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1.  Introduction 
doi:10.1098/rstb.2013.0501
PMCID: PMC4142022  PMID: 25135962
neurocomputation; exosomes; microRNAs; epigenetics; neural modality; homeoproteins
3.  Systems biology and cancer 
doi:10.1016/j.pbiomolbio.2011.07.009
PMCID: PMC4021577  PMID: 21843772
4.  Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing 
British Journal of Pharmacology  2012;167(5):932-945.
Concerns over cardiac side effects are the largest single cause of compound attrition during pharmaceutical drug development. For a number of years, biophysically detailed mathematical models of cardiac electrical activity have been used to explore how a compound, interfering with specific ion-channel function, may explain effects at the cell-, tissue- and organ-scales. With the advent of high-throughput screening of multiple ion channels in the wet-lab, and improvements in computational modelling of their effects on cardiac cell activity, more reliable prediction of pro-arrhythmic risk is becoming possible at the earliest stages of drug development. In this paper, we review the current use of biophysically detailed mathematical models of cardiac myocyte electrical activity in drug safety testing, and suggest future directions to employ the full potential of this approach.
LINKED ARTICLE
This article is commented on by Gintant, pp. 929–931 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02096.x
doi:10.1111/j.1476-5381.2012.02020.x
PMCID: PMC3492977  PMID: 22568589
arrhythmia; Torsade de Pointes; computer model; hERG; QT prolongation
5.  Top-down causation: an integrating theme within and across the sciences? 
Interface Focus  2011;2(1):1-3.
This issue of the journal is focused on ‘top-down (downward) causation'. The words in this title, however, already raise or beg many questions. Causation can be of many kinds. They form our ways of ordering our scientific understanding of the world, all the way from the reductive concept of cause as elementary objects exerting forces on each other, through to the more holistic concept of attractors towards which whole systems move, and to adaptive selection taking place in the context of an ecosystem. As for ‘top’ and ‘down’, in the present scientific context, these are clearly metaphorical, as some of the articles in this issue of the journal make clear. Do we therefore know what we are talking about? The meeting at the Royal Society on which this set of papers is based included philosophers as well as scientists, and some of those (Jeremy Butterfield, Barry Loewer, Alan Love, Samir Okasha and Eric Scerri) have contributed articles to this issue. We would like also to thank those (Claus Kiefer, Peter Menzies, Jerome Feldman and David Papineau) who contributed only to the discussion meeting. Their contributions were also valuable, both at the meeting and by influencing the articles that have been written by others. We include a glossary with this introduction, composed by one of us (O'Connor). The clarification of the use of words and their semantic frames is an important role of philosophy, and this was evident in the discussions at the meeting and is now evident in many of the articles published here. Moreover, philosophical analysis is not limited to the papers by the professional philosophers. The idea of top-down causation is intimately related to concepts of emergence; indeed, it is a key factor in strong theories of emergence.
doi:10.1098/rsfs.2011.0110
PMCID: PMC3262305
top-down causation; emergence; epiphenomenalism; biocomplexity
6.  A theory of biological relativity: no privileged level of causation 
Interface Focus  2011;2(1):55-64.
Must higher level biological processes always be derivable from lower level data and mechanisms, as assumed by the idea that an organism is completely defined by its genome? Or are higher level properties necessarily also causes of lower level behaviour, involving actions and interactions both ways? This article uses modelling of the heart, and its experimental basis, to show that downward causation is necessary and that this form of causation can be represented as the influences of initial and boundary conditions on the solutions of the differential equations used to represent the lower level processes. These insights are then generalized. A priori, there is no privileged level of causation. The relations between this form of ‘biological relativity’ and forms of relativity in physics are discussed. Biological relativity can be seen as an extension of the relativity principle by avoiding the assumption that there is a privileged scale at which biological functions are determined.
