Denis Noble CBE FRS FMedSci MAE (born 16 November 1936) is a British biologist who held the Burdon Sanderson Chair of Cardiovascular Physiology at the University of Oxford from 1984 to 2004 and was appointed Professor Emeritus and co-Director of Computational Physiology. He is one of the pioneers of systems biology and developed the first viable mathematical model of the working heart in 1960. He is also a philosopher of biology, and his books The Music of Life and Dance to the Tune of Life challenge the foundations of current biological sciences, question the central dogma, its unidirectional view of information flow, and its imposition of a bottom-up methodology for research in the life sciences. Phone: 01865 272528 Address: Sherrington Building, Parks Road, OX1 3PT
On the tenth anniversary of two key International Conference on Harmonisation (ICH) guidelines re... more On the tenth anniversary of two key International Conference on Harmonisation (ICH) guidelines relating to cardiac proarrhythmic safety, an initiative aims to consider the implementation of a new paradigm that combines in vitro and in silico technologies to improve risk assessment. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative (co-sponsored by the Cardiac Safety Research Consortium, Health and Environmental Sciences Institute, Safety Pharmacology Society and FDA) is a bold and welcome step in using computational tools for regulatory decision making. This review compares and contrasts the state-of-the-art tools from empirical to mechanistic models of cardiac electrophysiology, and how they can and should be used in combination with experimental tests for compound decision making.
Must higher level biological processes always be derivable from lower level data and mechanisms, ... more 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 determ...
The successful identification of drug targets requires an understanding of the high-level functio... more The successful identification of drug targets requires an understanding of the high-level functional interactions between the key components of cells, organs and systems, and how these interactions change in disease states. This information does not reside in the genome, or in the individual proteins that genes code for, it is to be found at a higher level. Genomics will succeed in revolutionising pharmaceutical research and development only if these interactions are also understood by determining the logic of healthy and diseased states. The rapid growth in biological databases, models of cells, tissues and organs, and in computing power has made it possible to explore functionality all the way from the level of genes to whole organs and systems. Combined with genomic and proteomic data, in silico simulation technology is set to transform all stages of drug discovery and development. The major obstacle to achieving this will be obtaining the relevant experimental data at levels hig...
Successful physiological analysis requires an understanding of the functional interactions betwee... more Successful physiological analysis requires an understanding of the functional interactions between the key components of cells, organs, and systems, as well as how these interactions change in disease states. This information resides neither in the genome nor even in the individual proteins that genes code for. It lies at the level of protein interactions within the context of subcellular, cellular, tissue, organ, and system structures. There is therefore no alternative to copying nature and computing these interactions to determine the logic of healthy and diseased states. The rapid growth in biological databases; models of cells, tissues, and organs; and the development of powerful computing hardware and algorithms have made it possible to explore functionality in a quantitative manner all the way from the level of genes to the physiological function of whole organs and regulatory systems. This review illustrates this development in the case of the heart. Systems physiology of the...
Models of the heart have been developed since 1960, starting with the discovery and modeling of p... more Models of the heart have been developed since 1960, starting with the discovery and modeling of potassium channels. The first models of calcium balance were made in the 1980s and have now reached a high degree of physiological detail. During the 1990s, these cell models were incorporated into anatomically detailed tissue and organ models.
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2009
Early development of ionic models for cardiac myocytes, from the pioneering modification of the H... more Early development of ionic models for cardiac myocytes, from the pioneering modification of the Hodgkin–Huxley giant squid axon model by Noble to the iconic DiFrancesco–Noble model integrating voltage-gated ionic currents, ion pumps and exchangers, Ca 2+ sequestration and Ca 2+ -induced Ca 2+ release, provided a general description for a mammalian Purkinje fibre (PF) and the framework for modern cardiac models. In the past two decades, development has focused on tissue-specific models with an emphasis on the sino-atrial (SA) node, atria and ventricles, while the PFs have largely been neglected. However, achieving the ultimate goal of creating a virtual human heart will require detailed models of all distinctive regions of the cardiac conduction system, including the PFs, which play an important role in conducting cardiac excitation and ensuring the synchronized timing and sequencing of ventricular contraction. In this paper, we present details of our newly developed model for the hu...
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2009
The need for tools to aid the description and sharing of biological models was highlighted at the... more The need for tools to aid the description and sharing of biological models was highlighted at the launch of the International Union of Physiological Sciences Physiome Project in 1997. This has resulted in the release, in 2001, of the CellML specifications ( http://www.cellml.org/specifications/ ). Cellular Open Resource (COR) was among the early adopters of this standard, eventually forming the first publicly available CellML-based modelling and collaboration environment. From the onset, COR was designed to provide an environment that could not only be used by experienced modellers, but also by experimentalists, teachers and students. It therefore tries to combine a user-friendly interface with a computationally efficient numerical engine. In this paper, we introduce the philosophy behind COR, explain its user interface and current functionality, including the editing and running of CellML files, highlight lessons learned from user feedback and problems experienced during the develo...
