Robert S. Kass, PhD

  • Hosack Professor of Pharmacology
  • Alumni Professor of Pharmacology (in Neuroscience)
Profile Headshot

Overview

The focus of Dr. Kass' research program is the structure and function of ion channels that are expressed primarily in the heart. Dr. Kass has directed NIH and/or NSF sponsored research for forty-two years that has contributed to our understanding of the fundamental cellular and molecular basis of cardiac electrical activity through a multidisciplinary approach bridging basic biophysical and clinical science. Contributions from this work include the cellular basis of calcium-dependent arrhythmogenic activity in the heart, basic mechanisms of action of calcium channel blocking drugs, and the molecular events underlying the control of the duration of electrical events in the heart during sympathetic nerve stimulation. His laboratory has focused on understanding the molecular physiology and pharmacology of congenital arrhythmias. These arrhythmias are caused by inherited mutations in genes coding for ion channels and/or ion channel related proteins expressed in the heart. This work has contributed to an understanding of gene-specific risk factors caused by mutation-induced changes in heart ion channel activity, and to the development of a mutation-specific approach to manage these disorders. The mutation-specific therapeutic strategy, verified in genotyped patients, has established the principle that two variants of the same genetic disorder require dramatically different therapeutic strategies for disease management based on biophysical properties of specific genetic lesions. This approach has evolved from close collaborations with clinical colleagues in which information is shared from clinic to basic laboratory and back to clinic. Additional studies are aimed at unraveling the structural basis of mutation-induced, and potentially lethal, disease phenotypes using approaches such as voltage-clamp fluorometry to directly measure movement of gating machinery in the ion channel of interest as well as biochemical methods of directly probing structures of region of ion channels that are hotspots for disease-causing mutations and the use of computer-based modeling to understand both structure and functional consequences of these mutations. Work has additionally more recently focused on potassium ion channel mutations that underlie a form of heritable pulmonary arterial hypertension. This work has provided information not only of novel pathways that contribute to this disease, but also to new routes of therapeutic management of this disorder. The goal of this approach is to unmask new and specific targets for the development of anti-arrhythmic drugs. Currently, work in the laboratory focused on the study of mechanisms underlying heritable arrhythmias in the context of complex genetic backgrounds has studied the cellular electrophysiology of cardiomyocytes differentiated from inducible pluripotent stem cells derived from family members of patients harboring disease-causing mutations. This approach has offered opportunities to screen drugs for effective disease management when multiple genes may be involved in the disease phenotype.

Academic Appointments

  • Hosack Professor of Pharmacology
  • Alumni Professor of Pharmacology (in Neuroscience)

Gender

  • Male

Credentials & Experience

Education & Training

  • BSc, 1968 Physics, University of Illinois, Urbana
  • PhD, 1972 Physics, University of Michigan, Ann Arbor

