Method for finding metabolic properties based on the general growth law. Liver examples. A General framework for biological modeling

We propose a method for finding metabolic parameters of cells, organs and whole organisms, which is based on the earlier discovered general growth law. Based on the obtained results and analysis of available biological models, we propose a general framework for modeling biological phenomena and discuss how it can be used in Virtual Liver Network project. The foundational idea of the study is that growth of cells, organs, systems and whole organisms, besides biomolecular machinery, is influenced by biophysical mechanisms acting at different scale levels. In particular, the general growth law uniquely defines distribution of nutritional resources between maintenance needs and biomass synthesis at each phase of growth and at each scale level. We exemplify the approach considering metabolic properties of growing human and dog livers and liver transplants. A procedure for verification of obtained results has been introduced too. We found that two examined dogs have high metabolic rates consuming about 0.62 and 1 gram of nutrients per cubic centimeter of liver per day, and verified this using the proposed verification procedure. We also evaluated consumption rate of nutrients in human livers, determining it to be about 0.088 gram of nutrients per cubic centimeter of liver per day for males, and about 0.098 for females. This noticeable difference can be explained by evolutionary development, which required females to have greater liver processing capacity to support pregnancy. We also found how much nutrients go to biomass synthesis and maintenance at each phase of liver and liver transplant growth. Obtained results demonstrate that the proposed approach can be used for finding metabolic characteristics of cells, organs, and whole organisms, which can further serve as important inputs for many applications in biology (protein expression), biotechnology (synthesis of substances), and medicine.Comment: 20 pages, 6 figures, 4 table

Boolean network model predicts cell cycle sequence of fission yeast

A Boolean network model of the cell-cycle regulatory network of fission yeast (Schizosaccharomyces Pombe) is constructed solely on the basis of the known biochemical interaction topology. Simulating the model in the computer, faithfully reproduces the known sequence of regulatory activity patterns along the cell cycle of the living cell. Contrary to existing differential equation models, no parameters enter the model except the structure of the regulatory circuitry. The dynamical properties of the model indicate that the biological dynamical sequence is robustly implemented in the regulatory network, with the biological stationary state G1 corresponding to the dominant attractor in state space, and with the biological regulatory sequence being a strongly attractive trajectory. Comparing the fission yeast cell-cycle model to a similar model of the corresponding network in S. cerevisiae, a remarkable difference in circuitry, as well as dynamics is observed. While the latter operates in a strongly damped mode, driven by external excitation, the S. pombe network represents an auto-excited system with external damping.Comment: 10 pages, 3 figure

Formal executable descriptions of biological systems

The similarities between systems of living entities and systems of concurrent processes may support biological experiments in silico. Process calculi offer a formal framework to describe biological systems, as well as to analyse their behaviour, both from a qualitative and a quantitative point of view. A couple of little examples help us in showing how this can be done. We mainly focus our attention on the qualitative and quantitative aspects of the considered biological systems, and briefly illustrate which kinds of analysis are possible. We use a known stochastic calculus for the first example. We then present some statistics collected by repeatedly running the specification, that turn out to agree with those obtained by experiments in vivo. Our second example motivates a richer calculus. Its stochastic extension requires a non trivial machinery to faithfully reflect the real dynamic behaviour of biological systems

Towards modular verification of pathways: fairness and assumptions

Modular verification is a technique used to face the state explosion problem often encountered in the verification of properties of complex systems such as concurrent interactive systems. The modular approach is based on the observation that properties of interest often concern a rather small portion of the system. As a consequence, reduced models can be constructed which approximate the overall system behaviour thus allowing more efficient verification. Biochemical pathways can be seen as complex concurrent interactive systems. Consequently, verification of their properties is often computationally very expensive and could take advantage of the modular approach. In this paper we report preliminary results on the development of a modular verification framework for biochemical pathways. We view biochemical pathways as concurrent systems of reactions competing for molecular resources. A modular verification technique could be based on reduced models containing only reactions involving molecular resources of interest. For a proper description of the system behaviour we argue that it is essential to consider a suitable notion of fairness, which is a well-established notion in concurrency theory but novel in the field of pathway modelling. We propose a modelling approach that includes fairness and we identify the assumptions under which verification of properties can be done in a modular way. We prove the correctness of the approach and demonstrate it on the model of the EGF receptor-induced MAP kinase cascade by Schoeberl et al.Comment: In Proceedings MeCBIC 2012, arXiv:1211.347

Designer Gene Networks: Towards Fundamental Cellular Control

The engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics.Comment: 35 pages, 8 figure

A Taxonomy of Causality-Based Biological Properties

We formally characterize a set of causality-based properties of metabolic networks. This set of properties aims at making precise several notions on the production of metabolites, which are familiar in the biologists' terminology. From a theoretical point of view, biochemical reactions are abstractly represented as causal implications and the produced metabolites as causal consequences of the implication representing the corresponding reaction. The fact that a reactant is produced is represented by means of the chain of reactions that have made it exist. Such representation abstracts away from quantities, stoichiometric and thermodynamic parameters and constitutes the basis for the characterization of our properties. Moreover, we propose an effective method for verifying our properties based on an abstract model of system dynamics. This consists of a new abstract semantics for the system seen as a concurrent network and expressed using the Chemical Ground Form calculus. We illustrate an application of this framework to a portion of a real metabolic pathway

Structural Kinetic Modeling of Metabolic Networks

To develop and investigate detailed mathematical models of cellular metabolic processes is one of the primary challenges in systems biology. However, despite considerable advance in the topological analysis of metabolic networks, explicit kinetic modeling based on differential equations is still often severely hampered by inadequate knowledge of the enzyme-kinetic rate laws and their associated parameter values. Here we propose a method that aims to give a detailed and quantitative account of the dynamical capabilities of metabolic systems, without requiring any explicit information about the particular functional form of the rate equations. Our approach is based on constructing a local linear model at each point in parameter space, such that each element of the model is either directly experimentally accessible, or amenable to a straightforward biochemical interpretation. This ensemble of local linear models, encompassing all possible explicit kinetic models, then allows for a systematic statistical exploration of the comprehensive parameter space. The method is applied to two paradigmatic examples: The glycolytic pathway of yeast and a realistic-scale representation of the photosynthetic Calvin cycle.Comment: 14 pages, 8 figures (color

On the emergence and evolution of artificial cell signaling networks

This PhD project is concerned with the evolution of Cell Signaling Networks (CSNs) in silico. CSNs are complex biochemical networks responsible for the coordination of cellular activities. We are investigating the possibility to build an evolutionary simulation platform that would allow the spontaneous emergence and evolution of Artificial Cell Signaling Networks (ACSNs). From a practical point of view, realizing and evolving ACSNs may provide novel computational paradigms for a variety of application areas. This work may also contribute to the biological understanding of the origins and evolution of real CSNs

Where Do You Get Your Protein? Or: Biochemical Realization

Biochemical kinds such as proteins pose interesting problems for philosophers of science, as they can be studied from the points of view of both biology and chemistry. The relationship between the biological functions of biochemical kinds and the microstructures that they are related to is the key question. This leads us to a more general discussion about ontological reductionism, microstructuralism, and multiple realization at the biology-chemistry interface. On the face of it, biochemical kinds seem to pose a challenge for ontological reductionism and hence motivate a dual theory of chemical and biological kinds, a type of pluralism about natural kinds. But it will be argued that the challenge, which is based on multiple realization, can be addressed. The upshot is that there are reasonable prospects for ontological reductionism about biochemical kinds, which corroborates natural kind monism