink)

Unlike the most well‐characterized prokaryotic polymerase, E. Coli DNA pol I, none of the eukaryotic polymerases have their own 5′ to 3′ exonuclease domain for nick translation and Okazaki fragment processing. In eukaryotes, FEN‐1 is an endo‐and exonuclease that carries out this function independently of the polymerase molecules. Only seven nucleases have been cloned from multicellular eukaryotic cells. Among these, FEN‐1 is intriguing because it has complex structural preferences; specifically, it cleaves at branched DNA structures. The cloning of FEN‐1 (...) permitted establishment of the first eukaryotic nuclease family, predicting that S. cerevisiae RAD2 (S. pombe Rad13) and its mammalian homolog, XPG, would have similar structural specficity. The FEN‐1 nuclease family includes several similar enzymes encoded by bacteriophages. The crystal structures of two enzymes in the FEN‐1 nuclease family have been solved and they provide a structural basis for the interesting steric requirements of FEN‐1 substrates. Because of their unique structural specificities, FEN‐1 and its family members have important roles in DNA replication, repair and, potentially, recombination. Recently, FEN‐1 was found to specifically associate with PCNA, explaining some aspects of FEN‐1 function during DNA replication and potentially in DNA repair. (shrink)

The expression of products encoded by the major histocompatibility complex (MHC) on tumor cells has recently been studied extensively. It has been found that many malignant tumor cells have their MHC antigens ‘switched‐off’ but that these antigens are re‐expressed following DNA‐mediated gene transfer, with increased tumor immunogenicity as a result and the consequence that these ‘transformed’ tumor cells are rejected in vivo.: This review will discuss approaches that have been taken to induce strong tumor‐specific immunity by the manipulation of (...) MHC expression on tumor cells. (shrink)

Mature spermatozoa are permeable to foreign DNA and RNA molecules. Here I propose a model, whereby extrachromosomal genetic information, mostly encoded in the form of RNA in somatic cells, can cross the Weismann barrier and reach epididymal spermatozoa. LINE‐1 retrotransposon‐derived reverse transcriptase (RT) can play key roles in the process by expanding the RNA‐encoded information. Retrotransposon‐encoded RT is stored in mature gametes, is highly expressed in early embryos and undifferentiated cells, and becomes downregulated in differentiated cells. (...) In turn, RT plays a role in developmental control, as its inhibition arrests developmental progression of early embryos with globally altered transcriptomic profiles. Thus, sperm cells act as recipients, and transgenerational vectors of somatically derived genetic information which they pass to the next generation with the potential to modify the fate of the developing embryos. (shrink)

ADP‐ribosylation is a post‐translational modification catalyzed by writer enzymes – ADP‐ribosyltransferases. The modification is part of many signaling events, can modulate the function and stability of target proteins, and often results in the recruitment of reader proteins that bind to the ADP‐ribosyl groups. Erasers are integral actors in these signaling events and reverse the modification. ADP‐ribosylation can be targeted with therapeutics and many inhibitors against writers exist, with some being in clinical use. Inhibitors against readers and erasers are sparser and (...) development of these has gained momentum only in recent years. Drug discovery has been hampered by the lack of specific tools, however many significant advances in the methods have recently been reported. We discuss assays used in the field with a focus on methods allowing efficient identification of small molecule inhibitors and profiling against enzyme families. While human proteins are focused, the methods can be also applied to bacterial toxins and virus encoded erasers that can be targeted to treat infectious diseases in the future. (shrink)

This paper discusses DNA-based stochastic optimizations under the constraint that the search starts from a given point in a search space. Generally speaking, a stochastic optimization method explores a search space and finds out the optimum or a sub-optimum after many cycles of trials and errors. This search process could be implemented efficiently by ``molecular computing'', which processes DNA molecules by the techniques of molecular biology to generate and evaluate a vast number of solution candidates at a time. We (...) assume the exploration starting from a single point, and propose a method to embody DNA-based optimization under this constraint, because this method has a promising application in the research field of protein engineering. In this application, a string of nucleotide bases encodes a protein possessing a specific activity, which could be given as a value of an objective function. Thus, a problem of obtaining a protein with the optimum or a sub-optimum about the desired activity corresponds to a combinatorial problem of obtaining a base sequence giving the optimum or a sub-optimum in the sequence space. Biologists usually modify a base sequence corresponding to a naturally occurring protein into another sequence giving a desired activity. In other words, they explore the space in the proximity of a natural protein as a start point. We first examined if the optimization methods that involve a single start point, such as simulated annealing, Gibbs sampler, and MH algorithms, can be implemented by DNA-based operations. Then, we proposed an application of genetic algorithm, and examined the performance of this application on a model fitness landscape by computer experiments. These experiments gave helpful guidelines in the embodiments of DNA-based stochastic optimization, including a better design of crossover operator. (shrink)

