Order without design

Experimental reality in molecular and cell biology, as revealed by advanced research technologies and methods, is manifestly inconsistent with the design perspective on the cell, thus creating an apparent paradox: where do order and reproducibility in living systems come from if not from design?I suggest that the very idea of biological design (whether evolutionary or intelligent) is a misconception rooted in the time-honored and thus understandably precious error of interpreting living systems/organizations in terms of classical mechanics and equilibrium thermodynamics. This error, introduced by the founders and perpetuated due to institutionalization of science, is responsible for the majority of inconsistencies, contradictions, and absurdities plaguing modern sciences, including one of the most startling paradoxes - although almost everyone agrees that any living organization is an open nonequilibrium system of continuous energy/matter flow, almost everyone interprets and models living systems/organizations in terms of classical mechanics, equilibrium thermodynamics, and engineering, i.e., in terms and concepts that are fundamentally incompatible with the physics of life.The reinterpretation of biomolecules, cells, organisms, ecosystems, and societies in terms of open nonequilibrium organizations of energy/matter flow suggests that, in the domain of life, order and reproducibility do not come from design. Instead, they are natural and inevitable outcomes of self-organizing activities of evolutionary successful, and thus persistent, organizations co-evolving on multiple spatiotemporal scales as biomolecules, cells, organisms, ecosystems, and societies. The process of self-organization on all scales is driven by economic competition, obeys empirical laws of nonequilibrium thermodynamics, and is facilitated and, thus, accelerated by memories of living experience persisting in the form of evolutionary successful living organizations and their constituents.     

Life, Autonomy and Cognition: An Organizational Approach to the Definition of the Universal Properties of Life

This article addresses the issue of defining the universal properties of living systems through an organizational approach, according to which the distinctive properties of life lie in the functional organization which correlates its physicochemical components in living systems, and not in these components taken separately. Drawing on arguments grounded in this approach, this article identifies autonomy, with a set of related organizational properties, as universal properties of life, and includes cognition within this set.     

Left/right,up/down: the role of endogenous electrical fields as directional signals in development,repair and invasion

A fundamental aspect of biological systems is their spatial organization. In development, regeneration and repair, directional signals are necessary for the proper placement of the components of the organism. Likewise, pathogens that invade other organisms rely on directional signals to target vulnerable areas. It is widely understood that chemical gradients are important directional signals in living systems. Less well recognized are electrical fields, which can also provide directional information. Small, steady electrical fields can directly guide cell movement and growth and can generate chemical gradients of charged macromolecules against the leveling action of diffusion. At the site of a lesion in an ion-transporting epithelium, for example, a substantial electrical field is instantly generated and may extend over many cell diameters. There are numerous other situations in which relatively long-range electrical fields have been shown to exist naturally. Recently, there has been substantial progress in identifying specific processes that are controlled, to some extent, by these endogenous electrical fields. This review highlights these recent data and discusses possible mechanisms by which the fields might affect biological processes.     

Probability in biology: Overview of a comprehensive theory of probability in living systems

Probability is closely related to biological organization and adaptation to the environment. Living systems need to maintain their organizational order by producing specific internal events non-randomly, and must cope with the uncertain environments. These processes involve increases in the probability of favorable events for these systems by reducing the degree of uncertainty of events. Systems with this ability will survive and reproduce more than those that have less of this ability. Probabilistic phenomena have been deeply explored using the mathematical theory of probability since Kolmogorov's axiomatization provided mathematical consistency for the theory. However, the interpretation of the concept of probability remains both unresolved and controversial, which creates problems when the mathematical theory is applied to problems in real systems. In this article, recent advances in the study of the foundations of probability from a biological viewpoint are reviewed, and a new perspective is discussed toward a comprehensive theory of probability for understanding the organization and adaptation of living systems.     

The cell theory--history, present state and prospects (on the 150th anniversary of the development of the cell theory)

The main stages of history of this most important biological conception are presented and the state of the modern cell theory and its future prospects are considered. Since 1839, when T. Schwann expounded his conception of the cell, a long pathway in cognition of the cell function and organization has been covered. From the original picture of the complex organism as a "cellular state", made up of relatively independent "elementary organisms", i.e. cells the modern biology has come to the idea of the cell as an integral system either being a part of a complex organism, or living free in the nature (protists). The cell represents certain qualitatively peculiar level in a complex evolutionary established hierarchy of biological systems. Some particular tight relations, existing between cytology, as a fundamental biological science and molecular biology, genetics, ecology and other biological disciplines are considered. The importance of the cell conception is ascertained for practical aims, especially in medicine.     