doi:10.1098/rsfs.2011.0067
PMCID: PMC3262309  PMID: 23386960
downward causation; biological relativity; cardiac cell model; scale relativity
8.  Resolving the M-cell debate: Why and how 
doi:10.1016/j.hrthm.2011.06.002
PMCID: PMC3156238  PMID: 21787998
9.  Modeling Cardiac Ischemia 
Myocardial ischemia is one of the main causes of sudden cardiac death, with 80% of victims suffering from coronary heart disease. In acute myocardial ischemia, the obstruction of coronary flow leads to the interruption of oxygen flow, glucose, and washout in the affected tissue. Cellular metabolism is impaired and severe electrophysiological changes in ionic currents and concentrations ensue, which favor the development of lethal cardiac arrhythmias such as ventricular fibrillation. Due to the burden imposed by ischemia in our societies, a large body of research has attempted to unravel the mechanisms of initiation, sustenance, and termination of cardiac arrhythmias in acute ischemia, but the rapidity and complexity of ischemia-induced changes as well as the limitations in current experimental techniques have hampered evaluation of ischemia-induced alterations in cardiac electrical activity and understanding of the underlying mechanisms. Over the last decade, computer simulations have demonstrated the ability to provide insight, with high spatiotemporal resolution, into ischemic abnormalities in cardiac electrophysiological behavior from the ionic channel to the whole organ. This article aims to review and summarize the results of these studies and to emphasize the role of computer simulations in improving the understanding of ischemia-related arrhythmias and how to efficiently terminate them.
doi:10.1196/annals.1380.029
PMCID: PMC3313589  PMID: 17132797
myocardial ischemia; computer simulations; cardiac arrhythmias; vulnerability to electric shocks
10.  Editorial 
Interface Focus  2010;1(1):1-2.
doi:10.1098/rsfs.2010.0385
PMCID: PMC3262238  PMID: 22419969
11.  Differential and integral views of genetics in computational systems biology 
Interface Focus  2010;1(1):7-15.
This article uses an integrative systems biological view of the relationship between genotypes and phenotypes to clarify some conceptual problems in biological debates about causality. The differential (gene-centric) view is incomplete in a sense analogous to using differentiation without integration in mathematics. Differences in genotype are frequently not reflected in significant differences in phenotype as they are buffered by networks of molecular interactions capable of substituting an alternative pathway to achieve a given phenotype characteristic when one pathway is removed. Those networks integrate the influences of many genes on each phenotype so that the effect of a modification in DNA depends on the context in which it occurs. Mathematical modelling of these interactions can help to understand the mechanisms of buffering and the contextual-dependence of phenotypic outcome, and so to represent correctly and quantitatively the relations between genomes and phenotypes. By incorporating all the causal factors in generating a phenotype, this approach also highlights the role of non-DNA forms of inheritance, and of the interactions at multiple levels.
doi:10.1098/rsfs.2010.0444
PMCID: PMC3262251  PMID: 22419970
genotype; phenotype; computational systems biology
12.  Systems medicine and integrated care to combat chronic noncommunicable diseases 
Genome Medicine  2011;3(7):43.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
doi:10.1186/gm259
PMCID: PMC3221551  PMID: 21745417
13.  Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk 
Cardiovascular Research  2011;91(1):53-61.
Aims
The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC50) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.
Methods and results
We collected multiple ion channel data (hERG, Na, l-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC50 values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.
Conclusion
The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.
doi:10.1093/cvr/cvr044
PMCID: PMC3112019  PMID: 21300721
Computer modelling; Drug development; Pharmacology; Risk prediction; Torsade-de-pointes
14.  The Cardiac Physiome: perspectives for the future 
Experimental physiology  2008;94(5):597-605.
The Physiome Project, exemplified by the Cardiac Physiome, is now 10 years old. In this article, we review past progress and future challenges in developing a quantitative framework for understanding human physiology that incorporates both genetic inheritance and environmental influence. Despite the enormity of the challenge, which is certainly greater than that facing the pioneers of the human genome project 20 years ago, there is reason for optimism that real and accelerating progress is being made.
