Denis Noble

• Doctor of Philosophy
• Professor Emeritus at University of Oxford

An appreciation of the late Andrew Packard FLS

The chapter provides a comprehensive account of biophysical models of cardiac pacemaker action potentials and how they have been improved over time by including additional components as they were discovered. Starting with ionic currents conducted via sodium, potassium and ‘leak’ channels, the addition of further selective ion channels, sodium-calci...

A unique exploration of teleonomy—also known as “evolved purposiveness”—as a major influence in evolution by a broad range of specialists in biology and the philosophy of science. The evolved purposiveness of living systems, termed “teleonomy” by chronobiologist Colin Pittendrigh, has been both a major outcome and causal factor in the history of li...

Life is definitively purposive and creative. Organisms use genes in controlling their destiny. This book presents a paradigm shift in understanding living systems. The genome is not a code, blueprint or set of instructions. It is a tool orchestrated by the system. This book shows that gene-centrism misrepresents what genes are and how they are used...

In recent times, self-interest has been seen as the main driving force of behaviour and function in organisms. This is particularly evident in the concept of the selfish gene. However, as elaborated in this book, living systems strongly depend on cooperative behaviour, which is found everywhere in nature. All the way from millions of minute bacteri...

We are writing this book as agents with a purpose. Agency and purposeful action is a defining property of all living systems. Yet modern science has presented a reductionist, gene-centred view of life, where life is reduced to biochemistry, particularly DNA and proteins. It has even carved out its own areas of study – genomics and proteomics – as i...

Artificial intelligence (AI) is a tool created by living organisms, us humans. Like the hydraulic robots of the seventeenth century which inspired Descartes’ mechanical view of organisms, AI has become the latest in a list of mechanical metaphors for life. Yet it is just as limited, just as much a mistaken view of organisms. It views life as just p...

Life is definitively purposive and creative. Organisms use genes in controlling their destiny. This book presents a paradigm shift in understanding living systems. The genome is not a code, blueprint or set of instructions. It is a tool orchestrated by the system. This book shows that gene-centrism misrepresents what genes are and how they are used...

Life is definitively purposive and creative. Organisms use genes in controlling their destiny. This book presents a paradigm shift in understanding living systems. The genome is not a code, blueprint or set of instructions. It is a tool orchestrated by the system. This book shows that gene-centrism misrepresents what genes are and how they are used...

Where is the living mind that thinks? Culture is the matrix of the mind. Organisms owe their social and mental abilities to the ‘nesting’ of causation between all levels of their functioning. Higher levels mould what the lower levels can do. This is how living systems can use their flexibility, from cultural and linguistic variability to the water-...

Life is definitively purposive and creative. Organisms use genes in controlling their destiny. This book presents a paradigm shift in understanding living systems. The genome is not a code, blueprint or set of instructions. It is a tool orchestrated by the system. This book shows that gene-centrism misrepresents what genes are and how they are used...

Standard evolutionary theory represents genes as the target of evolution. But organisms may functionally develop without alterations in their DNA, and they may also buffer changes in the DNA to retain function. It is organisms that are the agents in the process of evolution. Outside a living system, DNA is inactive, dead. Furthermore, many signific...

Living systems are characterised by intelligence. Treating organisms as gene-driven automata, blindly reacting to events, does not take account of their social or ecological being. Living systems anticipate the actions and reactions of other living systems. As in a chess game, anticipation can consider many options. Nevertheless, the chess analogy...

Life is definitively purposive and creative. Organisms use genes in controlling their destiny. This book presents a paradigm shift in understanding living systems. The genome is not a code, blueprint or set of instructions. It is a tool orchestrated by the system. This book shows that gene-centrism misrepresents what genes are and how they are used...

In the preceding chapters, we showed why the idea that living organisms are really driven by their genes is a profound misunderstanding of how living systems work. On the contrary, they are open systems at all levels of organisation. How things work at the molecular level is constrained and regulated at the cellular level. The interaction of cells...

If the dichotomy between replicator and vehicle is wrong, then what is it that replicates? The purpose of reproduction is not replication, at least not exactly. Reproduction brings about change. It shakes up the templates and provides new avenues to explore in adapting to a changing environment. It creates and propagates variation. But it also prov...

Conscious Agency is a major driver of evolution. Artificial Selection (i.e. Conscious Selection by human breeders) was the foil against which Charles Darwin defined Natural Selection. In later work, he extended Artificial Selection to other species. That ability for social (e.g. sexual) selection must have evolved. Jablonka and Ginsburg identify ma...

Gregor Mendel is generally presented as the ‘ignored and solitary founder of genetics’. This Moravian friar would have worked in strict isolation on the heredity of peas in the garden of his monastery, and his experiments would have been ignored by his contemporaries, before being ‘rediscovered’ independently by three botanists in 1900, 34 years af...

