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The Music of Life Sourcebook The Music of Life Sourcebook The Music of Life Sourcebook (version 6, August 2016) The Music of Life is a short book. Deliberately so. The aim was to use metaphorical stories and surprising ways of explaining modern biology to jolt the reader away from many of the serious misunderstandings of biological science that developed during the second half of the 20th century as molecular biology came to dominate the scene. There is nothing wrong with molecular biology as science. In leading up to the sequencing of the human genome it represents one of man’s greatest scientific achievements. But there is everything wrong in the way in which it is often presented. The genome is not ‘The Book of Life’. To judge from the reviews, The Music of Life has succeeded. It has worldwide sales exceeding 20,000 copies, and translations have been published in nine foreign languages, with more in preparation. The reviews are enthusiastic. Some of them are very perceptive and represent good literature in their own right. You can find many of them on the website www.musicoflife.website This sourcebook responds to a growing demand by readers who are hungry for more. What they want is chapter and verse on the sources for the claims in The Music of Life. What you will find here is an extensive series of review articles written after The Music of Life was published that spell out in detail what the sources are, and with full references to the literature. Each and every claim in the book is not only justified by these articles, those claims are extended as new evidence has appeared since the book was published and which establishes some of the revolutionary ideas even more firmly than was possible in 2006. Denis Noble, August 2016. Contents Noble D. (2008a). Claude Bernard, the first Systems Biologist, and the future of Physiology. Experimental Physiology 93, 16-26. The central ideas of The Music of Life are presented as ten principles of Systems Biology Noble D. (2008b). Genes and Causation. Philosophical Transactions of the Royal Society A 366, 3001-3015. Defining genes as DNA sequences requires a new view of genetic causation. This article introduces the ‘genetic differential effect problem’ and its solution. Kohl P & Noble D. (2009). Systems Biology and the Virtual Physiological Human. MolecularSystems Biology 5, 291-296. How Systems Biology relates to the Physiome Project and the VPH Project Noble D. (2010a). Biophysics and Systems Biology. Philosophical Transactions of the Royal Society A 368, 1125-1139. Outlines the molecular biological reasons why genetic determinism is incorrect. Introduces the reasons why neo- darwinism is based on an outdated view of genetics. Noble D. (2010b). “Letter from Lamarck”. Physiology News 78, 31. An imagined letter from Lamarck reveals what is wrong with popular perceptions of Lamarck, Darwin and the inheritance of acquired characteristics. Kohl P, Crampin E, Quinn TA & Noble D. (2010). Systems Biology: an approach. ClinicalPharmacology and Therapeutics 88, 25-33. Systems Biology is an approach, not a separate subject. This article focusses on the utility of the systems approach to biology. Noble D. (2011a). Differential and integral views of genetics in computational systems biology. Journal of the Royal Society Interface Focus 1, 7-15. This article develops the ‘genetic differential effect problem’ into a full view of the way in which we now need to analyse the relations between genes and phenotypes including the way in which reverse engineering can solve the problem. Noble D. (2011b). Neo-Darwinism, the Modern Synthesis, and Selfish Genes: are they of use in physiology? Journal of Physiology 589, 1007-1015. If the value of a scientific theory lies in its utility then neo-darwinism has been of negative value in physiology. The reasons are that the theory itself is confused about what genes are and what attributes may be ascribed to them. It is also incompatible with more recent developments in molecular biology. Noble, D. (2012). A Biological Theory of Relativity. No privileged level of causation. Journal of the Royal Society Interface Focus 2, 55- 74. This article provides a more complete statement of the Biological Theory of Relativity. Noble, D. (2013). Physiology is rocking the foundations of evolutionary biology, Experimental Physiology, 98, 1235-1243. Based on lectures given to several international congresses between 2010 and 2013, this article follows on from the Neo- Darwinism article to explain why experimental findings are breaking the rules of the modern synthesis and proposes an extended synthesis in which physiological function may have a role in determining genetic changes. Noble, D, Jablonka, E, Joyner, MJ, Muller, GB & Omholt, SW. (2014). Evolution evolves: physiology returns to centre stage. Journal of Physiology, 592, 2237-2244. This is an extensive Editorial for a Special Issue of the Journal of Physiology devoted to The integration of evolutionary biology with physiological science. Noble, D. (2015) Evolution beyond neo-Darwinism: a new conceptual framework. Journal