Introduction to biological complexity as a missing link in drug discovery

References

• Silvester NC, George CH. Searching for new cardiovascular drugs: towards improved systems for drug screening? Expert Opinion on Drug Discovery. 2011;6:1155–1170.
   PubMed Web of Science ®Google Scholar
• Gintant G, Sager PT, Stockbridge N. Evolution of strategies to improve cardiac safety testing. Nat Rev Drug Disc. 2016;15:457–471.
   PubMed Web of Science ®Google Scholar
• Soldner F, Jaenisch R. iPSC disease modeling. Science. 2012;338:1155–1156.
   PubMed Web of Science ®Google Scholar
• Denning C, Borgdoff V, Crutchley J, et al. Cardiomyocytes from human pluripotent stem cells: from laboratory curiosity to industrial biomedical platform. Biochim Biophys Acta. 2016;1863:1728–1748.
   PubMed Web of Science ®Google Scholar
• Goldring C, Antoine DJ, Bonner F, et al. Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury. Hepatology. 2017;65:710–721.
   PubMed Web of Science ®Google Scholar
• Goversen B, van der Heyden MAG, van Veen TAB, et al. The immature electrophysiological phenotype of iPSC-CMs still hampers in vitro drug screening: special focus on IK1. Pharm Ther. 2018;183:127–136.
   PubMed Web of Science ®Google Scholar
• Mossman K. The complexity paradox: the more answers we find, the more questions we have. Oxford: Oxford University Press; 2014.
   Google Scholar
• Perez-Nueno VI. Using quantitative systems pharmacology for novel drug discovery. Expert Opin Drug Discov. 2015;10:1315–1331.
   PubMed Web of Science ®Google Scholar
• Sorger PK, Allerheiligen SRB, Abernethy DR, et al. Quantitative and systems pharmacology in the post-genomic era: new approaches to discovering drugs and understanding therapeutic mechanisms. NIH White Paper by the QSP Workshop Group. 2001. [2018 May 10]. Available from http://www.nigms.nih.gov/training/documents/systemspharmawpsorger2011.pdf
   Google Scholar
• Golden F. Shaping life in the lab. Time Magazine. 1981;Mar 09.
   Google Scholar
• Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Disc. 2011;10:507–519.
   PubMed Web of Science ®Google Scholar
• Swinney DC. The value of translational biomarkers to phenotypic assays. Front Pharmacol. 2014;5:1–4.
   PubMed Web of Science ®Google Scholar
• Schlueter PJ, Peterson RT. Systematizing serendipity for cardiovascular drug discovery. Circulation. 2009;120:255–263.
   PubMed Web of Science ®Google Scholar
• George CH, Mitchell AN, Preece R, et al. Pleiotropic mechanisms of action of perhexiline in heart failure. Expert Opin Ther Pat. 2016;29:1049–1059.
   Google Scholar
• Chaitman BR, Skettino SL, Parker JO, et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–1382.
   PubMed Web of Science ®Google Scholar
• Lee L, Campbell R, Scheuermann-Freestone M, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005;112:3280–3288.
   PubMed Web of Science ®Google Scholar
• Antzelevitch C, Burashnikov A, Sicouri S, et al. Electrophysiological basis for the antiarrhythmic actions of ranolazine. Heart Rhythm. 2011;8:1281–1290.
   PubMed Web of Science ®Google Scholar
• Parikh A, Mantravadi R, Kozhevnikov D, et al. Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsade de pointes in long QT type 2. Heart Rhythm. 2012;9:953–960.
   PubMed Web of Science ®Google Scholar
• Kennedy JA, Unger SA, Horowitz J. Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol. 1996;52:273–280.
   PubMed Web of Science ®Google Scholar
• Ceccarelli SM, Chomienne O, Gubler M, et al. Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem. 2011;54:3109–3152.
   PubMed Web of Science ®Google Scholar
• Watanabe H, Chopra N, Laver D, et al. Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans. Nat Med. 2009;15:380–383.
