Systems biologists often distance themselves from reductionist approaches and formulate their aim as understanding living systems “as a whole.” Yet, it is often unclear what kind of reductionism they have in mind, and in what sense their methodologies would offer a superior approach. To address these questions, we distinguish between two types of reductionism which we call “modular reductionism” and “bottom-up reductionism.” Much knowledge in molecular biology has been gained by decomposing living systems into functional modules or through detailed (...) studies of molecular processes. We ask whether systems biology provides novel ways to recompose these findings in the context of the system as a whole via computational simulations. As an example of computational integration of modules, we analyze the first whole-cell model of the bacterium M. genitalium. Secondly, we examine the attempt to recompose processes across different spatial scales via multi-scale cardiac models. Although these models rely on a number of idealizations and simplifying assumptions as well, we argue that they provide insight into the limitations of reductionist approaches. Whole-cell models can be used to discover properties arising at the interfaces of dynamically coupled processes within a biological system, thereby making more apparent what is lost through decomposition. Similarly, multi-scale modeling highlights the relevance of macroscale parameters and models and challenges the view that living systems can be understood “bottom-up.” Specifically, we point out that system-level properties constrain lower-scale processes. Thus, large-scale modeling reveals how living systems at the same time are more and less than the sum of the parts. (shrink)

In the present study, we have demonstrated hysteresis phenomena in the excitability of single, enzymatically dissociated guinea pig ventricular myocytes. Membrane potentials were recorded with patch pipettes in the whole-cell current clamp configuration. Repetitive stimulation with depolarizing current pulses of constant cycle length and duration but varying strength led to predictable excitation (1:l) and non-excitation (1:0) patterns depending on current strength. In addition, transition between patterns depended on the direction of current intensity change and stable hysteresis loops were (...) obtained in stimulus:response pattern vs. current intensity plots in 14 cells. Increase of pulse duration and decrease of stimulation rate contributed to a reduction in hysteresis loop areas. Changes in amplitude and shape of the subthreshold responses during the transitions from one stable pattern to the other, suggested that activity led to an increase in membrane resistance, particularly in the voltage domain between resting potential, and threshold. Therefore, we modelled the dynamic behaviour of the single cells as a function of diastolic membrane resistance, using previously published analytical solutions. Numerical iteration of the analytical model equations closely reproduced the experimental hysteresis loops in both qualitative and quantitative ways. In particular, the effect of stimulation frequency on the model was similar to the experimental findings. The overall study suggests that the excitability pattern of guinea pig ventricular myocytes accounts for hysteresis and bistabilities when current intensity is allowed to fluctuate around threshold levels. (shrink)

We present a population density and moment-based description of the stochastic dynamics of domain $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type $${\text{Ca}}^{2+}$$ channels. Our approach accounts for the effect of heterogeneity of local $${\text{Ca}}^{2+}$$ signals on whole cell $${\text{Ca}}^{2+}$$ currents; however, in contrast with prior work, e.g., Sherman et al. :985–995, 1990), we do not assume that $${\text{Ca}}^{2+}$$ domain formation and collapse are fast compared to channel gating. We demonstrate the population density and moment-based modeling approaches using a 12-state (...) Markov chain model of an L-type $${\text{Ca}}^{2+}$$ channel introduced by Greenstein and Winslow :2918–2945, 2002). Simulated whole cell voltage clamp responses yield an inactivation function for the whole cell $${\text{Ca}}^{2+}$$ current that agrees with the traditional approach when domain dynamics are fast. We analyze the voltage-dependence of $${\text{Ca}}^{2+}$$ inactivation that may occur via slow heterogeneous domain [ $${\text{Ca}}^{2+}$$ ]. Next, we find that when channel permeability is held constant, $${\text{Ca}}^{2+}$$ -mediated inactivation of L-type channels increases as the domain time constant increases, because a slow domain collapse rate leads to increased mean domain [ $${\text{Ca}}^{2+}$$ ] near open channels; conversely, when the maximum domain [ $${\text{Ca}}^{2+}$$ ] is held constant, inactivation decreases as the domain time constant increases. Comparison of simulation results using population densities and moment equations confirms the computational efficiency of the moment-based approach, and enables the validation of two distinct methods of truncating and closing the open system of moment equations. In general, a slow domain time constant requires higher order moment truncation for agreement between moment-based and population density simulations. (shrink)

Synthetic biology is often understood in terms of the pursuit for well-characterized biological parts to create synthetic wholes. Accordingly, it has typically been conceived of as an engineering dominated and application oriented field. We argue that the relationship of synthetic biology to engineering is far more nuanced than that and involves a sophisticated epistemic dimension, as shown by the recent practice of synthetic modeling. Synthetic models are engineered genetic networks that are implanted in a natural cell environment. Their (...) construction is typically combined with experiments on model organisms as well as mathematical modeling and simulation. What is especially interesting about this combinational modeling practice is that, apart from greater integration between these different epistemic activities, it has also led to the questioning of some central assumptions and notions on which synthetic biology is based. As a result synthetic biology is in the process of becoming more “biology inspired.”. (shrink)

