# Denis Noble

Denis Noble CBE FRS FMedSci MAE (born 16 November 1936) is a British physiologist and 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. Noble established The Third Way of Evolution (TWE) project with James A. Shapiro which predicts that the entire framework of the modern synthesis will be replaced.

## Education

Noble was educated at Emanuel School and University College London (UCL). In 1958 he began his investigations into the mechanisms of heartbeat. This led to two seminal papers in Nature in 1960 giving the first experimentally-based mathematical simulation of the electrical rhythm of the heart, extensively developed with Richard Tsien in 1975, and with Dario DiFrancesco in 1985. All three articles form the foundations of modern electrophysiology of the heart. The 1985 article was included in 2015 in the Royal Society's 350 year celebration of the publication of Philosophical Transactions.
From this work it became clear that there was not a single oscillator which controlled heartbeat, but rather this was an emergent property of the feedback loops involving the various ion channels. In 1961 he obtained his PhD working under the supervision of Otto Hutter at UCL.

## Research

Noble's research focuses on using computer models of biological organs and organ systems to interpret function from the molecular level to the whole organism. Together with international collaborators, his team has used supercomputers to create the first virtual organ, the virtual heart.
As secretary-general of the International Union of Physiological Sciences 1993–2001, he played a major role, together with Peter Hunter, in launching the Physiome Project, an international project to use computer simulations to create the quantitative physiological models necessary to interpret the genome, and he was elected president of the IUPS at its world congress in Kyoto in 2009.
Noble is also a philosopher of biology, with many publications in journals and books of philosophy.
His books The Music of Life, Dance to the Tune of Life and Understanding Living Systems 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

### Reductionism

His 2006 book The Music of Life examines some of the basic aspects of systems biology, and is critical of the ideas of genetic determinism and genetic reductionism. He points out that there are many examples of feedback loops and "downward causation" in biology, and that it is not reasonable to privilege one level of understanding over all others. He also explains that genes in fact work in groups and systems, so that the genome is more like a set of organ pipes than a "blueprint for life". His 2016 book Dance to the Tune of Life sets these ideas out in a broad sweep from the general principle of relativity applied to biology, through to the role of purpose in evolution and to the relativity of epistemology.
He contrasts Richard Dawkins's famous statement in The Selfish Gene ("Now they [genes] swarm ... safe inside gigantic lumbering robots ... they created us, body and mind; and their preservation is the ultimate rationale for our existence") with an alternative view: "Now they [genes] are trapped in huge colonies, locked inside highly intelligent beings, moulded by the outside world, communicating with it by complex processes, through which, blindly, as if by magic, function emerges. They are in you and me; we are the system that allows their code to be read; and their preservation is totally dependent on the joy we experience in reproducing ourselves. We are the ultimate rationale for their existence". He then suggests that there is no empirical difference between these statements, and says that they differ in "metaphor" and "sociological or polemical viewpoint".
He argues that "the paradigms for genetic causality in biological systems are seriously confused" and that "The metaphors that served us well during the molecular biological phase of recent decades have limited or even misleading impacts in the multilevel world of systems biology. New paradigms are needed if we are to succeed in unravelling multifactorial genetic causation at higher levels of physiological function and so to explain the phenomena that genetics was originally about."

### The Third Way of Evolution

Noble has called for an extended evolutionary synthesis, and a replacement for the modern synthesis known as The Third Way of Evolution (TWE).
He has argued that from research in epigenetics, acquired characteristics can be inherited and in contrast to the modern synthesis, genetic change is "far from random" and not always gradual. He has also claimed that the central dogma of molecular biology has been broken as an "embodiment of the Weismann Barrier", and a new synthesis will integrate research from physiology with evolutionary biology.
Noble and James A. Shapiro established The Third Way of Evolution (TWE) project in 2014. The TWE which is also known as the "Integrated Synthesis" shares many similarities with the extended evolutionary synthesis but is more radical in its claims. The TWE consists of a group of researchers who provide a "Third Way" alternative to creationism and the modern synthesis. The TWE predicts that the modern synthesis will be replaced with an entirely new evolutionary framework. Similar to the extended evolutionary synthesis (EES), advocates cite examples of developmental bias, genetic assimilation, niche construction, non-genetic inheritance, phenotypic plasticity and other evolutionary processes. Shapiro's natural genetic engineering, a process described to account for novelty created in biological evolution is also important for the TWE. The difference between the extended synthesis and the TWE is that the latter calls for an entire replacement of the modern synthesis rather than an extension.
In 2023, evolutionary biologist Erik Svensson commented that "to date, there are few leading evolutionary biologists who have openly embraced the TWE" and it is unlikely that an entire replacement of the modern synthesis will occur as there has been little visibility of such a forthcoming paradigm shift during the past decade.

