The cell as the smallest DNA-based molecular computer

The pioneering work of Adleman (1994) demonstrated that DNA molecules in test tubes can be manipulated to perform a certain type of mathematical computation. This has stimulated a theoretical interest in the possibility of constructing DNA-based molecular computers. To gauge the practicality of realizing such microscopic computers, it was thought necessary to learn as much as possible from the biology of the living cell--presently the only known DNA-based molecular computer in existence. Here the recently developed theoretical model of the living cell (the Bhopalator) and its associated theories (e.g. cell language), principles, laws and concepts (e.g. conformons, IDS's) are briefly reviewed and summarized in the form of a set of five laws of 'molecular semiotics' (synonyms include 'microsemiotics', 'cellular semiotics', or 'cytosemiotics') the study of signs mediating measurement, computation, and communication on the cellular and molecular levels. Hopefully, these laws will find practical applications in designing DNA-based computing systems.     

Life as physics and chemistry: A system view of biology

Cellular life can be viewed as one of many physical natural systems that extract free energy from their environments in the most efficient way, according to fundamental physical laws, and grow until limited by inherent physical constraints. Thus, it can be inferred that it is the efficiency of this process that natural selection acts upon. The consequent emphasis on metabolism, rather than replication, points to a metabolism-first origin of life with the adoption of DNA template replication as a second stage development. This order of events implies a cellular regulatory system that pre-dates the involvement of DNA and might, therefore, be based on the information acquired as peptides fold into proteins, rather than on genetic regulatory networks. Such an epigenetic cell regulatory model, the independent attractor model, has already been proposed to explain the phenomenon of radiation induced genomic instability. Here it is extended to provide an epigenetic basis for the morphological and functional diversity that evolution has yielded, based on natural selection of the most efficient free energy transduction. Empirical evidence which challenges the current genetic basis of cell and molecular biology and which supports the above proposal is discussed.     

Prions: an evolutionary perspective.

Studies in both prion-due diseases in mammals and some non-Mendelian hereditary processes in yeasts have demonstrated that certain proteins are able to transmit structural information and self-replication. This induces the corresponding conformational changes in other proteins with identical or similar sequences. This ability of proteins may have been very useful during prebiotic chemical evolution, prior to the establishment of the genetic code. During this stage, proteins (proteinoids) must have molded and selected their structural folding units through direct interaction with the environment. The proteinoids that acquired the ability to propagate their conformations (which we refer to as conformons) would have acted as reservoirs and transmitters of a given structural information and hence could have acted as selectors for conformational changes. Despite the great advantage that arose from the establishment of the genetic code, the ability to propagate conformational changes did not necessarily disappear. Depending on the degree of involvement of this capacity in biological evolution, we propose two not mutually exclusive hypotheses: (i) extant prions could be an atavism of ancestral conformons, which would have co-evolved with cells, and (ii) the evolution of conformons would have produced cellular proteins, able to transmit structural information, and, in some cases, participating in certain processes of regulation and epigenesis. Therefore, prions could also be seen as conformons of a conventional infectious agent (or one that co-evolved with it independently) that, after a longer or shorter adaptive period, would have interacted with conformons from the host cells.     

Physical forces modulate cell differentiation and proliferation processes

Currently, the predominant hypothesis explains cellular differentiation and behaviour as an essentially genetically driven intracellular process, suggesting a gene‐centrism paradigm. However, although many living species genetic has now been described, there is still a large gap between the genetic information interpretation and cell behaviour prediction. Indeed, the physical mechanisms underlying the cell differentiation and proliferation, which are now known or suspected to guide such as the flow of energy through cells and tissues, have been often overlooked. We thus here propose a complementary conceptual framework towards the development of an energy‐oriented classification of cell properties, that is, a mitochondria‐centrism hypothesis based on physical forces‐driven principles. A literature review on the physical–biological interactions in a number of various biological processes is analysed from the point of view of the fluid and solid mechanics, electricity and thermodynamics. There is consistent evidence that physical forces control cell proliferation and differentiation. We propose that physical forces interfere with the cell metabolism mostly at the level of the mitochondria, which in turn control gene expression. The present perspective points towards a paradigm shift complement in biology.     