Synthetic biology is often understood in terms of the pursuit for well-characterized biological parts to create synthetic wholes. Accordingly, it has typically been conceived of as an engineering dominated and application oriented field. We argue that the relationship of synthetic biology to engineering is far more nuanced than that and involves a sophisticated epistemic dimension, as shown by the recent practice of synthetic modeling. Synthetic models are engineered genetic networks that are implanted in a natural cell environment. Their (...) construction is typically combined with experiments on model organisms as well as mathematical modeling and simulation. What is especially interesting about this combinational modeling practice is that, apart from greater integration between these different epistemic activities, it has also led to the questioning of some central assumptions and notions on which synthetic biology is based. As a result synthetic biology is in the process of becoming more “biology inspired.”. (shrink)

According to vitalism, living organisms differ from machines and all other inanimate objects by being endowed with an indwelling immaterial directive agency, ‘vital force,’ or entelechy . While support for vitalism fell away in the late nineteenth century many biologists in the early twentieth century embraced a non vitalist philosophy variously termed organicism/holism/emergentism which aimed at replacing the actions of an immaterial spirit with what was seen as an equivalent but perfectly natural agency—the emergent autonomous activity of the whole (...) organism. Organicists hold that organisms unlike machines are ‘more than the sum of their parts’ and predict that the vital properties of living things can never be explained in terms of mechanical analogies and that the reductionist agenda is doomed to failure. Here we review the current status of the mechanist and organicist conceptions of life particularly as they apply to the cell. We argue that despite the advances in biological knowledge over the past six decades since the molecular biological revolution, especially in the fields of genetics and cell biology the unique properties of living cells have still not been simulated in mechanical systems nor yielded to reductionist—analytical explanations. And we conclude that despite the dominance of the mechanistic–reductionist paradigm through most of the past century the possibility of a twentyfirst century organicist revival cannot be easily discounted. (shrink)

This paper is devoted to develop a nonlocal and time-delayed reaction-diffusion model for HIV infection within host cell-to-cell viral transmissions. In a bounded spatial domain, we study threshold dynamics in terms of basic reproduction numberR0for the heterogeneous model. Our results show that ifR0 1, virus will persist in the host environment.

Pluripotency can be considered a functional characteristic of pluripotent stem cells (PSCs) populations and their niches, rather than a property of individual cells. In this view, individual cells within the population independently adopt a variety of different expression states, maintained by different signaling, transcriptional, and epigenetics regulatory networks. In this review, we propose that generation of integrative network models from single cell data will be essential for getting a better understanding of the regulation of self‐renewal and differentiation. In particular, (...) we suggest that the identification of network stability determinants in these integrative models will provide important insights into the mechanisms mediating the transduction of signals from the niche, and how these signals can trigger differentiation. In this regard, the differential use of these stability determinants in subpopulation‐specific regulatory networks would mediate differentiation into different cell fates. We suggest that this approach could offer a promising avenue for the development of novel strategies for increasing the efficiency and fidelity of differentiation, which could have a strong impact on regenerative medicine. (shrink)

In the last decade it has become en vogue for cognitive comparative psychologists to study animal behavior in an ‘integrated’ fashion to account for both the ‘innate’ and the ‘acquired’. We will argue that these studies, instead of really integrating the concepts of ‘nature’ and ‘nurture’, rather cement this old dichotomy. They combine empty nativist interpretation of behavior systems with blatantly environmentalist explanations of learning. We identify the main culprit as the failure to take development seriously. While in some areas (...) of biology interest in the relationship between behavior and development has surged through topics such as extragenetic inheritance, niche construction, and phenotypic plasticity, this has gone almost completely unnoticed in the study of animal behavior in comparative psychology, and is frequently ignored in ethology too. The main aims of this paper are to clarify the relationship between the concepts of learning, experience, and development, and to investigate whether and how all three concepts can be usefully deployed in the study of animal behavior. This will require the full integration of the psychological study of behavior into biology, and of the idea of learning into a wider concept of experience. We lay out how, in a systems view of development, learning may just appear as one among many processes in which experience influences behavior. This new synthesis should help to overcome the age-old dualism between innate and acquired. It thereby opens up the possibility of developing scientifically more fruitful distinctions. (shrink)

Secretion is a fundamental cellular process involving the regulated release of intracellular products from cells. Physiological functions such as neurotransmission, or the release of hormones and digestive enzymes, are all governed by cell secretion. Anomalies in the processes involved in secretion contribute to the development and progression of diseases such as diabetes and other hormonal disorders. To unravel the mechanisms that govern such diseases, it is essential to understand how hormones, growth factors and neurotransmitters are synthesized and processed, and (...) how their signals are recognized, amplified and transmitted by intracellular signaling pathways in the target cells. Here, we discuss diverse aspects of the detailed mechanisms involved in secretion based on mathematical models. The models range from stochastic ones describing the trafficking of secretory vesicles to deterministic ones investigating the regulation of cellular processes that underlie hormonal secretion. In all cases, the models are closely related to experimental results and suggest theoretical predictions for the secretion mechanisms. (shrink)

