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Seth H. Weinberg, Ph.D. - VCU College of Engineering. Biotech One, Room 1070D,  Richmond, VA, US

Seth H. Weinberg, Ph.D. Seth H. Weinberg, Ph.D.

Assistant Professor, Department of Biomedical Engineering | VCU College of Engineering

Biotech One, Room 1070D, Richmond, VA, UNITED STATES

Dr. Weinberg's research focuses on computational physiology, specifically questions related to electrophysiology and mechanobiology.

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Biography

Dr. Weinberg received a BSE in Biomedical Engineering from Duke University in 2006 and a PhD in Biomedical Engineering from Johns Hopkins University in 2012. From 2012-2014, he was a post-doctoral research associate with the Biomathematics Initiative at the College of William & Mary. From 2014-2016, he was a Research Assistant Professor at the Virginia Modeling, Analysis, and Simulation Center (VMASC) at Old Dominion University.

Dr. Weinberg's research focuses on cardiac electrophysiology, mechanobiology, cell-extracellular matrix interactions, calcium signaling, nonlinear dynamics in biology and computational neuroscience.

His current projects include ion channel localization in cardiac conduction and disease, stochastic calcium release in cardiac cells, and modeling fibronectin assembly.

Industry Expertise (2)

Education/Learning Research

Areas of Expertise (7)

Computational physiology Cardiac electrophysiology Extracellular matrix assembly Nonlinear dynamics in biology Multicellular modeling Calcium signaling Computational Neuroscience

Education (2)

Duke University: BSE, Biomedical Engineering 2006

Summa cum laude

The Johns Hopkins University: PhD, Biomedical Engineering 2012

Affiliations (4)

  • Biophysical Society
  • Biomedical Engineering Society
  • American Heart Association
  • Society for Mathematical Biology

Media Appearances (1)

Biomedical engineering researchers' findings and methodology are game-changers

Phys.org  online

2017-06-15

A study by three researchers in VCU’s Department of Biomedical Engineering enhances understanding of a cell’s response to mechanical cues from its surrounding environment, a key regulator of cell function.

“Mechanotransduction Dynamics at the Cell-Matrix Interface” by assistant professor Seth Weinberg, Ph.D., student Devin Mair and associate professor Christopher Lemmon, Ph.D., employs a computational-experimental methodology with implications for further insights into mechanical interactions between cells.

The study, part of a project funded by a $1.8 million grant from the National Institutes of Health, appears in the May 2017 issue of Biophysical Journal.

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Research Grants (2)

A Computational Model of Traction Force-Induced Fibronectin Fibril Growth

National Institutes of Health - NIGMS R01 

2015-08-01

Fibrosis is responsible for nearly half of the deaths in the western world, and is seen in nearly all organ systems. It is characterized by aberrant assembly of extracellular matrix which is first established by the assembly of a matrix of fibrils consistin of the protein fibronectin (FN); once assembled, fibronectin fibrils can localize soluble, pro-fibrotic growth factors to the cell surface to create a self-sustaining feedback loop that facilitates furthr fibrosis. In this work, we will develop and experimentally validate a computational biophysical model that predicts FN fibril assembly and subsequent localized growth factor signaling to better understand the process of fibrosis.

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Mechanochemical Signaling Dynamics in Epithelial-Mesenchymal Transition

National Institutes of Health - NIGMS R01 

2018-03-01

Epithelial-­Mesenchymal Transition (EMT) is a key transdifferentiation event that is required for embryonic development and wound healing and is misregulated in several disease states including fibrotic disease and cancer. The initiating events that drive EMT require changes in the contractile forces acting on cell-­cell and cell-­matrix junctions and changes in cell markers. Here we will develop both novel computational and experimental platforms that predict and measure the key mechanical and biochemical signaling events in this system to understand how the interactions between mechanics and biochemical signaling drives this crucial process.

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Courses (2)

EGRB 215 Computational Methods in Biomedical Engineering I

Computational Methods in Biomedical Engineering I

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EGRB 601 Numerical Methods and Modeling in BME

Numerical Methods and Modeling in BME

Selected Articles (10)

Mechanotransduction Dynamics at the Cell-Matrix Interface Biophysical Journal

Seth H. Weinberg, Devin B. Mair, Christopher A. Lemmon

2017-05-09

The ability of cells to sense and respond to mechanical cues from the surrounding environment has been implicated as a key regulator of cell differentiation, migration, and proliferation. The extracellular matrix (ECM) is an oft-overlooked component of the interface between cells and their surroundings. Cells assemble soluble ECM proteins into insoluble fibrils with unique mechanical properties that can alter the mechanical cues a cell receives. In this study, we construct a model that predicts the dynamics of cellular traction force generation and subsequent assembly of fibrils of the ECM protein fibronectin (FN). FN fibrils are the primary component in primordial ECM and, as such, FN assembly is a critical component in the cellular mechanical response. The model consists of a network of Hookean springs, each representing an extensible domain within an assembling FN fibril. As actomyosin forces stretch the spring network, simulations predict the resulting traction force and FN fibril formation. The model accurately predicts FN fibril morphometry and demonstrates a mechanism by which FN fibril assembly regulates traction force dynamics in response to mechanical stimuli and varying surrounding substrate stiffness.

