Cerebellar Purkinje cells generate two distinct types of spikes, complex and simple spikes, both of which have conventionally been considered to be highly irregular, suggestive of certain types of stochastic processes as underlying mechanisms. Interestingly, however, the interspike interval structures of complex spikes have not been carefully studied so far. We showed in a previous study that simple spike trains are actually composed of regular patterns and single interspike intervals, a mixture that could not be explained by (...) a simple rate-modulated Poisson process. In the present study, we systematically investigated the interspike interval structures of separated complex and simple spike trains recorded in anaesthetized rats, and derived an appropriate stochastic model. We found that: (i) complex spike trains do not exhibit any serial correlations, so they can effectively be generated by a renewal process, (ii) the distribution of intervals between complex spikes exhibits two narrow bands, possibly caused by two oscillatory bands (0.5–1 and 4–8 Hz) in the input to Purkinje cells and (iii) the regularity of regular patterns and single interspike intervals in simple spike trains can be represented by gamma processes of orders, which themselves are drawn from gamma distributions, suggesting that multiple sources modulate the regularity of simple spike trains. (shrink)

What is a stem cell? The answer is seemingly obvious: a cell that is also a stem, or point of origin, for something else. Upon closer examination, however, this combination of ideas leads directly to fundamental questions about biological development. A cell is a basic category of living thing; a fundamental 'unit of life.' A stem is a site of growth; an active source that supports or gives rise to something else. Both concepts are deeply rooted in biological thought, with (...) rich and complex histories. The idea of a stem cell unites them, but the union is neither simple nor straightforward. This book traces the origins of the stem cell concept, its use in stem cell research today, and implications of the idea for stem cell experiments, their concrete results, and hoped-for clinical advances. (shrink)

Through statistical analysis of datasets describing single cell shape following systematic gene depletion, we have found that the morphological landscapes explored by cells are composed of a small number of attractor states. We propose that the topology of these landscapes is in large part determined by cell‐intrinsic factors, such as biophysical constraints on cytoskeletal organization, and reflects different stable signaling and/or transcriptional states. Cell‐extrinsic factors act to determine how cells explore these landscapes, and the topology of the landscapes (...) themselves. Informational stimuli primarily drive transitions between stable states by engaging signaling networks, while mechanical stimuli tune, or even radically alter, the topology of these landscapes. As environments fluctuate, the topology of morphological landscapes explored by cells dynamically adapts to these fluctuations. Finally we hypothesize how complex cellular and tissue morphologies can be generated from a limited number of simple cell shapes. (shrink)

The stem cell story is not a simple story but a complex narrative: one that requires careful analysis in order to identify major themes and plots. This paper offers an analysis of the ethics of the clinical application of stem cells and argues that even quite risky therapies can be ethical. These arguments cannot be used to justify all aspects of contemporary stem cell science, including human embryonic stem cell science, which remains theoretical and speculative. It is argued (...) that the homogenisation of stem cell science obscures the distinction between clinical application and experimental laboratory science in a morally problematic way. (shrink)

In Escherichia coli, the role of lacA, the third gene of the lactose operon, has remained an enigma. I suggest that its role is the consequence of the need for cells to have safety valves that protect them from the osmotic effect created by their permeases. Safety valves allow them to cope with the buildup of osmotic pressure under accidental transient conditions. Multidrug resistance (MDR) efflux, thus named because of our anthropocentrism, is ubiquitous. Yet, the formation of simple (...) leaks would result in futile influx/efflux cycles. Versatile modification enzymes with low sensitivity solve the problem if the modified metabolite is the one exported by MDR permeases. This may account for the pervasive presence of acetyl-transferases, such as LacA, associated to acetyl-metabolite exporters. This scenario of constraints imposed by efficient influx of metabolites provides us with a model that should be followed when constructing synthetic cells. (shrink)

During the formation of the brain, neuronal cell migration and neurite extension are controlled by extracellular guidance cues. Here, I discuss experiments showing that the messenger nitric oxide (NO) is an additional regulator of cell motility. NO is a membrane permeant molecule, which activates soluble guanylyl cyclase (sGC) and leads to the formation of cyclic GMP (cGMP) in target cells. The analysis of specific cells types in invertebrate models such as molluscs, insects and the medicinal leech provides insight (...) how NO and cyclic nucleotides affect the wiring of nervous systems by regulating cell and growth‐cone motility. Inhibition of the NOS and sGC enzymes combined with rescue experiments show that NO signalling orchestrates neurite outgrowth and filopodial dynamics, cell migration of enteric neurons, glial migration and axonogenesis of pioneer fibers. Cultured insect embryos are accessible model systems in which cellular mechanisms of NO‐induced cytoskeletal reorganizations can be analyzed in natural settings. Finally, I will outline some indications that NO may also regulate cell motility in the developing and regenerating vertebrate nervous system. BioEssays 27:495–505, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The cell assembly as a simple attractor cannot explain many cognitive phenomena. It must be a highly structured network that can sustain highly structured excitation patterns. Moreover, a cell assembly must be more widely distributed in space than on a square millimeter.