We review state‐of‐the‐art computational methods for constructing, from image data, generative statistical models of cellular and nuclear shapes and the arrangement of subcellular structures and proteins within them. These automated approaches allow consistent analysis of images of cells for the purposes of learning the range of possible phenotypes, discriminating between them, and informing further investigation. Such models can also provide realistic geometry and initial protein locations to simulations in order to better understand cellular and subcellular processes. To determine the structures (...) of cellular components and how proteins and other molecules are distributed among them, the generative modeling approach described here can be coupled with high throughput imaging technology to infer and represent subcellular organization from data with few a priori assumptions. We also discuss potential improvements to these methods and future directions for research. (shrink)

Estimation of the repartition of asynchronous cells in the cell cycle can be explained by two hypotheses:– - the cells are supposed to be distributed into three groups: cells with a 2c DNA content (G0/1 phase), cells with a 4c DNA content (G2+M phase) and cells with a DNA content ranging from 2c to 4c (S phase); – - there is a linear relationship between the amount of fluorescence emitted by the fluorescent probe which reveals the DNA and the (...) DNA content. According to these hypotheses, the cell cycle can be represented by the following equation. (shrink)

Unlike inert objects, organisms and their cells have the ability to initiate activity by themselves and thus change their properties or states even in the absence of an external cause. This crucial difference led us to search for principles suitable for the study organisms. We propose that cells follow the default state of proliferation with variation and motility, a principle of biological inertia. This means that in the presence of sufficient nutrients, cells will express their default state. We also propose (...) a principle of variation that addresses two central features of organisms, variation and historicity. To address interdependence between parts, we use a third principle, the principle of organization, more specifically, the notion of the closure of constraints. Within this theoretical framework, constraints are specific theoretical entities defined by their relative stability with respect to the processes they constrain. Constraints are mutually dependent in an organized system and act on the default state.Here we discuss the application and articulation of these principles for mathematical modeling of morphogenesis in a specific case, that of mammary ductal morphogenesis, with an emphasis on the default state. Our model has both a biological component, the cells, and a physical component, the matrix that contains collagen fibers. Cells are agents that move and proliferate unless constrained; they exert mechanical forces that act (i) on collagen fibers and (ii) on other cells. As fibers are organized, they constrain the cells’ ability to move and to proliferate. This model exhibits a circularity that can be interpreted in terms of the closure of constraints. Implementing our mathematical model shows that constraints to the default state are sufficient to explain the formation of mammary epithelial structures. Finally, the success of this modeling effort suggests a stepwise approach whereby additional constraints imposed by the tissue and the organism can be examined in silico and rigorously tested by in vitro and in vivo experiments, in accordance with the organicist perspective we embrace. (shrink)

Research in many fields of biology has been extremely successful in decomposing biological mechanisms to discover their parts and operations. It often remains a significant challenge for scientists to recompose these mechanisms to understand how they function as wholes and interact with the environments around them. This is true of the eukaryotic cell. Although initially identified in nineteenth-century cell theory as the fundamental unit of organisms, researchers soon learned how to decompose it into its organelles and chemical constituents (...) and have been highly successful in understanding how these carry out many operations important to life. The emphasis on decomposition is particularly evident in modern cell biology, which for the most part has viewed the cell as merely a locus of the mechanisms responsible for vital phenomena. The cell, however, is also an integrated system and for some explanatory purposes it is essential to recompose it and understand it as an organized whole. I illustrate both the virtues of decomposition (treating the cell as a locus) and recomposition (treating the cell as an object) with recent work on circadian rhythms. Circadian researchers have both identified critical intracellular operations that maintain endogenous oscillations and have also addressed the integration of cells into multicellular systems in which cells constitute units. Ó 2010 Elsevier Ltd. All rights reserved. (shrink)

Imagine cells that live in a high‐gradient magnetic field (HGMF). Through what mechanisms do the cells sense a non‐uniform magnetic field and how such a field changes the cell fate? We show that magnetic forces generated by HGMFs can be comparable to intracellular forces and therefore may be capable of altering the functionality of an individual cell and tissues in unprecedented ways. We identify the cellular effectors of such fields and propose novel routes in cell biology predicting (...) new biological effects such as magnetic control of cell‐to‐cell communication and vesicle transport, magnetic control of intracellular ROS levels, magnetically induced differentiation of stem cells, magnetically assisted cell division, or prevention of cells from dividing. On the basis of experimental facts and theoretical modeling we reveal timescales of cellular responses to high‐gradient magnetic fields and suggest an explicit dependence of the cell response time on the magnitude of the magnetic field gradient. (shrink)

Cancer is a paradigmatic case of a complex causal process; causes of cancer operate at a variety of temporal and spatial scales, and the respects in which these causes act and interact are diverse. There are, for instance, temporal order effects, organizational effects, structural effects, and dynamic relationships between causes operating at different temporal and spatial scales. Because of this complexity, models of cancer initiation and progression often involve deliberate choices to focus on one time scale, one causal pathway, or (...) one aspect of cancer’s dynamics. As in most of biology, modeling cancer involves simplification and idealization. At the same time, theoretical perspectives inform the construction of these models. Such perspectives might involve viewing cancer ‘as’ a genetic disease, metabolic disease, stem cell disease, an infectious disease, or a disease of tissue disorganization. This paper will argue that purportedly competing theoretical views of cancer are not at odds, but can be viewed as mutually informative. Models are most often developed in the service of asking very specific questions, and this requires limiting our view of the phenomena to a specific temporal or spatial scale, a particular cause, or a particular outcome, dynamic, or pattern. Thus, while some models may seem at odds, often they are simply concerned with different questions, or, they are complementary and mutually informative. I hope to bring this case to bear on debates among philosophers of science over perspectivism and realism, as well pluralism about the aims and scope of scientific theory. (shrink)

