The Music of Life Glasba življenja Principles of Systems Biology With thanks to the Japanese Paper ArtistAn insect? or 内a violin? 藤 英 Denis Noble Oxford University 治 Hideharu Naito Out of the Box, Maribor, 15th May 2012
The story of the Silmans and the CD 001110100111100111000100 001110100001100111000100(from The Music of Life, chapter 1).
What directs the Music of Life? Genes? Or are they the pipesplayed in a huge organ(ism)?
The organ of 25,000 pipes From The MUSIC of LIFE, Chapter 2
The string section of the Wanamaker organ in Philadelphia (28,482 pipes)
The Story of the Chinese Emperor 秦 始 皇? and the poor farmer 貧 窮 農 (The Music of Life chapter 2). 民
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 24,999 10 289 = 312,487,500 With more realistic assumptions about # of genes in eachfunction, the figures are huge : at 100/function (~ 1.5 e302); for all combinations (~ 2 e166713) 10 72403 ! (The MUSIC of LIFE, chapter 2).
1072403Total number of atoms in the universe ≈ ? How large is this number?Compare it with the largest object we know: The UNIVERSE
1072403Total number of atoms in the universe ≈ 1080 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).
A novel view of DarwninismThe Silmans find some tropical islands The Music of Life chapter 8
The Silmans’ errorWith acknowledgement: drawing by Leonardocell Vinci Human spermatozoon fertilizing an egg da The Queen’s collection in Windsor Castle
Some principles of Systems Biology Second principleTransmission of information is NOT one-waySo, the ‘central dogma’ of biology is insufficient or even incorrect!(Shapiro, J. A. 2011, Evolution. A view from the 21st Century. FTPress)There is ‘downward causation’ from all levelsThis 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)
Some principles of Systems BiologyNoble, D. 2008 Claude Bernard, the first Systems Biologist, and the future of Physiology. Experimental Physiology 93, 16-26 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
NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463. Unravelling complexity Need to work in an integrative way at all levels: Systems level organism triggers of organ Systems level cell signalling tissue controls of cellular gene expression Epigenetic sub-cellular marking by pathways all levels protein Protein machinery gene reads genesThere are feed-downs as well as upward between all these levels
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 adrenalineEm Rhythm abolished when All 3 protein levels up-regulated interaction preventedIKrICaL If is example of fail-safe ‘redundancy’
Systems Biology & downward causes: Who first thought of it?The various forms of causation can be tracedback to Aristotle but the first clear statement of the influence of the whole on the parts can be found in Spinoza 1663
Who first thought of it? 1663Let us imagine, with your permission, a little worm, living in theblood, able to distinguish by sight the particles of blood, lymph etc.and to reflect on the manner in which each particle, on meeting withanother particle, either is repulsed, or communicates a portion of itsown motion. This little worm would live in the blood, in the sameway as we live in a part of the universe, and would consider eachparticle of blood, not as a part, but as a whole. He would be unable todetermine, how all the parts are modified by the general nature ofblood, and are compelled by it to adapt themselves, so as to stand in afixed relation to one another.(Benedict de Spinoza, 1663, Letter XV to Henry Oldenberg, p. 291)Henry Oldenburg was the first Secretary of The Royal Society
Some principles of Systems Biology Fourth principle Theory of (biological) RelativityThere 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-linearityMost knockouts do not reveal function (80% in yeast – Hillenmeyeret al, Science, 320, 362-365, 2008)
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 aset of instructions. There is no easy way to separate instructionsfrom 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
Some principles of Systems Biology Seventh principle There are no programs at any other levelThe ‘music of With thanks to the life’does not Japanese Paper Artist have a conductor 内藤英治 Hideharu Naito Thomas Lemberger (2006), EMBO Reports, 7, 12, 1200
Some principles of Systems Biology Eighth principleNo programs at any level – including the brain! The MUSIC of LIFE, chapter 9.
Some principles of Systems Biology Ninth principle The self is an integrative process not an object or substanceThe MUSIC of LIFE, chapters 9 and 10.Descartes was wrong, and so are many modern neuroscientistsBennett, M.R. and P.M.S. Hacker, Philosophical Foundations ofNeuroscience. 2003, Oxford: Blackwell Publishing.East Asian philosophers (Taoists 道教, Buddhists仏教) were right (無二邊 non-dualism)
JupiteriansA final story from The Music of Life Chapter 10
There are are ‘priests’dressed in colourful robes
The Jupiterians practise a specialform of ‘prayer’ -- meditation
Monastery libraryThere are scriptures Hei-in-sa, Korea84,000 ‘books’52 million ‘words’ God? “No-thing – Self/soul? “No-self – it’s a process” why do you ask that question?” I think therefore I am? “No-’I’ – “Thinking – so being”
Non sai tu che la nostra anima è composta di armonia?No words are needed for those who understand musicDo you not know that our soul is composed of harmony? Leonardo da Vinci Trattato della Pittura
The Music of Life Thank you !! Hvala !! Out of the Box, Maribor, 15th May 2012