In its last round of publications in September 2012, the Encyclopedia Of DNA Elements (ENCODE) assigned a biochemical function to most of the human genome, which was taken up by the media as meaning the end of ‘Junk DNA’. This provoked a heated reaction from evolutionary biologists, who among other things claimed that ENCODE adopted a wrong and much too inclusive notion of function, making its dismissal of junk DNA merely rhetorical. We argue that this criticism rests on misunderstandings concerning (...) the nature of the ENCODE project, the relevant notion of function and the claim that most of our genome is junk. We argue that evolutionary accounts of function presuppose functions as ‘causal roles’, and that selection is but a useful proxy for relevant functions, which might well be unsuitable to biomedical research. Taking a closer look at the discovery process in which ENCODE participates, we argue that ENCODE’s strategy of biochemical signatures successfully identified activities of DNA elements with an eye towards causal roles of interest to biomedical research. We argue that ENCODE’s controversial claim of functionality should be interpreted as saying that 80 % of the genome is engaging in relevant biochemical activities and is very likely to have a causal role in phenomena deemed relevant to biomedical research. Finally, we discuss ambiguities in the meaning of junk DNA and in one of the main arguments raised for its prevalence, and we evaluate the impact of ENCODE’s results on the claim that most of our genome is junk. (shrink)

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA‐approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non‐specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. Bach1 (...) is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy. (shrink)

Engineered microbes are of great potential utility in biotechnology and basic research. In principle, a cell can be built from scratch by assembling small molecule sets with auto‐catalytic properties. Alternatively, DNA can be isolated or directly synthesized and molded into a synthetic genome using existing genomic blueprints and molecular biology tools. Activating such a synthetic genome will yield a synthetic cell. Here we examine obstacles associated with this latter approach using a model system whereby a donor genome from H. (...) influenzae is fragmented, and the pieces are then modified and reassembled stepwise in an E. coli host cell. There are obstacles associated with this strategy related to DNA transfer, DNA replication, cross‐talk in gene regulation and compatibility of gene products between donor and host. Encouragingly, analysis of gene expression indicates widespread transcription of H. influenzae genes in E. coli, and analysis of gap locations in H. influenzae and other microbial genome assemblies reveals few genes routinely incompatible with E. coli. In conclusion, rebuilding and booting a genome remains a feasible and pragmatic approach to creating a synthetic microbial cell. BioEssays 29:580–590, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

RNA can catalyse chemical reactions through its ability to fold into complex three‐dimensional structures and to specifically bind small molecules and divalent metal ions. The 2′‐hydroxyl groups of the ribose moieties contribute to this exceptional reactivity of RNA, compared to DNA. RNA is not only able to catalyse phosphate ester transfer reactions in ribonucleic acids, but can also show aminoacyl esterase activity, and is probably able to promote peptide bond formation. Bearing its potential for functioning both as a (...) genome and as a gene product, RNA is suitable for in vitro evolution experiments enabling the selection of molecules with new properties. The growing repertoire of RNA catalysed reactions will establish RNA as a primordial molecule in the evolution of life. (shrink)

While heredity is predominantly controlled by what deoxyribonucleic acid (DNA) sequences are passed from parents to their offspring, a small but growing number of traits have been shown to be regulated in part by the non‐genetic inheritance of information. Transgenerational epigenetic inheritance is defined as heritable information passed from parents to their offspring without changing the DNA sequence. Work of the past seven decades has transitioned what was previously viewed as rare phenomenology, into well‐established paradigms by which numerous traits (...) can be modulated. For the most part, studies in model organisms have correlated transgenerational epigenetic inheritance phenotypes with changes in epigenetic modifications. The next steps for this field will entail transitioning from correlative studies to causal ones. Here, we delineate the major molecules that have been implicated in transgenerational epigenetic inheritance in both mammalian and non‐mammalian models, speculate on additional molecules that could be involved, and highlight some of the tools which might help transition this field from correlation to causation. (shrink)