Model organisms are central to contemporary biology and studies of embryogenesis in particular. Biologists utilize only a small number of species to experimentally elucidate the phenomena and mechanisms of development. Critics have questioned whether these experimental models are good representatives of their targets because of the inherent biases involved in their selection (e.g., rapid development and short generation time). A standard response is that the manipulative molecular techniques available for experimental analysis mitigate, if not counterbalance, this concern. But the most (...) powerful investigative techniques and molecular methods are applicable to single-celled organisms (‘microbes’). Why not use unicellular rather than multicellular model organisms, which are the standard for developmental biology? To claim that microbes are not good representatives takes us back to the original criticism leveled against model organisms. Using empirical case studies of microbes modeling ontogeny, we break out of this circle of reasoning by showing: (a) that the criterion of representation is more complex than earlier discussions have emphasized; and, (b) that different aspects of manipulability are comparable in importance to representation when deciding if a model organism is a good model. These aspects of manipulability harbor the prospect of enhancing representation. The result is a better understanding of how developmental biologists conceptualize research using experimental models and suggestions for underappreciated avenues of inquiry using microbes. More generally, it demonstrates how the practical aspects of experimental biology must be scrutinized in order to understand the associated scientific reasoning. (shrink)

The cell is not only the structural, physiological, and developmental unit of life, but also the reproductive one. So far, however, this aspect of the cell has received little attention from historians and philosophers of biology. I will argue that cell theory had far-reaching consequences for how biologists conceptualized the reproductive relationships between germs and adult organisms. Cell theory, as formulated by Theodor Schwann in 1839, implied that this relationship was a specific and lawful one, that (...) is, that germs of a certain kind, all else being equal, would produce adult organisms of the same kind, and vice versa. Questions of preformation and epigenesis took on a new meaning under this presupposition. The question then became one of whether cells could be considered as autonomous agents producing adult organisms of a given species, or whether they were the product of external, organizing forces and thus only a stage in the development of the whole organism. This question became an important issue for nineteenth-century biology. As I will demonstrate, it was the view of cells as autonomous agents which helped both Charles Darwin and Gregor Mendel to think of inheritance as a lawful process. (shrink)

This paper uses autocatalytic networks to model discontinuous cultural transitions involving cross-domain transfer, using as an illustrative example, artworks inspired by the oldest-known uncontested example of figurative art: the carving of the Hohlenstein-Stadel Löwenmensch, or lion-human. Autocatalytic networks provide a general modeling setting in which nodes are not just passive transmitters of activation; they actively galvanize, or “catalyze” the synthesis of novel nodes from existing ones This makes them uniquely suited to model how new structure grows out of earlier (...) structure, i.e., cumulative, generative network growth. They have been used to model the origin and early evolution of biological life, and the emergence of cognitive structures capable of undergoing cultural evolution. We conducted a study in which six individual creators and one group generated music, prose, poetry, and visual art inspired by the Hohlenstein-Stadel Löwenmensch, and answered questions about the process. The data revealed four through-lines by which they expressed the Löwenmensch in an alternative art form: lion-human hybrid, subtracting from the whole to reveal the form within, deterioration, and waiting to be found with a story to tell. Autocatalytic networks were used to model how these four spontaneously derived through-lines form a cultural lineage from Löwenmensch to artist to audience. We used the resulting data from three creators to model the cross-domain transfer from inspirational source to creative product. These four spontaneously-generated threads of cultural continuity formed the backbone of this Löwenmensch-inspired cultural lineage, enabling culture to evolve even in the face of discontinuity at the level conventional categories or domains. We know of no other theory of cultural evolution that accommodates cross-domain transfer or other forms of discontinuity. The approach paves the way for a broad scientific framework for the origins of evolutionary processes. (shrink)

Understanding modeling in biology requires understanding how biology is organized as a discipline and how this organization influences the research practices of biologists. Biology includes a wide range of sub-disciplines, such as cell biology, population biology, evolutionary biology, molecular biology, and systems biology among others. Biologists in sub-disciplines such as cell, molecular, and systems biology believe that the use of a few experimental models allows them to discover biological universals, whereas biologists in sub-disciplines such as ecology and (...) evolutionary biology believe that the use of many different experimental and mathematical models is necessary in order to do this. Many practitioners of both approaches misunderstand best practices of modeling, especially those related to model testing. We stress the need for biologists to better engage with best practices and for philosophers of biology providing normative guidance for biologists to better engage with current developments in biology. This is especially important as biology transitions from a “data-poor” to a “data-rich” discipline. If 21st century biology is going to capitalize on the unprecedented availability of ecological, evolutionary, and molecular data, of computational resources, and of mathematical and statistical tools, biologists will need a better understanding of what modeling is and can be. (shrink)

