Stochastic Biochemical Reaction Networks Research Articles

Approximating solutions of the Chemical Master equation using neural networks

SummaryThe Chemical Master Equation (CME) provides an accurate description of stochastic biochemical reaction networks in well-mixed conditions, but it cannot be solved analytically for most systems of practical interest. Although Monte Carlo methods provide a principled means to probe system dynamics, the large number of simulations typically required can render the estimation of molecule number distributions and other quantities infeasible. In this article, we aim to leverage the representational power of neural networks to approximate the solutions of the CME and propose a framework for the Neural Estimation of Stochastic Simulations for Inference and Exploration (Nessie). Our approach is based on training neural networks to learn the distributions predicted by the CME from relatively few stochastic simulations. We show on biologically relevant examples that simple neural networks with one hidden layer can capture highly complex distributions across parameter space, thereby accelerating computationally intensive tasks such as parameter exploration and inference.

Cytomorphic Electronic Systems: A review and perspective.

Boltzmann-exponential thermodynamic laws govern noisy molecular flux in chemical reactions as well as noisy subthreshold electron current flux in transistors. These common mathematical laws enable one to map and simulate arbitrary stochastic biochemical reaction networks in highly efficient cytomorphic systems built on subthreshold analog circuits. Such simulations can accurately model noisy, nonlinear, asynchronous, stiff, and non-modular feedback dynamics in interconnected networks in the physical circuits, automatically. The scaling in simulation time for stochastic networks with the number of reactions or molecules is constant in cytomorphic systems. In contrast, it grows rapidly in digital systems, which are not parallelizable. Therefore, cytomorphic systems enable large-scale supercomputing systems-biology simulations of arbitrary and highly computationally intensive biochemical reaction networks that can nevertheless be compiled to them via digitally programmable parameters and connectivity. We outline how cytomorphic systems can be utilized for rapid drug-cocktail formulation and discovery in future pandemics like COVID-19; can simulate networks important in cancer; and can help automate the design of synthetic biological circuits, e.g. a synthetic biological operational amplifier for robust and precise drug delivery. Thus, just as neuromorphic systems have enabled multiple applications in A.I., cytomorphic systems will enable multiple applications in biology and medicine.

Synchronization in Stochastic Biochemical Oscillators Subject to Common Multiplicative Extrinsic Noise

In this work we study the level of synchronization in stochastic biochemical reaction networks that support stable mean-field limit cycles and are subject to common external switching noise. Synchr...

Simulation and inference algorithms for stochastic biochemical reaction networks: from basic concepts to state-of-the-art.

Stochasticity is a key characteristic of intracellular processes such as gene regulation and chemical signalling. Therefore, characterizing stochastic effects in biochemical systems is essential to understand the complex dynamics of living things. Mathematical idealizations of biochemically reacting systems must be able to capture stochastic phenomena. While robust theory exists to describe such stochastic models, the computational challenges in exploring these models can be a significant burden in practice since realistic models are analytically intractable. Determining the expected behaviour and variability of a stochastic biochemical reaction network requires many probabilistic simulations of its evolution. Using a biochemical reaction network model to assist in the interpretation of time-course data from a biological experiment is an even greater challenge due to the intractability of the likelihood function for determining observation probabilities. These computational challenges have been subjects of active research for over four decades. In this review, we present an accessible discussion of the major historical developments and state-of-the-art computational techniques relevant to simulation and inference problems for stochastic biochemical reaction network models. Detailed algorithms for particularly important methods are described and complemented with Matlab® implementations. As a result, this review provides a practical and accessible introduction to computational methods for stochastic models within the life sciences community.

Computing the Projected Reachable Set of Stochastic Biochemical Reaction Networks Modeled by Switched Affine Systems

A fundamental question in systems biology is what combinations of mean and variance of the species present in a stochastic biochemical reaction network are attainable by perturbing the system with an external signal. To address this question, we show that the moments evolution in any generic network can be either approximated or, under suitable assumptions, computed exactly as the solution of a switched affine system. We then propose a new method to approximate the reachable set of such a switched affine system. A remarkable feature of our approach is that it allows one to easily compute projections of the reachable set for pairs of moments of interest, without requiring the computation of the full reachable set, which can be prohibitive for large networks. As a second contribution, we also show how to select the external signal in order to maximize the probability of reaching a target set. To illustrate the method, we study a renowned model of the controlled gene expression and we derive estimates of the reachable set, for the protein mean and variance, that are more accurate than those available in the literature and consistent with experimental data.

