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Denis Noble, University of Oxford, UK The music of life http://obc2012.outofthebox.si/
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The Music of Life Glasba življenja
Principles of Systems Biology
Denis Noble Oxford University
or
a violin?
With thanks to the
Japanese Paper Artist
内 藤 英 治
Hideharu Naito
An insect?
Out of the Box, Maribor, 15th May 2012
The story of the Silmans
and the CD
(from The Music of Life, chapter 1).
001110100001100111000100 001110100111100111000100
Or are they the pipes
played in a huge organ(ism)?
What directs the Music of Life?
Genes?
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
(The Music of Life chapter 2).
貧
窮
農 民
• • • • • • •
• • • • • • • •
16 32 64 128
>1000 >30,000
3 million
Square 36:
all the rice
in the palace
Square 50:
all the rice
in China
Square 64:
all the surface
of the world
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
= 312,487,500 With more realistic assumptions about # of genes in each
function, the figures are huge : at 100/function (~ 1.5 e302);
10289
1072403 ! for all combinations (~ 2 e166713)
(The MUSIC of LIFE, chapter 2).
1072403 Total number of atoms in the universe ≈ ?
How large is this number?
Compare it with the largest object we know:
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).
Total number of atoms in the universe ≈ 1080
1072403
A novel view of Darwninism
The Silmans find some tropical islands
The Music of Life chapter 8
The Silmans’ error
With acknowledgement: drawing by Leonardo da Vinci
The Queen’s collection in Windsor Castle
Human spermatozoon fertilizing an egg cell
Some principles of Systems Biology
So, 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 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)
Second principle
Transmission of information is NOT one-way
Some principles of Systems Biology
Noble, D. 2008 Claude Bernard, the first Systems Biologist, and the future
of Physiology. Experimental Physiology 93, 16-26
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
First principle
Biological functionality is multi-level
NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463.
Unravelling complexity
Need to work in an integrative way at all levels:
organism
organ
tissue
cellular
sub-cellular
pathways
protein
gene
There are feed-downs as well as upward between all these levels
Systems level
triggers of
cell signalling Systems level
controls of
gene expression
Protein machinery
reads genes
Epigenetic
marking by
all levels
Example of protein interaction in a cell model
Reconstructing the heart’s pacemaker
Sinus rhythm generated by ion channel interaction
ICaL
IKr
Em
If is example of fail-safe ‘redundancy’
Rhythm abolished when
interaction prevented
Acceleration of sinus rhythm by adrenaline
All 3 protein levels up-regulated
Cell
potential
Proteins
channels
Downward causation
Systems Biology & downward causes:
Who first thought of it?
The various forms of causation can be traced
back to Aristotle but the first clear statement
of the influence of the whole on the parts
can be found in Spinoza 1663
Let us imagine, with your permission, a little worm, living in the
blood, able to distinguish by sight the particles of blood, lymph etc.
and to reflect on the manner in which each particle, on meeting with
another particle, either is repulsed, or communicates a portion of its
own motion. This little worm would live in the blood, in the same
way as we live in a part of the universe, and would consider each
particle of blood, not as a part, but as a whole. He would be unable to
determine, how all the parts are modified by the general nature of
blood, and are compelled by it to adapt themselves, so as to stand in a
fixed 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
Who first thought of it? 1663
Some principles of Systems Biology
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, 362-365, 2008)
Fourth principle
Theory of (biological) Relativity
Some principles of Systems Biology
(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
Sixth principle
There is no ‘genetic program’
Some principles of Systems Biology
The ‘music of
life’does not
have a
conductor
With thanks to the
Japanese Paper Artist
内藤英治
Hideharu Naito
Seventh principle
There are no programs at any other level
Thomas Lemberger (2006), EMBO Reports, 7, 12, 1200
Some principles of Systems Biology
The MUSIC of LIFE, chapter 9.
Eighth principle
No programs at any level – including the brain!
Some principles of Systems Biology
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)
Ninth principle
The self is an integrative process
not an object or substance
Jupiterians
A final story from The Music of Life
Chapter 10
Jupiterians
The Music of Life, chapter 10
The first humans to visit this new world
They find intelligent beings
They find buildings that are,
to all intents and purposes,
CATHEDRALS
They are
ornate
treasures
There are are ‘priests’
dressed in colourful robes
The Jupiterians practise a special
form of ‘prayer’ -- meditation
God? “No-thing –
why do you ask that question?” Self/soul? “No-self – it’s a process”
I think therefore I am? “No-’I’ –
“Thinking – so being”
There are scriptures
84,000 ‘books’
52 million ‘words’
Monastery library
Hei-in-sa, Korea
海印寺Hei-in-sa, Korea
No words are needed for those who understand music
Non sai tu che la nostra anima è composta di armonia?
Do 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