In the multidisciplinary field of developmental cognitive neuroscience, statistical associations between levels of description play an increasingly important role. One example of such associations is the observation of correlations between relatively common gene variants and individual differences in behavior. It is perhaps surprising that such associations can be detected despite the remoteness of these levels of description, and the fact that behavior is the outcome of an extended developmental process involving interaction of the whole organism with a variable environment. (...) Given that they have been detected, how do such associations inform cognitive-level theories? To investigate this question, we employed a multiscale computational model of development, using a sample domain drawn from the field of language acquisition. The model comprised an artificial neural network model of past-tense acquisition trained using the backpropagation learning algorithm, extended to incorporate population modeling and genetic algorithms. It included five levels of description—four internal: genetic, network, neurocomputation, behavior; and one external: environment. Since the mechanistic assumptions of the model were known and its operation was relatively transparent, we could evaluate whether cross-level associations gave an accurate picture of causal processes. We established that associations could be detected between artificial genes and behavioral variation, even under polygenic assumptions of a many-to-one relationship between genes and neurocomputational parameters, and when an experience-dependent developmental process interceded between the action of genes and the emergence of behavior. We evaluated these associations with respect to their specificity, to their developmental stability, and to their replicability, as well as considering issues of missing heritability and gene–environment interactions. We argue that gene–behavior associations can inform cognitive theory with respect to effect size, specificity, and timing. The model demonstrates a means by which researchers can undertake multiscale modeling with respect to cognition and develop highly specific and complex hypotheses across multiple levels of description. (shrink)

The cell is not only the structural, physiological, and developmental unit of life, but also the reproductive one. So far, however, this aspect of the cell has received little attention from historians and philosophers of biology. I will argue that cell theory had far-reaching consequences for how biologists conceptualized the reproductive relationships between germs and adult organisms. Cell theory, as formulated by Theodor Schwann in 1839, implied that this relationship was a specific and lawful one, that (...) is, that germs of a certain kind, all else being equal, would produce adult organisms of the same kind, and vice versa. Questions of preformation and epigenesis took on a new meaning under this presupposition. The question then became one of whether cells could be considered as autonomous agents producing adult organisms of a given species, or whether they were the product of external, organizing forces and thus only a stage in the development of the whole organism. This question became an important issue for nineteenth-century biology. As I will demonstrate, it was the view of cells as autonomous agents which helped both Charles Darwin and Gregor Mendel to think of inheritance as a lawful process. (shrink)

This selection of texts should interest those who study analytical philosophy of history, methodology of history, and historical sociology. It contains contributions by Polish historians and philosophers since 1931, with pride of place given to the work of the Poznań school in the philosophy of science and humanities. With Jerzy Kmita, Leszek Nowak, and Jerzy Topolski as its leaders, it emerged in late 1960s as a synthesis of Marxism and the Polish brand of logical positivism known as the Lwow-Warsaw school. (...) Most papers discuss or exemplify various forms of idealization in historical research. Although the papers demonstrate the usefulness of modeling in historical sociology and nonnarrative history, the collection as a whole does not provide realistic examples to substantiate the Poznań school's stronger claim of the decomposability of historical narratives into separate strips related to hierarchically ordered “essential factors.”. (shrink)

Design patterns are generalized solutions to frequently recurring problems. They were initially developed by architects and computer scientists to create a higher level of abstraction for their designs. Here, we extend these concepts to cell biology to lend a new perspective on the evolved designs of cells' underlying reaction networks. We present a catalog of 21 design patterns divided into three categories: creational patterns describe processes that build the cell, structural patterns describe the layouts of reaction networks, and (...) behavioral patterns describe reaction network function. Applying this pattern language to the E. coli central metabolic reaction network, the yeast pheromone response signaling network, and other examples lends new insights into these systems. (shrink)

The processes of wound healing and bone regeneration and problems in tissue engineering have been an active area for mathematical modeling in the last decade. Here we review a selection of recent models which aim at deriving strategies for improved healing. In wound healing, the models have particularly focused on the inflammatory response in order to improve the healing of chronic wound. For bone regeneration, the mathematical models have been applied to design optimal and new treatment strategies for normal (...) and specific cases of impaired fracture healing. For the field of tissue engineering, we focus on mathematical models that analyze the interplay between cells and their biochemical cues within the scaffold to ensure optimal nutrient transport and maximal tissue production. Finally, we briefly comment on numerical issues arising from simulations of these mathematical models. (shrink)

The principles of automation (automatism and programming) in the unfolding of spatio-temporal patterns during animal development are deduced from experimental data reconsidered from the point of view of cell sociology. The developmental programme in the egg is not part of the genetic information but a part of the cytoplasmic information. Throughout development cells store extra-cellular information released by their neighbours in the form of cytoplasmic information. Successive determinations cannot be considered as successive reprogrammings of cells: each one consists of (...) a selection of one specific programme from the total information previously stored. This programme specifies cell interactions in the determined population as a whole; it is very imprecise and is progressively completed during the course of further differentiation by information released by neighbouring cell populations. Complicated patterns may emerge from only two homogeneous populations involved in distinct differentiation pathways and confronting each other. Consequently the egg developmental programme provides gene effectors and specific physico-chemical conditions necessary for the starting of at least two distinct differentation pathways. Experimental data suggest that there are two components in this programme. One is a molecular machinery which starts at fertilization in the whole cytoplasm. It yields two programmes of differentiation, typically first an endodermal and then an ectodermal one. The other component of the egg developmental programme, which does not require specific information, allows the interception of the first (endodermal) programme. The application of informatics to developmental automatism is discussed in the latter part of the paper. (shrink)