Committees, Societies, Councils

Biophysical Society

Honors & Awards

1967 Phi Eta Sigma (Engineering Honor Society) 

1968 Phi Beta Kappa, High Distinction in Physics 

1969 Danforth Fellow (University of Michigan) 

1978 Research Career Development Award (NHLBI) 

1982 Excellence in Teaching (University of Rochester) 

1989 Distinguished Lecturer, 8th Symposium on Calcium Antagonists, Tokyo, Japan 

2002 Dean's Lecturer: Cornell University School of Medicine 

2007 Keynote Lecturer Case Western Reserve/Metro Health Research Symposium  

2009 Dean's Distinguished Lecture in the Basic Sciences, Columbia University 

2010 Keynote Lecturer, Australian Physiological Society 

2012 Keynote Lecturer, Society for General Physiologist

Research

The focus of Dr. Kass' research program is the structure and function of ion channels that are expressed primarily in the heart. Dr. Kass has directed NIH and/or NSF sponsored research for forty-two years that has contributed to our understanding of the fundamental cellular and molecular basis of cardiac electrical activity through a multidisciplinary approach bridging basic biophysical and clinical science. Contributions from this work include the cellular basis of calcium-dependent arrhythmogenic activity in the heart, basic mechanisms of action of calcium channel blocking drugs, and the molecular events underlying the control of the duration of electrical events in the heart during sympathetic nerve stimulation. His laboratory has focused on understanding the molecular physiology and pharmacology of congenital arrhythmias. These arrhythmias are caused by inherited mutations in genes coding for ion channels and/or ion channel related proteins expressed in the heart. This work has contributed to an understanding of gene-specific risk factors caused by mutation-induced changes in heart ion channel activity, and to the development of a mutation-specific approach to manage these disorders. The mutation-specific therapeutic strategy, verified in genotyped patients, has established the principle that two variants of the same genetic disorder require dramatically different therapeutic strategies for disease management based on biophysical properties of specific genetic lesions. This approach has evolved from close collaborations with clinical colleagues in which information is shared from clinic to basic laboratory and back to clinic. Additional studies are aimed at unraveling the structural basis of mutation-induced, and potentially lethal, disease phenotypes using approaches such as voltage-clamp fluorometry to directly measure movement of gating machinery in the ion channel of interest as well as biochemical methods of directly probing structures of region of ion channels that are hotspots for disease-causing mutations and the use of computer-based modeling to understand both structure and functional consequences of these mutations. Work has additionally more recently focused on potassium ion channel mutations that underlie a form of heritable pulmonary arterial hypertension. This work has provided information not only of novel pathways that contribute to this disease, but also to new routes of therapeutic management of this disorder. The goal of this approach is to unmask new and specific targets for the development of anti-arrhythmic drugs. Currently, work in the laboratory focused on the study of mechanisms underlying heritable arrhythmias in the context of complex genetic backgrounds has studied the cellular electrophysiology of cardiomyocytes differentiated from inducible pluripotent stem cells derived from family members of patients harboring disease-causing mutations. This approach has offered opportunities to screen drugs for effective disease management when multiple genes may be involved in the disease phenotype.

Research Interests

  • Biophysics/Ion Channels
  • Cellular/Molecular/Developmental Neuroscience

Selected Publications

Cashman, J.R., et al., Antiarrhythmic Hit to Lead Refinement in a Dish Using Patient-Derived iPSC Cardiomyocytes. J Med Chem, 2021. 64(9): p. 5384-5403.

Johnson, M., et al., Human iPSC-derived cardiomyocytes and pyridyl-phenyl mexiletine analogs. Bioorg Med Chem Lett, 2021. 46: p. 128162.

McKeithan, W.L., et al., Reengineering an Antiarrhythmic Drug Using Patient hiPSC Cardiomyocytes to Improve Therapeutic Potential and Reduce Toxicity. Cell Stem Cell, 2020. 27(5): p. 813-821 e6.

Li, Y., et al., Regulation of IKs Potassium Current by Isoproterenol in Adult Cardiomyocytes Requires Type 9 Adenylyl Cyclase. Cells, 2019. 8(9).

Shandell, M.A., et al., Detection of Nav1.5 Conformational Change in Mammalian Cells Using the Noncanonical Amino Acid ANAP. Biophys J, 2019. 117(7): p. 1352-1363.

Bohnen MS, Ma L, Zhu N, Qi H, McClenaghan C, Gonzaga-Jauregui C, et al. Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension. Circ Genom Precis Med. 2018;11(10):e002087.

Peng G, Barro-Soria R, Sampson KJ, Larsson HP, and Kass RS. Gating mechanisms underlying deactivation slowing by two KCNQ1 atrial fibrillation mutations. Sci Rep. 2017;7:45911.

Barro-Soria R, Ramentol R, Liin SI, Perez ME, Kass RS, and Larsson HP. KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions. Proc Natl Acad Sci U S A. 2017;114(35):E7367-E76.

Bohnen MS, Roman-Campos D, Terrenoire C, Jnani J, Sampson KJ, Chung WK, et al. The Impact of Heterozygous KCNK3 Mutations Associated With Pulmonary Arterial Hypertension on Channel Function and Pharmacological Recovery. J Am Heart Assoc. 2017;6(9).

Bohnen MS, Peng G, Robey SH, Terrenoire C, Iyer V, Sampson KJ, et al. Molecular Pathophysiology of Congenital Long QT Syndrome. Physiol Rev. 2017;97(1):89-134.

Eng G, Lee BW, Protas L, Gagliardi M, Brown K, Kass RS, et al. Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes. Nat Commun. 2016;7:10312.

Lorberbaum T, Sampson KJ, Chang JB, Iyer V, Woosley RL, Kass RS, et al. Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation. J Am Coll Cardiol. 2016;68(16):1756-64.

Lorberbaum T, Sampson KJ, Woosley RL, Kass RS, and Tatonetti NP. An Integrative Data Science Pipeline to Identify Novel Drug Interactions that Prolong the QT Interval. Drug Saf. 2016;39(5):433-41.

Iyer V, Roman-Campos D, Sampson KJ, Kang G, Fishman GI, and Kass RS. Purkinje Cells as Sources of Arrhythmias in Long QT Syndrome Type 3. Sci Rep. 2015;5:13287.

Iyer V, Sampson KJ, and Kass RS. Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber. PLoS One. 2014;9(6):e97720.

Terrenoire C, Wang K, Tung KW, Chung WK, Pass RH, Lu JT, et al. Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. J Gen Physiol. 2013;141(1):61-72.