Abstract: The paper reports on the development of a simulation platform for computational experim... more Abstract: The paper reports on the development of a simulation platform for computational experiments in order to investigate the dynamics of technological collaborations and the emergence of persistent innovation networks. It describes a simulation platform that supports the implementation of an abstract model of an innovation network and its first application to the Biotechnology sector. We start by motivating our approach from a methodological perspective by introducing simulation techniques as a tool for theory development. The ...
We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of bi... more We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena. An objective is to build better, working hypotheses of plausible mechanisms. A synthetic model is an extant hypothesis: execution produces an observable mechanism and phenomena. Mobile objects representing compounds carry information enabling components to distinguish between them and react accordingly when different compounds are studied simultaneously. We argue that the familiar inductive approaches contribute to the general inefficiencies being experienced by pharmaceutical R&D, and that use of synthetic approaches accelerates and improves R&D decision-making and thus the drug development process. A reason is that synthetic models encourage and facilitate abductive scientific reasoning, a primary means of knowledge creation and creative cognition. When synthetic models are executed, we observe different aspects of knowledge in action from different perspectives. These models can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete while moving us closer to personalized medicine.
Proceedings of the 25th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE Cat. No.03CH37439), 2003
Page 1. Proceedings of the 25* Annual Intemational Conference of the IEEE EMBS Cancun, Mexico Sep... more Page 1. Proceedings of the 25* Annual Intemational Conference of the IEEE EMBS Cancun, Mexico September 17-21,2003 Similarity Measures for Automated Comparison of In Silico and In Vitro Experimental Results Glen E. P. Ropella, Dev A. Nag and C. Anthony Hunt' ...
Proceedings of the 25th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE Cat. No.03CH37439), 2003
The development of any given biological model is driven by the experimental context in which it w... more The development of any given biological model is driven by the experimental context in which it will be used. Hence, computer models are often overfitted to a single, unique, experimental context and fail to be useful in other situations. So doing severely limits the model's usefulness, effectively blocking inferential extensions to somewhat different conditions. To solve this problem, multiple, separate
Currently, most biomedical models exist in isolation. It is often difficult to reuse or integrate... more Currently, most biomedical models exist in isolation. It is often difficult to reuse or integrate models or their components, in part because they are not modular. Modular components allow the modeler to think more deeply about the role of the model and to more completely address a modeling project's requirements. In particular, modularity facilitates component reuse and model integration for models with different use cases, including the ability to exchange modules during or between simulations. The heterogeneous nature of biology and vast range of wet-lab experimental platforms call for modular models designed to satisfy a variety of use cases. We argue that software analogs of biological mechanisms are reasonable candidates for modularization. Biomimetic software mechanisms comprised of physiomimetic mechanism modules offer benefits that are unique or especially important to multi-scale, biomedical modeling and simulation. We present a general, scientific method of modularizi...
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2008
Will enzyme induction (EI) within different hepatic lobular zones, following initial exposure to ... more Will enzyme induction (EI) within different hepatic lobular zones, following initial exposure to a single xenobiotic, be homogeneous or heterogeneous? Wet-lab EI experiments, as formulated, are infeasible. The In Silico Liver (ISL) was designed in part to explore plausible answers to such questions. The ISL is synthetic, physiologically based, fine-grained, and multi-agent. It has been validated against in situ drug disposition data. Results from simulation experiments falsified the hypothesis that a uniform distribution of simulated drug passing through an ISL will produce uniform EI. The results may have a hepatic counterpart. We discuss methodological considerations regarding multi-level observation and manipulation of livers and this new class of models.
Software design is much more important for individual-based models (IBMs) than it is for conventi... more Software design is much more important for individual-based models (IBMs) than it is for conventional models,for three reasons. First,the results of an IBM are the emergent properties of a system of interacting agents that exist only in the software; unlike analytical model results,an IBMs outcomes can be reproduced only by exactly reproduc- ing its software implementation. Second,outcomes of an IBM
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2004
We have built a collection of flexible, hepatomimetic, in silico components. Some are agent-based... more We have built a collection of flexible, hepatomimetic, in silico components. Some are agent-based. We assemble them into devices that mimic aspects of anatomic structures and the behaviors of hepatic lobules (the primary functional unit of the liver) along with aspects of liver function. We validate against outflow profiles for sucrose administered as a bolus to isolated, perfused rat livers (IPRLs). Acceptable in silico profiles are experimentally indistinguishable from those of the in situ referent based on similarity measure values. The behavior of these devices is expected to cover expanding portions of the behavior space of real livers and their components. These in silico livers will provide powerful tools for understanding how the liver functions in normal and diseased states, at multiple levels of organization.
To facilitate integration and reconciliation between similar experiments, we need relativistic an... more To facilitate integration and reconciliation between similar experiments, we need relativistic analogues that can be independent of experimental protocols; yet reasonably represent biological components and interactions among them, along with hypothesized mechanistic details. We designed, constructed and validated an analogue of a recirculating, isolated perfused liver used in a study of drug interactions between digoxin, rifampicin and quinidine. We believe these analogues can evolve into executable biological knowledge embodiments that provide concrete instances of knowledge and means to falsify mechanistic hypotheses.