Before a cell divides into two daughter cells, it typically doubles not only its DNA, but also its mass. Numerous studies in cells ranging from yeast to mammals have shown that cellular growth, stimulated by nutrients and/or growth factor signaling, is a prerequisite for cell cycle progression in most types of cells. The textbook view of growth‐regulated cell cycles is that growth signaling activates the transcription of G1 Cyclin genes to induce cell proliferation, and also stimulates (...) anabolic metabolism and cell growth in parallel. However, genetic knockout tests in model organisms indicate that this is not the whole story, and new studies show that additional, “smarter” mechanisms help to coordinate the cell cycle with growth itself. Here we summarize recent advances in this field, and discuss current models in which growth signaling regulates cell proliferation by targeting core cell cycle regulators via non‐transcriptional mechanisms. (shrink)

We are essentially a society of cells that come from a single cell, the fertilised egg. Research in cell biology has made major advances that are relevant to medicine and our understanding of life. Our understanding of the role of genes and proteins is impressive. But is this science dangerous? The whole of Western literature has not been kind to cell scientists and is filled with images of scientists meddling with nature, with disastrous results.1 Just consider (...) Shelley’s Frankenstein, Goethe’s Faust and Huxley’s Brave New World. One will search with very little success for a novel in which scientists come out well—the persistent image is that of scientists as a group unconcerned with ethical issues.There is a fear and distrust of cell science, particularly genetic engineering, leading to genetically modified foods, genetic modification of humans, cloning and stem cells. There is something of a revulsion in humankind’s meddling with nature and a longing for a Rousseauish-like return to golden age of innocence. There is anxiety that scientists lack both wisdom and social responsibility and are so motivated by ambition that they will follow their research anywhere, no matter what the consequences. Scientists are repeatedly referred to as “playing God”. Many of these criticisms coexist with the hope, particularly in medicine, that science will provide cures to all major illnesses, such as cancer, heart disease and genetic disabilities such as cystic fibrosis. But is cell science dangerous and what are the special social responsibilities of scientists? It is worth noting one irony: although scientists are blamed for making us live in a high-risk society, it is only because of science that we know about these risks, such as those related to health.The media must bear much of the responsibility for the misunderstanding of genetics as genetic pornography is, …. (shrink)

Cancer is a complex disease, necessitating research on many different levels; at the subcellular level to identify genes, proteins and signaling pathways associated with the disease; at the cellular level to identify, for example, cell-cell adhesion and communication mechanisms; at the tissue level to investigate disruption of homeostasis and interaction with the tissue of origin or settlement of metastasis; and finally at the systems level to explore its global impact, e.g. through the mechanism of cachexia. Mathematical models have (...) been proposed to identify key mechanisms that underlie dynamics and events at every scale of interest, and increasing effort is now being paid to multi-scale models that bridge the different scales. With more biological data becoming available and with increased interdisciplinary efforts, theoretical models are rendering suitable tools to predict the origin and course of the disease. The ultimate aims of cancer models, however, are to enlighten our concept of the carcinogenesis process and to assist in the designing of treatment protocols that can reduce mortality and improve patient quality of life. Conventional treatment of cancer is surgery combined with radiotherapy or chemotherapy for localized tumors or systemic treatment of advanced cancers, respectively. Although radiation is widely used as treatment, most scheduling is based on empirical knowledge and less on the predictions of sophisticated growth dynamical models of treatment response. Part of the failure to translate modeling research to the clinic may stem from language barriers, exacerbated by often esoteric model renderings with inaccessible parameterization. Here we discuss some ideas for combining tractable dynamical tumor growth models with radiation response models using biologically accessible parameters to provide a more intuitive and exploitable framework for understanding the complexity of radiotherapy treatment and failure. (shrink)

Conversation, talk, the communicative process, can be compared to the symphonic play of a piece of music. There is an orchestra, the musicians, whose tones and notes must flow, complement and harmonize with one another. There is a main theme. As the music builds variations on the theme are played, and new themes and subthemes are introduced. The basinett responds to the strings, the bass emphasizes the mood of the violin, while the french horn adds a new melody. The subtlety (...) and evenness of flow, the seeming simplicity of the piece, the rich interleaving of subdevelopments, variations, tangents, and recapitulations, are what make a piece of music great.Coherent communication is much the same. It looks easy. It flows. It seems effortless. In reality, of course, it is rich and complex, in both form and content. As in music, conversants may begin a conversation slowly, tentatively, with some simple (or complex) topic in mind. Slowly the momentum builds, the connections surface, and the themes become defined. As in music, these themes are then elaborated upon in various ways. Topic elaborations often spawn their own variations. New themes and subthemes are introduced. All the while, as in music, original themes reappear and are interwoven with the new ones. The twists and turns of the conversation seem to occur effortlessly.In music, there is usually one composer in control of which instrument plays next; one composer who is in charge of what the instrument will say. There is a single coordinator of theme introductions, developments, variations, and interweavings. The composition is done off-line and usually involves editing and re-editing for flaws. In discourse, however, we have on-line development with multiple parties responsible for flow coordination. All parties have to organize their own turns, themes, and variations, in addition to their being able to integrate these items into co-conversants'.In their book, “Understanding Computers and Cognition,” Winograd and Flores (1987) cite the following from Gadamer (Winograd and Flores, 1987, p. 32):It is not so much our judgments as it is our prejudices that constitute our being ... the historicity of our existence entails that prejudices, in the literal sense of the word, constitute the initial directedness of our whole ability to experience. Prejudices are biases of our openness to the world. They are simply conditions whereby we experience something — whereby what we encounter says something to us. (Gadamer, Philosophical Hermeneutics, 1976, p. 9). (shrink)