### Principles of Systems Biology

Noble has proposed Ten Principles of Systems Biology:
* Biological functionality is multi-level
* Transmission of information is not one way
* DNA is not the sole transmitter of inheritance
* The theory of biological relativity: there is no privileged level of causality
* Gene ontology will fail without higher-level insight
* There is no genetic program
* There are no programs at any other level
* There are no programs in the brain
* The self is not an object
* There are many more to be discovered; a genuine 'theory of biology' does not yet exist

### Career

* 1961–1963 – Assistant lecturer in Physiology, University College London
* 1961–1963 – Vice-warden of Connaught Hall (University of London)
* 1963–1984 – Fellow and tutor, Balliol College, Oxford. University Lecturer in Physiology
* 1967–2024 – Editor-in Chief of Progress in Biophysics and Molecular Biology
* 1969–1970 – Visiting professor and visiting scientist of the Canadian MRC
* 1971–1989 – Head (praefectus) of the Balliol College Graduate Centre at Holywell Manor
* 1975–1985 – Leader of MRC Programme Grant team
* 1983–1985 – Vice-master of Balliol College
* 1986 – co-founder of Save British Science, now the Campaign for Science and Engineering
* 1984–2004 – Burdon Sanderson Professor of Cardiovascular Physiology, Oxford University
* 1984–2004 – Professorial fellow, Balliol College
* From 2004 – Emeritus professor of Cardiovascular Physiology, Oxford University
* From 2004 – Emeritus fellow of Balliol College, Oxford
* From 2004 – Director of Computational Physiology, Oxford
* 2003–2007 – Adjunct professor, Xi’an Jiaotong University, Shaanxi province, China
* From 2005 – Visiting professor, Osaka University, Japan
* 2009–2017 – President, International Union of Physiological Sciences
* From 2009 – Co-founder and editor-in-chief of Voices from Oxford
* 2011–2017 – Editor in chief of Interface Focus
* From 2014 – Member and co-founder of The Third Way of Evolution
* From 2021 – Co-Founder Oxford Longevity Project

