The Music of Life A new paradigm for biology

Transcription

1 The Music of Life A new paradigm for biology Denis Noble University of Oxford isei, CSEP, MCISB Manchester University Wednesday 25 November 2009 NOBLE, D The Music of Life, OUP Paperback

2 Evolution: The modern synthesis (Julian Huxley 1942) Synthesis between Darwinian natural selection, particulate (Mendelian) genetics, and Weissman s barrier (separation of germ cells and soma cells) Often called neo-darwinism Popularised by The Selfish Gene, Dawkins 1976

3 Evolution: the modern synthesis Gene-centred view of natural selection (random mutations) Impossibility of inheritance of acquired characteristics ( Larmarckism ) Distinction between replicator (genes) and vehicle (phenotype) Buttressed by The Central Dogma of Molecular Biology (Crick)

4 Some principles of Systems Biology Noble, D Claude Bernard, the first Systems Biologist, and the future of Physiology. Experimental Physiology 93, First principle Biological functionality is multi-level Genes do nothing on their own. They are simply databases. (There is no genetic program ) Physiological functions use many genes in collaboration Determining the level at which a function is integrated is one of the aims of Systems Biology

5 The genome and combinatorial explosion Assume each function depends on 2 genes (absurd, but still instructive) Total number of possible functions would be 0.5 x 25,000 x 24, = 312,487,500 With more realistic assumptions about # of genes in each function, the figures are huge : at 100/function (~ 1.5 e 302 ); for all combinations (~ 2 e ) ! (The MUSIC of LIFE, chapter 2).

6 Total number of atoms in the universe? How large is this number? Compare it with the largest object we know: The UNIVERSE

7 Total number of atoms in the universe There wouldn t be enough material in the whole universe for nature to have tried out all the possible interactions even over the long period of billions of years of the evolutionary process (The MUSIC of LIFE chapter 2).

8 Some principles of Systems Biology Second principle Transmission of information is NOT one-way So, the central dogma of biology is insufficient or even incorrect! (Shapiro, J. A Revisiting the Central Dogma in the 21st Century. Annals of the New York Academy of Sciences 1178, 6-28) There is downward causation from all levels This influences gene expression, and gene marking (epigenetic inheritance) Lamarckism is not so obviously false as is sometimes made out (John Maynard Smith, Evolutionary Genetics, OUP, 1998)

9 NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, Unravelling complexity Need to work in an integrative way at all levels: Systems level triggers of cell signalling Epigenetic marking by all levels organism organ tissue cellular sub-cellular pathways protein gene Systems level controls of gene expression Protein machinery reads genes There are feed-downs as well as upward between all these levels

10 Cardiac Cell Model Construction Channels I K1 I K I to I Cl ICa Receptors Ang II ß1 M2 Substrates I Na Glucose Ca NO Fatty Acids ATP Amino Acids ph H/Lactate I Na/K I NaCa Na/H Na/HCO3 Cl/OH Cl/HCO3 Carriers

11 Example of protein interaction in a cell model Reconstructing the heart s pacemaker Sinus rhythm generated by ion channel interaction Acceleration of sinus rhythm by adrenaline E m I Kr I CaL Rhythm abolished when interaction prevented All 3 protein levels up-regulated I f is example of fail-safe redundancy

12 Downward causation Cell potential Proteins channels

13 Model of sinus node i bna & i f Example of gene knock-out E m I f I bna 20% 40% 60% 80% 100% Noble, D., J. C. Denyer, H.F. Brown. & D DiFrancesco (1992). Proc Royal Society B 250:

14 The solution to the genetic differential effect problem Reverse engineering of genetically buffered knockouts and mutations Noble, D. (2008) Genes and Causation. Phil Trans Roy Soc series A

15 First i f blocker developed by Servier (France) Ivabradine (Procoralan) November 2005 Procoralan (ivabradine, Servier), the first selective and specific I f inhibitor, has received marketing authorization in 27 European countries from the European Medicines Evaluation Agency (EMEA) for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers.

16 Some principles of Systems Biology Third principle DNA is NOT the sole transmitter of inheritance We all inherit a complete egg cell DNA marking methylation, histone marking and other processes (maternal factors can transmit through generations) Epigenetic marking can also be transmitted through sperm line (perhaps via RNA) We should invert the usual question: What prevents inheritance of acquired characteristics? Jane Qiu (2006) Unfinished Symphony, Nature, 441, Jablonka & Lamb (1995) Epigenetic inheritance and Evolution (OUP)

17 The two main components o DNA methylation Methyl markers added to certain DNA bases repress gene activity The two main components of Epigenetic marking Histone modification Chemical tags can attach to histone tails which then modify gene activity Jane Qiu (Nature,2006)

18 The Guardian, 14 February 2007 Weaver et al The Journal of Neuroscience, February 14, (7):

19 Inheritance of epigenetic information Anway, M. D., Leathers, C. & Skinner, M. K Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147, The observations demonstrate that an environmental compound (an endocrine disruptor) can induce transgenerational (four generations were followed) disease states or abnormalities, and this suggests a potential epigenetic etiology and molecular basis of adult onset disease.