This chapter offers a review of standard views about the requirements for natural selection to shape evolution and for the sorts of ‘units’ on which selection might operate. It then summarizes traditional arguments for genic selectionism, i.e., the view that selection operates primarily on genes (e.g., those of G. C. Williams, Richard Dawkins, and David Hull) and traditional counterarguments (e.g., those of William Wimsatt, Richard Lewontin, and Elliott Sober, and a diffuse group based on life history strategies). It then offers (...) a series of responses to the arguments, based on more contemporary considerations from molecular genetics, offered by Carmen Sapienza. A key issue raised by Sapienza concerns the degree to which a small number of genes might be able to control much of the variation relevant to selection operating on such selectively critical organs as hearts. The response to these arguments suggests that selection acts on many levels at once and that sporadic selection, acting with strong effects, can act successively on different key traits (and genes) while maintaining a balance among many potentially conflicting demands faced by organisms within an evolving lineage. (shrink)

This chapter offers a review of standard views about the requirements for natural selection to shape evolution and for the sorts of ‘units’ on which selection might operate. It then summarizes traditional arguments for genic selectionism, i.e., the view that selection operates primarily on genes (e.g., those of G. C. Williams, Richard Dawkins, and David Hull) and traditional counterarguments (e.g., those of William Wimsatt, Richard Lewontin, and Elliott Sober, and a diffuse group based on life history strategies). It then offers (...) a series of responses to the arguments, based on more contemporary considerations from molecular genetics, offered by Carmen Sapienza. A key issue raised by Sapienza concerns the degree to which a small number of genes might be able to control much of the variation relevant to selection operating on such selectively critical organs as hearts. The response to these arguments suggests that selection acts on many levels at once and that sporadic selection, acting with strong effects, can act successively on different key traits (and genes) while maintaining a balance among many potentially conflicting demands faced by organisms within an evolving lineage. (shrink)

In this article we criticize the way in which the concept of information is used in the biological sciences. First, we start by giving a revised and larger definition of genetic information, by underlining the fact that the linear sequence map of the human genome is an incomplete description of our genetic information. This is because information on genome function and gene regulation is also encoded in the way DNA molecule is folded up with proteins to form chromatin structures. (...) Secondly, we point forward the need of constructing a theory in which the informational language (code, program, computation) so characteristic of molecular biology be completed by (and somehow translated into) the language of dynamical systems (phase space, bifurcations, trajectories) and the language of topology (deformations, plasticity, forms). Our traditional modes of system representation, involving fixed sets of sequential states together with imposed mechanical laws, strictly pertain to an extremely limited class of systems that can be called simple (static) systems or mechanisms. Biological systems are not in this class, and they must be called complex or dynamic. Complex systems can only be in some sense approximated, locally and temporally, by simple ones. Such a fundamental change of viewpoint leads to a number of theoretical and experimental consequences. (shrink)

The existence claim of a "genetic program" encoded in the DNA molecule which controls biological processes such as development has been examined. Sources of belief in such an entity are found in the rhetoric of Mendelian genetics, in the informationist speculations of Schrodinger and Delbruck, and in the instrumental efficacy found in the use of certain viral, and molecular genetic techniques. In examining specific research models, it is found that attempts at tracking the source of biological control always leads (...) back to the complex state of a cell as a whole, the organizational structure of which is not itself encoded in the DNA. It is argued that the "genetic program" is not an existing biological entity and its philosophical and heuristic status is challenged. (shrink)

African trypanosomes, which cause sleeping sickness in man and other mammals, are able to evade immune destruction in their hosts by altering the expression of a major cell surface molecule, the variant surface glycoprotein (VSG). The VSGs are encoded by a multigene family, and antigenic variation occurs when the trypanosome switches from expression of one VSG gene to another. This switching process involves changes in the arrangement of the trypanosome genomic DNA.