We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made (...) in the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell‐based regenerative medicine for diseases of lung and airways. (shrink)

The aim of this article is to show how a tumor can modify energy substrates fluxes in the brain to support its own growth. To address this question we use a modeling approach to explain brain nutrient kinetics. In particular we set up a system of 17 equations for oxygen, lactate, glucose concentrations and cells number in the brain. We prove the existence and uniqueness of nonnegative solutions and give bounds on the solutions. We also provide numerical simulations.

The recent development of RNA replicating protocells and capsules that enclose complex biosynthetic cascade reactions are encouraging signs that we are gradually getting better at mastering the complexity of biological systems. The road to truly cellular compartments is still very long, but concrete progress is being made. Compartmentalization is a crucial natural methodology to enable control over biological processes occurring within the living cell. In fact, compartmentalization has been considered by some theories to be instrumental in the creation of (...) life. With the advancement of chemical biology, artificial compartments that can mimic the cell as a whole, or that can be regarded as cell organelles, have recently received much attention. The membrane between the inner and outer environment of the compartment has to meet specific requirements, such as semi‐permeability, to allow communication and molecular transport over the border. The membrane can either be built from natural constituents or from synthetic polymers, introducing robustness to the capsule. (shrink)

The pursuit of mechanistic explanations in biology has produced a great deal of knowledge about the parts, operations, and organization of mechanisms taken to be responsible for biological phenomena. Holist critics have often raised important criticisms of proposed mechanistic explanations, but until recently holists have not had alternative research strategies through which to advance explanations. This paper argues both that the results of mechanistic strategies has forced mechanists to confront ways in which whole systems affect their components and that (...) new representational and modeling strategies are providing tools for understanding these effects of whole systems upon components. Drawing from research on the mechanism responsible for circadian rhythms in mammals, I develop two examples in which mechanistic analysis is being integrated into a more holist perspective: research revealing intercellular integration of circadian mechanisms with those involved in cell metabolism and research revealing that stable␣rhythms are dependent on how individual cells in the suprachiasmatic nucleus synchronize with each other to generate regular rhythms. Tools such as network diagramming and computational modeling are providing means to integrate mechanistic models into accounts of whole systems. (shrink)

Hebbian cell-assembly theory and attractor networks are good starting points for modeling cortical processing. Detailed cell models can be useful in understanding the dynamics of attractor networks. Cell assemblies are likely to be distributed, with the cortical column as the local processing unit. Synaptic memory may be dominant in all but the first couple of seconds.

The transition period brings about a need of working out the social strategy. It optimizes the social processes and helps to use carefully the resources of the society. Its essence is a human being measure of the social things (phenomena and processes) since a human being is the system forming element of a social system. Then it is necessary to analyze a human being as a system himself for concretizing the content of «a human being measure». A human being is (...) researched by the whole complex of the sciences. The humanities take a specific place. Them subject is the specific features of a human being, the consciousness of a man which defines a whole him life activities. Therefore the humanities play a leading part in the system researches of a human being. But there is significant to integrate the humanitarian knowledge himself. The hierarchy of the approaches is such: philosophical – culturological – ethnological –philological (folklore). This hierarchy gives opportunity to form the system knowledge beginning from interpreting the essence of a human being as the norm of his activities to its concrete characteristics. The hypothetic many levels model of the human activities (as analysis shows, cultural-anthropological by its content)serves as means for the well-founded choice of the future, the appreciation of the present through its prism, the electoral relation to the past and the purposeful influence on the social policy. (shrink)

A delightful book to get the whole picture of simulation applications in developmental biology and easily readable for those who would like to overlook the field in one quick sweep. If you would like to get a more detailed perspective, a great number of literature references provides this opportunity.