The Hodgkin Cycle describes the interaction between electrical potentials and ion channel currents that enables impulses and rhythms to be generated in excitable cells. Contrary to most diagrams of that interaction, there can be no one‐way flow around the cycle, which is therefore better represented as a causal ring in which the different forms of...

Life is purposefully creative in a continuous process of maintaining integrity; it adapts to counteract change. This is an ongoing, iterative process. Its actions are essentially directed to this purpose. Life exists to exist. Physiology is the study of purposeful living function. Function necessarily implies purpose. This was accepted all the way...

Life is purposefully creative in a continuous process of maintaining integrity; it adapts to counteract change. This is an ongoing, iterative process. Its actions are essentially directed to this purpose. Life exists to exist. Physiology is the study of purposeful living function. Function necessarily implies purpose. This was accepted all the way...

Living organisms are open systems for which it is necessarily true that there can be no causal closure at molecular levels that ignores the influence imposed by functional organisation at higher levels. Our chapter considers the empirical and conceptual nature of the principles that agency exists and that there is no privileged level of causation....

The idea of The Selfish Gene, first published in 1976, grew out of the Modern Synthesis of evolutionary biology formulated by Julian Huxley in 1942, and more specifically from George Williams' Adaptation and Natu - ral Selection in 1966. It presents a severely narrowed down version of Huxley's synthesis, which developed in the 1960s following the f...

There is an inherent tension in Quantitative Systems Pharmacology (QSP) between the need to incorporate mathematical descriptions of complex physiology and drug targets with the necessity of developing robust, predictive and well-constrained models. In addition to this there is no "gold standard" for model development and assessment in QSP. Moreove...

The extensive range and depth of the twenty commentaries on my target article (Noble, 2021) confirms that something has gone deeply wrong in biology. A wide range of biologists has more than met my invitation for “others to pitch in and develop or counter my arguments.” The commentaries greatly develop those arguments. Also remarkably, none raise i...

Karl Popper’s ideas on evolution in his 1986 Medawar lecture were remarkably close to Charles Darwin’sDarwin, C. original distinction between artificial and natural selection, but at odds with the Modern Synthesis in giving an active role to organisms in the process of evolution. His ideas were also compatible with recent work showing the role of t...

In this paper, we demonstrate (1) how harnessing stochasticity can be the basis of creative agency; (2) that such harnessing can resolve the apparent conflict between reductionist (micro-level) accounts of behaviour and behaviour as the outcome of rational and value-driven (macro-level) decisions; (3) how neurophysiological processes can instantiat...

There are strong parallels between the evolutionary origin of species within populations of organisms and new concepts for the origin of cancers within cell populations in the tissues of the body. The analogy is that cancers can be regarded as a new somatic species developing within the host organism. In both cases, understanding the processes invo...

The Modern Synthesis has dominated biology for 80 years. It was formulated in 1942, a decade before the major achievements of molecular biology, including the Double Helix and the Central Dogma. When first formulated in the 1950s these discoveries and concepts seemed initially to completely justify the central genetic assumptions of the Modern Synt...

The common belief that the neo-Darwinian Modern Synthesis (MS) was buttressed by the discoveries of molecular biology is incorrect. On the contrary those discoveries have undermined the MS. This article discusses the many processes revealed by molecular studies and genome sequencing that contribute to evolution but nonetheless lie beyond the strict...

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are in...

In an accompanying paper [2], we developed the Shorten [3] model of skeletal muscle by incorporating equations such as surface calcium fluxes. In further research in this paper, we succeeded in reproducing muscle cramp, as well as its prevention and reversal, by investigating muscle contraction and cramp, in which calcium regulatory networks are in...

Stochastic processes at molecular, cellular and higher levels in organisms are not simply noise. Organisms also use stochasticity at all levels to generate new DNA sequences, as in the immune system, and new forms of behaviour, as in the nervous system. The harnessing of stochasticity therefore endows organisms with the means to actively influence...

Background : Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to a subgroup of coronaviruses rampant in bats for centuries. It caused the coronavirus disease 2019 (COVID-19) pandemic. Most patients recover, but a minority of severe cases experience acute respiratory distress or an inflammatory storm devastating many organs that...

We describe a major development of the Shorten et al. (Shorten et al., 2007) model of skeletal muscle electrophysiology, biochemistry, and mechanics. The model was developed by incorporating equations for sarcolemmal transport of calcium ions, including L-type calcium channel, sodium-calcium exchange, calcium pump, and background calcium channel. T...

We describe a major development of the Shorten et al. (Shorten et al., 2007) model of skeletal muscle electrophysiology, biochemistry, and mechanics. The model was developed by incorporating equations for sarcolemmal transport of calcium ions, including L-type calcium channel, sodium-calcium exchange, calcium pump, and background calcium channel. T...

