Papers by C. Anthony Hunt
Toxicological Sciences, Jan 29, 2019
Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice of... more Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity.
Software engineering (SE) and modeling and simulation (M&S) methods are maturing rapidly. Wit... more Software engineering (SE) and modeling and simulation (M&S) methods are maturing rapidly. With maturity comes an infrastructure necessary and useful for constructing engineering artifacts. However, this infrastructure constrains the development and evolution of research models, which must be open-ended and flexible enough to to facilitate hypothesis formation and falsification and, thereby, complement wet-lab and clinical studies. Biomedical research models intentionally avoid constraining infrastructure because their core usage pattern demands agility and exploratory modification. At the same time, progress in machine learning, formal methods, and evolutionary computation may provide more agile methods for the analysis and synthesis of research models without the constraints implied by more traditional SE and M&S. We propose that a crucial step toward such agile methods is an ability to automatically measure the granularity of models. And we examine two natural but inadequate candidates for such a measure in the hope that it will evoke discussion.
EPiC series in computing, Mar 11, 2020
Studying biological systems is difficult because of complexity, variability, and uncertainty. Con... more Studying biological systems is difficult because of complexity, variability, and uncertainty. Conceptual models and diagrams are useful in conveying ideas about how a biological phenomenon are thought to be generated. However, sophisticated modeling and simulation methods are needed to discover mechanism-based explanations. Presented herein is a new and unique methodology for this application. Using virtual experiment methods, we recently provided a plausible solution to a problem that had eluded and perplexed pharmacologists and toxicologists for more than 40 years. We describe how virtual and real-world experimentation can be complementary, and propose a way to partially automate the methodology to expedite research.
EPiC series in computing, Mar 11, 2020
An improved understanding of in vivo ⇔ in vitro changes is crucial in identifying and mitigating ... more An improved understanding of in vivo ⇔ in vitro changes is crucial in identifying and mitigating factors contributing to in vitro-in vivo extrapolation (IVIVE) inaccuracies in predicting the hepatic clearance of substances. We argue that a model mechanism-based virtual culture (vCulture) ⇔ virtual mouse (vMouse) (or vRat or vHuman) experiment approach can identify factors contributing to IVIVE disconnects. Doing so depends on having evidence that six Translational Requirements have been achieved. We cite evidence that the first four have been achieved. The fifth Requirement is that differences in measures of vCompound disposition between vCulture and vMouse are attributable solely to the micro-architectural, physiomimetic features, and uncertainties built into the vLiver and vMouse but are absent from the vCulture. The objective of this work is to first improve on a vCulture architecture used previously and then use results of virtual experiments to verify that its use enables the fifth Translational Requirement to be achieved. We employ two different idealized vCompounds, which map to highly permeable real compounds at the extreme ends of the intrinsic clearance spectrum. Virtual intrinsic clearance = Exposure rate per vHPC. At quasi-steady state, results for vCompound-1 are independent of the dosing rate. The average per-vHPC Exposure rates (taken over the whole vLiver in vMouse experiments) are the same (within the variance of the Experiments) as those in vCulture. However, they are location dependent within the vLiver. For vCompound-2, there are dosing rate differences and average per-vHPC Exposure rates within the vLiver are also location dependent. When we account for dosing rate differences, we see again that average per-vHPC Exposure rates averaged over the whole vLiver in vMouse experiments are the same as those in vCulture. Thus, the differences in per vHPC Exposure rate within the vLiver for both vCompounds are attributable solely to
PLOS Computational Biology, Apr 7, 2011
The study of epithelial morphogenesis is fundamental to increasing our understanding of organ fun... more The study of epithelial morphogenesis is fundamental to increasing our understanding of organ function and disease. Great progress has been made through study of culture systems such as Madin-Darby canine kidney (MDCK) cells, but many aspects of even simple morphogenesis remain unclear. For example, are specific cell actions tightly coupled to the characteristics of the cell's environment or are they more often cell state dependent? How does the single lumen, single cell layer cyst consistently emerge from a variety of cell actions? To improve insight, we instantiated in silico analogues that used hypothesized cell behavior mechanisms to mimic MDCK cystogenesis. We tested them through in vitro experimentation and quantitative validation. We observed novel growth patterns, including a cell behavior shift that began around day five of growth. We created agent-oriented analogues that used the cellular Potts model along with an Iterative Refinement protocol. Following several refinements, we achieved a degree of validation for two separate mechanisms. Both survived falsification and achieved prespecified measures of similarity to cell culture properties. In silico components and mechanisms mapped to in vitro counterparts. In silico, the axis of cell division significantly affects lumen number without changing cell number or cyst size. Reducing the amount of in silico luminal cell death had limited effect on cystogenesis. Simulations provide an observable theory for cystogenesis based on hypothesized, cell-level operating principles.
