Hiroyuki Kuwahara

An efficient and exact stochastic simulation method to analyze rare events in biochemical systems

In robust biological systems, wide deviations from highly controlled normal behavior may be rare, yet they may result in catastrophic complications. While in silico analysis has gained an appreciation as a tool to offer insights into system-level properties of biological systems, analysis of such rare events provides a particularly challenging computational problem. This paper proposes an efficient stochastic simulation method to analyze rare events in biochemical systems. Our new approach can substantially increase the frequency of the rare events of interest by appropriately manipulating the underlying probability measure of the system, allowing high-precision results to be obtained with substantially fewer simulation runs than the conventional direct Monte Carlo simulation. Here, we show the algorithm of our new approach, and we apply it to the analysis of rare deviant transitions of two systems, resulting in several orders of magnitude speedup in generating high-precision estimates compared with the conventional Monte Carlo simulation.

Learning Genetic Regulatory Network Connectivity from Time Series Data

Recent experimental advances facilitate the collection of time series data that indicate which genes in a cell are expressed. This information can be used to understand the genetic regulatory network that generates the data. Typically, Bayesian analysis approaches are applied which neglect the time series nature of the experimental data, have difficulty in determining the direction of causality, and do not perform well on networks with tight feedback. To address these problems, this paper presents a method to learn genetic network connectivity which exploits the time series nature of experimental data to achieve better causal predictions. This method first breaks up the data into bins. Next, it determines an initial set of potential influence vectors for each gene based upon the probability of the genes expression increasing in the next time step. These vectors are then combined to form new vectors with better scores. Finally, these influence vectors are competed against each other to determine the final influence vector for each gene. The result is a directed graph representation of the genetic networks repression and activation connections. Results are reported for several synthetic networks with tight feedback showing significant improvements in recall and runtime over Yus dynamic Bayesian approach. Promising preliminary results are also reported for an analysis of experimental data for genes involved in the yeast cell cycle.

The Design of a Genetic Muller C-Element

Synthetic biology uses engineering principles to design circuits out of genetic materials that are inserted into bacteria to perform various tasks. While synthetic combinational Boolean logic gates have been constructed, there are many open issues in the design of sequential logic gates. One such gate common in most asynchronous circuits is the Muller C-element, which is used to synchronize multiple independent processes. This paper proposes a novel design for a genetic Muller C-element using transcriptional regulatory elements. The design of a genetic Muller C-element enables the construction of virtually any asynchronous circuit from genetic material. There are, however, many issues that complicate designs with genetic materials. These complications result in modifications being required to the normal digital design procedure. This paper presents two designs that are logically equivalent to a Muller C-element. Mathematical analysis and stochastic simulation, however, show that only one functions reliably.

Regulating the total level of a signaling protein can vary its dynamics in a range from switch like ultrasensitivity to adaptive responses

Biological signaling networks can exhibit rich response dynamics including ultrasensitivity, adaptation to persistent stimuli and oscillations. Previous modeling efforts have considered the proteins in these networks as two‐state entities and their total levels as fixed quantities. However, inside the cell, most molecules are in constant flux because of various processes such as degradation, synthesis, binding of scaffold proteins and release from vesicles. The resulting freedom in the amount of signaling protein that is available for signaling has not been explored. Here, we analyze the response dynamics of a signaling protein when it enters the signaling pool in one state (modified or unmodified) and exits in both states. When the exit rates of these two states are comparable, a persistent stimulus results in step responses and can produce ultrasensitivity, as shown previously. However, we find that when the exit rates are imbalanced, the signaling protein gives transient responses to persistent stimuli even though the system does not have any explicit feedback. Further, these rates determine the signal range over which the system is responsive. Building small networks from signaling proteins with different exit rates, we show that these systems can exhibit rich behavior. Taken together, these findings indicate that altering the total level of signaling proteins can significantly change their response and provide additional richness in system dynamics. We discuss relevant biological examples in which regulating total protein levels could be exploited to alter signaling behavior.

Production-passage-time approximation: a new approximation method to accelerate the simulation process of enzymatic reactions

Given the substantial computational requirements of stochastic simulation, approximation is essential for efficient analysis of any realistic biochemical system. This paper introduces a new approximation method to reduce the computational cost of stochastic simulations of an enzymatic reaction scheme which in biochemical systems often includes rapidly changing fast reactions with enzyme and enzyme-substrate complex molecules present in very small counts. Our new method removes the substrate dissociation reaction by approximating the passage time of the formation of each enzyme-substrate complex molecule which is destined to a production reaction. This approach skips the firings of unimportant yet expensive reaction events, resulting in a substantial acceleration in the stochastic simulations of enzymatic reactions. Additionally, since all the parameters used in our new approach can be derived by the Michaelis-Menten parameters which can actually be measured from experimental data, applications of this approximation can be practical even without having full knowledge of the underlying enzymatic reaction. Furthermore, since our approach does not require a customized simulation procedure for enzymatic reactions, it allows biochemical systems that include such reactions to still take advantage of standard stochastic simulation tools. Here, we apply this new method to various enzymatic reaction systems, resulting in a speedup of orders of magnitude in temporal behavior analysis without any significant loss in accuracy.

Learning genetic regulatory network connectivity from time series data

Recent experimental advances facilitate the collection of time series data that indicate which genes in a cell are expressed. This paper proposes an efficient method to generate the genetic regulatory network inferred from time series data. Our method first encodes the data into levels. Next, it determines the set of potential parents for each gene based upon the probability of the gene’s expression increasing. After a subset of potential parents are selected, it determines if any genes in this set may have a combined effect. Finally, the potential sets of parents are competed against each other to determine the final set of parents. The result is a directed graph representation of the genetic network’s repression and activation connections. Our results on synthetic data generated from models for several genetic networks with tight feedback are promising.

Production-passage-time approximation: a new approximation method to accelerate the simulation process of enzymatic reactions.

Given the substantial computational requirements of stochastic simulation, approximation is essential for efficient analysis of any realistic biochemical system. This paper introduces a new approximation method to reduce the computational cost of stochastic simulations of an enzymatic reaction scheme which in biochemical systems often includes rapidly changing fast reactions with enzyme and enzyme-substrate complex molecules present in very small counts. Our new method removes the substrate dissociation reaction by approximating the passage time of the formation of each enzyme-substrate complex molecule which is destined to a production reaction. This approach skips the firings of unimportant yet expensive reaction events, resulting in a substantial acceleration in the stochastic simulations of enzymatic reactions. Additionally, since all the parameters used in our new approach can be derived by the Michaelis-Menten parameters which can actually be measured from experimental data, applications of this approximation can be practical even without having full knowledge of the underlying enzymatic reaction. Here, we apply this new method to various enzymatic reaction systems, resulting in a speedup of orders of magnitude in temporal behavior analysis without any significant loss in accuracy. Furthermore, we show that our new method can perform better than some of the best existing approximation methods for enzymatic reactions in terms of accuracy and efficiency.

SBOLme: a Repository of SBOL Parts for Metabolic Engineering.

The Synthetic Biology Open Language (SBOL) is a community-driven open language to promote standardization in synthetic biology. To support the use of SBOL in metabolic engineering, we developed SBOLme, the first open-access repository of SBOL 2-compliant biochemical parts for a wide range of metabolic engineering applications. The URL of our repository is http://www.cbrc.kaust.edu.sa/sbolme .