A Collaboration Between Cornell and Gene Network Sciences Principal Investigators: Robert F. Gilmour, Jr., PhD Professor of Physiology Associate Dean for Research and Graduate Education College of Veterinary Medicine Cornell University Jeffrey J. Fox, MS, PhD Vice President Cardiovascular Research Gene Network Sciences

©2009 Gene Network Sciences, Inc. All rights reserved. Please do not distribute outside of Lockheed Martin.. GNS Basics Molecular Biology Chemistry Bioinformatics Mathematics Computational Physics Computer Science Clinical Medicine Privately-held computational biotechnology company Incorporated in 2000 out of Cornell University Offices in Cambridge, MA and Ithaca, NY Successfully partnered with several top pharmaceutical companies & leading academic institutions & clinics Majority shareholder of Fina Technologies, Inc. – quantitative finance and e-commerce start-up financed by media/information conglomerate Reed Elsevier

Gene Network Sciences Jeffrey J. Fox

A Collaboration Between Cornell and Gene Network Sciences Objectives:  Develop a detailed computer model of the electrical activity of the canine ventricular myocyte (CVM model)  Develop software to utilize the CVM model for in silico drug testing  Develop software to utilize any computer model for simulations and drug testing

How did we get started?  Previously established working relationship between Physics graduate student (JJ Fox) and advisor (RF Gilmour)  Previously established connection between GNS and Cornell (GNS co-founders former Cornell Physics graduate students)  Good communication between all parties and good understanding of academia by the industry partners - and vice versa  Natural scientific basis for collaboration

Publications Pre-SBIR  Fox JJ, McHarg JL, Gilmour RF Jr: Ionic mechanism of cardiac alternans. American Journal of Physiology 282:H516-H530,  Fox JJ, Riccio ML, Hua F, Bodenschatz E, Gilmour RF Jr: Spatiotemporal transition to conduction block in cardiac tissue. Circulation Research 90: ,  Fox JJ, Gilmour RF Jr, Bodenschatz E: Conduction block in one dimensional heart fibers. Physical Review Letters 89: ,  Fox JJ, Bodenschatz E, Gilmour RF Jr: Period-doubling instability and memory in cardiac tissue. Physical Review Letters 89: ,  Fox JJ, Riccio ML, Drury P, Werthman A, Gilmour RF Jr: Dynamic mechanism for conduction block in heart tissue. New Journal of Physics 5: , 2003.

What worked?

Grants  NIH R43 HL073536, “Data-driven model of cardiac function and dysfunction”, JJ Fox, PI, RF Gilmour Jr, Consultant, , $100,000  NIH R43 HL079709, “Computer model of canine cardiac signaling networks”, JJ Fox, PI, RF Gilmour Jr, Consultant, , $100,000  NIH R43 HL077938, “Software for simulating cardiac electrical activity”, JJ Fox, PI, RF Gilmour Jr, Consultant, , $99,960  NIH R44 HL077938, “Simulation software for cardiac arrhythmia risk assessment”, JJ Fox, PI, RF Gilmour Jr, PI Consortium, ; $749, 921 ($110,037 to RFG)  NIH R01 HL075515, “Computer model of the canine ventricle”, RF Gilmour Jr, PI, ; $1,674,000 ($1,037,000 to GNS).

What worked?

CVM model ~ 13 state variables ~ 60 parameters I to I K1 I Kr I Ks I Kp I NaC a Na + Ca 2+ I NaK K+K+ Na + I Ca I Ca,b I Na,b I p(Ca) I Ca,K I Na J p(Ca) J leak J release I i = g i ·(V - E i ) g i = f(V,t) Pump Exchanger Voltage-gated ion channel Non-voltage-gated ion channel = ∑I i dVdV dtdt