High‐precision tumor targeting with conventional therapeutics is based on the concept of the ideal drug as a “magic bullet”; this became possible after techniques were developed for production of monoclonal antibodies (mAbs). Innovative DNA technologies have revolutionized this area and enhanced clinical efficiency of mAbs. The experience of applying small‐size recombinant antibodies (monovalent binding fragments and their derivatives) to cancer targeting showed that even high‐affinity monovalent interactions provide fast blood clearance but only modest retention time on the target antigen. (...) Conversion of recombinant antibodies into multivalent format increases their functional affinity, decreases dissociation rates for cell‐surface and optimizes biodistribution. In addition, it allows the creation of bispecific antibody molecules that can target two different antigens simultaneously and do not exist in nature. Different multimerization strategies used now in antibody engineering make it possible to optimize biodistribution and tumor targeting of recombinant antibody constructs for cancer diagnostics and therapy. BioEssays 30:904–918, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

A recurrent theme in ethnomethodological research is that of instructed actions. Contrary to the classic traditions in the social and cognitive sciences, which attribute logical priority or causal primacy to instructions, rules, and structures of action, ethnomethodologists investigate the situated production of actions which enable such formulations to stand as adequate accounts. Consequently, a recitation of formal structures can not count as an adequate sociological description, when no account is given of the local production ofwhat those structures describe. The natural (...) sciences can be described as a domain of practical action in whichthe use of methods enables the intersubjective reproduction of naturalistic observations and experiments. As numerous sociological studies of laboratory practices have shown, the achievement of intersubjective order cannot be reduced to formal methods; instead, it arises from the work of custom-fitting relevant methods to the local circumstances of the research. In this paper we discuss a possible extension of this idea to cover two intertwined aspects of molecular biology: (1) the work of following instructions on how to perform routine laboratory procedures, and (2) the relationship between cellular orders and the encoded instructions contained in the DNA molecule. We suggest that a classic conception of scientific action is implied by the way formal instructions are treated as a primary basis, both for molecular biologists' actions and the cellular functions they study, and we envision an ethnomethodological alternative to those conceptions of social and biological order. (shrink)

Splicing is an efficient and precise mechanism that removes noncoding regions from a single primary RNA transcript. Cutting and rejoining of the segments occurs on nascent RNA. Trans-splicing between small specialized RNAs and a primary transcript has been known in some organisms but recent papers show that trans-splicing between two RNA molecules containing different coding regions is the normal mode in a Drosophila gene.1-3 The mod(mdg4) gene produces 26 different mRNAs encoding as many protein isoforms. The differences lie (...) in alternative 3′ exons encoded by different transcriptional units and spliced to the 5′ common region by a surprising trans-splicing mechanism. BioEssays 24:988–991, 2002. © 2002 Wiley-Periodicals, Inc. (shrink)