Deformability, dynamics, and remodeling of cytoskeleton of the adherent living cell

A trail of evidence has led to an unexpected intersection of topical issues in condensed matter physics and cytoskeletal biology. On the one hand, the glass transition and the jammed state are two outstanding unsolved problems; such systems are out-of-equilibrium, disordered, and their transitions between solid-like and liquid-like states are not understood. On the other hand, cellular systems are increasingly being considered as interconnected maps of protein interactions that are highly specific and tightly regulated but, even when such comprehensive maps become available, they may be insufficient to define biological function at the integrative level because they do not encompass principles that govern dynamics at intermediate (meso) scales of organization. It is interesting, therefore, that the cytoskeleton of the living cell shows physical properties and remodeling dynamics with all the same signatures as soft inert condensed systems, although with important differences as well. Data reviewed here suggest that trapping, intermittency, and approach to kinetic arrest represent mesoscale features of collective protein-protein interactions linking underlying molecular events to integrative cellular functions such as crawling, contraction and remodeling. Because these are crucial cell functions, this synthesis may offer new perspectives on a variety of disorders including infectious disease, cardiovascular disease, asthma and cancer.     

Chemical approaches to the investigation of cellular systems

Biochemistry in the context of a living cell or organism is complicated by many variables such as supramolecular organization, cytoplasmic viscosity, and substrate heterogeneity. While these variables are easily excluded or avoided in reconstituted systems, they must be dealt with in cellular environments. New developments have allowed researchers to begin probing the inner workings of the cell to gain new insight into cell function and metabolism. Advances in cellular imaging and in small molecule-controlled gene expression, signal transduction and cell surface modification are discussed in this review. These techniques have permitted the study of molecular components within the context of living cells.     

Understanding the Emergence of Cellular Organization

More than one researcher is currently proposing that the notion of information become an important element for defining living systems as well as for explaining conditions that make their origins possible. During the pre-biotic era, the type of compounds encountered would mainly have been very simple in nature and might have been immersed in the natural dynamic of the physical world and in processes of self-organization. It is furthermore quite possible that they formed a relationship between and among certain types of processes that here we are specifically proposing as central for the emergence of cell organization. Consequently, an important initial step towards constructing a theory of biological information is to ask ourselves the question: how do biological systems process information? In this way, we will be contributing to the proposals of this paper where we seek to identify general principles that govern biological computing and that deal with biosemiotic approaches as they are defended in naturalistic normative terms.     

Causality, randomness, intelligibility, and the epistemology of the cell

Because the basic unit of biology is the cell, biological knowledge is rooted in the epistemology of the cell, and because life is the salient characteristic of the cell, its epistemology must be centered on its livingness, not its constituent components. The organization and regulation of these components in the pursuit of life constitute the fundamental nature of the cell. Thus, regulation sits at the heart of biological knowledge of the cell and the extraordinary complexity of this regulation conditions the kind of knowledge that can be obtained, in particular, the representation and intelligibility of that knowledge. This paper is essentially split into two parts. The first part discusses the inadequacy of everyday intelligibility and intuition in science and the consequent need for scientific theories to be expressed mathematically without appeal to commonsense categories of understanding, such as causality. Having set the backdrop, the second part addresses biological knowledge. It briefly reviews modern scientific epistemology from a general perspective and then turns to the epistemology of the cell. In analogy with a multi-faceted factory, the cell utilizes a highly parallel distributed control system to maintain its organization and regulate its dynamical operation in the face of both internal and external changes. Hence, scientific knowledge is constituted by the mathematics of stochastic dynamical systems, which model the overall relational structure of the cell and how these structures evolve over time, stochasticity being a consequence of the need to ignore a large number of factors while modeling relatively few in an extremely complex environment.     

Means, Advantages and Limits of Merging Biology with Technology

The natural world spent billions of years in solution-finding during evolution, which could benefit Technology. How do we put that in a nutshell? Biological systems are more complex than the most complex current technology. Any given functiofi and effect are simultaneously coordinated and linked with others at many levels of biological organisation-from cell organelle to organism, to population and ecosystem. Technology does not have tools to deal with the complexity and “goalintendedness“ of living systems. But limits for interaction exist on both sides-Biological science itself is also too empirical and not mature enough to provide a solid base for correlating living with technical systems. Moving towards a synthesis, where engineers can utilize the vast amount of available biological data, we suggest using a tool called “Theory of Inventive Problem Solving“ (TRIZ) and clarifying some important methodological issues, which have not previously been recognised in bionic engineering: 1) Requirement for more appropriate definitions of “system“, “effect“, “function“, “law“ and “rule“. 2) Requirement for understanding or even measuring the degree of contradiction or analogy between functions in biological and artificial and/or non-living engineering system-there is no simple direct correlation between what engineers find useful and what biology does.     