Applied general equilibrium models have received considerable attention and scrutiny in the public debate over the North American Free Trade Agreement. This collection brings together the leading AGE models that have been constructed to analyse NAFTA. A variety of approaches to modelling trade liberalization are taken in these studies, including multi-country and multi-sectoral models, models that focus on institutional features of particular sectors affecting multinational firms and rules of origin, and models with some inter-temporal structure. Further, by constructing stylized models, (...) theoretical linkages have been identified that drive numerical results in the larger AGE models. The volume also assesses what can be learned about the likely economic effects of NAFTA from the collection of studies taken as a whole. Areas in need of further study have been highlighted. (shrink)

We present a model of steady state solute and water reabsorption along the rat proximal tubule. Major co-and counter-transport systems in the apical and basolateral cell membranes are described using kinetic descriptions based on data from the flows and solute concentrations along the length of the proximal tubule as a function of filtration rate and peritubular solute concentrations. We show that for many aspects of proximal tubule transport physiology this kinetics-based model is an adequate representation of the mammalian proximal (...) tubule. (shrink)

Pantographs are important devices on high-speed trains. When a train runs at a high speed, concave and convex parts of the train cause serious airflow disturbances and result in flow separation, eddy shedding, and breakdown. A strong fluctuation pressure field will be caused and transformed into aerodynamic noises. When high-speed trains reach 300 km/h, aerodynamic noises become the main noise source. Aerodynamic noises of pantographs occupy a large proportion in far-field aerodynamic noises of the whole train. Therefore, the problem (...) of aerodynamic noises for pantographs is outstanding among many aerodynamics problems. This paper applies Detached Eddy Simulation to conducting numerical simulations of flow fields around pantographs of high-speed trains which run in the open air. Time-domain characteristics, frequency-domain characteristics, and unsteady flow fields of aerodynamic noises for pantographs are obtained. The acoustic boundary element method is used to study noise radiation characteristics of pantographs. Results indicate that eddies with different rotation directions and different scales are in regions such as pantograph heads, hinge joints, bottom frames, and insulators, while larger eddies are on pantograph heads and bottom frames. These eddies affect fluctuation pressures of pantographs to form aerodynamic noise sources. Slide plates, pantograph heads, balance rods, insulators, bottom frames, and push rods are the main aerodynamic noise source of pantographs. Radiated energies of pantographs are mainly in mid-frequency and high-frequency bands. In high-frequency bands, the far-field aerodynamic noise of pantographs is mainly contributed by the pantograph head. Single-frequency noises are in the far-field aerodynamic noise of pantographs, where main frequencies are 293 Hz, 586 Hz, 880 Hz, and 1173 Hz. The farther the observed point is from the noise source, the faster the sound pressure attenuation will be. When the distance of two adjacent observed points is increased by double, the attenuation amplitude of sound pressure levels for pantographs is around 6.6 dB. (shrink)

The collection and storage of human tissue samples has been present in medicine for centuries, however, biobanking has recently become a dedicated activity. The technological developments that have allowed the isolation, storage and long term viability of human cells ex vivo, and to obtain relevant scientific information, including genetic information, open tremendous possibilities for advancing biomedical research. At the same time, these possibilities have raised complex ethical issues regarding tissue donors, researchers using samples and society awareness of biobanking as a (...) whole. This article aims to review the operation of stem cell biobanks, related ethical issues and the legal framework in Spain. Special consideration will be given to the new but revolutionary appearance of induced pluripotent stem cells. Most of the topics discussed here will be in the framework of banking adult derived stem cells, which do not entail in themselves any significant ethical dilemma. (shrink)

Between 1946 and 1960, a new phenomenon emerged in the field of bacteriology. "Bacterial sex," as it was called, revolutionized the study of genetics, largely by making available a whole new class of cheap, fast-growing, and easily manipulated organisms. But what was "bacterial sex?" How could single-celled organisms have "sex" or even be sexually differentiated? The technical language used in the scientific press -- the public and inalienable face of 20th century science -- to describe this apparently neuter organism (...) was explicit: the cells "copulated," had "intimate contract," "conjugal unions," and engaged in "ménage à trois" relationships. And yet, to describe bacteria as sexually reproducing organisms, the definition of sex itself had to change. Despite manifold contradictions and the availability of alternative language, the notion of sexually active (even promiscuous) single-celled organisms has persisted, even into contemporary textbooks on cell biology and genetics. In this paper I examine the ways in which bacteria were brought into the genetic fold, sexualized, and given gender; I also consider the issues underlying the durability of "bacterial sex.". (shrink)

In this paper I will compare two conceptions of basic elements or units of living organisms from the second half of the nineteenth century: Goodsir’s cellular centers and Bütschli’s protoplam. The comparison will be made from the proposition of a nucleoplasmic form, and the referred conceptions are historical expressions of this general form. The nutrition center is a form that combines the functions of nutrition, germination and reproduction, responsible for the production of tissues, organs, tumors and the whole organism (...) from the fertilized egg. Microscopic foams produce organic differentiation through dynamic stabilization of the surface tension between the alveoli. I will conclude critically by discussing the relationship of these two expressions in terms of their continuity or exhaustion as scientific achievements of the biology of the period cited. (shrink)

In this paper I will compare two conceptions of basic elements or units of living organisms from the second half of the nineteenth century: Goodsir’s cellular centers and Bütschli’s protoplam. The comparison will be made from the proposition of a nucleoplasmic form, and the referred conceptions are historical expressions of this general form. The nutrition center is a form that combines the functions of nutrition, germination and reproduction, responsible for the production of tissues, organs, tumors and the whole organism (...) from the fertilized egg. Microscopic foams produce organic differentiation through dynamic stabilization of the surface tension between the alveoli. I will conclude critically by discussing the relationship of these two expressions in terms of their continuity or exhaustion as scientific achievements of the biology of the period cited. (shrink)