“Evolvability,” writes Evelyn Fox Keller, “refers to the capacity to generate any kind of heritable phenotypic variation upon which selection can act” . Whether one considers genes or organisms, the potential to adapt and evolve, to respond flexibly to a changing environment, is now recognized by many biologists as itself a trait actively favored by natural selection. Keller correctly presents this idea as an antidote to an old notion of genetic stability. She seems not to appreciate how well it applies (...) to her own subject.The Century of the Gene is Keller's latest collection of linked essays, six tidy, intelligent shovelfuls from her ongoing effort to undermine the claims of mainstream molecular biology and to substitute from the scientific margins an alternative interpretation. This project stems from her philosophical biography of the geneticist Barbara McClintock, published in 1983. In her Nobel speech, also from 1983, McClintock wrote of the genome as a dynamic “sensitive organ of the cell,” responsive, flexible, and interacting with the environment. For half a century, McClintock had railed at biologists that genes must be studied not as autonomous, independently acting units but rather as parts of an exquisite whole, acting in concert. Keller celebrated this in McClintock's work, though many have read Keller as applying to this view of nature a gloss of feminism that McClintock rejected. More recently, among other projects, Keller has criticized the “master molecule” concept in biology, examined the use of metaphor in science, and celebrated Christiane Nüsslein‐Vollhard's studies in developmental biology. Through it all, she maintains a fascination with gender and with language as shapers of scientific thought.Here Keller explores what she sees as the divergent histories of studies of genes and use of the term “gene.” While scientists continue to talk of genes much as they have done for a century now—as stable, discrete units directing the activities of the cell and the development of the organism—the molecular biology of the last forty years has seen a breaking down of the boundaries of the gene, physically, chemically, and physiologically. Keller begins by attacking the notion of genetic stability—whence the introductory quotation about evolvability. Next she explores the idea of genetic regulation, the fact that genes do not make anything, nor do they literally control anything. The molecular biologist's version of the chicken‐and‐egg problem is: Which comes first—proteins or genes? Proteins read the DNA that provides the instructions to make more proteins. Keller argues for chickens.The most important idea in the book is Keller's distinction between a developmental program and a genetic program. The former is a sequence of ontological steps in the life of an organism; it does not presuppose that all steps in the program are encoded in genes or that all steps are determined prior to the beginning of development. Developmental programs may be derived empirically, independently of genetic analysis. In contrast, the genetic program is a more recent idea that does locate the program instructions in the nucleus in the fertilized egg. For Keller, genetic programs carry implications of determinism, a restriction of vision in our attempts to understand nature.The term “gene,” Keller concludes, has outlived its utility. Molecular biologists no longer work with anything so discrete as genes. Their own data, she argues, show that genes and genomes are flexible, modular, and interactive. Keller wishes for, but does not offer, a new term or set of terms that would better reflect current understanding of genetics and development.If biologists have shown that the gene concept is outmoded, why don't they know it? Keller's answer is that the biologists have not yet recognized the implications of their own results; their language lags behind their knowledge. Eventually, she believes, either they will drop the term “gene” or biology must suffocate in its shell. Yet the changes she describes have been under way for decades and biology shows no signs of slowing. Keller recognizes this, and in the conclusion she briefly acknowledges the obvious solution to the conundrum: that biology continues to grow because of, not despite, this linguistic flexibility. This important idea deserves fuller treatment.As with the gene in nature, so with the word “gene” in the scientific lexicon: its very evolvability is selected for, a crucial trait that ensures its survival. (shrink)

Life on earth is bound together by a common heritage, centered around a molecule that is present in almost every living cell of every living creature. Deoxyribonucleic acid (DNA), composed of four base pairs, the nucleic acids thymine, adenine, cytosine, and guanine, encodes the data that directs, in conjunction with the environment, the development and metabolism of all nondependent living creatures. Except for some viruses that rely only on ribonucleic acid (RNA), all living things are built by the interaction of (...) DNA and RNA within cells and their environments. There is no worldwide consensus yet as to whether portions of the human genome should be granted intellectual property protection, as indeed they are in the United States and a number of other nations. DNA posed numerous challenges to the legal framework for patent protection and may suggest developing an entirely new social and legal category recognizing its uniqueness. (shrink)

The most striking region of structural differentiation of a eukaryotic chromosome is the kinetochore. This chromosomal domain plays an integral role in the stability and propagation of genetic material to the progeny cells during cell division. The DNA component of this structure, which we refer to as the centromere, has been localized to a small region of 220–250 base pairs within the chromosomes from the yeast Saccharomyces cerevisiae. The centromere DNA (CEN) is organized in a unique structure in the (...) cell nucleus and is required for chromosome stability during both mitotic and meiotic cell cycles. The centromeres from one chromosome can stabilize small circular minichromosomes or other yeast chromosomes. The centromeres may therefore interact with the same components of the segregation apparatus regardless of the chromosome in which they reside. The CEN DNA does not encode any regulatory RNAs or proteins, but rather is a cis‐acting element that provides genetic stability to adjacent DNA sequences. (shrink)

Life is perpetuated through a single-cell bottleneck between generations in many organisms. Here, I highlight that this cell holds information in two distinct stores: in the linear DNA sequence that is replicated during cell divisions, and in the three-dimensional arrangement of molecules that can change during development but is recreated at the start of each generation. These two interdependent stores of information – one replicating with each cell division and the other cycling with a period of one generation – (...) coevolve while perpetuating an organism. Unlike the genome sequence, the arrangement of molecules, including DNA, RNAs, proteins, sugars, lipids, etc., is not well understood. Because this arrangement and the genome sequence are transmitted together from one generation to the next, analysis of both is necessary to understand evolution and origins of inherited diseases. Recent developments suggest that tools are in place to examine how all the information to build an organism is encoded within a single cell, and how this cell code is reproduced in every generation. Life relies on the information for making organisms that is encoded in single cells and transmitted between generations. These cell codes include interdependent stores of information that replicate and that cycle. Understanding evolution and the origins of inherited diseases requires analysis of cell codes. (shrink)