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Revealing the Concealed Nature of Long-QT Type 3 Syndrome Circulation: Arrhythmia and Electrophysiology

2017-02-17

Background—Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long-QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction because of reduced sodium current driving force, termed “self-attenuation.” We tested the novel hypothesis that self-attenuation can “mask” the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs).

Methods and Results—Acute interstitial edema was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, acute interstitial edema exacerbated action potential duration prolongation and produced EADs, in particular, at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, whereas for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs.

Conclusions—We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.

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Impaired Sarcoplasmic Reticulum Calcium Uptake and Release Promote Electromechanically and Spatially Discordant Alternans: A Computational Study Clinical Medicine Insights: Cardiology

2016

Cardiac electrical dynamics are governed by cellular-level properties, such as action potential duration (APD) restitution and intracellular calcium (Ca) handling, and tissue-level properties, including conduction velocity restitution and cell–cell coupling. Irregular dynamics at the cellular level can lead to instabilities in cardiac tissue, including alternans, a beat-to-beat alternation in the action potential and/or the intracellular Ca transient.

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Microdomain calcium fluctuations alter temporal dynamics in models of calcium-dependent signaling cascades and synaptic vesicle release Neural Computation

2016

Ca2+-dependent signaling is often localized in spatially restricted microdomains and may involve only 1 to 100 Ca2+ ions. Fluctuations in the microdomain Ca2+ concentration Ca2+ can arise from a wide range of elementary processes, including diffusion, Ca2+ influx, and association/dissociation with Ca2+ binding proteins or buffers. However, it is unclear to what extent these fluctuations alter Ca2+-dependent signaling.

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Calcium Ion Fluctuations Alter Channel Gating in a Stochastic Luminal Calcium Release Site Model IEEE/ACM Transactions on Computational Biology and Bioinformatics

2016

Stochasticity and small system size effects in complex biochemical reaction networks can greatly alter transient and steady-state system properties. A common approach to modeling reaction networks, which accounts for system size, is the chemical master equation that governs the dynamics of the joint probability distribution for molecular copy number.

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Spatial discordance and phase reversals during alternate pacing in discrete-time kinematic and cardiomyocyte ionic models Chaos: An Interdisciplinary Journal of Nonlinear Science

Alternans, a beat-to-beat alternation in the cardiac action potential duration (APD), is a dynamical instability linked with the initiation of arrhythmias and sudden cardiac death, and arises via a period-doubling bifurcation when myocytes are stimulated at fast rates. In this study, we analyze the stability of a propagating electrical wave in a one-dimensional cardiac myocyte model in response to an arrhythmogenic rhythm known as alternate pacing.

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Membrane capacitive memory alters spiking in neurons described by the fractional-order Hodgkin-Huxley model PLoS ONE

Excitable cells and cell membranes are often modeled by the simple yet elegant
parallel resistor-capacitor circuit. However, studies have shown that the passive properties
of membranes may be more appropriately modeled with a non-ideal capacitor, in which the
current-voltage relationship is given by a fractional-order derivative.

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Ca 2+-activation kinetics modulate successive puff/spark amplitude, duration and inter-event-interval correlations in a Langevin model of stochastic Ca 2+ release Mathematical Biosciences

Through theoretical analysis of the statistics of stochastic calcium (Ca 2+) release (ie, the amplitude, duration and inter-event interval of simulated Ca 2+ puffs and sparks), we show that a Langevin description of the collective gating of Ca 2+ channels may be a good approximation to the corresponding Markov chain model when the number of Ca 2+ channels per Ca 2+ release unit (CaRU) is in the physiological range.

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High frequency stimulation of cardiac myocytes: A theoretical and computational study Chaos: An Interdisciplinary Journal of Nonlinear Science

High-frequency stimulation (HFS) has recently been identified as a novel approach for
terminating life-threatening cardiac arrhythmias. HFS elevates myocyte membrane potential and blocks electrical conduction for the duration of the stimulus. However, low amplitude HFS can induce rapidly firing action potentials, which may reinitiate an arrhythmia. The cellular level mechanisms underlying HFS-induced electrical activity are not well understood.

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The Influence of Ca 2+ Buffers on Free [Ca 2+] Fluctuations and the Effective Volume of Ca 2+ Microdomains Biophysical Journal

Intracellular calcium (Ca 2+) plays a significant role in many cell signaling pathways, some of which are localized to spatially restricted microdomains. Ca 2+ binding proteins (Ca 2+ buffers) play an important role in regulating Ca 2+ concentration ([Ca 2+]). Buffers typically slow [Ca 2+] temporal dynamics and increase the effective volume of Ca 2+ domains.

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