   PubMed Web of Science ®Google Scholar
• van der Werf C, Kannankeril PJ, Sacher F, et al. Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. J Am Coll Cardiol. 2011;57:2244–2254.
   PubMed Web of Science ®Google Scholar
• Sikkel MB, Collins TP, Rowlands C, et al. Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current. Cardiovasc Res. 2013;98:286–296.
   PubMed Web of Science ®Google Scholar
• Hilliard FA, Steele DS, Laver D, et al. Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass. J Mol Cell Cardiol. 2010;48:293–301.
   PubMed Web of Science ®Google Scholar
• Liu N, Denegri M, Ruan Y, et al. Flecainide exerts an antiarrhythmic effect in a mouse model of catecholaminergic polymorphic ventricular tachycardia by increasing the threshold for triggered activity. Circ Res. 2011;109:291–295.
   PubMed Web of Science ®Google Scholar
• Sikkel MB, Collins TP, Rowlands C, et al. Triple mode of action of flecainide in catecholaminergic polymorphic ventricular tachycardia: reply. Cardiovasc Res. 2013;98:327–328.
   PubMed Web of Science ®Google Scholar
• Steele DS, Hwang H-S, Knollmann BC. Triple mode of action of flecainide in catecholaminergic polymorphic ventricular tachycardia. Cardiovasc Res. 2013;98:326–328.
   PubMed Web of Science ®Google Scholar
• Yang P-C, Moreno JD, Miyake CY, et al. In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia. J Physiol. 2016;594:567–593.
   PubMed Web of Science ®Google Scholar
• Williams AJ, Bannister ML, Thomas NL, et al. Questioning flecainide’s mechanism of action in the treatment of catecholaminergic polymorphic ventricular tachycardia. J Physiol. 2016;594:6431–6432.
   PubMed Web of Science ®Google Scholar
• Bannister ML, Alvarez-Laviada A, Thomas NL, et al. Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor. Br J Pharmacol. 2016;173:2446–2459.
   PubMed Web of Science ®Google Scholar
• Bannister ML, Thomas NL, Sikkel MB, et al. The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2. Circ Res. 2015;116:1324–1335.
   PubMed Web of Science ®Google Scholar
• Fang Y. Troubleshooting and deconvoluting label-free cell phenotypic assays in drug discovery. J Pharm Tox Methods. 2013;67:69–81.
   PubMed Web of Science ®Google Scholar
• Wooley JC, Lin HS. Catalyzing inquiry at the interface of computing and biology. Wooley JC, HS L, editors. Washington, USA: National Academies Press; 2005.
   Google Scholar
• George CH, Parthimos D, Silvester NC. A network-oriented perspective on cardiac calcium signaling. Am J Physiol Cell Physiol. 2012;303:C897–C910.
   PubMed Web of Science ®Google Scholar
• Sarkar AX, Christini DJ, Sobie EA. Exploiting mathematical models to illuminate electrophysiological variability between individuals. J Physiol. 2012;590:2555–2567.
   PubMed Web of Science ®Google Scholar
• Gomez JF, Cardona K, Trenor B. Lessons learned from multi-scale modeling of the failing heart. J Mol Cell Cardiol. 2015;89:146–159.
   PubMed Web of Science ®Google Scholar
• Balazsi G, van Oudenaarden A, Collins JJ. Cellular decision making and biological noise: from microbes to mammals. Cell. 2011;144:910–925.
   PubMed Web of Science ®Google Scholar
• Bhalla US, Iyengar R. Emergent properties of networks of biological signaling pathways. Science. 1999;283:381–387.
   PubMed Web of Science ®Google Scholar
• Jordan JD, Landau EM, Iyengar R. Signaling networks: the origins of cellular multitasking. Cell. 2000;103:193–200.
   PubMed Web of Science ®Google Scholar
• Barabasi A-L, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human disease. Nat Rev Genet. 2011;12:56–68.