Computer Applications in Industry and Engineering, 2009
Abstract We have constructed a synthetic in silico model for representing the dynamics of leukocy... more Abstract We have constructed a synthetic in silico model for representing the dynamics of leukocyte rolling, activation, and adhesion on substrate-coated flow chambers. Software components were designed, instantiated, verified, plugged together, and then operated in ways that can ...
Journal of Critical Care, Dec 1, 2007
Journal of Critical Care, Volume 22, Issue 4, Pages 341, December 2007, Authors:Jonathan Tang; C.... more Journal of Critical Care, Volume 22, Issue 4, Pages 341, December 2007, Authors:Jonathan Tang; C. Anthony Hunt.
Increasing model reuse and facilitating repurposing is expected to expand simulation use for bett... more Increasing model reuse and facilitating repurposing is expected to expand simulation use for better understanding biological phenomena. We demonstrate doing so in the context of liver diseases caused by toxic exposure to xenobiotics. A clinical goal is improved mechanistic explanations of how damage is generated, which can lead to new strategies to block and/or reverse injury. A goal for this work is to provide concrete, plausible explanations for acetaminophen induced liver injury (AILI) in mice. We instantiate mechanistic hypotheses that map to cellular damage and repair pathways and begin identifying plausible simulated causal cascades capable of generating the characteristic AILI spatial and temporal patterns. We use discrete event simulation of agent-based, multiscale, biomimetic models and Monte Carlo sampling. We use an Iterative Refinement protocol for implementing and validating/falsifying mechanistic hypotheses on a previously validated In Silico Liver. We simulated an observed necrosis pattern. Further approach improvement will yield new methods that combine iterations of in-silico and wet-lab experiments.
A common problem in medicine is that a single therapy, such as a drug, can have different effects... more A common problem in medicine is that a single therapy, such as a drug, can have different effects on different individuals. The vision of personalized medicine is to design and apply therapies, especifically pharmaceuticals, based on an individual's genotype, which significantly influences how biological mechanisms mediate the effects of drugs. The resulting variability in effects can either occur over different individuals (or inter-strain in the case of laboratory animals), or within an individual over time (or intra-strain in the case of laboratory animals). An example is variability of necrosis across mouse strains caused by a dose of acetaminophen (APAP) through APAP induced liver injury (AILI). We performed virtual agent-directed experiments in silico on biomimetic mouse analogs to help explain such variability. We found that the biomimetically plausible changes in certain critical mechanisms involved in AILI can mimic the intra- and inter-strain variability of necrosis in mice observed in wet-lab experiments.
Spring Simulation Multiconference, Apr 14, 2008
Agent-Directed Simulation, Apr 3, 2011
Frontiers in neuroinformatics, 2018
Modeling and simulation in computational neuroscience is currently a research enterprise to bette... more Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical disciplines. In this manuscript, we introduce some basic concepts that will be important in the development of credible clinical neuroscience models: reproducibility and replicability; verification and validation; model configuration; and procedures and processes for credible mechanistic multiscale modeling. We also discuss how ga...