of Experimental Biology, 218, 7-13. This article analyses the conceptual basis of neo-Darwinism to reveal its inconsistencies and why it needs replacement by an integrative, multi-mechanism approach to evolutionary biology. Noble, D. (2015) Conrad Waddington and the origin of epigenetics. Journal of Experimental Biology, 218, 816-818. Conrad Waddington invented the term epigenetics. He also performed experiments that demonstrated the assimilation of epigenetic changes into the genome, thus demonstrating the existence of the inheritance of acquired characteristics. Exp Physiol 93.1 pp 16–26 16 Experimental Physiology – Paton Lecture Claude Bernard, the first systems biologist, and the future of physiology Denis Noble Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK The first systems analysis of the functioning of an organism was Claude Bernard’s concept of the constancy of the internal environment (le milieu int´erieur), since it implied the existence of control processes to achieve this. He can be regarded, therefore, as the first systems biologist. The new vogue for systems biology today is an important development, since it is time to complement reductionist molecular biology by integrative approaches. Claude Bernard foresaw thatthiswouldrequiretheapplicationofmathematicstobiology.ThisaspectofClaudeBernard’s work has been neglected by physiologists, which is why we are not as ready to contribute to the development of systems biology as we should be. In this paper, I outline some general principles that could form the basis of systems biology as a truly multilevel approach from a physiologist’s standpoint. We need the insights obtained from higher-level analysis in order to succeed even at the lower levels. The reason is that higher levels in biological systems impose boundary conditions on the lower levels. Without understanding those conditions and their effects, we will be seriously restricted in understanding the logic of living systems. The principles outlined are illustrated with examples from various aspects of physiology and biochemistry. Applying and developing these principles should form a major part of the future of physiology. (Received 4 August 2007; accepted after revision 3 October 2007; first published online 26 October 2007) Corresponding author D. Noble: Department of Physiology, Anatomy and Genetics, Parks Road, Oxford OX1 3PT, UK. [email protected] Historical introduction both to my claim that he was the first systems biologist and to the challenge that physiology faces today. Claude Bernard was Sir William Paton’s great physiological What was Claude Bernard’s problem? It was that hero. When the Physiological Society celebrated its the chemists had created ‘organic’ molecules. This was centenary in 1976, Bill contributed a paper to the a major development, since people had thought since historical part of the meeting concerning one of Bernard’s Lemery’s´ Cours de Chymie (published in 1675) that there experiments on curare and drawing attention to the were three completely separate classes of compounds: important role his ideas played in the foundation of mineral, vegetable and animal. The first break in this the Society in 1876 (Paton, 1976). The reasons for his idea came from the work of Lavoisier (1784), who admirationofClaudeBernardarenothardtofind.Bernard showed that all compounds from vegetable and animal was a superb experimentalist, as the history of his work sources always contained at least carbon and hydrogen, on digestion shows (Holmes, 1974). He also displayed and frequently nitrogen and phosphorus. This work his skills in many other areas of physiology and he laid bridged the vegetable–animal chemical boundary, but it out the principles of his science in his highly influential left intact the boundary between the living and non- Introductional’´ ` etude de la M´edecine Exp´erimentale living. In fact, Berzelius (1815) even proposed that (Bernard, 1865, 1984), in which he revealed himself to organic compounds were produced by laws different from be a great thinker as well as a great experimentalist. The inorganic compounds; the idea that there was a specific theoreticalproblemheaddressedisonethatisveryrelevant vital force that could not operate outside living systems. In 1828, however, Wohler¨ succeeded in creating urea from ammonium cyanate. The distinction between organic and This article is based on the Paton Lecture delivered with the same title non-organic origins was further weakened by Kolbe who, to the Life Sciences 2007 meeting in Glasgow in July 2007. in 1845, synthesized acetic acid from its elements. Many C 2008 The Author. Journal compilation C 2008 The Physiological Society DOI: 10.1113/expphysiol.2007.038695 Downloaded from ep.physoc.org at University Of Oxford on January 2, 2008 Exp Physiol 93.1 pp 16–26 Systems biology and the future of physiology 17 other discoveries of this kind (Finar, 1964) led to the idea The problem physiology faces today both resembles that that life itself could be reduced to chemistry and physics. faced by Bernard and differs from it.
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