Individual cell-based models of the spatial-temporal organization of multicellular systems--achievements and limitations.

Computational approaches of multicellular assemblies have reached a stage where they may contribute to unveil the processes that underlie the organization of tissues and multicellular aggregates. In this article, we briefly review and present some new results on a number of 3D lattice free individual cell-based mathematical models of epithelial cell populations. The models we consider here are parameterized by bio-physical and cell-biological quantities on the level of an individual cell. Eventually, they aim at predicting the dynamics of the biological processes on the tissue level. We focus on a number of systems, the growth of cell populations in vitro, and the spatial-temporal organization of regenerative tissues. For selected examples we compare different model approaches and show that the qualitative results are robust with respect to many model details. Hence, for the qualitative features and largely for the quantitative features many model details do not matter as long as characteristic biological features and mechanisms are correctly represented. For a quantitative prediction, the control of the bio-physical and cell-biological parameters on the molecular scale has to be known. At this point, slide-based cytometry may contribute. It permits to track the fate of cells and other tissue subunits in time and validated the organization processes predicted by the mathematical models.     

Heterogeneous cell mechanical properties: an atomic force microscopy study.

Atomic force microscopy (AFM) is a non-invasive microscopy to explore living biological systems like cells in liquid environment. Thus AFM is an appropriate tool to investigate surface chemical modification and its influence on biological systems. In particular, control over biomaterial surface chemistry can result in a regulated cell response. This report investigates the influence of adhesive and non-adhesive surfaces on the cell morphology and the influence of the cytoskeleton structure on the local mechanical properties. In this study, the main work concerns a thorough investigation of the height images obtained with an AFM as therecorded images provide the evolution of the mechanical properties of the cell as function of its local structure. Information on the cell elasticity due to the cytoskeleton organization is deduced when comparing the AFM tip indentation depth versus the distance between the cytoskeleton bundles for the different samples.     

Anticipatory Functions, Digital-Analog Forms and Biosemiotics: Integrating the Tools to Model Information and Normativity in Autonomous Biological Agents

We argue that living systems process information such that functionality emerges in them on a continuous basis. We then provide a framework that can explain and model the normativity of biological functionality. In addition we offer an explanation of the anticipatory nature of functionality within our overall approach. We adopt a Peircean approach to Biosemiotics, and a dynamical approach to Digital-Analog relations and to the interplay between different levels of functionality in autonomous systems, taking an integrative approach. We then apply the underlying biosemiotic logic to a particular biological system, giving a model of the B-Cell Receptor signaling system, in order to demonstrate how biosemiotic concepts can be used to build an account of biological information and functionality. Next we show how this framework can be used to explain and model more complex aspects of biological normativity, for example, how cross-talk between different signaling pathways can be avoided. Overall, we describe an integrated theoretical framework for the emergence of normative functions and, consequently, for the way information is transduced across several interconnected organizational levels in an autonomous system, and we demonstrate how this can be applied in real biological phenomena. Our aim is to open the way towards realistic tools for the modeling of information and normativity in autonomous biological agents.     

Autogenesis: the evolution of replicative systems

Questions concerning the nature and origin of living systems and the hierarchy of their evolutionary processes are considered, and several problems which arise in connection with formerly developed theories--the autopoiesis of Maturana & Varela, the POL theory of Haukioja and the earlier developed evolutionary theory of Csányi--are discussed. The organization of living systems, the use of informational terms and the question how reproduction can enter into their characterization, problems of autonomy and identity are included in the list. It is suggested that replication--a copying process achieved by a special network of interrelatedness of components and component-producing processes that produces the same network as that which produced them--characterizes the living organization. The information "used" in this copying process, whether it is stored by special means or distributed in the whole system, is called replicative information. A theoretical model is introduced for the spontaneous emergence of replicative organization, called autogenesis. Autogenesis commences in a system by an organized "small" subsystem, referred to as AutoGenetic System Precursor (AGSP), which conveys replicative information to the system. During autogenesis, replicative information increases in system and compartment(s) form. A compartment is the co-replicating totality of components. The end state of autogenesis is an invariantly self-replicating organization which is unable to undergo further intrinsic organizational changes. It is suggested that replicative unities--such as living organisms--evolve via autogenesis. Levels of evolution emerge as a consequence of the relative autonomy of the autogenetic unities. On the next level they can be considered as components endowed with functions and a new autogenetic process can commence. Thus evolution proceeds towards its end state through the parallel autogenesis of the various levels. In terms of applications, ontogenesis is dealt with in detail as an autogenetic process as is the autogenesis of the biosphere and the global system.     

