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Cellular Biophysics

Michael D Stern, MD, Chief

The Cellular Biophysics Section continues a 30 year program of studying the mechanisms by which calcium acts as a signaling molecule within individual heart muscle cells, to trigger the contraction of the muscle and regulate the membrane ion currents that synchronize the beating of the whole heart. We use a combination of experimental measurements using fluorescent probes in single cells, together with extensive mathematical modeling of the underlying molecular physics, utilizing NIH supercomputing resources. In recent years we have concentrated on the process of calcium-induced calcium release, in which small calcium signals trigger larger ones, resulting in propagated wavelets of calcium that play a crucial role in generating both the normal heart rhythm and life-threatening arrhythmias.

 

A spinoff from our modeling work is a separate project studying the in-silico evolution of populations of virtual organisms. This work aims to find abstract, underlying regularities in the working of Darwinian natural selection, which may apply also to cultural evolution.

 

List of Portfolio/Research Areas

•Cardiac excitation contraction coupling

•Calcium sparks and CICR by ryanodine receptors

•Simulation of calcium dynamics in pacemaker cells

•Mechanism of the "calcium clock" underlying the normal heart rate

•Intra-cellular dynamics in human heart cells

•Simulation of "artificial life" virtual organisms

•Theoretical studies of evolutionary mechanisms underlying human behavior

 

Findings and Publications

 

Maltsev AV, Maltsev VA, Stern MD. Clusters of calcium release channels harness the Ising phase transition to confine their elementary intracellular signals. Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7525-7530. PMID:28674006. PMCID: PMC5530665 

Maltsev AV, Parsons SP, Kim MS, Tsutsui K, Stern MD, Lakatta EG, Maltsev VA, Monfredi O. Computer algorithms for automated detection and analysis of local Ca2+ releases in spontaneously beating cardiac pacemaker cells. PLoS One. 2017 Jul 6;12(7):e0179419. PMID:28683095. PMCID: PMC5500000 

Maltsev AV, Maltsev VA, Stern MD. Stabilization of diastolic calcium signal via calcium pump regulation of complex local calcium releases and transient decay in a computational model of cardiac pacemaker cell with individual release channels. PLoS Comput Biol. 2017 Aug 8;13(8):e1005675. PMID:28792496. PMCID: PMC5562330 

Monfredi O, Tsutsui K, Ziman B, Stern MD, Lakatta EG, Maltsev VA. Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: insights from recording multiple ion currents in each cell. Am J Physiol Heart Circ Physiol. 2018 Mar 1;314(3):H403-H414. PMID:28916636. PMCID: PMC5899256 

Tsutsui K, Monfredi OJ, Sirenko-Tagirova SG, Maltseva LA, Bychkov R, Kim MS, Ziman BD, Tarasov KV, Tarasova YS, Zhang J, Wang M, Maltsev AV, Brennan JA, Efimov IR, Stern MD, Maltsev VA, Lakatta EG. A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells. Sci Signal. 2018 Jun 12;11(534). PMID:29895616. PMCID: PMC6138244 

Kim MS, Maltsev AV, Monfredi O, Maltseva LA, Wirth A, Florio MC, Tsutsui K, Riordon DR, Parsons SP, Tagirova S, Ziman BD, Stern MD, Lakatta EG, Maltsev VA. Heterogeneity of calcium clock functions in dormant, dysrhythmically and rhythmically firing single pacemaker cells isolated from SA node. Cell Calcium. 2018 Sep;74:168-179. PMID:30092494. PMCID: PMC6402562 

Maltsev AV, Stern MD, Maltsev VA. Mechanisms of Calcium Leak from Cardiac Sarcoplasmic Reticulum Revealed by Statistical Mechanics. Biophys J. 2019 Jun 4;116(11):2212-2223. PMID:31103231.  PMC Pending 

Stern MD, Maltseva LA, Juhaszova M, Sollott SJ, Lakatta EG, Maltsev VA. Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells.  J Gen Physiol. 2014 May;143(5):577-604. doi: 10.1085/jgp.201311123. 

Maltsev, V. A., Yaniv, Y., Maltsev, A. V., Stern, M. D., & Lakatta, E. G. (2014). Modern Perspectives on Numerical Modeling of Cardiac Pacemaker Cell. Journal of Pharmacological Sciences, 125(1), 6–38. 

Stern, M. D., Ríos, E., & Maltsev, V. A. (2013). Life and death of a cardiac calcium spark. The Journal of General Physiology, 142(3), 257–274. http://doi.org/10.1085/jgp.201311034 

Maltsev, A. V., Maltsev, V. A., Mikheev, M., Maltseva, L. A., Sirenko, S. G., Lakatta, E. G., & Stern, M. D. (2011). Synchronization of Stochastic Ca2+Release Units Creates a Rhythmic Ca2+ Clock in Cardiac Pacemaker Cells. Biophysical Journal, 100(2), 271–283. http://doi.org/10.1016/j.bpj.2010.11.081 

Stern, M. D. (2010). Patrimony and the Evolution of Risk-Taking. PLoS ONE, 5(7), e11656. http://doi.org/10.1371/journal.pone.0011656 

Josephson, I. R., Guia, A., Lakatta, E. G., Lederer, W. J., & Stern, M. D. (2010). Ca2+-dependent components of inactivation of unitary cardiac L-type Ca2+channels. The Journal of Physiology, 588(Pt 1), 213–223. http://doi.org/10.1113/jphysiol.2009.178343 

Stern, M. D. (1999). Emergence of homeostasis and “noise imprinting” in an evolution model. Proceedings of the National Academy of Sciences of the United States of America, 96(19), 10746–10751. 

Stern, M. D., Song, L.-S., Cheng, H., Sham, J. S. K., Yang, H. T., Boheler, K. R., & Ríos, E. (1999). Local Control Models of Cardiac Excitation–Contraction Coupling  : A Possible Role for Allosteric Interactions between Ryanodine Receptors. The Journal of General Physiology, 113(3), 469–489. 

Cheng, H., Song, L. S., Shirokova, N., González, A., Lakatta, E. G., Ríos, E., & Stern, M. D. (1999). Amplitude distribution of calcium sparks in confocal images: theory and studies with an automatic detection method. Biophysical Journal, 76(2), 606–617. 

Stern, M. D., Pizarro, G., & Ríos, E. (1997). Local Control Model of Excitation–Contraction Coupling in Skeletal Muscle. The Journal of General Physiology, 110(4), 415–440. 

Stern, M.D., (1993). Two-fiber laser Doppler velocimetry in blood: Monte Carlo simulation in three dimensions. Appl Opt. 1993 Feb 1;32(4):468-76. doi: 10.1364/AO.32.000468. 

Stern, M. D. (1992). Theory of excitation-contraction coupling in cardiac muscle. Biophysical Journal, 63(2), 497–517.