When a cell divides, it produces two daughter cells initially connected by a cytokinesis bridge, which is eventually cut through abscission. One of the two daughter cells inherits a bridge “remnant”, which has been proposed to be degraded by autophagy. The fate and function of remnants is attracting increasing attention, as their accumulation appears to influence proliferation versus differentiation of the daughter cells. Here, we present a simple model for bridge and remnant turnover in a dynamic (...) cell population. We demonstrate that remnant proportions depend on the ratio of remnant and bridge lifetimes to the cell population doubling time. Our results yield new alternative interpretations for published experimental data, leading us to believe that autophagy‐independent pathways for remnant degradation may exist. In addition, using the model, we determined experimentally inaccessible parameters such as remnant lifetime. Our model proves to be a useful tool for studying bridge and remnant populations. (shrink)

The expression of epithelial cell adhesion and cytoskeletal genes is orchestrated by an apparently unique set of rules. No tissue‐specific transactivator proteins have been found to drive them; only ubiquitous factors are utilized. In non‐epithelial cells, they are actively repressed. Moreover, it was recently found that a single protein (adenovirus E1a) coordinately represses non‐epithelial genes while inducing epithelial genes. A simple model is offered to explain how epithelial gene expression is coordinated. Under this model, the epithelial cell gene (...) expression program is a transcriptional ‘default’; that is, it occurs in the absence of tissue‐specific transactivation. Conversion to this default requires only that mesenchymal transactivators are not expressed, or that central ‘integrator’ proteins are inactive. In their absence, mesenchymal gene expression cannot occur. Moreover, because the repressors cease to be expressed, the epithelial genes are induced. Oncogenes generally cause the breakdown of the epithelial phenotype ‐ generating carcinomas ‐ so genes such as E1a that cause epithelial conversion may prove useful for both understanding and controlling cancer. (shrink)

differential from bottom to top, depth of fluid, and the coefficients of expansion, viscosity and thermal Bénard convection, is one of the more intensely conductivity of the fluid. Even though it is a simple studied dissipative systems, both theoretically and..

When we perceive the external world, our brain has to deal with the incompleteness and uncertainty associated with sensory inputs, memory and prior knowledge. In theoretical neuroscience probabilistic approaches have received a growing interest recently, as they account for the ability to reason with incomplete knowledge and to efficiently describe perceptive and behavioral tasks. How can the probability distributions that need to be estimated in these models be represented and processed in the brain, in particular at the single cell level? (...) We consider the basic function carried out by photoreceptor cells which consists in detecting the presence or absence of light. We give a system-level understanding of the process of phototransduction based on a bayesian formalism: we show that the process of phototransduction is equivalent to a temporal probabilistic inference in a Hidden Markov Model (HMM), for estimating the presence or absence of light. Thus, the biochemical mechanisms of phototransduction underlie the estimation of the current state probability distribution of the presence of light. A classical descriptive model describes the interactions between the different molecular messengers, ions, enzymes and channel proteins occurring within the photoreceptor by a set of nonlinear coupled differential equations. In contrast, the probabilistic HMM model is described by a discrete recurrence equation. It appears that the binary HMM has a general solution in the case of constant input. This allows a detailed analysis of the dynamics of the system. The biochemical system and the HMM behave similarly under steady-state conditions. Consequently a formal equivalence can be found between the biochemical system and the HMM. Numerical simulations further extend the results to the dynamic case and to noisy input. All in all, we have derived a probabilistic model equivalent to a classical descriptive model of phototransduction, which has the additional advantage of assigning a function to phototransduction. The example of phototransduction shows how simple biochemical interactions underlie simple probabilistic inferences. (shrink)

Cellular reprogramming can manipulate the identity of cells to generate the desired cell types1– 3. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells4– 7. By contrast, chemical stimulation by exposure to small molecules offers an alternative approach that can manipulate cell fate in a simple and highly controllable manner8– 10. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome2,11,12 and (...) reduced plasticity13,14; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming. Here we demonstrate, by creating an intermediate plastic state, the chemical reprogramming of human somatic cells to human chemically induced pluripotent stem cells that exhibit key features of embryonic stem cells. The whole chemical reprogramming trajectory analysis delineated the induction of the intermediate plastic state at the early stage, during which chemical-induced dedifferentiation occurred, and this process was similar to the dedifferentiation process that occurs in axolotl limb regeneration. Moreover, we identified the JNK pathway as a major barrier to chemical reprogramming, the inhibition of which was indispensable for inducing cell plasticity and a regeneration-like program by suppressing pro-inflammatory pathways. Our chemical approach provides a platform for the generation and application of human pluripotent stem cells in biomedicine. This study lays foundations for developing regenerative therapeutic strategies that use well-defined chemicals to change cell fates in humans. (shrink)

Contrary to the rarity of totipotent cells in animals, almost every cell formed by a fungus can function as a “stem cell”. The multicellular fruiting bodies of basidiomycete fungi consist of the same kind of filamentous hyphae that form the feeding phase, or mycelium, of the organism, and visible cellular differentiation is almost nonexistent. Mushroom primordia develop from masses of converging hyphae, and the stipe (or stem), cap, and gills are clearly demarcated within the embryonic fruiting body long before (...) the organ expands and unfolds through water uptake and cell wall loosening.aThough frequent references are made to gilled mushrooms in this article, the totipotent nature of fruiting body cells and lack of meristems is also applicable to basidiomycetes that spread their spore‐producing tissues inside tubes (e.g., boletes), over spines and rippled surfaces, or form spores in cavities within the fruiting body. Even in the mature mushroom, every hypha retains its totipotency. Among animals, only sponges exhibit a similar degree of developmental flexibility, which is interesting, because these simple metazoans may be relatively close relatives of fungi. BioEssays 24:949–952, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Many states in the U.S. have adopted policies regarding human embryonic stem cell (hESC) research in the last few years. Some have arrived at these policies through legislative debate, some by referendum, and some by executive order. New York has chosen a unique structure for addressing policy decisions regarding this morally controversial issue by creating the Empire State Stem Cell Board with two Committees—an Ethics Committee and a Funding Committee. This essay explores the pros and cons of various policy arrangements (...) for making public policy decisions about morally controversial issues in bioethics (as well as other issues) through the lens of Deliberative Democracy, focusing on the principles of reciprocity, publicity, and accountability. Although New York's unique mechanism potentially offers an opportunity to make policy decisions regarding a morally controversial subject like hESC research in accord with the principles of Deliberative Democracy, this essay demonstrates its failure to do so in actual fact. A few relatively simple changes could make New York's program a real model for putting Deliberative Democracy into practice in making policy decisions regarding controversial bioethical issues. (shrink)