Efficient simulation of intrinsic, extrinsic and external noise in biochemical systems.

Motivation Biological cells operate in a noisy regime influenced by intrinsic, extrinsic and external noise, which leads to large differences of individual cell states. Stochastic effects must be taken into account to characterize biochemical kinetics accurately. Since the exact solution of the chemical master equation, which governs the underlying stochastic process, cannot be derived for most biochemical systems, approximate methods are used to obtain a solution. Results In this study, a method to efficiently simulate the various sources of noise simultaneously is proposed and benchmarked on several examples. The method relies on the combination of the sigma point approach to describe extrinsic and external variability and the τ -leaping algorithm to account for the stochasticity due to probabilistic reactions. The comparison of our method to extensive Monte Carlo calculations demonstrates an immense computational advantage while losing an acceptable amount of accuracy. Additionally, the application to parameter optimization problems in stochastic biochemical reaction networks is shown, which is rarely applied due to its huge computational burden. To give further insight, a MATLAB script is provided including the proposed method applied to a simple toy example of gene expression. Availability and implementation MATLAB code is available at Bioinformatics online. Contact flassig@mpi-magdeburg.mpg.de. Supplementary information Supplementary data are available at Bioinformatics online.

Fast and Precise Emulation of Stochastic Biochemical Reaction Networks With Amplified Thermal Noise in Silicon Chips.

The analysis and simulation of complex interacting biochemical reaction pathways in cells is important in all of systems biology and medicine. Yet, the dynamics of even a modest number of noisy or stochastic coupled biochemical reactions is extremely time consuming to simulate. In large part, this is because of the expensive cost of random number and Poisson process generation and the presence of stiff, coupled, nonlinear differential equations. Here, we demonstrate that we can amplify inherent thermal noise in chips to emulate randomness physically, thus alleviating these costs significantly. Concurrently, molecular flux in thermodynamic biochemical reactions maps to thermodynamic electronic current in a transistor such that stiff nonlinear biochemical differential equations are emulated exactly in compact, digitally programmable, highly parallel analog "cytomorphic" transistor circuits. For even small-scale systems involving just 80 stochastic reactions, our 0.35-μm BiCMOS chips yield a 311× speedup in the simulation time of Gillespie's stochastic algorithm over COPASI, a fast biochemical-reaction software simulator that is widely used in computational biology; they yield a 15500× speedup over equivalent MATLAB stochastic simulations. The chip emulation results are consistent with these software simulations over a large range of signal-to-noise ratios. Most importantly, our physical emulation of Poisson chemical dynamics does not involve any inherently sequential processes and updates such that, unlike prior exact simulation approaches, they are parallelizable, asynchronous, and enable even more speedup for larger-size networks.

Efficient simulation of intrinsic, extrinsic and external noise in biochemical systems.

MotivationBiological cells operate in a noisy regime influenced by intrinsic, extrinsic and external noise, which leads to large differences of individual cell states. Stochastic effects must be taken into account to characterize biochemical kinetics accurately. Since the exact solution of the chemical master equation, which governs the underlying stochastic process, cannot be derived for most biochemical systems, approximate methods are used to obtain a solution.ResultsIn this study, a method to efficiently simulate the various sources of noise simultaneously is proposed and benchmarked on several examples. The method relies on the combination of the sigma point approach to describe extrinsic and external variability and the τ-leaping algorithm to account for the stochasticity due to probabilistic reactions. The comparison of our method to extensive Monte Carlo calculations demonstrates an immense computational advantage while losing an acceptable amount of accuracy. Additionally, the application to parameter optimization problems in stochastic biochemical reaction networks is shown, which is rarely applied due to its huge computational burden. To give further insight, a MATLAB script is provided including the proposed method applied to a simple toy example of gene expression.Availability and implementationMATLAB code is available at Bioinformatics online.Supplementary information Supplementary data are available at Bioinformatics online.

Reduction of multiscale stochastic biochemical reaction networks using exact moment derivation.