Metabolomics, including lipidomics, is emerging as a quantitative biology approach for the assessment of energy flow through metabolism and information flow through metabolic signaling; thus, providing novel insights into metabolism and its regulation, in health, healthy ageing and disease. In this forward‐looking review we provide an overview on the origins of metabolomics, on its role in this postgenomic era of biochemistry and its application to investigate metabolite role and (bio)activity, from model systems to human population studies. We present the challenges (...) inherent to this analytical science, and approaches and modes of analysis that are used to resolve, characterize and measure the infinite chemical diversity contained in the metabolome (including lipidome) of complex biological matrices. In the current outbreak of metabolic diseases such as cardiometabolic disorders, cancer and neurodegenerative diseases, metabolomics appears to be ideally situated for the investigation of disease pathophysiology from a metabolite perspective. (shrink)

An interpretive system for the IBM 704 computer permitting interpretation of the genetic pattern of a numeric symbioorganism as a game strategy has been developed. Selection for best performance in a simple game has been applied in a preliminary experiment. An objective method to measure the quality of a game played is described. The results presented in the article show a small but significant improvement of game quality during a period of 2300 generations.The general characteristics of the phenomena observed (...) are similar to those of preceding evolution experiments . However, a startling infection process caused by a parasite whose behaviour was influenced by the game competition is described. The parasite never developed an independent game strategy to any degree of efficiency and was entirely dependent on its host organism for game competitions with, and transmission of the infection to, uninfected hosts.The consequences of substituting the reproduction and mutation rules used in the preceding evolution experiments are discussed. Particularly, the use of rules applying the reproduction pattern ofDNA-molecules is considered, and the theoretic aspects of symbiogenetic evolution experiments based onDNA-norm are discussed. A few inferences concerning the origin and history of terrestrial life suggested by the results of the symbiogenesis experiments are presented.Ein interpretierendes System für die IBM 704 Rechenmaschine, dass Interpretation des genetischen Modells von einem numerischen Symbio-organismus wie eine Spiel Strategie, erlaubt, wurde entwickelt. Eine Forführung für Fähigkeit in einem einfachen Spiel wurde angewandt in einem preliminarisches Experiment. Eine objektive Methode zur Messung der Qualität des betreffenden Spiels wurde beschrieben. Die in dem Artikel angegebenen Resultate zeigen eine kleine, aber bedeutende Verbesserung der Spiel-Qualität während einr Periode von 2300 Generationen.Die allgemeinen Kennziechen von den beobachteten Phänomenen sind denen von vorhergehenden Evolutions-Experimenten ähnlich . Jedoch, ein überraschender Infektions-Prozess, verursacht durch einen Parasit, wessen Verhalten beinflusst wurde durch die Spiel-Konkurrenz, wurde beschrieben. Der Parasit entwickelte niemals eine unabhängige Spiel-Strategie zu irgendeinem Masze von Fähigkeit und war ganz abhängig von seinem Gastherr-Organismus für Spiel-Konkurrenz mit, und Überbringung von der Infektion auf, uninfektierte Gäste.Die Folgerungen von dem Ersetzen der Fortpflanzung und Mutations-Regeln , angewandt in vorhergehenden Evolutions-Experimente wurden besprochen. Besonders der Gebrauch von Regeln welche das FortpflanzungsModell von DNA-Molekülen anwenden wurde betrachtet, und die theorethischen Aspekte von Symbiogenetischen Evolutions-Experimenten basiert auf DNA-Norm wurden besprochen. Einige Schlussfolgerungen in Bezug auf die Entstehung und Geschichte von dem Erdenleben suggeriert durch die Resultate von den Symbiogenese-Experimenten wurden gezeigt. (shrink)

The European Legacy, Volume 17, Issue 5, Page 711-712, August 2012.

