About the Lab

The Disease Biophysics Group (DBG) at Harvard University is an interdisciplinary team of biologists, physicists, engineers and material scientists actively researching the structure/function relationship in cardiac, neural, and vascular smooth muscle tissue engineering. We seek to quantify cellular mechanotransduction at the single-cell and tissue level to understand the effect on electrophysiology and disease states.

Cardiac Research

Our group’s primary research focus is on understanding cellular mechanotransduction in the heart. Specifically, we are interested in how extracellular matrix and cytoskeletal architecture potentiate and modulate the activation of mechanochemical and mechanoelectrical signaling pathways and genetic programs in cardiac cells and tissues. In order to study these mechanisms at different spatial scales, we use cellular and tissue engineering techniques that allow us to build custom-designed cardiac myocytes and ventricular tissue constructs as experimental preparations.

Why are we interested in this problem of biological scaling in the heart?

The Cardiac Arrhythmia Suppression Trial (CAST) of the late 1980’s was a clinical trial designed to test the hypothesis that suppression of premature ventricular contractions (PVC) with Class I antiarrhythmics (blockers of excitatory sodium currents) would reduce arrhythmic death risk. The trial was ended prematurely by the FDA when the mortality rate of those patients on encainide and flecainide, the Class I drugs studied, nearly quadrupled the mortality rates of those patients on placebo. Subsequent studies of antiarrhythmic drugs indicate that drugs that alter ion channel kinetics often show little or no benefit in the suppression of ventricular tachycardia and ventricular fibrillation. To date, there is no clinically reliable means of treating cardiac arrhythmias medicinally.

How are we approaching this problem?

We hypothesize that single channel blockade antiarrhythmic strategies were inherently flawed because they target a single scale (molecular level) without considering the fact that the pathogenesis of arrhythmias transcends multiple levels of integration, i.e., it is a multiscale problem. We propose that increasing the spatial scale of the drug target search, from single proteins to protein networks, will result in the development of more effective antiarrhythmic medicinal therapies. Thus, we take a multiscale approach, by targeting several spatial magnitudes simultaneously. At the length scale of a single cell, we study the cytoskeletal networks that span the entirety of the cardiac myocyte and modulate the kinetics of many of the more than half dozen ion channels that contribute to the cardiac action potential. More specifically, we investigate 1) how the cardiac myocyte cytoskeleton self-assembles; and, 2) the role of cytoskeletal architecture modulating action potential morphology and calcium metabolism. In tissue-scale studies, we investigate cell ensembles and correlate their behavior to larger tissue and whole heart function. Cell-cell mechanocoupling, via cell adhesion proteins and extracellular matrix, undoubtedly contributes to the electrical synchrony amongst cardiac myocytes. Here, more specific studies are directed towards investigating how the mechanical continuity amongst cardiac myocytes modulates electrical excitability and may contribute to the wavebreaks that mark the transition from ventricular tachycardia to ventricular fibrillation.

Immunofluorescence Staining of Micropatterned Cardiac Myocytes

FIGURE: Microcontact Printing used to control Cardiomyocyte geometry and cellular architecture. For all Images: Sarcomeric actin labeled in green, sarcomeric alpha-actinin (Z-lines) marked in red, nucleus marked in blue.
A: Adult Rat Cardiac Myocyte without structural modification (nucleus not shown).
B: Neonatal Rat Cardiac Myocyte without structural modification, cultured on a monolayer of extracellular matrix protein.
C: Neonatal Rat Cardiac Myocyte cultured on a rectangular island of extracellular matrix protein.
D: Neonatal Rat Cardiac Myocyte cultured on a triangular island of extracellular matrix protein.
E: Neonatal Rat Cardiac Myocyte cultured on a square island of extracellular matrix protein.
F: Neonatal Rat Cardiac Myocyte cultured on a circular island of extracellular matrix protein.

Detection, Characterization and Visualization of Calcium Sparks In Micropatterned Cardiac Myocytes
Primary Investigator: Mark Bray, Ph.D.

The cytoarchitecture of the myocyte has been determined to be critical in understanding not only mechanical contraction of the cell but also electrical propagation. Knowledge of this mechanotransduction mechanism has implications in the treatment of stretch-activated arrhythmias, as well as understanding the role of the extracellular environment on intracellular signaling pathways. Our objective is to micropattern myocytes into various shapes and examine spark occurrence as a function of cell shape. The expectation is that cell shapes which incorporate regions of high mechanical cellular stress will modulate calcium spark characteristics as the cytoskeleton reconfigures itself accordingly. A critical and novel component of this project is the development of software able to detect and visualize sparks in two-dimensions.