Introduction: To expand our ability to test current concepts about system and organ function with... more Introduction: To expand our ability to test current concepts about system and organ function within organisms in normal and disease states we need a new class of discrete, event-driven simulation models that achieve a higher level of biological realism across multiple scales, while being sufficiently flexible to represent different aspects of the biology. Here we provide the first description of such models, one that is focused on the rat liver. We use a middle-out design strategy that begins with primary parenchymal units. The models are sufficiently flexible to represent different aspects of hepatic biology, including heterogeneous microenvironments. Model components are designed to be easily joined and disconnected, and to be replaceable and reusable. The models function within a multitier, in silico apparatus designed to support iterative experimentation on models that will have extended life cycles. Results: Validation uses two sets of solute outflow profile data from experimen...
Journal of Pharmacology and Experimental Therapeutics, 2010
Hepatic drug disposition is different in normal and diseased livers. Different disease types alte... more Hepatic drug disposition is different in normal and diseased livers. Different disease types alter disposition differently. What are the responsible micromechanistic changes and how do they influence drug movement within the liver? We provide plausible, concrete answers for two compounds, diltiazem and sucrose, in normal livers and two different types of cirrhotic rat livers: chronic pretreatment of rats with carbon tetrachloride (CCl(4)) and alcohol caused different types of cirrhosis. We started with simulated disposition data from normal, multilevel, physiologically based, object-oriented, discrete event in silico livers (normal ISLs) that validated against diltiazem and sucrose disposition data from normal livers. We searched the parameter space of the mechanism and found three parameter vectors that enabled matching the three wet-lab data sets. They specified micromechanistic transformations that enabled converting the normal ISL into two different types of diseased ISLs. Disease caused lobular changes at three of six levels. The latter provided in silico disposition data that achieved a prespecified degree of validation against wet-lab data. The in silico transformations from normal to diseased ISLs stand as concrete theories for disease progression from the disposition perspective. We also developed and implemented methods to trace objects representing diltiazem and sucrose during disposition experiments. This allowed valuable insight into plausible disposition details in normal and diseased livers. We posit that changes in ISL micromechanistic details may have disease-causing counterparts.
Abstract: The paper reports on the development of a simulation platform for computational experim... more Abstract: The paper reports on the development of a simulation platform for computational experiments in order to investigate the dynamics of technological collaborations and the emergence of persistent innovation networks. It describes a simulation platform that supports the implementation of an abstract model of an innovation network and its first application to the Biotechnology sector. We start by motivating our approach from a methodological perspective by introducing simulation techniques as a tool for theory development. The ...
We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of bi... more We provide a rationale for and describe examples of synthetic modeling and simulation (M&S) of biological systems. We explain how synthetic methods are distinct from familiar inductive methods. Synthetic M&S is a means to better understand the mechanisms that generate normal and disease-related phenomena observed in research, and how compounds of interest interact with them to alter phenomena. An objective is to build better, working hypotheses of plausible mechanisms. A synthetic model is an extant hypothesis: execution produces an observable mechanism and phenomena. Mobile objects representing compounds carry information enabling components to distinguish between them and react accordingly when different compounds are studied simultaneously. We argue that the familiar inductive approaches contribute to the general inefficiencies being experienced by pharmaceutical R&D, and that use of synthetic approaches accelerates and improves R&D decision-making and thus the drug development process. A reason is that synthetic models encourage and facilitate abductive scientific reasoning, a primary means of knowledge creation and creative cognition. When synthetic models are executed, we observe different aspects of knowledge in action from different perspectives. These models can be tuned to reflect differences in experimental conditions and individuals, making translational research more concrete while moving us closer to personalized medicine.
Proceedings of the 25th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE Cat. No.03CH37439), 2003
Page 1. Proceedings of the 25* Annual Intemational Conference of the IEEE EMBS Cancun, Mexico Sep... more Page 1. Proceedings of the 25* Annual Intemational Conference of the IEEE EMBS Cancun, Mexico September 17-21,2003 Similarity Measures for Automated Comparison of In Silico and In Vitro Experimental Results Glen E. P. Ropella, Dev A. Nag and C. Anthony Hunt' ...
Proceedings of the 25th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE Cat. No.03CH37439), 2003
The development of any given biological model is driven by the experimental context in which it w... more The development of any given biological model is driven by the experimental context in which it will be used. Hence, computer models are often overfitted to a single, unique, experimental context and fail to be useful in other situations. So doing severely limits the model's usefulness, effectively blocking inferential extensions to somewhat different conditions. To solve this problem, multiple, separate
Currently, most biomedical models exist in isolation. It is often difficult to reuse or integrate... more Currently, most biomedical models exist in isolation. It is often difficult to reuse or integrate models or their components, in part because they are not modular. Modular components allow the modeler to think more deeply about the role of the model and to more completely address a modeling project's requirements. In particular, modularity facilitates component reuse and model integration for models with different use cases, including the ability to exchange modules during or between simulations. The heterogeneous nature of biology and vast range of wet-lab experimental platforms call for modular models designed to satisfy a variety of use cases. We argue that software analogs of biological mechanisms are reasonable candidates for modularization. Biomimetic software mechanisms comprised of physiomimetic mechanism modules offer benefits that are unique or especially important to multi-scale, biomedical modeling and simulation. We present a general, scientific method of modularizi...
