Denis Noble, University of Oxford, UK The music of life http://obc2012.outofthebox.si/

1. The Music of Life
Glasba življenja
Principles of Systems Biology
With thanks to the
Japanese Paper Artist
An insect?
or
内
a violin?
藤
英
Denis Noble
Oxford University
治
Hideharu Naito
Out of the Box, Maribor, 15th May 2012

2. The story of the Silmans
and the CD
001110100111100111000100
001110100001100111000100
(from The Music of Life, chapter 1).

3. What directs the Music of Life?
Genes?
Or are they the pipes
played in a huge organ(ism)?

4. The organ of 25,000 pipes
From The MUSIC of LIFE, Chapter 2

5. The string section of the Wanamaker
organ in Philadelphia (28,482 pipes)

6. The Story of the Chinese Emperor
秦
始
皇?
and the poor farmer
貧
窮
農
(The Music of Life chapter 2).
民

14. • • • • • • 16 32 64 128
• •• •• ••••
>1000 >30,000
3 million

15. Square 36:
all the rice
in the palace

16. Square 50:
all the rice
in China

17. Square 64:
all the surface
of the world

18. 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 each
function, the figures are huge : at 100/function (~ 1.5 e302);
for all combinations (~ 2 e166713)
10 72403 !
(The MUSIC of LIFE, chapter 2).

19. 1072403
Total number of atoms in the universe ≈ ?
How large is this number?
Compare it with the largest object we know:
The UNIVERSE

20. 1072403
Total 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).

21. A novel view of Darwninism
The Silmans find some tropical islands
The Music of Life chapter 8

22. The Silmans’ error
With acknowledgement: drawing by Leonardocell Vinci
Human spermatozoon fertilizing an egg da
The Queen’s collection in Windsor Castle

23. 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. 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)

24. Some principles of Systems Biology
Noble, 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

25. 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 genes
There are feed-downs as well as upward between all these levels

26. 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
Em
Rhythm abolished when
All 3 protein levels up-regulated
interaction prevented
IKr
ICaL
If is example of fail-safe ‘redundancy’

27. Downward causation
Cell
potential
Proteins
channels

28. 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

29. Who first thought of it?
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

30. 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, 362-365, 2008)

31. 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

32. Some principles of Systems Biology
Seventh principle
There are no programs at any other level
The ‘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

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

35. 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)

36. Jupiterians
A final story from The Music of Life
Chapter 10

37. Jupiterians
The Music of Life, chapter 10

39. The first humans to visit this new world

41. They find intelligent beings

42. They find buildings that are,
to all intents and purposes,
CATHEDRALS

43. They are
ornate
treasures

44. There are are ‘priests’
dressed in colourful robes

45. The Jupiterians practise a special
form of ‘prayer’ -- meditation

46. Monastery library
There are scriptures Hei-in-sa, Korea
84,000 ‘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”

47. 海印寺Hei-in-sa, Korea

49. Non sai tu che la nostra anima è composta di armonia?
No words are needed for those who understand music
Do you not know that our soul is composed of harmony?
Leonardo da Vinci
Trattato della Pittura

50. The Music of Life
Thank you !!
Hvala !!
Out of the Box, Maribor, 15th May 2012