I propose a T‐cell receptor (TcR)‐based mechanism by which immunity mediates both “genetic self” and “microbial self” thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross‐reactivity with “self,” resulting in selection for a TcR repertoire mimicking “genetic self.” Second, evolution has selected for a “microbial self” that mimics “genetic self” so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism (...) for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR‐microbiome mimicry “holoimmunity” to denote immune tolerance to the “holobiont self.” Logically, microbiome‐host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross‐react with host antigens producing “holoautoimmunity.”. (shrink)

Stem cell biology and systems biology are two prominent new approaches to studying cell development. In stem cell biology, the predominant method is experimental manipulation of concrete cells and tissues. Systems biology, in contrast, emphasizes mathematical modeling of cellular systems. For scientists and philosophers interested in development, an important question arises: how should the two approaches relate? This essay proposes an answer, using the model of Waddington’s landscape to triangulate between stem cell and systems approaches. This simple abstract (...) model represents development as an undulating surface of hills and valleys. Originally constructed by C. H. Waddington to visually explicate an integrated theory of genetics, development and evolution, the landscape model can play an updated unificatory role. I examine this model’s structure, representational assumptions, and uses in all three contexts, and argue that explanations of cell development require both mathematical models and concrete experiments. On this view, the two approaches are interdependent, with mathematical models playing a crucial but circumscribed role in explanations of cell development. (shrink)

How Darwin's “endless forms most beautiful” have evolved remains one of the most exciting questions in biology. The significant variety of bacterial shapes is most likely due to the specific advantages they confer with respect to the diverse environments they occupy. While our understanding of the mechanisms generating relatively simple shapes has improved tremendously in the last few years, the molecular mechanisms underlying the generation of complex shapes and the evolution of shape diversity are largely unknown. The emerging field (...) of bacterial evolutionary cell biology provides a novel strategy to answer this question in a comparative phylogenetic framework. This relatively novel approach provides hypotheses and insights into cell biological mechanisms, such as morphogenesis, and their evolution that would have been difficult to obtain by studying only model organisms. We discuss the necessary steps, challenges, and impact of integrating “evolutionary thinking” into bacterial cell biology in the genomic era. (shrink)

In this essay, I defend three Simple Views concerning human beings. First, that the human embryo is, from the one-cell stage onwards, a single unitary organism. Second, that when an embryo twins, it ceases to exist and two new embryos come into existence. And third, that you and I are essentially human organisms. This cluster of views shows that it is not necessary to rely on co-location, or other obscure claims, in understanding human embryogenesis.

Heterogeneity in mitochondrial content has been previously suggested as a major contributor to cellular noise, with multiple studies indicating its direct involvement in biomedically important cellular phenomena. A recently published dataset explored the connection between mitochondrial functionality and cell physiology, where a non‐linearity between mitochondrial functionality and cell size was found. Using mathematical models, we suggest that a combination of metabolic scaling and a simple model of cell death may account for these observations. However, our findings also suggest the (...) existence of alternative competing hypotheses, such as a non‐linearity between cell death and cell size. While we find that the proposed non‐linear coupling between mitochondrial functionality and cell size provides a compelling alternative to previous attempts to link mitochondrial heterogeneity and cell physiology, we emphasise the need to account for alternative causal variables, including cell cycle, size, mitochondrial density and death, in future studies of mitochondrial physiology. (shrink)

The mode and timing of germ-cell specification has been studied in diverse organisms, however, the molecular mechanism regulating germ-cell-fate determination remains to be elucidated. In some model organisms, maternal germ-cell determinants play a key role. In mouse embryos, some germ-line-specific gene products exist as maternal molecules and play critical roles in a pluripotential cell population at preimplantation stages. From those cells, primordial germ cells (PGCs) are specified by extracellular signaling mediated by tissue, as well as cell–cell interaction during (...) gastrulation. Thus, establishment of germ-cell lineage in mammalian embryos appears to be regulated by a multistep process, including formation and maintenance of a pluripotential cell population, as well as specification of PGCs. PGCs can be generated from pluripotential embryonic stem (ES) cells in a simple monolayer culture in which tissue interaction does not occur. This raises the possibility that ES cells, as well as, possibly, pluripotential cells in preimplantation embryos, are more closely related to the PGC precursors than pluripotential cells after implantation. BioEssays 27:136–143, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