### Publications

Noble has published over 700 articles in academic journals, including Nature, Science, PNAS, Journal of Physiology, Progress in Biophysics & Molecular Biology, and many articles in the national press. He is the (co-)author and/or editor of many books, including:
* The Initiation of the Heartbeat. Oxford: Clarendon Press. 1975. ISBN 978-0-19-857154-4. OCLC 569495557 – via Internet Archive.
* Jack, J. J. B.; Noble, Denis; Tsien, R. W. (1975). Electric Current Flow in Excitable Cells. Oxford: Clarendon Press. ISBN 978-0-19-857365-4. OCLC 1633990.
* Noble, Denis; Powell, Trevor (1987). Electrophysiology of Single Cardiac Cells. London: Academic Press. ISBN 978-0-12-520040-0. OCLC 20692607.
* Montefiore, Alan; Noble, Denis, eds. (2023). "Scientific Introduction," "Intentional Action and Physiology," and "What do Intentions do?". Goals, No Goals and Own Goals: A Debate on Goal-Directed and Intentional Behaviour. London: Routledge. doi:10.4324/978100318555. ISBN 978-1-000-41499-8. OCLC 1420169188.
* Allen, T. Jeff A.; Noble, Denis; Reuter, Harald (1989). Sodium-Calcium Exchange. Oxford [England]: Oxford University Press. ISBN 978-0-19-854735-8. OCLC 610553885 – via Internet Archive.
* Noble, Denis; Earm, Yung E. (1993). Ionic Channels and Effect of Taurine on the Heart. Developments in Cardiovascular Medicine. Vol. 141. Boston, MA: Springer US. doi:10.1007/978-1-4615-3074-9. ISBN 978-1-4613-6342-2. OCLC 852789046.
* Boyd, C. A. R.; Noble, Denis (1993). The Logic of life : the challenge of integrative physiology. Oxford: Oxford University Press. ISBN 978-0-19-262417-8. OCLC 27975536.
* Noble, Denis; Vincent, Jean Didier; Ádám, György (1997). The Ethics of Life. Paris: UNESCO. ISBN 978-92-3-103422-0. OCLC 39358856.
* The Music of Life: Biology beyond the Genome. Oxford University PressOxford. 8 June 2006. doi:10.1093/oso/9780199295739.001.0001. ISBN 978-0-19-929573-9. OCLC 1406782814. Partial preview from Google Books.
* The Selected Papers of Denis Noble CBE FRS: A Journey in Physiology Towards Enlightenment. London, Singapore: Imperial College Press ; Distributed by World Scientific Publishing. 2012. ISBN 978-1-84816-842-8. OCLC 769546978.
* Edelstein, Larry; Smythies, John R.; Quesenberry, Peter J.; Noble, Denis; et al., eds. (2019). "Exomes, gemmuls, pangenesis and Darwin". Exosomes: a Clinical Compendium. San Diego: Elsevier Science & Technology. ISBN 978-0-12-816054-1. OCLC 1127115445. Partial preview from Google Books.
* Rattigan, Benedict; Noble, Denis; et al., eds. (2023). "The Interdependence of Order and Disorder: How Complexity Arises in the Living and the Inanimate Universe". The Language of Symmetry. Boca Raton: CRC Press, Taylor & Francis Group. ISBN 978-1-003-30698-6. OCLC 1350435643. Partial preview from Google Books.
* Noble, Raymond; Noble, Denis (2023). Understanding Living Systems. Cambridge, United Kingdom: Cambridge University Press. ISBN 978-1-009-27739-6. OCLC 1378603076.
* Noble, Denis; Noble, Raymond (2023). "How Purposive Agency Became Banned from Evolutionary Biology". In Corning, Peter A.; Kauffman, Stuart A.; Noble, Denis; et al. (eds.). Evolution "On Purpose": Teleonomy in Living Systems. Cambridge, Massachusetts: The MIT Press. ISBN 978-0-262-37601-3. OCLC 1348644515. Partial preview from Google Books.

## Awards and honours

His major invited lectures include the Darwin Lecture for the British Association in 1966, the Nahum Lecture at Yale in 1977 and the Ueda lecture at Tokyo University in 1985 and 1990. He was President of the Medical Section of the British Science Association 1991–92. Many further invited lectures during his election as Secretary-General (1993-2001) and President (2009-2017) of IUPS.
In 1979 he was elected a Fellow of the Royal Society. His nomination for the Royal Society reads:
   Distinguished for the discovery of slowly activated potassium currents in the heart and a quantitative analysis of their role in controlling repolarization and pacemaker activity; the discovery of the ionic mechanisms by which adrenaline increases heart rate. He has shown that therapeutic levels of cardiac glycosides may increase, rather than decrease, potassium gradients in the heart, and has published an analytical treatment of membrane excitation theory and cable theory that provides a modern basis for the concepts of safety factor, liminal length, excitation time constants and the phenomenon of repetitive firing.
He was elected an Honorary Member of the Royal College of Physicians in 1988 and an Honorary Fellow in 1994, an Honorary Member of the American Physiological Society in 1996 and of the Physiological Society of Japan in 1998. In 1989 he was elected a Member of the Academia Europaea. In 1998, he also became a founding Fellow of the Academy of Medical Sciences. In 1998 he was awarded a CBE. In 2021 he was elected a Fellow of the IUPS Academy. In 2022 he was elected a Fellow of The Linnean Society (FLS)
He has honorary doctorates from the University of Sheffield (2004), the Université de Bordeaux (2005) and the University of Warwick (2008).
He is an Honorary Foreign Member of the Académie Royale de Médecine de Belgique (1993), of the Istituto Lombardo Accademia di Scienze e Lettere, and received the Pavlov Medal of the Russian Academy of Sciences (2004). In 2022 he was elected Foreign Member of the Russian Academy of Sciences and was also awarded the Lomonosov Gold Medal.

## Personal life

Noble was born in London in 1936 to working-class tailors, George and Ethel Noble.
He plays classical guitar and sings Occitan troubadour and folk songs (Oxford Trobadors). In addition to English, he has lectured in French, Italian, Performance with Nadau & Peiraguda Occitan, Japanese and Korean.