The 26th Annual International Conference of the IEEE Engineering in Medicine and Biology Society
StarLogo, an agent-based modeling and simulation platform, was used to simulate adsorption-mediat... more StarLogo, an agent-based modeling and simulation platform, was used to simulate adsorption-mediated transcytosis of a molecule from the lumen side of a cell membrane to the abluminal extra-cellular fluid (ECF). The model contains small non-diffusible substrate molecules, transporters, and substrate-transporter agents. The "reaction" is a transporter combining with the substrate which then crosses the cell cytoplasm. The substrate that is deposited on the ECF side becomes the "product." Results showed characteristics consistent with Michaelis-Menten enzyme kinetics. The model can serve as an example of agent-based modeling and simulation.
Theoretical Biology and Medical Modelling, Sep 27, 2011
We review grounding issues that influence the scientific usefulness of any biomedical multiscale ... more We review grounding issues that influence the scientific usefulness of any biomedical multiscale model (MSM). Groundings are the collection of units, dimensions, and/or objects to which a variable or model constituent refers. To date, models that primarily use continuous mathematics rely heavily on absolute grounding, whereas those that primarily use discrete software paradigms (e.g., object-oriented, agentbased, actor) typically employ relational grounding. We review grounding issues and identify strategies to address them. We maintain that grounding issues should be addressed at the start of any MSM project and should be reevaluated throughout the model development process. We make the following points. Grounding decisions influence model flexibility, adaptability, and thus reusability. Grounding choices should be influenced by measures, uncertainty, system information, and the nature of available validation data. Absolute grounding complicates the process of combining models to form larger models unless all are grounded absolutely. Relational grounding facilitates referent knowledge embodiment within computational mechanisms but requires separate model-to-referent mappings. Absolute grounding can simplify integration by forcing common units and, hence, a common integration target, but context change may require model reengineering. Relational grounding enables synthesis of large, composite (multi-module) models that can be robust to context changes. Because biological components have varying degrees of autonomy, corresponding components in MSMs need to do the same. Relational grounding facilitates achieving such autonomy. Biomimetic analogues designed to facilitate translational research and development must have long lifecycles. Exploring mechanisms of normal-to-disease transition requires model components that are grounded relationally. Multi-paradigm modeling requires both hyperspatial and relational grounding.
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.
Drug Metabolism and Disposition, Jan 28, 2008
PLOS ONE, Jul 22, 2022
Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation met... more Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms. The virtual culture is a software analog of hepatocytes in vitro, and the virtual human maps to hepatocytes within a liver within an idealized model human. Mobile objects (virtual compounds) map to amounts of xenobiotics. Earlier versions of the two systems achieved quantitative validation targets for intrinsic clearance (virtual culture) and hepatic clearance (virtual human). The major difference between the two systems is the spatial organization of the virtual hepatocytes. For each pair of experiments (virtual culture, virtual human), hepatocytes are configured the same. Probabilistic rules govern virtual compound movements and interactions with other objects. We focus on highly permeable virtual compounds and fix their extracellular unbound fraction at one of seven values (0.05-1.0). Hepatocytes contain objects that can bind and remove compounds, analogous to metabolism. We require that, for a subset of compound properties, per-hepatocyte compound exposure and removal rates during culture experiments directly predict corresponding measures made during virtual human experiments. That requirement serves as a cross-system validation target; we identify compound properties that enable achieving it. We then change compound properties, ceteris paribus, and provide model mechanism-based explanations for when and why measures made during culture experiments under-(or over-) predict corresponding measures made during virtual human experiments. The results show that, from the perspective of compound removal, the organization of hepatocytes within virtual livers is more efficient than within cultures, and the greater the efficiency difference, the larger the underprediction. That relationship is noteworthy because most in vitro-to-in vivo extrapolation methods abstract away the structural organization of
The FASEB Journal, Apr 1, 2019
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Papers by C. Anthony Hunt