In the nineteenth century protozoology and early cell biology intersected through the nexus of Darwin's theory of evolution. As single-celled organisms, amoebae offered an attractive focus of study for researchers seeking evolutionary relationships between the cells of humans and other animals, and their primitive appearance made them a favourite model for the ancient ancestor of all living things. Their resemblance to human and other metazoan cells made them popular objects of study among morphologists, physiologists, and even those investigating (...) animal behaviour. The amoeba became the exemplar of the new protoplasmic cell concept of mid-century and because its apparent simplicity made it widely generalizable it became a popular subject in a breadth of experimental investigations and theoretical speculations. It was able to do this because "the amoeba" denotes not a particular organism, but a general type of behaviour common to the cells of a range of protozoa, simple plants and higher animals. Its status as an exemplary cell also rested upon auxiliary philosophical assumptions about what constitutes a primitive characteristic and the thesis that evolution is a progressive development of order from chaos. (shrink)

The first stage of the human embryonic stem(ES) cell research debate revolved aroundfundamental questions, such as whether theresearch should be done at all, what types ofresearch may be done, who should do theresearch, and how the research should befunded. Now that some of these questions arebeing answered, we are beginning to see thenext stage of the debate: the battle forproperty rights relating to human ES cells. The reason why property rights will be a keyissue in this debate is (...) class='Hi'>simple and easy tounderstand: it costs a great deal of money todo this research, to develop new products, andto implement therapies; and private companies,researchers, and health professionals requirereturns on investments and reimbursements forgoods and services. This paper considersarguments for and against property rightsrelating to ES cells defends the followingpoints: (1) It should be legal to buy and sellES cells and products. (2) It should be legalto patent ES cells, products, and relatedtechnologies. (3) It should not be legal tobuy, sell, or patent human embryos. (4) Patentson ES cells, products, and related technologiesshould not be excessively broad. (5) Patents onES cells, products, and related technologiesshould be granted only when applicants statedefinite, plausible uses for their inventions. (6) There should be a research exemption in EScell patenting to allow academic scientists toconduct research in regenerative medicine. (7)It may be appropriate to take steps to preventcompanies from using patents in ES cells,products, and related technologies only toblock competitors. (8) As the field ofregenerative medicine continues to develop,societies should revisit issues relating toproperty rights on a continuing basis in orderto develop policies and develop regulations tomaximize the social, medical, economic, andscientific benefits of ES cell research andproduct development. (shrink)

A fundamental claim associated with parallel distributed processing theories of cognition is that knowledge is coded in a distributed manner in mind and brain. This approach rejects the claim that knowledge is coded in a localist fashion, with words, objects, and simple concepts, that is, coded with their own dedicated representations. One of the putative advantages of this approach is that the theories are biologically plausible. Indeed, advocates of the PDP approach often highlight the close parallels between distributed representations (...) learned in connectionist models and neural coding in brain and often dismiss localist theories as biologically implausible. The author reviews a range a data that strongly challenge this claim and shows that localist models provide a better account of single-cell recording studies. The author also contrast local and alternative distributed coding schemes and argues that common rejection of grandmother cell theories in neuroscience is due to a misunderstanding about how localist models behave. The author concludes that the localist representations embedded in theories of perception and cognition are consistent with neuroscience; biology only calls into question the distributed representations often learned in PDP models. (shrink)

The case is made here for stricter regulations on the use of cell phones while driving. I review, contextualize, and expand on a phenomenological account of distracted driving that I have developed across a series of papers. This account remains consistent with the empirical literature on the driver distraction of cell phones, but it also offers an alternative theory on why the distraction of cell phone conversation poses such a considerable danger. My argument is that cell phone distraction results from (...) learned perceptual habits, and that breaking these deeply engrained habits is no simple matter. (shrink)

Vulval development in the Caenorhabditis elegans hermaphrodite represents a simple, genetically tractable system for studying how cell signaling events control cell fata decisions. Current models suggest that proper specification of vulval cell fates relies on the integration of multiple signaling systems, including one that involves a receptor tyrosine kinase (RTK)→Ras→mitogen activated protein kinase (MAPK) cascade and one that involves a LIN‐12/Notch family receptor. In this review, we first discuss how genetic strategies are being used to identify and analyze components (...) that control vulval cell fate decisions. We then describe the different signaling systems that have been elucidated and how they relate to one another. Finally, we highlight several recently characterized genes that encode positive regulators, negative regulators or potential targets of the RTK→Ras→MAPK cascade involved in vulval induction. (shrink)

In possible scenarios on the origin of life, protocells represent the precursors of the first living cells. To study such hypothetical protocells, giant vesicles are being widely used as a simple model. Lipid vesicles can undergo complex morphological changes enabling self‐reproduction such as growth, fission, and extra‐ and intravesicular budding. These properties of vesicular systems may in some way reflect the mechanism of reproduction used by protocells. Moreover, remarkable similarities exist between the morphological changes observed in giant vesicles (...) and bacterial L‐form cells, which represent bacteria that have lost their rigid cell wall, but retain the ability to reproduce. L‐forms feature a dismantled cellular structure and are unable to carry out classical binary fission. We propose that the striking similarities in morphological transitions of L‐forms and giant lipid vesicles may provide insights into primitive reproductive mechanisms and contribute to a better understanding of the origin and evolution of mechanisms of cell reproduction.Editor's suggested further reading in BioEssays Synthesizing artificial cells from giant unilamellar vesicles: State‐of‐the art in the development of microfluidic technology Abstract. (shrink)