   PubMed Web of Science ®Google Scholar
• Barabasi A-L, Oltvai ZN. Network biology: understanding the cell’s functional organization. Nat Rev Genet. 2004;5:101–113.
   PubMed Web of Science ®Google Scholar
• Verspignani A. The fragility of interconnected networks. Nature. 2010;464:984–985.
   PubMed Web of Science ®Google Scholar
• Bers DM. Cardiac excitation–contraction coupling. Nature. 2002;415:198–205.
   PubMed Web of Science ®Google Scholar
• Jeong H, Tombor B, Albert R, et al. The large-scale organization of metabolic networks. Nature. 2000;407:651–654.
   PubMed Web of Science ®Google Scholar
• Stockbridge N, Blank M, Hausner EA, et al. Evaluating the renal safety of investigational new drugs: where should we be going? Clin Pharmacol Ther. 2017;102:387–388.
   PubMed Web of Science ®Google Scholar
• Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol. 2000;1:11–21.
   PubMed Web of Science ®Google Scholar
• Kholodenko B, Yaffe MB, Kolch W. Computational approaches for analyzing information flow in biological networks. Sci Signal. 2012;5:re1.
   PubMed Web of Science ®Google Scholar
• Milo R, Shen-Orr S, Itzkovitz S, et al. Network motifs: simple building blocks of complex networks. Science. 2002;298:824–827.
   PubMed Web of Science ®Google Scholar
• Kenakin T. Functional selectivity and biased receptor signaling. J Pharm Exp Ther. 2001;336:296–302.
   Google Scholar
• Pomatto LCD, Davies KJA. The role of declining adaptive homeostasis in ageing. J Physiol. 2017;595:7275–7309.
   PubMed Web of Science ®Google Scholar
• Lipsitz LA, Goldberger AL. Loss of ‘complexity’ and aging. Potential applications of fractals and chaos theory to senescence. JAMA. 1992;267:1806–1809.
   PubMed Web of Science ®Google Scholar
• Lewis KJ, Silvester NC, Barberini-Jammaers SR, et al. A new system for profiling drug-induced calcium signal perturbation in human embryonic stem cell-derived cardiomyocytes. J Biomol Screen. 2015;20:330–340.
   PubMed Web of Science ®Google Scholar
• George CH, Edwards DH. Decoding Ca2+ signals as a non-electrophysiological method for assessing drug toxicity in stem cell-derived cardiomyocytes. In: Clements M, Roquemore E, editors. Stem cell-derived methods in toxicology, methods in pharmacology and toxicology. New York: Springer; 2017. p. 173–190.
   Google Scholar
• George CH. Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? Cardiovasc Res. 2008;77:302–314.
   PubMed Web of Science ®Google Scholar
• Mackey MC, Glass L. Oscillation and chaos in physiological control systems. Science. 1977;197:287–289.
   PubMed Web of Science ®Google Scholar
• Glass L. Synchronization and rhythmic processes in physiology. Nature. 2001;410:277–284.
   PubMed Web of Science ®Google Scholar
• Glass L, Zeng W-Z. Complex bifurcations and chaos in simple theoretical models of cardiac oscillations. Ann N Y Acad Sci. 2006;591:316–327.
   Google Scholar
• Morrison SF. Central control of body temperature. F1000Research. 2016;5:880.
   Google Scholar
• Kirsch GE, Trepakova ES, Brimecombe JC, et al. Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern. J Pharm Exp Ther. 2004;50:93–101.
   Google Scholar
• Windley MJ, Mann SA, Vandenberg JI, et al. Temperature effects on kinetics of Kv11.1 durg block have important consequences for in silico proarrhythmic risk prediction. Mol Pharmacol. 2016;90:1–11.
   PubMed Web of Science ®Google Scholar
• Gaeta SA, Christini DJ. Non-linear dynamics of cardiac alternans: subcellular to tissue-level mechanisms of arrhythmia. Front Physiol. 2012;3:157.
   PubMed Web of Science ®Google Scholar
• Montagutelli X. Effect of genetic background on the phenotype of mouse mutations. J Am Soc Nephrol. 2000;11:S101–S105.