The problem of stability in population dynamics concerns many domains of application in demography, biology, mechanics and mathematics. The problem is highly generic and independent of the population considered (human, animals, molecules,…). We give in this paper some examples of population dynamics concerning nucleic acids interacting through direct nucleic binding with small or cyclic RNAs acting on mRNAs or tRNAs as translation factors or through protein complexes expressed by genes and linked to DNA as transcription factors. The networks (...) made of these interactions between nucleic acids (considered respectively as edges and nodes of their interaction graph) are complex, but exhibit simple emergent asymptotic behaviours, when time tends to infinity, called attractors. We show that the quantity called attractor entropy plays a crucial role in the study of the stability and robustness of such genetic networks. (shrink)

According to the BSM- Supergravitation Unified Theory (BSM-SG), the energy is indispensable feature of matter, while the matter possesses hierarchical levels of organization from a simple to complex forms, with appearance of fields at some levels. Therefore, the energy also follows these levels. At the fundamental level, where the primary energy source exists, the matter is in its primordial form, where two super-dense fundamental particles (FP) exist in a classical pure empty space (not a physical vacuum). They are associated with (...) the Planck scale parameters of frequency and distance and interact by Supergravitational forces. These forces are inverse proportional to the cube of distance at pure empty space and they are based on frequency interactions. Since the two FPs have different intrinsic frequencies, the SG forces appear different for interactions between the like and unlike FPs and may change the sign. This primordial form of matter exists in the super-heavy black holes located in the center of each well formed galaxy. The next upper level of matter organization includes the underlying structure of the physical vacuum, called a Cosmic Lattice, and the structure of elementary particles. They have common substructure elements obtained by specific crystallization process preceding the formation of the observable galaxies. The Cosmic Lattice, forming a space known as a physical vacuum, is responsible for the existence and propagation of the physical fields: electrical, magnetic, Newtonian gravity and inertia. The energy of physical vacuum is in two forms: Static (enormous) and Dynamic (weak). The Static energy is directly related to the Newtonian mass by the Einstein equation E = mc^2 and it is a primary source of the nuclear energy. The Dynamic energy is responsible for the existence of the electric and magnetic fields, the constant speed of light and the quantum mechanical properties of the physical vacuum. The next upper energy level is the dynamical energy of excited atoms and molecules. At this level a hidden energy wells exit, such as the internal energy of the electron and the internal energy of atoms with more than one electron. The next upper energy level is at some organic molecules and particularly in the biomolecules that contain ring atomic structures. In such a structure, some quantum states are not emitted immediately, but rotating in the ring. While in organic molecules the energy stored in such a ring is released by a chemical process, in the long chain molecule of proteins in the living organism the stored energy can be released simultaneously by triggering. A huge number of atomic rings are contained in the DNA strands. The release of the energy stored in DNA, for example, is an avalanche process that causes an emission of entangled photons possessing a strong penetrating capability. A sequence of entangled photons emitted by DNA should carry the genetic information encoded by the cordons. This mechanism, predicted in BSM-SG theory, is very important for intercommunication between the cells of the living organism. The next upper level of energy organization may exist in the brain. The brain is an organ of a most abundant number of atomic rings, while its tissue environment might permit complex energy interactions. The human brain contains billions of atomic rings. The next hypothetical upper level of energy organization is an information field, physically existed outside, but connected with the living brain. It corresponds to a specific field known as aura, while the possibility of its existence is still not accepted by the main stream science. The problem is that this field could not be detected by the currently existing technical means used for EM communications. The BSM-SG predicts that this field might differ from the EM field we use for communication, but it is a subject of a further theoretical development that must be supported by experiments using specifically designed technical means. According to the BSM-SG theory, the energy conversion from the primary energy source to the complex levels of matter and field organization is a permanent syntropic process based on complex resonance interactions. (shrink)