Bioengineering analyses of physiological systems use the computational solution of physical conse... more Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization--from proteins to cells, tissues, organs and organ systems--these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline.
On the tenth anniversary of two key International Conference on Harmonisation (ICH) guidelines re... more On the tenth anniversary of two key International Conference on Harmonisation (ICH) guidelines relating to cardiac proarrhythmic safety, an initiative aims to consider the implementation of a new paradigm that combines in vitro and in silico technologies to improve risk assessment. The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative (co-sponsored by the Cardiac Safety Research Consortium, Health and Environmental Sciences Institute, Safety Pharmacology Society and FDA) is a bold and welcome step in using computational tools for regulatory decision making. This review compares and contrasts the state-of-the-art tools from empirical to mechanistic models of cardiac electrophysiology, and how they can and should be used in combination with experimental tests for compound decision making.
Must higher level biological processes always be derivable from lower level data and mechanisms, ... more 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 determ...
The successful identification of drug targets requires an understanding of the high-level functio... more The successful identification of drug targets requires an understanding of the high-level functional interactions between the key components of cells, organs and systems, and how these interactions change in disease states. This information does not reside in the genome, or in the individual proteins that genes code for, it is to be found at a higher level. Genomics will succeed in revolutionising pharmaceutical research and development only if these interactions are also understood by determining the logic of healthy and diseased states. The rapid growth in biological databases, models of cells, tissues and organs, and in computing power has made it possible to explore functionality all the way from the level of genes to whole organs and systems. Combined with genomic and proteomic data, in silico simulation technology is set to transform all stages of drug discovery and development. The major obstacle to achieving this will be obtaining the relevant experimental data at levels hig...
Successful physiological analysis requires an understanding of the functional interactions betwee... more Successful physiological analysis requires an understanding of the functional interactions between the key components of cells, organs, and systems, as well as how these interactions change in disease states. This information resides neither in the genome nor even in the individual proteins that genes code for. It lies at the level of protein interactions within the context of subcellular, cellular, tissue, organ, and system structures. There is therefore no alternative to copying nature and computing these interactions to determine the logic of healthy and diseased states. The rapid growth in biological databases; models of cells, tissues, and organs; and the development of powerful computing hardware and algorithms have made it possible to explore functionality in a quantitative manner all the way from the level of genes to the physiological function of whole organs and regulatory systems. This review illustrates this development in the case of the heart. Systems physiology of the...
Models of the heart have been developed since 1960, starting with the discovery and modeling of p... more Models of the heart have been developed since 1960, starting with the discovery and modeling of potassium channels. The first models of calcium balance were made in the 1980s and have now reached a high degree of physiological detail. During the 1990s, these cell models were incorporated into anatomically detailed tissue and organ models.
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2009
Early development of ionic models for cardiac myocytes, from the pioneering modification of the H... more Early development of ionic models for cardiac myocytes, from the pioneering modification of the Hodgkin–Huxley giant squid axon model by Noble to the iconic DiFrancesco–Noble model integrating voltage-gated ionic currents, ion pumps and exchangers, Ca 2+ sequestration and Ca 2+ -induced Ca 2+ release, provided a general description for a mammalian Purkinje fibre (PF) and the framework for modern cardiac models. In the past two decades, development has focused on tissue-specific models with an emphasis on the sino-atrial (SA) node, atria and ventricles, while the PFs have largely been neglected. However, achieving the ultimate goal of creating a virtual human heart will require detailed models of all distinctive regions of the cardiac conduction system, including the PFs, which play an important role in conducting cardiac excitation and ensuring the synchronized timing and sequencing of ventricular contraction. In this paper, we present details of our newly developed model for the hu...
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences, 2009
The need for tools to aid the description and sharing of biological models was highlighted at the... more The need for tools to aid the description and sharing of biological models was highlighted at the launch of the International Union of Physiological Sciences Physiome Project in 1997. This has resulted in the release, in 2001, of the CellML specifications ( http://www.cellml.org/specifications/ ). Cellular Open Resource (COR) was among the early adopters of this standard, eventually forming the first publicly available CellML-based modelling and collaboration environment. From the onset, COR was designed to provide an environment that could not only be used by experienced modellers, but also by experimentalists, teachers and students. It therefore tries to combine a user-friendly interface with a computationally efficient numerical engine. In this paper, we introduce the philosophy behind COR, explain its user interface and current functionality, including the editing and running of CellML files, highlight lessons learned from user feedback and problems experienced during the develo...