Randomness and multilevel interactions in biology

The dynamic instability of living systems and the “superposition” of different forms of randomness are viewed, in this paper, as components of the contingently changing, or even increasing, organization of life through ontogenesis or evolution. To this purpose, we first survey how classical and quantum physics define randomness differently. We then discuss why this requires, in our view, an enriched understanding of the effects of their concurrent presence in biological systems’ dynamics. Biological randomness is then presented not only as an essential component of the heterogeneous determination and intrinsic unpredictability proper to life phenomena, due to the nesting of, and interaction between many levels of organization, but also as a key component of its structural stability. We will note as well that increasing organization, while increasing “order”, induces growing disorder, not only by energy dispersal effects, but also by increasing variability and differentiation. Finally, we discuss the cooperation between diverse components in biological networks; this cooperation implies the presence of constraints due to the particular nature of bio-entanglement and bio-resonance, two notions to be reviewed and defined in the paper.     

The Theory of Tensegrity and Spatial Organization of Living Matter

There is still no consensus on the mechanisms regulating the formation and maintenance of morphological structures in the individual development of living organisms. The hypothesis that the mechanical forces are important for biological morphogenesis was put forward more than 100 years ago. In recent decades, studies indicating the regulatory role of mechanical stresses at different levels of organization of life have appeared. The signaling mechanisms that are responsible for the reception of mechanical influences and reprogramming of the properties of cells and tissues are studied. Since the mid-1970s, the principles of selfstressed structures or the tensegrity (tensional integrity) theory have been applied to understand the structure and functions of living structures in statics and dynamics. According to this standpoint, the cell can be represented as a self-stressed structure in which microtubules function as rigid rods and microfilaments serve as elastic threads. Such a system is anchored to extracellular matrix through cellular contacts, since it is adjusted to the external patterns of mechanical stresses. The notion of living systems as self-stressed structures provides a fresh look at the mechanotransduction, developing organism integrity, and biological morphogenesis. Although the application of the ideas of tensegrity to biological systems has not yet received broad support among biologists, the influence of these ideas on the formation of modern mechanobiology and understanding the crucial role of cytoskeletal structures in cellular processes should be mentioned.     

Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile

We present a strategy for generating and analyzing comprehensive genetic-interaction maps, termed E-MAPs (epistatic miniarray profiles), comprising quantitative measures of aggravating or alleviating interactions between gene pairs. Crucial to the interpretation of E-MAPs is their high-density nature made possible by focusing on logically connected gene subsets and including essential genes. Described here is the analysis of an E-MAP of genes acting in the yeast early secretory pathway. Hierarchical clustering, together with novel analytical strategies and experimental verification, revealed or clarified the role of many proteins involved in extensively studied processes such as sphingolipid metabolism and retention of HDEL proteins. At a broader level, analysis of the E-MAP delineated pathway organization and components of physical complexes and illustrated the interconnection between the various secretory processes. Extension of this strategy to other logically connected gene subsets in yeast and higher eukaryotes should provide critical insights into the functional/organizational principles of biological systems.     

Biological effects of electromagnetic fields

Life on earth has evolved in a sea of natural electromagnetic (EM) fields. Over the past century, this natural environment has sharply changed with introduction of a vast and growing spectrum of man-made EM fields. From models based on equilibrium thermodynamics and thermal effects, these fields were initially considered too weak to interact with biomolecular systems, and thus incapable of influencing physiological functions. Laboratory studies have tested a spectrum of EM fields for bioeffects at cell and molecular levels, focusing on exposures at athermal levels. A clear emergent conclusion is that many observed interactions are not based on tissue heating. Modulation of cell surface chemical events by weak EM fields indicates a major amplification of initial weak triggers associated with binding of hormones, antibodies, and neurotransmitters to their specific binding sites. Calcium ions play a key role in this amplification. These studies support new concepts of communication between cells across the barriers of cell membranes; and point with increasing certainty to an essential physical organization in living matter, at a far finer level than the structural and functional image defined in the chemistry of molecules. New collaborations between physical and biological scientists define common goals, seeking solutions to the physical nature of matter through a strong focus on biological matter. The evidence indicates mediation by highly nonlinear, nonequilibrium processes at critical steps in signal coupling across cell membranes. There is increasing evidence that these events relate to quantum states and resonant responses in biomolecular systems, and not to equilibrium thermodynamics associated with thermal energy exchanges and tissue heating.