The human major histocompatibility complex (MHC), on the short arm of chromosome 6, represents one of the most extensively characterised regions of the human genome. This ∼4 Mb segment of DNA contains genes encoding the polymorphic MHC class I and class II molecules which are involved in antigen presentation during an immune response. Recently the whole of the MHC has been cloned in cosmids and/or yeast artificial chromosomes (YACs) and large portions have been characterised for the presence of novel (...) genes. Many unrelated genes, both housekeeping and tissue specific, have been identified and the gene density in some regions is now approaching one gene every few kilobases. Some of the novel genes encode proteins involved in the intracellular processing and transport of antigens that are presented by MHC class I molecules. Others, however, have no obvious role in the immune response. The MHC is located in the chromosome band 6p21.3 which is a Giemsa (G)‐light band. The detection of such a large number of functional genes (at least 70) in this region is compatible with the idea that both housekeeping and tissue‐specific genes are localised predominantly in G‐light bands. (shrink)

For many years, there has been a gap in our capacity to study the structure and organization of chromosomal DNA molecules. The very small genomes of some viruses and bacteriophages (≤ 50,000 bp or 50 kb) are amenable to analysis by conventional gel electrophoresis, while the extremely large DNA molecules (> 100,000 kb) comprising the chromosomes of higher eukaryotes have been analysed under the light microscope, using a range of banding and in situ hybridization techniques. However, intact (...) DNA molecules with sizes between these two extremes have been largely inaccessible experimentally. This gap has recently been bridged with the development of two‐dimensional electrophoretic procedures that allow the separation and purification of chromosome‐sized DNA molecules ranging from ∼ 50 kb to several thousand kb.1–3 There are currently two variations of the technique in use: pulsed field gradient (PFG) gel electrophoresis1,2 and orthogonal‐field‐alteration gel electrophoresis (OFAGE).3 Both are based on a common principle, differing primarily in the geometry of the electrodes. Already, they have been employed to determine the approximate chromosome sizes and numbers for a variety of lower eukaryotes, including yeast and several protozoa.2–10 These ‘molecular karyotypes’ provide fundamental information about the genomic organization of each organism, and allow very rapid construction of linkage maps. Surprisingly, they have also revealed a remarkable plasticity in the genomes of several lower eukaryotes. (shrink)

Pax genes are a family of development control genes that encode nuclear transcription factors. They are characterized by the presence of the paired domain, a conserved amino acid motif with DNA‐binding activity. Originally, paired‐box‐containing genes were detected in Drosophila malenogaster, where they exert multiple functions during embryogenesis. In vertebrates, Pax genes are also involved in embryogenesis. Mutations in four out of nine characterized Pax genes have been associated with either congenital human diseases such as Waardenburg syndrome (PAX3), Aniridia (PAX6), Peter's (...) anomaly (PAX6), renal coloboma syndrome (PAX2), Small eye (Pax6), (Pax21Neu), which all show defects in development. Recently, analysis of spontaneous and transgenic mouse mutants has revealed that vertebrate Pax genes are key regulators during organogenesis of kidney, eye, ear, nose, limb muscles, vertebral column and brain. Like their Drosophila counterparts, vertebrate Pax genes are involved in pattern formation during embryogenesis, possibly by determiing the time and place of organ initiation of morphogenesis. For most tissues, however, the nature of the primary development action of Pax transcription factors remains to be elucidated. One predominant theme is signal transduction during tissue interactions, which may lead to a position‐specific regulation of cell proliferation. (shrink)

A model for kinetics of circular substrate cleavage by restriction endonuclease was formulated. The aim of the analysis of the model was to extract kinetic constants for all target sites from time- dependence of fragment concentration in reaction products. That was proved to be possible for molecules with an odd number of fragments only. A symmetry of the molecules with an even number of fragment is the cause. A solution for molecules with an odd number of fragments (...) was found and methods for dealing with the other molecules were suggested. (shrink)

Using a novel enumeration task, we examined the encoding of spatial information during subitizing. Observers were shown masked presentations of randomly-placed discs on a screen and were required to mark the perceived locations of these discs on a subsequent blank screen. This provided a measure of recall for object locations and an indirect measure of display numerosity. Observers were tested on three stimulus durations and eight numerosities. Enumeration performance was high for displays containing up to six discs—a higher subitizing range (...) than reported in previous studies. Error in the location data was measured as the distance between corresponding stimulus and response discs. Overall, location errors increased in magnitude with larger numerosities and shorter display durations. When errors were computed as disc distance from display centroid, results suggest a compressed representation by observers. Additionally, enumeration and localization accuracy increased with display regularity. (shrink)