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2008
Will enzyme induction (EI) within different hepatic lobular zones, following initial exposure to ... more Will enzyme induction (EI) within different hepatic lobular zones, following initial exposure to a single xenobiotic, be homogeneous or heterogeneous? Wet-lab EI experiments, as formulated, are infeasible. The In Silico Liver (ISL) was designed in part to explore plausible answers to such questions. The ISL is synthetic, physiologically based, fine-grained, and multi-agent. It has been validated against in situ drug disposition data. Results from simulation experiments falsified the hypothesis that a uniform distribution of simulated drug passing through an ISL will produce uniform EI. The results may have a hepatic counterpart. We discuss methodological considerations regarding multi-level observation and manipulation of livers and this new class of models.
Software design is much more important for individual-based models (IBMs) than it is for conventi... more Software design is much more important for individual-based models (IBMs) than it is for conventional models,for three reasons. First,the results of an IBM are the emergent properties of a system of interacting agents that exist only in the software; unlike analytical model results,an IBMs outcomes can be reproduced only by exactly reproduc- ing its software implementation. Second,outcomes of an IBM
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2004
We have built a collection of flexible, hepatomimetic, in silico components. Some are agent-based... more We have built a collection of flexible, hepatomimetic, in silico components. Some are agent-based. We assemble them into devices that mimic aspects of anatomic structures and the behaviors of hepatic lobules (the primary functional unit of the liver) along with aspects of liver function. We validate against outflow profiles for sucrose administered as a bolus to isolated, perfused rat livers (IPRLs). Acceptable in silico profiles are experimentally indistinguishable from those of the in situ referent based on similarity measure values. The behavior of these devices is expected to cover expanding portions of the behavior space of real livers and their components. These in silico livers will provide powerful tools for understanding how the liver functions in normal and diseased states, at multiple levels of organization.
To facilitate integration and reconciliation between similar experiments, we need relativistic an... more To facilitate integration and reconciliation between similar experiments, we need relativistic analogues that can be independent of experimental protocols; yet reasonably represent biological components and interactions among them, along with hypothesized mechanistic details. We designed, constructed and validated an analogue of a recirculating, isolated perfused liver used in a study of drug interactions between digoxin, rifampicin and quinidine. We believe these analogues can evolve into executable biological knowledge embodiments that provide concrete instances of knowledge and means to falsify mechanistic hypotheses.
Introduction: To expand our ability to test current concepts about system and organ function with... more Introduction: To expand our ability to test current concepts about system and organ function within organisms in normal and disease states we need a new class of discrete, event-driven simulation models that achieve a higher level of biological realism across multiple scales, while being sufficiently flexible to represent different aspects of the biology. Here we provide the first description of such models, one that is focused on the rat liver. We use a middle-out design strategy that begins with primary parenchymal units. The models are sufficiently flexible to represent different aspects of hepatic biology, including heterogeneous microenvironments. Model components are designed to be easily joined and disconnected, and to be replaceable and reusable. The models function within a multitier, in silico apparatus designed to support iterative experimentation on models that will have extended life cycles. Results: Validation uses two sets of solute outflow profile data from experimen...
Journal of Pharmacology and Experimental Therapeutics, 2010
Hepatic drug disposition is different in normal and diseased livers. Different disease types alte... more Hepatic drug disposition is different in normal and diseased livers. Different disease types alter disposition differently. What are the responsible micromechanistic changes and how do they influence drug movement within the liver? We provide plausible, concrete answers for two compounds, diltiazem and sucrose, in normal livers and two different types of cirrhotic rat livers: chronic pretreatment of rats with carbon tetrachloride (CCl(4)) and alcohol caused different types of cirrhosis. We started with simulated disposition data from normal, multilevel, physiologically based, object-oriented, discrete event in silico livers (normal ISLs) that validated against diltiazem and sucrose disposition data from normal livers. We searched the parameter space of the mechanism and found three parameter vectors that enabled matching the three wet-lab data sets. They specified micromechanistic transformations that enabled converting the normal ISL into two different types of diseased ISLs. Disease caused lobular changes at three of six levels. The latter provided in silico disposition data that achieved a prespecified degree of validation against wet-lab data. The in silico transformations from normal to diseased ISLs stand as concrete theories for disease progression from the disposition perspective. We also developed and implemented methods to trace objects representing diltiazem and sucrose during disposition experiments. This allowed valuable insight into plausible disposition details in normal and diseased livers. We posit that changes in ISL micromechanistic details may have disease-causing counterparts.
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Papers by Glen Ropella