Conformon-driven biopolymer shape changes in cell modeling

Conceptual models of the atom preceded the mathematical model of the hydrogen atom in physics in the second decade of the 20th century. The computer modeling of the living cell in the 21st century may follow a similar course of development. A conceptual model of the cell called the Bhopalator was formulated in the mid-1980s, along with its twin theories known as the conformon theory of molecular machines and the cell language theory of biopolymer interactions [Ann. N.Y. Acad. Sci. 227 (1974) 211; BioSystems 44 (1997) 17; Ann. N.Y. Acad. Sci. 870 (1999a) 411; BioSystems 54 (2000) 107; Semiotica 138 (1-4) (2002a) 15; Fundamenta Informaticae 49 (2002b) 147]. The conformon theory accounts for the reversible actions of individual biopolymers coupled to irreversible chemical reactions, while the cell language theory provides a theoretical framework for understanding the complex networks of dynamic interactions among biopolymers in the cell. These two theories are reviewed and further elaborated for the benefit of both computational biologists and computer scientists who are interested in modeling the living cell and its functions. One of the critical components of the mechanisms of cell communication and cell computing has been postulated to be space- and time-organized teleonomic (i.e. goal-directed) shape changes of biopolymers that are driven by exergonic (free energy-releasing) chemical reactions. The generalized Franck-Condon principle is suggested to be essential in resolving the apparent paradox arising when one attempts to couple endergonic (free energy-requiring) biopolymer shape changes to the exergonic chemical reactions that are catalyzed by biopolymer shape changes themselves. Conformons, defined as sequence-specific mechanical strains of biopolymers first invoked three decades ago to account for energy coupling in mitochondria, have been identified as shape changers, the agents that cause shape changes in biopolymers. Given a set of space- and time-organized teleonomic shape changes of biopolymers driven by conformons, all of the functions of the cell can be accounted for in molecular terms-at least in principle. To convert a conceptual model of the cell into a computer model, it is necessary to represent the conceptual model in an algebraic language. To this end, we have begun to apply the process algebra of Milner [Communicating and Mobile Systems: The pi-calculus, Cambridge University Press, Cambridge, 1999] to develop what is here called the "shape algebra," capable of describing complex and mobile patterns of interactions among biomolecules leading to cell functions.     

Epithelial topology

It is universally accepted that genetic control over basic aspects of cell and molecular biology is the primary organizing principle in development and homeostasis of living systems. However, instances do exist where important aspects of biological order arise without explicit genetic instruction, emerging instead from simple physical principles, stochastic processes, or the complex self-organizing interaction between random and seemingly unrelated parts. Being mostly resistant to direct genetic dissection, the analysis of such emergent processes falls into a grey area between mathematics, physics and molecular cell biology and therefore remains very poorly understood. We recently proposed a mathematical model predicting the emergence of a specific non-Gaussian distribution of polygonal cell shapes from the stochastic cell division process in epithelial cell sheets; this cell shape distribution appears to be conserved across a diverse set of animals and plants.1 The use of such topological models to study the process of cellular morphogenesis has a long history, starting almost a century ago, and many insights from those original works influence current experimental studies. Here we review current and past literature on this topic while exploring some new ideas on the origins and implications of topological order in proliferating epithelia.     

Basic statistical recipes for the emergence of biochemical discernment

An essential step towards understanding life would be to identify the very basic mechanisms responsible for the discerning behaviour of living biochemical systems, absent from randomly reacting chemical soups. One intuitively feels that this question goes beyond the particular nature of the biological molecules and should relate to general physical principles. The pre-eminent physicist Ludwig Boltzmann early envisioned life as a struggle for entropy, in concordance with the subsequent principle of self-organization out of equilibrium. Re-examination of elementary steady state biochemical systems from a statistical perspective supports this view and shows that sigmoidal responses arising from microstates elimination, are sufficient to explain innermost characteristics of life, including its capacity to convert random molecular interactions into accurate biological reactions. A primary operating strategy to achieve this goal is the introduction of time-irreversible transitions in molecular state conversion cycles by injection of free energy, which confers decisional capacity to single macromolecules. Selected examples from various fields of molecular biology such as enzymology and gene expression, are provided to show that these non-equilibrium steady state mechanisms remain important in contemporary biochemical systems. But in addition, information archiving allowed the emergence of the time-reversible counterparts of these mechanisms, mediated by evolutionary pre-organized macromolecular complexes capable of generating discernment in a non-dissipative manner.     

Organisms of deep sea hydrothermal vents as a source for studying adaptation and evolution

It has been postulated that life originated in a similar environment to those of deep sea hydrothermal vents. These environments are located along volcanic ridges and are characterized by extreme conditions such as unique physical properties (temperature, pressure), chemical toxicity, and absence of photosynthesis. However, numerous living organisms have been discovered in these hostile environments, including a variety of microorganisms and many animal species which live in intimate and complex symbioses with sulfo-oxidizing and methanotrophic bacteria. Recent proteomic analyses of the endosymbiont ofRiftia pachyptila and genome sequences of some free living and symbiotic bacteria have provided complementary information about the potential metabolic and genomic capacities of these organisms. The evolution of these adaptive strategies is connected with different mechanisms of genetic adaptation including horizontal gene transfer and . various structural and functional mutations. Therefore, the organisms in this environment are good models for studying the evolution of prokaryotes and eukaryotes as well as different aspects of the biology of adaptation. This review describes some current research concerning metabolic and plausible genetic adaptations of organisms in a deep sea environment, usingRiftia pachyptila as model.     