   PubMed Web of Science ®Google Scholar
• Jelcick AS, Yuan Y, Leehy BD, et al. Genetic variations strongly influence phenotypic outcome in the mouse retina. PLoS One. 2011;6:e21858.
   PubMed Web of Science ®Google Scholar
• Graham J, Swarts JL, Mooney M, et al. Extensive homeostatic T cell phenotypic variation within the collaborative cross. Cell Rep. 2017;21:2313–2325.
   PubMed Web of Science ®Google Scholar
• Bers DM. Excitation–contraction coupling and contractile force. 2nd ed. Kluwer Academic Publishers, Dordrecht, Boston; 2001.
   Google Scholar
• Boileau E, George CH, Parthimos D, et al. Synergy between intercellular communication and intracellular Ca2+ handling in arrhythmogenesis. Ann Biomed Engineer. 2015;43:1614–1625.
   PubMed Web of Science ®Google Scholar
• Lee EK, Tran DD, Keung W, et al. Machine learning of human pluripotent stem cell-derived engineered cardiac tissue contractility for automated drug classification. Stem Cell Rep. 2017;9:1560–1572.
   PubMed Web of Science ®Google Scholar
• Perrone-Filardi P, Coca A, Galderisi M, et al. Non-invasive cardiovascular imaging for evaluating subclinical target organ damage in hypertensive patients. Eur Heart J Cardiovasc Imag. 2017;18:945–960.
   PubMed Web of Science ®Google Scholar
• Halcox JPJ, Wareham K, Cardew A, et al. Assessment of remote heart rhythm sampling using the AliveCor heart monitor to screen for atrial fibrillation- the REHEARSE-AF study. Circulation. 2017;136:1784–1794.
   PubMed Web of Science ®Google Scholar
• Jones AR, Edwards DH, Cummins MJ, et al. A systemized approach to investigate Ca2+ synchronization in clusters of human induced pluripotent stem-cell derived cardiomyocytes. Front Cell Dev Biol. 2016;3:89.
   PubMedGoogle Scholar
• Junker JP, van Oudenaarden A. Every cell is special: genome-wide studies add a new dimension to single-cell biology. Cell. 2014;157:8–12.
   PubMed Web of Science ®Google Scholar
• Kane C, Du DTM, Hellen N, et al. The fallacy of assigning chamber specificity to iPSC cardiac myocytes from action potential morphology. Biophys J. 2016;110:281–283.
   PubMed Web of Science ®Google Scholar
• Nakamura N, Yamazawa T, Okubo Y, et al. Temporal switching and cell-to-cell variability in Ca2+ release activity in mammalian cells. Mol Syst Biol. 2009;5:247.
   PubMed Web of Science ®Google Scholar
• Quaranta V, Garbett S. Not all noise is waste. Nat Methods. 2010;7:269–272.
   PubMed Web of Science ®Google Scholar
• Waks Z, Klein AM, Silver PA. Cell-to-cell variability of alternative RNA splicing. Mol Syst Biol. 2011;7:506.
   PubMed Web of Science ®Google Scholar
• Ward LD, Kellis M. Interpreting noncoding genetic variation in complex traits and human disease. Nat Biotech. 2012;30:1095–1106.
   PubMed Web of Science ®Google Scholar
• Heisenberg W. Physics and philosophy: the revolution in modern science, Harper and brothers publishers, New York. 1958.
   Google Scholar
• Broido AD, Clauset A. Scale-free networks are rare. arXiv:180103400 [physicssoc-ph]. 2018.
   Google Scholar
• Klarreich E Scant evidence of power laws found in real-world networks. Quanta Magazine. 2018;20180215.
   Google Scholar
• Tran HJ, Speyer G, Kiefer J, et al. Contextualization of drug-mediator relations using evidence networks. BMC Bioinformatics. 2017;18(Suppl 7):252.
   PubMedGoogle Scholar