Biochemical reaction networks (BRNs) in a cell frequently consist of reactions with disparate timescales. The stochastic simulations of such multiscale BRNs are prohibitively slow due to high computational cost for the simulations of fast reactions. One way to resolve this problem uses the fact that fast species regulated by fast reactions quickly equilibrate to their stationary distribution while slow species are unlikely to be changed. Thus, on a slow timescale, fast species can be replaced by their quasi-steady state (QSS): their stationary conditional expectation values for given slow species. As the QSS are determined solely by the state of slow species, such replacement leads to a reduced model, where fast species are eliminated. However, it is challenging to derive the QSS in the presence of nonlinear reactions. While various approximation schemes for the QSS have been developed, they often lead to considerable errors. Here, we propose two classes of multiscale BRNs which can be reduced by deriving an exact QSS rather than approximations. Specifically, if fast species constitute either a feedforward network or a complex balanced network, the reduced model based on the exact QSS can be derived. Such BRNs are frequently observed in a cell as the feedforward network is one of fundamental motifs of gene or protein regulatory networks. Furthermore, complex balanced networks also include various types of fast reversible bindings such as bindings between transcriptional factors and gene regulatory sites. The reduced models based on exact QSS, which can be calculated by the computational packages provided in this work, accurately approximate the slow scale dynamics of the original full model with much lower computational cost.

Recursively constructing analytic expressions for equilibrium distributions of stochastic biochemical reaction networks.

Noise is often indispensable to key cellular activities, such as gene expression, necessitating the use of stochastic models to capture its dynamics. The chemical master equation (CME) is a commonly used stochastic model of Kolmogorov forward equations that describe how the probability distribution of a chemically reacting system varies with time. Finding analytic solutions to the CME can have benefits, such as expediting simulations of multiscale biochemical reaction networks and aiding the design of distributional responses. However, analytic solutions are rarely known. A recent method of computing analytic stationary solutions relies on gluing simple state spaces together recursively at one or two states. We explore the capabilities of this method and introduce algorithms to derive analytic stationary solutions to the CME. We first formally characterize state spaces that can be constructed by performing single-state gluing of paths, cycles or both sequentially. We then study stochastic biochemical reaction networks that consist of reversible, elementary reactions with two-dimensional state spaces. We also discuss extending the method to infinite state spaces and designing the stationary behaviour of stochastic biochemical reaction networks. Finally, we illustrate the aforementioned ideas using examples that include two interconnected transcriptional components and biochemical reactions with two-dimensional state spaces.

Reduction for Stochastic Biochemical Reaction Networks with Multiscale Conservations

Biochemical reaction networks frequently consist of species evolving on multiple timescales. Stochastic simulations of such networks are often computationally challenging and therefore various methods have been developed to obtain sensible stochastic approximations on the timescale of interest. One of the rigorous and popular approaches is the multiscale approximation method for continuous time Markov processes. In this approach, by scaling species abundances and reaction rates, a family of processes parameterized by a scaling parameter is defined. The limiting process of this family is then used to approximate the original process. However, we find that such approximations become inaccurate when combinations of species with disparate abundances either constitute conservation laws or form virtual slow auxiliary species. To obtain more accurate approximation in such cases, we propose here an appropriate modification of the original method.

Regularized maximum likelihood estimation of sparse stochastic monomolecular biochemical reaction networks

A sparse parameter matrix estimation method is proposed for identifying a stochastic monomolecular biochemical reaction network system. Identification of a reaction network can be achieved by estimating a sparse parameter matrix containing the reaction network structure and kinetics information. Stochastic dynamics of a biochemical reaction network system is usually modeled by a chemical master equation (CME) describing the time evolution of probability distributions for all possible states. This paper considers closed monomolecular reaction systems for which an exact analytical solution of the corresponding chemical master equation can be derived. The estimation method presented in this paper incorporates the closed-form solution into a regularized maximum likelihood estimation (MLE) for which model complexity is penalized. A simulation result is provided to verify performance improvement of regularized MLE over least-square estimation (LSE), which is based on a deterministic mass-average model, in the case of a small population size.