With historical hindsight, it can be little questioned that the view of protozoa as unicellular organisms was important for the development of the discipline of protozoology. In the early years of this century, the assumption of unicellularity provided a sound justification for the study of protists: it linked them to the metazoa and supported the claim that the study of these “simple” unicellular organisms could shed light on the organization of the metazoan cell. This prospect was significant, given the (...) state of cytology circa 1910. In the wake of the major gains made in understanding nuclear division in the last two decades of the nineteenth century, cytology was suddenly confronted with many, seemingly less penetrable, problems. Several aspects of nuclear organization still remained unexplained, and recent research had revealed the presence in the cytoplasm of structures whose functions in cell life were unknown. Classical methods of cytology, relying on descriptive, morphological analysis, seemed ill equipped to resolve these questions.Hertwig's program for protozoology, grounded in the assumption of the fundamental unity of organization in protozoa and metazoa, offered a potential means for investigating these and other problems of cell theory. Linked to mainstream cytology, protozoology was advocated as a means of experimentally investigating key biolobical processes — reproduction, metabolism, and organelle morphology and physiology — less accessible in higher organisms. Protozoa were hailed as prime experimental organisms, in which cell structure and function could be more easily studied. Unlike the metazoan cell, they could be subjected to controlled experiments in which the external environment was modified and the effects monitored. Protozoa offered, in other words, a promising experimental means by which to investigate the cell — its structures and its processes.The success of this program within Germany was soon apparent. In contrast to the rather neglected state of the discipline in 1900, protozoology began to be recognized as more than a somewhat obscure area of study for specialists. In practical terms, this translated into greater numbers of students attracted to the field, increased institutional support for the discipline, and its elevation in status within the biological sciences as new developments, particularly in connection with medical applications, began to draw attention to the field.64The unicellular hypothesis also promoted the internal development of the science. It provided a rationale for introducing the various techniques used in cytology, embryology, physiology, and the new field of biochemistry as suitable research tools for protozoology as well. This vastly extended the research possibilities and facilitated the understanding of, among other things, protozoan organization, modes of reproduction, and evolutionary relationships. The new experimental grounding of the discipline in turn fitted in well with developments in biology at large: in contrast to the descriptive methodology that had predominated in the nineteenth century, this new experimental program placed protozoology at the forefront of the early twentieth-century movement to make biology an experimental science comparable to physics and chemistry.Yet the criticism of the unicellular hypothesis can also be seen as having served a valuable function within the development of the discipline. It focused attention on the study of protists as organisms in their own right, not simply as models for metazoan cells. More generally, it helped to remind biologists of the particular evolutionary assumptions that supported this conception. Dobell and other British critics pointed out, among other things, the association between the theory of recapitulation and the interpretation of protozoa as unicellular organisms. At the time when the recapitulation theory and the germ-layer doctrine were in decline, it was important to stress how these evolutionary ideas also entered into the contemporary concepts of subsidiary specialties. This was as true for protozoology as it was for cell theory itself. The chromidial theory, in its various guises, and the binuclearity hypothesis did in fact contain elements of recapitulationist reasoning, and they were open to criticism for the same kind of overly speculative theorizing that characterized this evolution theory. Dobell's critique forced protozoologists and cell theorists alike to review the theoretical postulates guiding their investigations.In the absence of further historical studies, it is hard to evaluate the consequences of this debate in later years. The issue was not whether protozoa were the precursors of metazoa — both sides accepted this. They disagreed over which particular protozoon had served as the ancestral form, and this, in turn, influenced their stance on the question of unicellularity. The situation is little changed today. Because the former question is still an open one, the latter remains so too. Both of the models for the origin of multicellular organisms — colonies of ciliates versus multinucleate protists — are still presented as possible mechanisms in modern textbooks of evolution. Unable to judge the dispute in terms of the ultimate validity of the competing conceptions, the historian requires other criteria. It perhaps becomes more important to evaluate the issues in the context of the internal and external stimulus they provided the discipline.65 In these terms, and from the present historical vantage point, Hertwig's research program for protozoology, based upon the unicellular hypothesis, appears to have been a successful one. (shrink)

The concept of complexity has become very important in theoretical biology. It is a many faceted concept and too new and ill defined to have a universally accepted meaning. This review examines the development of this concept from the point of view of its usefulness as a criteria for the study of living systems to see what it has to offer as a new approach. In particular, one definition of complexity has been put forth which has the necessary precision and (...) rigor to be considered as a useful categorization of systems, especially as it pertains to those we call living. This definition, due to Robert Rosen, has been developed in a number of works and involves some deep new concepts about the way we view systems. In particular, it focuses on the way we view the world and actually practice science through the use of the modelling relation. This mathematical object models the process by which we assign meaning to the world we perceive. By using the modelling relation, it is possible to identify the subjective nature of our practices and deal with this issue explicitly. By so doing, it becomes clear that our notion of complexity and especially its most popular manifestations, is in large part a product of the historical processes which lead to the present state of scientific epistemology. In particular, it is a reaction to the reductionist/mechanistic view of nature which can be termed the Newtonian Paradigm. This approach to epistemology has dominated for so long that its use as a model has become implicit in most of what we do in and out of science. The alternative to this approach is examined and related to the special definition of complexity given by Rosen. Some historical examples are used to emphasize the dependence of our view of what is complex in a popular sense on the ever changing state of our knowledge. The role of some popular concepts such as chaotic dynamics are examined in this context. The fields of artificial life and related areas are also viewed from the perspective of this rigorous view of complexity and found lacking. The notion that in some way life exists at the edge of chaos is examined from the perspective of the second law of thermodynamics given by Schneider and Kay. Finally, the causal elements in complex systems are explored in relation to complexity. Rosen has shown that a clear difference in causal relations exists between complex and simple systems and that this difference leads to a uniquely useful definition of what we mean by living. Rosen makes it very clear that the class of systems which are complex is a much larger class than those which we call living. For that reason, the focus of this review will be on complexity as a stepping stone towards the deeper question of what makes a system alive. (shrink)