40 years ago a single experiment upset a decade of painstaking research on the mechanisms of rhythm generation in the heart. It did so by turning a theory of pacemaker activity upside down. Instead of attributing rhythm to decaying potassium current carrying outward current, it attributed the pacemaker depolarization to the slow activation of a cha...

The original version of this article was revised due to a retrospective Open Access order.

Xin Su Ning (XSN), a China patented and certified multi-herbal medicine, has been available in China since 2005 for treating cardiac ventricular arrhythmia including arrhythmia induced by ischemic heart diseases and viral myocarditis, without adverse reactions being reported. It is vitally important to discover pharmacologically how XSN as a multic...

In this paper we present a review of progress in addressing the challenge to understand and describe the vast complexity and multi-level organisation associated with biological systems. We begin with a review of past and current approaches, key lessons, and unresolved challenges, which require a new conceptual framework to address them. After summa...

In this paper we present a review of progress in addressing the challenge to understand and describe the vast complexity and multi-level organization associated with biological systems. We begin with a review of past and current approaches, key lessons, and unresolved challenges, which require a new conceptual framework to address them. After summa...

In this paper we present a review of progress in addressing the challenge to understand and describe the vast complexity and multi-level organization associated with biological systems. We begin with a review of past and current approaches, key lessons, and unresolved challenges, which require a new conceptual framework to address them. After summa...

SCHOLARLY ARTICLE"Forum: Artificial Intelligence, Artificial Agency and Artificial Life"19 Sep 2019, RUSI Journal, 164(5-6):120-144Co-authors De Angelis E, Hossaini A, Noble R, Noble D, Soto AM...10.1080/03071847.2019.1694264

Since the Principle of Biological Relativity was formulated and developed there have been many implementations in a wide range of biological fields. The purpose of this article is to assess the status of the applications of the principle and to clarify some misunderstandings. The principle requires circular causality between levels of organization....

We argue that (1) emergent phenomena are real and important; (2) for many of these, causality in their development and maintenance is necessarily circular; (3) the circularity occurs between levels of organization; (4) although the forms of causation can be different at different levels, there is no privileged level of causation a priori: the forms...

Mudanpi, a herbal medicine prepared from the root bark of Paeonia Suffruticosa, was traditionally used for thousands of years to ‘remove pathogenic heat from blood'. Previous studies showed that Mudanpi has a significant cardioprotective effect against cardiac ischemia (Ma et al 1984), and its active component, paeonol, inhibits the pacemaker poten...

Choice in the behavior of organisms involves novelty, which may be unpredictable. Yet in retrospect, we can usually provide a rationale for the choice. A deterministic view of life cannot explain this. The solution to this paradox is that organisms can harness stochasticity through which they can generate many possible solutions to environmental ch...

The question whether evolution is blind is usually presented as a choice between no goals at all (‘the blind watchmaker’) and long-term goals which would be external to the organism, for example in the form of special creation or intelligent design. The arguments either way do not address the question whether there are short-term goals within rathe...

“We have only scratched the surface of the problems of biological complexity. They won’t be solved merely by collecting more data. We are awash with data. What is needed is a framework of theory within which we can see our way through the forest of data to find the clues to understanding complexity. I see philosophy as playing a major role here sin...

Stochasticity is harnessed by organisms to generate functionality. Randomness does not, therefore, necessarily imply lack of function or 'blind chance' at higher levels. In this respect, biology must resemble physics in generating order from disorder. This fact is contrary to Schrödinger's idea of biology generating phenotypic order from molecular-...

Recent advances suggest that the concept of information might hold the key to unravelling the mystery of life's nature and origin. Fresh insights from a broad and authoritative range of articulate and respected experts focus on the transition from matter to life, and hence reconcile the deep conceptual schism between the way we describe physical an...

Those national societies within the IUPS community that have hosted World Congresses in recent years will know well that an enormous amount of work is involved and that the planning has to be done years in advance. Rio 2017 is no exception. The planning started way back at the General Assembly in

This focused issue of Progress in Biophysics and Molecular Biology is entitled "From the century of the genome to the century of the organism: New theoretical approaches." It was developed during Ana M. Soto’s tenure as Blaise Pascal Chair of Biology 2013-15 at the Ecole Normale Superieure (ENS, Paris, France). Giuseppe Longo was the Pascal Chair h...

Drug-induced pro-arrhythmic risk has been one of the main causes for drug candidate failure and has even led to compound withdrawn from the market. A new cardiac safety paradigm that combines in-vitro screening of multiple ion channels and in-silico tools, particularly biophysically-detailed cardiac electrophysiology models, has been encouraged by...

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 (c...