doi:10.1113/expphysiol.2008.044099
PMCID: PMC2854146  PMID: 19098089
15.  Biophysics and systems biology 
Biophysics at the systems level, as distinct from molecular biophysics, acquired its most famous paradigm in the work of Hodgkin and Huxley, who integrated their equations for the nerve impulse in 1952. Their approach has since been extended to other organs of the body, notably including the heart. The modern field of computational biology has expanded rapidly during the first decade of the twenty-first century and, through its contribution to what is now called systems biology, it is set to revise many of the fundamental principles of biology, including the relations between genotypes and phenotypes. Evolutionary theory, in particular, will require re-assessment. To succeed in this, computational and systems biology will need to develop the theoretical framework required to deal with multilevel interactions. While computational power is necessary, and is forthcoming, it is not sufficient. We will also require mathematical insight, perhaps of a nature we have not yet identified. This article is therefore also a challenge to mathematicians to develop such insights.
doi:10.1098/rsta.2009.0245
PMCID: PMC3263808  PMID: 20123750
cell biophysics; systems biology; computational biology; mathematical biology
16.  Could there be a Synthesis between Western and Oriental Medicine, and with Sasang Constitutional Medicine in Particular? 
Attitudes towards oriental medicine are changing for two major reasons. The first is that many patients, even in the West, are choosing to use its practitioners and methods. The second is that the rise of Systems Biology may offer a better basis for dialogue, and even for synthesis, between the oriental and Western traditions. However, a lot of work is needed to clear the way for such dialogue and synthesis. Much of this work should be devoted to clarifying the meanings of the terms used, and the framework of theory and practice within which oriental methods operate. But it is also necessary for Systems Biology itself to mature as a discipline, particularly at the higher levels of biological organization since it is at these levels that oriental medicine derives its ideas and practice. Higher level Systems Biology could be a basis for interpretation of the Korean version of oriental medicine: Sasang constitutional medicine since it seeks patient specific analysis and treatment, and the mathematical methods of systems biology could be used to analyze the central concept of balance in Sasang.
doi:10.1093/ecam/nep101
PMCID: PMC2741627  PMID: 19745006
oriental medicine; Physiome Project; Sasang constitutional medicine; Systems Biology
17.  Systems biology and the virtual physiological human 
doi:10.1038/msb.2009.51
PMCID: PMC2724980  PMID: 19638973
18.  Origins of Systems Biology in William Harvey’s Masterpiece on the Movement of the Heart and the Blood in Animals 
In this article we continue our exploration of the historical roots of systems biology by considering the work of William Harvey. Central arguments in his work on the movement of the heart and the circulation of the blood can be shown to presage the concepts and methods of integrative systems biology. These include: (a) the analysis of the level of biological organization at which a function (e.g. cardiac rhythm) can be said to occur; (b) the use of quantitative mathematical modelling to generate testable hypotheses and deduce a fundamental physiological principle (the circulation of the blood) and (c) the iterative submission of his predictions to an experimental test. This article is the result of a tri-lingual study: as Harvey’s masterpiece was published in Latin in 1628, we have checked the original edition and compared it with and between the English and French translations, some of which are given as notes to inform the reader of differences in interpretation.
doi:10.3390/ijms10041658
PMCID: PMC2680639  PMID: 19468331
William Harvey; heart rhythm; circulation of the blood; mathematical deduction: experimental verification; systems biology
20.  Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing 
British Journal of Pharmacology  2012;167(5):932-945.
Concerns over cardiac side effects are the largest single cause of compound attrition during pharmaceutical drug development. For a number of years, biophysically detailed mathematical models of cardiac electrical activity have been used to explore how a compound, interfering with specific ion-channel function, may explain effects at the cell-, tissue- and organ-scales. With the advent of high-throughput screening of multiple ion channels in the wet-lab, and improvements in computational modelling of their effects on cardiac cell activity, more reliable prediction of pro-arrhythmic risk is becoming possible at the earliest stages of drug development. In this paper, we review the current use of biophysically detailed mathematical models of cardiac myocyte electrical activity in drug safety testing, and suggest future directions to employ the full potential of this approach.
LINKED ARTICLE
This article is commented on by Gintant, pp. 929–931 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02096.x
doi:10.1111/j.1476-5381.2012.02020.x
PMCID: PMC3492977  PMID: 22568589
arrhythmia; Torsade de Pointes; computer model; hERG; QT prolongation

Results 1-20 (20)