The development of synthetic biology calls for accurate understanding of the critical functions that allow construction and operation of a living cell. Besides coding for ubiquitous structures, minimal genomes encode a wealth of functions that dissipate energy in an unanticipated way. Analysis of these functions shows that they are meant to manage information under conditions when discrimination of substrates in a noisy background is preferred over a simple recognition process. We show here that many of these functions, including transporters (...) and the ribosome construction machinery, behave as would behave a material implementation of the informationmanaging agent theorized by Maxwell almost 150 years ago and commonly known as Maxwell’s demon (MxD). A core gene set encoding these functions belongs to the minimal genome required to allow the construction of an autonomous cell. These MxDs allow the cell to perform computations in an energy-efficient way that is vastly better than our contemporary computers. (shrink)

Stimulation of airway myocytes by contractile agents such as acetylcholine (ACh) activates a Ca2+-activated Cl– current (IClCa) which may play a key role in calcium homeostasis of airway myocytes and hence in airway reactivity. The aim of the present study was to model IClCa in airway smooth muscle cells using a computerised model previously designed for simulation of cardiac myocyte functioning. Modelling was based on a simple resistor-battery permeation model combined with multiple binding site activation by calcium. In (...) order to validate the model, a combination of equations, used to mimic [Ca2+]i response to ACh stimulation, were incorporated into the model. The results indicate that the model developed in this article accounts for experimental recordings and electrophysiological characteristics of this current in airway smooth muscle cells, with parameter values consistent with those calculated from experimental data. Such a model may thus be used to predict IClCa functioning, though additional experimental data from airway myocytes would be useful to more accurately determine some parameter values of the model. (shrink)

As a moral philosopher, the perspective I will take in this chapter is one of argumentation and informed judgment about two main questions: whether individuals should ever choose to conduct human embryonic stem cell research, and whether the law should permit this type of research. I will also touch upon a secondary question, that of whether the government ought to pay for this type of research. I will discuss some of the main arguments at stake, and explain how the ethical (...) conflict over these questions differs from the political conflict over them. I will be guided throughout by the assumption that the unique scientific and clinical promise of human embryonic stem cell research is significant. Those who have doubts about this assumption should consult other chapters in this volume in which the issue is addressed directly. I begin with one of the basic facts relevant to the ethical issue of stem cell research: you and I, along with everybody else we know, developed out of clumps of primordial cells, which happen to be the very same clumps that serve as the source for human embryonic stem cells in the laboratory. Let us call these “source cells” for short, since they can be used in this way. Each individual has developed into whatever she is now out of a one-celled animal, which then became a blastocyst, a multi-celled human embryo. These blastocysts are partly made up of an inner mass of cells, and the body of every adult person has developed out of this inner mass. It is this very same clump from the inner part of the blastocyst that consists of source cells for human embryonic stem 1 cell research. These cells can be extracted and grown into a laboratory specimen of extraordinary interest to scientists. Before discussing the significance of the fact that all humans originate from these source cells, it is useful to begin by asking some perhaps rather simple-minded questions about how any one of us knows this fact to be true in the first place. How do I know that I developed from a single cell, and then a blastocyst? In my own case, the main way I know this is that other people have told me so.. (shrink)

In gonad‐bearing animals gametogenesis can be divided into three main phases. During embryonic development the primordial gem cells move towards the gonadal primordia. A long, intra‐gonadal phase follows during which the germ cells grow and differentiate. Mature germ cells are finally released from the gonads and brought to the exterior. Thus, germ cells are successively motile, non‐motile and motile again. This complex life history is given here a simple evolutionary interpretation. The basic assumption is that (...) primitive Metazoa already had germ cells, but no gonads to harbour them. Higher animals acquired gonads, which sequestered the germ cells, thus creating the temporary confinement experienced by germ cells in most present‐day Metazoa. This evolutionalry scheme may explain why several steps of germ cell differentation are totally or partially independent of the gonads. These steps presumably existed in primitive, gonad‐free Metazoa, and conserved their autonomy in higher animals. (shrink)

An early step in sporulation of the bacterium Bacillus subtilis, is the formation of two compartments in the developing sporangium: the mother cell and the forespore. These compartments differ in their programs of gene expression and developmental fate. The establishment of cell type within this simple developmental program, is accomplished by the compartmentalization of sigma subunits of RNA polymerase. The localization of these sigma factors results in compartment‐specific gene expression. Recent experiments have elucidated some of the early steps in (...) the establishment of 3V cell type. After septum formation, the activity of the sigma factor, σF, is confined to the forespore compartment. This, in turn, results in the localized expression of another developmental sigma factor, σG. The forespore localization of these two sigma factors, establishes the forespore line of gene expression. σF and σG also regulate mother cell events. σF activity in the forespore regulates the proteolytic processing of σE within the mother cell compartment. The localization σE activity leads to mother cell expression of another sigma factor, pro‐σK The proteolytic processing of pro‐σK to mature σK is controlled by the forespore sigma factor, σG Mature σK then directs the transcription of mother cell specific genes. Therefore, the initial localization of σF activity to the forespore compartment, orchestrates the establishment of cell type in both forespore and mother cell compartments. (shrink)