From computational quantum chemistry to computational biology: experiments and computations are (full) partners

Computations are being integrated into biological research at an increasingly fast pace. This has not only changed the way in which biological information is managed; it has also changed the way in which experiments are planned in order to obtain information from nature. Can experiments and computations be full partners? Computational chemistry has expanded over the years, proceeding from computations of a hydrogen molecule toward the challenging goal of systems biology, which attempts to handle the entire living cell. Applying theories from ab initio quantum mechanics to simplified models, the virtual worlds explored by computations provide replicas of real-world phenomena. At the same time, the virtual worlds can affect our perception of the real world. Computational biology targets a world of complex organization, for which a unified theory is unlikely to exist. A computational biology model, even if it has a clear physical or chemical basis, may not reduce to physics and chemistry. At the molecular level, computational biology and experimental biology have already been partners, mutually benefiting from each other. For the perception to become reality, computation and experiment should be united as full partners in biological research.     

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.     

Protein phosphorylation: a motive force for adaptive evolution

Spontaneity and diversity are the intrinsic properties of protein phosphorylation. They provide living systems with opportunities for polyvariant transformation of expressed genetic information and alteration of their energy metabolism under change of living conditions. Thus, protein phosphorylation can be regarded as a molecular mechanism for adaptation and selection of mutant proteins useful for the cell, i.e. a motive force for adaptive evolution.     

Opportunities at the interface of chemistry and biology

The combination of the tools and principles of chemistry, together with the tools of modern molecular biology, allow us to create complex synthetic and natural molecules, and processes with novel biological, chemical and physical properties. This article illustrates the tremendous opportunity that lies at this interface of chemistry and biology by describing a number of examples, ranging from efforts to expand the genetic code of living organisms to the use of combinatorial methods to generate biologically active synthetic molecules.     

Modularity: a new perspective in biology

Several decades of research in biochemistry and molecular biology have been devoted for studies on isolated enzymes and proteins. Recent high throughput technologies in genomics and proteomics have resulted in avalanche of information about several genes, proteins and enzymes in variety of living systems. Though these efforts have greatly contributed to the detailed understanding of a large number of individual genes and proteins, this explosion of information has simultaneously brought out the limitations of reductionism in understanding complex biological processes. The genes or gene products do not function in isolation in vivo. A delicate and dynamic molecular architecture is required for precision of the chemical reactions associated with "life". In future, a paradigm shift is, therefore, envisaged, in biology leading to exploration of molecular organizations in physical and genomic context, a subtle transition from conventional molecular biology to modular biology. A module can be defined as an organization of macromolecules performing a synchronous function in a given metabolic pathway. In modular biology, the biological processes of interest are explored as complex systems of functionally interacting macromolecules. The present article describes the perceptions of the concept of modularity, in terms of associations among genes and proteins, presenting a link between reductionist approach and system biology.     

Opportunities at the interface of chemistry and biology

The combination of the tools and principles of chemistry, together with the tools of modern molecular biology, allow us to create complex synthetic and natural molecules, and processes with novel biological, chemical and physical properties. This article illustrates the tremendous opportunity that lies at this interface of chemistry and biology by describing a number of examples, ranging from efforts to expand the genetic code of living organisms to the use of combinatorial methods to generate biologically active synthetic molecules.     

Opportunities at the interface of chemistry and biology

The combination of the tools and principles of chemistry, together with the tools of modern molecular biology, allow us to create complex synthetic and natural molecules, and processes with novel biological, chemical and physical properties. This article illustrates the tremendous opportunity that lies at this interface of chemistry and biology by describing a number of examples, ranging from efforts to expand the genetic code of living organisms to the use of combinatorial methods to generate biologically active synthetic molecules.     

Cell Physician: Reading Cell Motion

Cell motility is an essential phenomenon in almost all living organisms. It is natural to think that behavioral or shape changes of a cell bear information about the underlying mechanisms that generate these changes. Reading cell motion, namely, understanding the underlying biophysical and mechanochemical processes, is of paramount importance. The mathematical model developed in this paper determines some physical features and material properties of the cells locally through analysis of live cell image sequences and uses this information to make further inferences about the molecular structures, dynamics, and processes within the cells, such as the actin network, microdomains, chemotaxis, adhesion, and retrograde flow. The generality of the principals used in formation of the model ensures its wide applicability to different phenomena at various levels. Based on the model outcomes, we hypothesize a novel biological model for collective biomechanical and molecular mechanism of cell motion.