A Collaboration Between Cornell andGene Network Sciences

Principal Investigators:

Robert F. Gilmour, Jr., PhDProfessor of PhysiologyAssociate Dean for Research and Graduate EducationCollege of Veterinary MedicineCornell University

Jeffrey J. Fox, MS, PhDVice PresidentCardiovascular ResearchGene Network Sciences

©2009 Gene Network Sciences, Inc. All rights reserved.Please do not distribute outside of Lockheed Martin..

GNS Basics

Privately-held computationalbiotechnology 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

http://www.gnsbiotech.com/

Gene Network Sciences

Jeffrey J. Fox

A Collaboration Between Cornell andGene 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, 2002. Fox JJ, Riccio ML, Hua F, Bodenschatz E, Gilmour RF Jr:

Spatiotemporal transition to conduction block in cardiac tissue. Circulation Research 90:297-304, 2002.

Fox JJ, Gilmour RF Jr, Bodenschatz E: Conduction block in one dimensional heart fibers. Physical Review Letters 89: 198101, 2002.

Fox JJ, Bodenschatz E, Gilmour RF Jr: Period-doubling instability and memory in cardiac tissue. Physical Review Letters 89: 138101, 2002.

Fox JJ, Riccio ML, Drury P, Werthman A, Gilmour RF Jr: Dynamic mechanism for conduction block in heart tissue. New Journal of Physics 5:101.1-101.14, 2003.

What worked? Secured ample funding for initial stages of

collaboration Developed one of the most highly used computer Developed one of the most highly used computer

models of cardiac electrical activitymodels of cardiac electrical activity Generated new software for model simulationsGenerated new software for model simulations Fostered long-term collaborative relationship that Fostered long-term collaborative relationship that

generated information beyond the original objectivesgenerated information beyond the original objectives

Grants NIH R43 HL073536, “Data-driven model of cardiac function and

dysfunction”, JJ Fox, PI, RF Gilmour Jr, Consultant, 2003-2004, $100,000

NIH R43 HL079709, “Computer model of canine cardiac signaling networks”, JJ Fox, PI, RF Gilmour Jr, Consultant, 2004-2005, $100,000

NIH R43 HL077938, “Software for simulating cardiac electrical activity”, JJ Fox, PI, RF Gilmour Jr, Consultant, 2004-2005, $99,960

NIH R44 HL077938, “Simulation software for cardiac arrhythmia risk assessment”, JJ Fox, PI, RF Gilmour Jr, PI Consortium, 2006-2008; $749, 921 ($110,037 to RFG)

NIH R01 HL075515, “Computer model of the canine ventricle”, RF Gilmour Jr, PI, 2003-2008; $1,674,000 ($1,037,000 to GNS).

What worked? Secured ample funding for initial stages of Secured ample funding for initial stages of

collaborationcollaboration Developed one of the most highly used computer

models of cardiac electrical activity Generated new software for model simulationsGenerated new software for model simulations Fostered long-term collaborative relationship that Fostered long-term collaborative relationship that

generated information beyond the original objectivesgenerated information beyond the original objectives

CVM model~ 13 state variables~ 60 parameters

Ito IK1 IKr IKs IKp

INaCaNa+

Ca2+

INaKK+

Na+

ICa ICa,bINa,b

Ip(Ca)ICa,K

INa

Jp(Ca)

Jleak

Jrelease

Ii = gi·(V - Ei)

gi = f(V,t)

Pump

Exchanger

Voltage-gated ion channelNon-voltage-gated ion channel

= ∑IidVdt

CVM model

CitationsOver 100 citations

Title: Reaction-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: 849-868   Published: APR 2009

Title: Repolarization 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 reentry Author(s): Cherry EM, Evans SJSource: JOURNAL OF THEORETICAL BIOLOGY   Volume: 254   Issue: 3 Pages: 674-690   Published: OCT 7 2008

Title: Calsequestrin-mediated mechanism for cellular calcium transient alternans Author(s): Restrepo JG, Weiss JN, Karma ASource: BIOPHYSICAL JOURNAL   Volume: 95   Issue: 8 Pages: 3767-3789   Published: OCT 15 2008

Title: Indeterminacy of spatiotemporal cardiac alternans Author(s): Zhao XPSource: PHYSICAL REVIEW E   Volume: 78   Issue: 1 Article Number: 011902   Part: Part 1   Published: JUL 2008

What worked? Secured ample funding for initial stages of Secured ample funding for initial stages of

collaborationcollaboration Developed one of the most highly used computer Developed one of the most highly used computer

models of cardiac electrical activitymodels of cardiac electrical activity Generated new software for model simulations Fostered long-term collaborative relationship that Fostered long-term collaborative relationship that

generated information beyond the original objectivesgenerated information beyond the original objectives

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 30:837-854, 2008.

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, 2008.

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. 38:609-616, 2007.

Zhou Q, Zygmunt A, Cordeiro J, Siso-Nadal F, Miller RE, Buzzard GT, Gilmour RF Jr, Fox JJ. Identification of IKr 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 20070249948, October 25, 2007.

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, 2007.

Fox, J. J., Hill, C. C., and Periwal, V. “Scale free network inference methods.” US Patent Application 20030144823, July 31, 2003.

What worked? Secured ample funding for initial stages of Secured ample funding for initial stages of

collaborationcollaboration Developed one of the most highly used computer Developed one of the most highly used computer

models of cardiac electrical activitymodels of cardiac electrical activity Generated new software for model simulationsGenerated new software for model simulations Fostered long-term collaborative relationship that

generated information beyond the original objectives

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, 2006.

Siso-Nadal F, Otani NF, Gilmour RF Jr, Fox JJ: Boundary-induced reentry in homogeneous excitable tissue. Physical Review E 78: 031925, 2008.

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 118:1123-1129, 2008.

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