20 Inheritance of epigenetic information Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y. (2005) Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish (Carassius auratus) Enucleated Eggs. Biology of Reproduction 72, Goldfish 26 Carp 33 Carp nucleus in Goldfish egg 28?

21 Inheritance of epigenetic information Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y. (2005) Cytoplasmic Impact on Cross-Genus Cloned Fish Derived from Transgenic Common Carp (Cyprinus carpio) Nuclei and Goldfish (Carassius auratus) Enucleated Eggs. Biology of Reproduction 72, Goldfish 26 Carp 33 Carp nucleus in Goldfish egg 28 X-ray photographs showed that the vertebral number of six cloned fish was of the enucleated egg providing goldfish type, ranging from 26 to 28. In contrast, the vertebral number of nuclear-donor common carp was These data suggest that the goldfish egg cytoplasm plays an important role in regulating the somite development and vertebral number in the nuclear transplants.

22 If the central dogma is insecure, how safe is neo-darwinism? OUP 1995 MIT Press, 2005 Jablonka & Lamb, 1995, 2005

23 Some principles of Systems Biology Fourth principle Theory of (biological) Relativity There is no privileged level of causality in biological systems (multi-level analysis therefore necessary) Natural selection is multi-level (Gould not Dawkins) The levels are not equivalent because of non-linearity Most knockouts do not reveal function (80% in yeast Hillenmeyer et al, Science, 320, , 2008)

24 Some principles of Systems Biology Fifth principle Gene ontology will fail without higher-level insight Most genes (and gene modules) are ancient. They functioned in forms of life lacking many forms of functionality Genes are like linguistic metaphors : re-use, multiple use, very common Analogy with the evolution of language What then is a gene? A stretch of DNA? A protein code? A function?

25 Some principles of Systems Biology Sixth principle There is no genetic program (term invented by Monod & Jacob) Enrico Coen : Organisms are not simply manufactured according to a set of instructions. There is no easy way to separate instructions from the process of carrying them out, to distinguish plan from execution. The Art of Genes (OUP 1999) Denis Noble (2006) The MUSIC of LIFE (OUP), chapter 4

26 Some principles of Systems Biology Seventh principle There are no programs at any other level The music of life does not have a conductor With thanks to the Japanese Paper Artist 内藤英治 Hideharu Naito Thomas Lemberger (2006), EMBO Reports, 7, 12, 1200

27 Some principles of Systems Biology Eighth principle No programs at any level including the brain! The MUSIC of LIFE, chapter 9.

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29 We are poised for the greatest revolution of all understanding consciousness understanding the very mechanism that made those earlier revolutions possible! As Crick often reminded us, it's a sobering thought that all our motives, emotions, desires, cherished values and ambitions even what each of us regards as his very own "self" are merely the activity of a hundred billion tiny wisps of jelly in the brain. He referred to this as the "astonishing hypothesis" the title of his last book. (Echoed by Jim Watson's quip "There are only molecules everything else is sociology"). THE ASTONISHING FRANCIS CRICK by V.S. Ramachandran

30 As I was leaving he said Rama, I think the secret of consciousness lies in the claustrum don't you? Why else would this one tiny structure be connected to so many areas in the brain? and he gave me a sly, conspiratorial wink. It was the last time I saw him. THE ASTONISHING FRANCIS CRICK by V.S. Ramachandran

31 Some principles of Systems Biology Ninth principle The self is an integrative process not an object or substance The MUSIC of LIFE, chapters 9 and 10. Descartes was wrong, and so are many modern neuroscientists Bennett, M.R. and P.M.S. Hacker, Philosophical Foundations of Neuroscience. 2003, Oxford: Blackwell Publishing. East Asian philosophers (Taoists 道教, Buddhists 仏教 ) were right ( 無二邊 non-dualism)

32 Some principles of Systems and Computational Biology Tenth principle There are many more to be discovered! The theory of biology does not yet exist. That is the challenge for Systems Biology

33 Concluding remarks Molecular genetics takes us from genes to proteins but no further (Noble D (2008), Genes and Causation, Phil Trans Roy Soc A, ) The protein interactions we observe are a tiny fraction of those theoretically possible (Feytmans, Noble & Peitsch (2005), Trans Comp Sys Biol 1, 44-49) Mere computation, even spectacularly successful, is not in itself a theory Seeking such theories is the great challenge of Systems Biology Claude Bernard : the application of mathematics to natural phenomena is the aim of all science.

34 Noble, 1960 Nature 188,