Fifteen years into the 21st century, the landscape of opportunities for the physiological sciences within biology and medicine has become much clearer, and thankfully it is much brighter. This is an important development since, by contrast, the last 30 years of the previous century had become a

Biological relativity and the Problem of causality Raymond and Denis Noble University College London and University of Oxford Modern biological science tends to apply a mechanistic and reductionist concept of causality. In this view the function of the organism can be explained by the function of its parts and the function of the organism has no...

Experimental results in epigenetics and related fields of biological research show that the Modern Synthesis (neo-Darwinist) theory of evolution requires either extension or replacement. This article examines the conceptual framework of neo-Darwinism, including the concepts of 'gene', 'selfish', 'code', 'program', 'blueprint', 'book of life', 'repl...

At the closing ceremony of the Congress in Kyoto, Japan, in 2009, the President of IUPS made a clear promise on behalf of the whole of Council: What on earth does IUPS exist for? We need to give back to you, to the young and upcoming physiologists the conviction that we are creating the environment

The distinction between “object” and “process” is an important one in this chapter. But like many ways in which we have difficulty matching language to what we conceive as reality, the distinction is not absolute. It can be context dependent. A spiral storm cloud is a process in the sense that it is formed as an attractor from many component elemen...

The history of the constitution perspective in medical care dates back thousands of years and extends from the East to the West. Among the various forms of constitutional medicine, Sasang constitutional medicine (SCM) is a holistic, tailored medical approach that is based on a well-structured theoretical system that includes physiopathological disc...

It is well known that Leonardo da Vinci made several drawings of the human male anatomy. The early drawings (before 1500) were incorrect in identifying the origin of semen, where he followed accepted teaching of his time. It is widely thought that he did not correct this mistake, a view that is reflected in several biographies. In fact, he made a l...

New Findings What is the topic of this review? Have recent experimental findings in evolutionary biology concerning the transmission of inheritance opened the way to a reintegration of physiology with evolutionary biology? What advances does it highlight? The answer is yes, and that this requires a new synthesis between evolutionary theory and expe...

The recent growth of the systems approach to biology provides a better conceptual framework within which to interpret holistic approaches to medicine. The reason is that systems biology respects the way in which the whole constrains the parts to behave in ways that are different from what they would do in isolation. Holistic treatments depend on th...

This article explores the relativistic principle that there is no privileged scale of causality in biology to clarify the relationships between genomes and phenotypes. The idea that genetic causes are primary views the genome as a program. Initially, that view was vindicated by the discovery of mutations and knockouts that have large and specific e...

This lecture 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 freq...

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-, tis...

Early modelling of cardiac cells (1960-1980) was based on extensions of the Hodgkin-Huxley nerve axon equations with additional channels incorporated, but after 1980 it became clear that processes other than ion channel gating were also critical in generating electrical activity. This article reviews the development of models representing almost al...

IUPS speaks for the international community of physiological scientists, with adhering member societies, associations, and academies from over 50 countries worldwide. Its council has members drawn from all continents. Through its nominating committee, IUPS tries to ensure that it is carefully

Global sensitivity analysis is critical in understanding the role of ionic currents variability in modulating cellular electrophysiological properties of ventricular myocytes as well as in assessing the cardiac single cell arrhythmic risk biomarkers. This work involves a systematic investigation into the sensitivity of various preclinical cellular...

Cardiac simulation is used to integrate information on drug action to predict side effects on the whole heart. Could simulation begin to replace animal models?

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,...

Intracellular cardiac Ca2+ handling involves interactions of numerous distinct cellular and macromolecular structures. Such interactions coordinate the complicated behaviors of individual processes into spatial and temporal coherent patterns of Ca2+ sparks, oscillations and traveling waves. Understanding the dynamical behaviors and functional roles...

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...

With scale relativity theory, Laurent Nottale has provided a powerful conceptual and mathematical framework with numerous validated predictions that has fundamental implications and applications for all sciences. We discuss how this extended framework reviewed in Nottale (Found Sci 152 (3):101–152, 2010a) may help facilitating integration across mu...

The ability to produce rhythmic, spontaneous contractions is a primary function of the heart, and it has intrigued generations of cardiac physiologists in the search for the underlying processes. Spontaneous electrical activity was recorded intracellularly from cardiac tissue by Silvio Weidmann since the mid-1950s. 1 In the early 1960s, the first n...

Based on the similarity between a reentrant wave in cardiac tissue and a vortex in fluid dynamics, the authors hypothesised that a new non-dimensional index, like the Reynolds number in fluid dynamics, may play a critical role in categorising reentrant wave dynamics. Therefore the goal of the present study is to devise a new index to characterise e...

The systems approach to complex biological problems has rapidly gained ground during the first decade of this century. There are several reasons for this development. An important one is that while the achievement of sequencing the complete human genome, and those of other species, has been of great benefit to fundamental science, for example in co...