Le XIVe siècle peut sans nul doute être considéré comme «l’âge d’or» de la mystique en Angleterre. Parmi les noms de R. Rolle, W. Hilton, J. de Norwich, l’auteur du Nuage d’Inconnaissance occupe une place importante, gardant un anonymat manifestement recherché. Il apparaît très vraisemblable que cet Anonyme ait longtemps et assidûment fréquenté les milieux cartusiens, s’il n’a pas été lui-même chartreux, avant peut-être de choisir une vie plus radicalement érémitique. Le but de son œuvre est l’union à Dieu par (...) le détachement absolu, union au Tout-Autre selon le mode apophatique légué par Denys le pseudo-Aréopagite dont il se réclame explicitement, et auquel il emprunte le titre de son principal ouvrage. Il revendique également l’influence de Grégoire de Nysse, de saint Augustin, de Richard de Saint-Victor dont il traduira en anglais le Benjamin minor, et laisse clairement entendre qu’il a lu Thomas d’Aquin, saint Bernard et Guillaume de Saint-Thierry. Mais il est une influence profonde et non avouée qu’il nous a semblé intéressant de dégager ici; il s’agit de celle du Miroir des Simples âmes anéanties de Marguerite Porete. (shrink)

Simple epithelial keratins K8 and K18 are components of the intracellular cytoskeleton in the cells of the single‐layered sheet tissues inside the body. As members of the intermediate filament family of proteins, their function has been a matter for debate since they were first discovered. Whilst there is an indisputable case for a structural cell‐reinforcing function for keratins in the mutilayered squamous epithelia of external barrier tissues, some very different stress‐protective features now seem to be emerging for the (...) simple epithelial keratins. Even the emerging evidence of pathological mutations in K8/K18 looks very different from mutations in stratified epithelial keratins. K8/K18‐like keratins were probably the first to evolve and, whilst stratified epithelial (keratinocyte) keratins have diversified into a large group of keratins highly specialised for providing mechanical stability, the simple epithelial keratins have retained early features that may protect the internal epithelia from a broader range of stresses, including osmotic stress and chemical toxicity. BioEssays 25:748–758, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Dans la série de principes auxquels un Mémoire pour Gabriel Cramer rédigé par Condillac début 1747 ramène le système monadologique de Leibniz, le principe de l’ingrédience de la matière par les êtres simples ou monades échappe à la critique. Condillac accorde le principe [P1] les monades sont les premiers éléments de la matière. Il rejette seulement les deux principes subalternes [P2] les monades ont un principe interne de tous leurs changements et [P3] chaque état passager d’une monade représente sous un (...) certain point de vue l’univers, qui sous-tendent la notion de perceptions inconscientes. Composée dans la même période, la dissertation anonyme Les Monades est tout entière organisée en vue de la démonstration par Condillac en personne de la vérité de la thèse monadologique il y a des composés, donc il y a des êtres simples et de son corrélat, le principe la matière a pour éléments des êtres simples. Une analyse minutieuse des procédés argumentatifs déployés dans Les Monades permet d’interpréter cette défense de la thèse monadologique comme une remise en cause par Condillac en 1747 de l’hétérogénéité qu’il a maintenue en 1746 dans l’ Essai sur l’origine des connaissances humaines entre l’étendue et les qualités dites secondes. En donnant en son nom propre une preuve (opposée à celle par la raison suffisante dans l’ Ontologia de Wolff) de la vérité de la thèse monadologique, Condillac essaie de fonder une parfaite phénoménalisation de l’étendue. La dissertation Les Monades ne doit pas être vue simplement comme un préliminaire à la critique des systèmes abstraits dans le Traité des systèmes de 1749. La tentative d’une monadologie réformée dans la dissertation de 1747 marque le commencement d’une interrogation sur l’idée d’étendue appelée à se poursuivre dans le Traité des sensations de 1754. (shrink)

Causal complexities involved in biological phenomena often generate ambiguous experimental results that may create epistemic niches for new approaches and interpretations. The exploration for new approaches may foment momentum of larger epistemological shifts, and thereby introduce the possibilities of adopting new technologies. This paper describes British molecular biologist Robin Holliday’s cell aging research from 1963 to the 1980s that transformed from simple hypothesis testing to working on various alternative and integrative approaches designed to deal with complex data. In the (...) 1960s, hoping to use biochemical investigations of cells to settle a debate about whether DNA mutations or protein errors caused aging, Holliday carried out a series of experiments with fruit flies, fungi, and human fibroblast cells. The results seemed to demonstrate that cytoplasmic protein errors caused cell aging. However, other scientists obtained contradictory results and raised issues about potential flaws in Holliday’s experiments. In the 1970s, working as the director of the Genetics Division of the National Institute for Medical Research in Mill Hill, United Kingdom, Holliday relied on available talents of his associates, including computational expertise, to explore alternative hypotheses and approaches. By the early 1980s, they had worked out an epigenetic explanation and had established integrative, evolutionary models of cell aging that incorporated both DNA mutations and protein errors as critical factors. By delineating Holliday’s research path from simply testing hypotheses to integrating multiple factors involved in aging, this paper offers an account of the difficulties in targeting molecular cause in cell aging around the 1970s, whose failures nevertheless opened up an epistemic niche for integration. (shrink)