Iterative experiment design guides the characterization of a light-inducible gene expression circuit

Systems biology rests on the idea that biological complexity can be better unraveled through the interplay of modeling and experimentation. However, the success of this approach depends critically on the informativeness of the chosen experiments, which is usually unknown a priori. Here, we propose a systematic scheme based on iterations of optimal experiment design, flow cytometry experiments, and Bayesian parameter inference to guide the discovery process in the case of stochastic biochemical reaction networks. To illustrate the benefit of our methodology, we apply it to the characterization of an engineered light-inducible gene expression circuit in yeast and compare the performance of the resulting model with models identified from nonoptimal experiments. In particular, we compare the parameter posterior distributions and the precision to which the outcome of future experiments can be predicted. Moreover, we illustrate how the identified stochastic model can be used to determine light induction patterns that make either the average amount of protein or the variability in a population of cells follow a desired profile. Our results show that optimal experiment design allows one to derive models that are accurate enough to precisely predict and regulate the protein expression in heterogeneous cell populations over extended periods of time.

Regularized Maximum Likelihood Estimation of Sparse Stochastic Monomolecular Biochemical Reaction Networks

A sparse parameter estimation method is proposed for identifying a stochastic monomolecular biochemical reaction network system. Identification of a reaction network can be achieved by estimating a sparse parameter matrix containing the reaction network structure and kinetics information. Stochastic dynamics of a biochemical reaction network system is usually modeled by a chemical master equation, which is composed of several ordinary differential equations describing the time evolution of probability distributions for all possible states. This paper considers closed monomolecular reaction systems for which an exact analytical solution of the corresponding chemical master equation is available. The estimation method presented in this paper incorporates the closed-form solution into a regularized maximum likelihood estimation (MLE) for which model complexity is penalized, whereas most of existing studies on sparse reaction network identification use deterministic models for regularized least-square estimation. A simulation result is provided to verify performance improvement of the presented regularized MLE over the least squares (LSE) based on a deterministic mass-average model in the case of a small population size. Improved reaction structure detection is achieved by adding a penalty term for ℓ1 regularization to the exact maximum likelihood function.

Efficient calculation of steady state probability distribution for stochastic biochemical reaction network

The Steady State (SS) probability distribution is an important quantity needed to characterize the steady state behavior of many stochastic biochemical networks. In this paper, we propose an efficient and accurate approach to calculating an approximate SS probability distribution from solution of the Chemical Master Equation (CME) under the assumption of the existence of a unique deterministic SS of the system. To find the approximate solution to the CME, a truncated state-space representation is used to reduce the state-space of the system and translate it to a finite dimension. The subsequent ill-posed eigenvalue problem of a linear system for the finite state-space can be converted to a well-posed system of linear equations and solved. The proposed strategy yields efficient and accurate estimation of noise in stochastic biochemical systems. To demonstrate the approach, we applied the method to characterize the noise behavior of a set of biochemical networks of ligand-receptor interactions for Bone Morphogenetic Protein (BMP) signaling. We found that recruitment of type II receptors during the receptor oligomerization by itself doesn't not tend to lower noise in receptor signaling, but regulation by a secreted co-factor may provide a substantial improvement in signaling relative to noise. The steady state probability approximation method shortened the time necessary to calculate the probability distributions compared to earlier approaches, such as Gillespie's Stochastic Simulation Algorithm (SSA) while maintaining high accuracy.

Efficient parametric analysis of the chemical master equation through model order reduction

BackgroundStochastic biochemical reaction networks are commonly modelled by the chemical master equation, and can be simulated as first order linear differential equations through a finite state projection. Due to the very high state space dimension of these equations, numerical simulations are computationally expensive. This is a particular problem for analysis tasks requiring repeated simulations for different parameter values. Such tasks are computationally expensive to the point of infeasibility with the chemical master equation.ResultsIn this article, we apply parametric model order reduction techniques in order to construct accurate low-dimensional parametric models of the chemical master equation. These surrogate models can be used in various parametric analysis task such as identifiability analysis, parameter estimation, or sensitivity analysis. As biological examples, we consider two models for gene regulation networks, a bistable switch and a network displaying stochastic oscillations.ConclusionsThe results show that the parametric model reduction yields efficient models of stochastic biochemical reaction networks, and that these models can be useful for systems biology applications involving parametric analysis problems such as parameter exploration, optimization, estimation or sensitivity analysis.