FIGURE: Fluorescence map of square cell (top left) and with background fluorescence subtracted (bottom left). Visualization of spark boundaries with respect to (x,y,t), shown in red (right).

Visualization of Calcium Sparks in Cardiac Myocytes

Estimation of Contractile Stress on Cardiac Myocytes
Primary Investigator: Poling Kuo, M.D.

We hypothesize that mechanical coupling between cells plays a critical role both in the normal and pathological development of cardiac tissues. We are using traction force microscopy to map the contractile stresses of micropatterned neonatal rat cardiomyocytes.

FIGURE: Relative stress field of cardiac myocytes exhibited by red vectors. The bottom black scale bar represents 10 um.

Analysis of Traction Forces In Contractile Cardiac Myocytes
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What's New

Thank you to our Summer Students! August 16th, 2017

Thank you to all the undergraduate students who spent time working in the lab over the summer. We wish you all the best this school year!

 

Jenny Wang, United States Military Academy at West Point
Daniel Gray, United States Military Academy at West Point
Nikita Pereverzin, United States Military Academy at West Point
Kathryn Dula, United States Military Academy at West Point
Daniel Drennan, Nicholls State University
Michael Ferris, James Madison University
Karla Rivera, Barry University
John Doyle, University of Massachusetts at Lowell
Madeleine Dahl, Salem State University
Nikita Budnik, McGill University
Karaghen Hudson, Harvard University
Sayo Eweje, Harvard University
Michael Peters, Harvard University
Gabriela Berner, Harvard University

Welcome Dr. Ardoña! August 15th, 2017

The DBG would like to extend a warm welcome to our newest postdoctoral fellow, Dr. Herdeline Ardoña. Herdeline recently completed her Ph.D. in Chemistry at Johns Hopkins University,  where she was a part of Prof. Tovar’s lab.  Welcome, Herdeline!

Welcome Dr. Liu! June 23rd, 2017

The DBG would like to extend a warm welcome to our newest postdoctoral fellow, Dr. Qihan Liu. Qihan completed his Ph.D. in Prof. Zhigang Suo’s lab here at Harvard University, where he focused on the mechanics and physics of soft materials.  Welcome, Qihan!

Farewell Jack! June 16th, 2017

The DBG would like to wish Jack Zhou all the best as he leaves us for his next adventure – Medical School. Congratulations Jack!

The DBG welcomes the Orientation and Reach-Back Training class of the U.S. Army May 22nd, 2017

The DBG had the pleasure of hosting the Orientation and Reach-Back Training (ORBT) training class of the U.S. Army Research, Development and Engineering Command (RDECOM) Field Assistance in Science and Technology (FAST) program on May 17, 2017. ORBT is a multi-week mission overview program for senior-level Army officers, non-commissioned officers and Department of the Army civilians on the mechanisms for identifying and resolving technology capability gaps for units in their area of operation. The class visit to Professor (Lieutenant Colonel, Reserves) Parker’s Lab is their only visit to a Lab outside the Department of Defense.

The class met with DBG veterans and attended presentations on Stronger, Tougher, and Lighter Soldier Protection Systems; Nanofiber Scaffolds for Wound Healing/Dressings; Traumatic Brain Injury – Understanding Disease Mechanisms; Fibrous Scaffolds for Tissue Engineered Foods; Cells as Engineering Materials – the Cyborg Ray Project; Cuttlefish Inspired Camouflage; and our unique program for embedding Artists-In- Residence in the Lab.

Guests included members from the U.S. Army Research, Development, and Engineering Command (RDECOM); U.S. Army Engineer Research and Development Center (ERDC); U.S. Army Corps of Engineers; Army Research Laboratory; and RDECOM Research, Development and Engineering Centers.

Pictured below are (clockwise from bottom left): DBG Artist-in- Residence Karaghen Hudson (Harvard Class of 2018); Ms. Valerie Carney (ERDC); Dr. Aimee Poda (ERDC); Dr. (Colonel, Reserves) Steve Hart (RDECOM); Veteran and Program Coordinator John Laursen (Army Retired); Dr. Jerry Ballard (ERDC); Mr. Nathan Frantz (US Army Corps of Engineers); Visiting Scholar and Brigadier General Michael D. Phillips (USA Retired); Dr. Samantha Chambers RDECOM Science Advisor to the XVIII Airborne Corps; and Lieutenant Colonel Jovanna Nelson.