Novel methods such as mass‐spectrometry enable a view of the proteomes of cells in unprecedented detail. Recently, these efforts have culminated in quantitative measurements of the number of copies per cell for most expressed proteins in organisms ranging from bacteria to mammalian cells. Here, we estimate the expected total number of proteins per unit of cell volume using known parameters related to the composition of cells such as the fraction of cell mass that is protein, and the (...) average protein length. Using simple arguments, we estimate a range of 2–4 million proteins per cubic micron (i.e. 1 fL) in bacteria, yeast, and mammalian cells. Interestingly, we find that measured values that are reported for fission yeast and mammalian cells are often about 3–10 times lower. We discuss this apparent discrepancy and how to use the estimate as benchmark to recalibrate proteome‐wide quantitative censuses or to revisit assumptions about cell composition. (shrink)

Mitotic entry and exit are switch‐like transitions that are driven by the activation and inactivation of Cdk1 and mitotic cyclins. This simple on/off reaction turns out to be a complex interplay of various reversible reactions, feedback loops, and thresholds that involve both the direct regulators of Cdk1 and its counteracting phosphatases. In this review, we summarize the interplay of the major components of the system and discuss how they work together to generate robustness, bistability, and irreversibility. We propose that (...) it may be beneficial to regard the entry and exit reactions as two separate reversible switches that are distinguished by differences in the state of phosphatase activity, mitotic proteolysis, and a dramatic rearrangement of cellular components after nuclear envelope breakdown, and discuss how the major Cdk1 activity thresholds could be determined for these transitions. (shrink)

It is shown how the 300 rays associated with the antipodal pairs of vertices of a 120-cell (a four-dimensional regular polytope) can be used to give numerous “parity proofs” of the Kochen–Specker theorem ruling out the existence of noncontextual hidden variables theories. The symmetries of the 120-cell are exploited to give a simple construction of its Kochen–Specker diagram, which is exhibited in the form of a “basis table” showing all the orthogonalities between its rays. The basis table consists of (...) 675 bases (a basis being a set of four mutually orthogonal rays), but all the bases can be written down from the few listed in this paper using some simple rules. The basis table is shown to contain a wide variety of parity proofs, ranging from 19 bases (or contexts) at the low end to 41 bases at the high end. Some explicit examples of these proofs are given, and their implications are discussed. (shrink)

EEG and synaptic action fields provide experimental and theoretical entry points into brain complexity. Such entry is distinguished from the core system of cell assemblies assumed to underlie cognitive processing. The global theory of synaptic action predicts several new properties of EEG, providing limited penetration into brain complexity.

The quantitative study of regulation of cell growth and proliferation began with the development of the technique for monolayer culture of vertebrate cells in the late 1960s. The basic parameters were defined in the early physiological studies, which continued through the next decade. These included specific and non-specific growth factors and the requirement for continuous exposure to such factors through most of the G1 period for progression to S. In the course of this work, the diversity of biochemical responses (...) and the critical role of increased protein synthesis and accumulation for the onset of DNA synthesis were elucidated. In particular, a central role of free cytosolic Mg2+ in direct regulation of protein synthesis and in ancillary processes as a response to membrane perturbation was established. Eventually, the physiological era was superseded by the molecular era beginning in the 1980s. This work focussed on specific receptors for growth factors that entrained a protein kinase cascade, which terminated in a higher frequency of initiation of protein synthesis. However, the molecular studies virtually ignored the key results of the physiological era. Recent studies of the penultimate molecular steps in the regulatory pathway of protein synthesis, however, have supported a model of growth regulation involving membrane perturbation and MgATP2− concentration, results that integrate the findings of the physiological and molecular eras. The resulting relatively simple “membrane, magnesium mitosis” (MMM) model of proliferation control can explain the seeming paradox of the variety of specific and non-specific growth-enhancing treatments that are mediated by the plasma membrane and which bring about a shared, complex but coordinated growth response that drives cell proliferation. BioEssays 27:311–320, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The set of 60 real rays in four dimensions derived from the vertices of a 600-cell is shown to possess numerous subsets of rays and bases that provide basis-critical parity proofs of the Bell-Kochen-Specker (BKS) theorem (a basis-critical proof is one that fails if even a single basis is deleted from it). The proofs vary considerably in size, with the smallest having 26 rays and 13 bases and the largest 60 rays and 41 bases. There are at least 90 basic (...) types of proofs, with each coming in a number of geometrically distinct varieties. The replicas of all the proofs under the symmetries of the 600-cell yield a total of almost a hundred million parity proofs of the BKS theorem. The proofs are all very transparent and take no more than simple counting to verify. A few of the proofs are exhibited, both in tabular form as well as in the form of MMP hypergraphs that assist in their visualization. A survey of the proofs is given, simple procedures for generating some of them are described and their applications are discussed. It is shown that all four-dimensional parity proofs of the BKS theorem can be turned into experimental disproofs of noncontextuality. (shrink)

Siphonous seaweeds, which constitute a vital component of coral reefs, are structurally simple, single‐celled coenocytic macroscopic green algae. Kim et al.1 have recently shown the extraordinary wound‐repair and propagation mechanism of one such siphonous green alga—Bryopsis plumosa. Nucleocytoplasmic aggregates, which are released after injury to this plant, are membraneless structures that can survive in seawater for 10–20 minutes, before they are surrounded by a gelatinous envelope. Subsequently, a cell membrane and cell wall are synthesized around each of these aggregates (...) and the resulting individual cells, so formed, develop into new plants. This report represents a significant advance in our understanding of wound response and, more significantly, is probably the first example of transient survival of life without a cell membrane! BioEssays 24:588–590, 2002. © 2002 Wiley Periodicals, Inc. (shrink)