Bioengineering analyses of physiological systems use the computational solution of physical conse... more Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization--from proteins to cells, tissues, organs and organ systems--these methods have the potential to link patient-specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web-accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer-intensive discipline.
Exosomes: A Clinical Compendium is a comprehensive and authoritative account of exosomes in the c... more Exosomes: A Clinical Compendium is a comprehensive and authoritative account of exosomes in the context of biomarkers, diagnostics and therapeutics across a wide spectrum of medical disciplines, as well as their role in cell-cell communication. It is intended to serve as a reference source for clinicians, physicians and research scientists who wish to gain insight into the most recent advances in this rapidly growing field.
The exosome revolution may well be the greatest advance in physiology and medicine since antibiotics. The discovery of their epigenetic role in intercellular signaling in virtually all tissues is a major breakthrough in our understanding of how cells function.
Key features
•Provides readers with a broad and timely overview of exosomes in health and disease, closing with a thought-provoking chapter on transgenerational inheritance, Darwin and Lamarck.
•Summarizes the most recent laboratory and clinical findings on exosomes across numerous medical disciplines, thereby offering readers a broad-ranging and solid foundation for prospective investigative efforts
•Twenty-one chapters authored by a global team of peer-acknowledged experts, each representing a key medical discipline
Preparing this ambitious Special Issue has challenged everyone involved: authors, reviewers, and guest editors. The editors solicited contributions from many leading figures in a broad array of scientific and philosophical disciplines, with emphasis on phenomenological approaches to philosophy (Section I). The motivating force was the conviction that if we could find a viable bridge for the gap between the " two cultures " 1 of science and philosophy, fundamental problems in each camp could be addressed more fruitfully than ever before, and a new kind of science be born. We believe the unprecedented cross-fertilization of ideas from this initiative may furnish seeds from which that new, better integrated, and more effective approach to science may arise. This Special Issue consists of forty papers. For each one, multiple reviewers were solicited, with at least one reviewer from each " culture " (a scientist and a philosopher). In many cases, several rounds of revision were carried out. Needless to say, this required great patience and dedication of all participants. The editors gratefully acknowledge the contributions of our authors, and of our anonymous reviewers, who worked long and hard on the papers we sent them with no compensation for their efforts. We also wish to thank the Elsevier editorial and production team for the support they gave us in bringing this project to fruition. We hope the reader will find this effort to marry science and philosophy both meaningful and enjoyable. We would now like to offer a synoptic overview of the Special Issue, section by section and paper by paper.
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Papers by Denis Noble
The exosome revolution may well be the greatest advance in physiology and medicine since antibiotics. The discovery of their epigenetic role in intercellular signaling in virtually all tissues is a major breakthrough in our understanding of how cells function.
Key features
•Provides readers with a broad and timely overview of exosomes in health and disease, closing with a thought-provoking chapter on transgenerational inheritance, Darwin and Lamarck.
•Summarizes the most recent laboratory and clinical findings on exosomes across numerous medical disciplines, thereby offering readers a broad-ranging and solid foundation for prospective investigative efforts
•Twenty-one chapters authored by a global team of peer-acknowledged experts, each representing a key medical discipline
http://www.sciencedirect.com/science/journal/00796107/119/3
Preparing this ambitious Special Issue has challenged everyone involved: authors, reviewers, and guest editors. The editors solicited contributions from many leading figures in a broad array of scientific and philosophical disciplines, with emphasis on phenomenological approaches to philosophy (Section I). The motivating force was the conviction that if we could find a viable bridge for the gap between the " two cultures " 1 of science and philosophy, fundamental problems in each camp could be addressed more fruitfully than ever before, and a new kind of science be born. We believe the unprecedented cross-fertilization of ideas from this initiative may furnish seeds from which that new, better integrated, and more effective approach to science may arise. This Special Issue consists of forty papers. For each one, multiple reviewers were solicited, with at least one reviewer from each " culture " (a scientist and a philosopher). In many cases, several rounds of revision were carried out. Needless to say, this required great patience and dedication of all participants. The editors gratefully acknowledge the contributions of our authors, and of our anonymous reviewers, who worked long and hard on the papers we sent them with no compensation for their efforts. We also wish to thank the Elsevier editorial and production team for the support they gave us in bringing this project to fruition. We hope the reader will find this effort to marry science and philosophy both meaningful and enjoyable. We would now like to offer a synoptic overview of the Special Issue, section by section and paper by paper.