CVM model

Citations Over 100 citations Title: Reaction-diffusion systems for the macroscopic bidomain model of the cardiac electric fieldReaction-diffusion systems for the macroscopic bidomain model of the cardiac electric field Author(s): Veneroni MSource: NONLINEAR ANALYSIS-REAL WORLD APPLICATIONS Volume: 10 Issue: 2 Pages: Published: APR 2009 Title: Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac deathRepolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death Author(s): Sridhar A, Nishijima Y, Terentyev D, et al.Source: AMERICAN JOURNAL OF PHYSIOLOGY REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Volume: 295 Issue: 5 Pages: R1463-R1472 Published: NOV 2008 Title: Properties of two human atrial cell models in tissue: Restitution, memory, propagation, and reentryProperties of two human atrial cell models in tissue: Restitution, memory, propagation, and reentry Author(s): Cherry EM, Evans SJSource: JOURNAL OF THEORETICAL BIOLOGY Volume: 254 Issue: 3 Pages: Published: OCT Title: Calsequestrin-mediated mechanism for cellular calcium transient alternansCalsequestrin-mediated mechanism for cellular calcium transient alternans Author(s): Restrepo JG, Weiss JN, Karma ASource: BIOPHYSICAL JOURNAL Volume: 95 Issue: 8 Pages: Published: OCT Title: Indeterminacy of spatiotemporal cardiac alternansIndeterminacy of spatiotemporal cardiac alternans Author(s): Zhao XPSource: PHYSICAL REVIEW E Volume: 78 Issue: 1 Article Number: Part: Part 1 Published: JUL 2008

What worked?

 Buzzard GT, Fox JJ, Siso-Nadal F: Sharp interface and voltage conservation in the phase field method: Application to cardiac electrophysiology. SIAM Journal of Scientific Computation 30: ,  Rand DR, Zhou Q, Buzzard GT, Fox JJ: Computationally efficient strategy for modeling the effect of ion current modifiers. IEEE Transactions in Biomedical Engineering 55:3-13,  Fox JJ, Buzzard GT, Miller R, Siso-Nadal F: Massively parallel simulation of cardiac electrical wave propagation on Blue Gene. In: Parallel Computing: Architectures, Algorithms and Applications (Proceedings of the International Conference ParCo 2007). John von Neumann Institute for Computing, Julich, NIC Series, Vol. 38: ,  Zhou Q, Zygmunt A, Cordeiro J, Siso-Nadal F, Miller RE, Buzzard GT, Gilmour RF Jr, Fox JJ. Identification of I Kr kinetics and drug binding in native myocytes. (in preparation) Publications Post-SBIR

Patents  Gilmour, R.F., Fox, J.J, and Riccio, M. “Method of identifying strategies for treatment or prevention of ventricular fibrillation and ventricular tachycardia.” US Patent Application , October 25,  Fox, J.J., Rand, D.G., Zhou, Q., and Buzzard, G.T. “Systems and methods for testing and modeling drug effects.” US Patent Application 11/799052, April 30,  Fox, J. J., Hill, C. C., and Periwal, V. “Scale free network inference methods.” US Patent Application , July 31, 2003.

What worked?

 Christini DJ, Karma A, Riccio ML, Culianu CA, Fox JJ, Gilmour RF Jr: Control of electrical alternans in canine cardiac Purkinje fibers. Physical Review Letters 96:104101,  Siso-Nadal F, Otani NF, Gilmour RF Jr, Fox JJ: Boundary-induced reentry in homogeneous excitable tissue. Physical Review E 78: ,  Gelzer ARM, Koller ML, Otani NO, Fox JJ, Enyeart M, Bartoli CR, Riccio ML, Moïse NS, Gilmour RF Jr: Dynamic mechanism for initiation of ventricular fibrillation in vivo – antifibrillatory effects through modulation of restitution parameters. Circulation 118: ,  Siso-Nadal F, Buzzard GT, Miller RE, Otani NF, Fenton FH, Cherry EM, Gilmour RF Jr, Fox JJ. Role of dynamical and anatomical heterogeneities in the onset of arrhythmia. (in preparation) Publications Post-SBIR

What didn’t work?  Protracted negotiation of initial Phase I contract  Little or no interaction on the business side between Cornell and GNS  No commercially viable product produced  Cardiovascular research unit of GNS not sustainable