The principles of Systems Biology

1
The principles of Systems Biology illustrated
using the virtual heart
Denis Noble University of Oxford ECCS 2007
Dresden Wednesday 3rd October 2007
NOBLE, D The Music of Life, OUP 2006. NOBLE, D La
Musique de la Vie, Seuil, 2007
2
? Systems Biology ? What is it? Who invented
it? Whos doing it? Who pays?
3
1865 Publication of Claude Bernards
classic Introduction à létude de la médecine
expérimentale
4
Highest systems property The living organism
does not really exist in the milieu extérieur
but in the liquid milieu intérieur .. a complex
organism should be looked upon as an
assemblage of simple organisms . that live in
the liquid milieu intérieur. Lêtre vivant
nexiste pas vraiment au milieu extérieur, mais
dans le liquide du milieu intérieur. Un organisme
complexe doit être vu comme un assemblage
dorganismes simples qui vivent dans le milieu
intérieur.
5
On mathematics The most useful path for
physiology and medicine to follow now is to seek
to discover new facts instead of trying to reduce
to equations the facts which science already
possesses
6
BUT the application of mathematics to natural
phenomena is the aim of all science, because the
expression of the laws of phenomena should always
be mathematical. Cette application des
mathématiques aux phénomènes naturels est le but
de toute science, parce que lexpression de la
loi des phénomènes doit toujours être
mathématique. Il faudrait pour cela, que les
données soumises au calcul fussent des résultats
de faits suffisamment analysés, de manière à
être sûr quon connaît complètement les
conditions des phénomènes entre lesquels on veut
établir une équation.
7
The problem we face today both resembles that
faced by Bernard and differs from it. New form
of reductionism genetic determinism (le
programme génétique) But we now have more
facts than we can handle data explosion at all
levels. The reverse of the situation in
Bernards time.
8
Some principles of Systems Biology
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
9

• Consider the number of combinations of r objects
  taken out of n objects. Then
• nPr n(n-1)(n-2) (n-r1) n !/(n-r) !

(Feytmans, Noble Peitsch, 2005, Transactions on
Computational Systems Biology, 1, 44-49).
10
Illustrative calculation
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
10289
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)
1072403 !
11
There wouldnt 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).
12
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! There is
downward causation from all levels This
influences gene expression, and gene marking
(epigenetic inheritance Qiu 2006) Lamarckism
is not so obviously false as is sometimes made
out (John Maynard Smith, Evolutionary Genetics,
OUP, 1998)
Jane Qiu (2006) Unfinished Symphony, Nature, 441,
143-145
13
The reductionist causal chain

They genes created us body and mind Richard
Dawkins, The Selfish Gene Well, no, they didnt!
I know one approach that will fail, which is to
start with genes, make proteins from them and
to try to build things bottom-up Sydney Brenner,
2001
organism organ tissue cellular
sub-cellular pathways protein gene
14
Selfish Genes
Now they swarm in huge colonies, safe inside
gigantic lumbering robots, sealed off from the
outside world, communicating with it by tortuous
indirect routes, manipulating it by remote
control. They are in you and me they created
us, body and mind and their preservation is the
ultimate rationale for our existence. Dawkins,
The Selfish Gene, 1976, pp 19-20
readers .. Should imbibe the fundamental truth
that an organism is a tool of DNA rather than the
other way round Dawkins, The Extended Phenotype
p 159
15
Genes as Prisoners
Now they are trapped in huge colonies, locked
inside highly intelligent beings, moulded by the
outside world, communicating with it by complex
processes, through which, blindly, as if by
magic, function emerges. They are in you and me
we are the system that allows their code to be
read. And their preservation is totally dependent
on the joy we experience in reproducing
ourselves. We are the ultimate rationale for
their existence.
(Our joy not theirs!)
The fundamental truth is that an organism is the
only tool by which DNA can express functionality,
by which the Book of Life can be read. DNA
alone is inert - - -
dead
16
Truth science or politics? fact or metaphor?
Now they swarm in huge colonies, safe
inside gigantic lumbering robots, sealed off
from the outside world, communicating with it by
tortuous indirect routes, manipulating it by
remote control. They are in you and me they
created us, body and mind and their
preservation is the ultimate rationale for
our existence
Now theyre trapped in huge colonies, locked
inside highly intelligent beings, moulded by the
outside world, communicating with it by complex
processes, through which, blindly, as if by
magic, function emerges. They are in you and
me we are the system that allows their code to
be read. Our joy is their transmission. We are
the ultimate rationale for their existence.
Our joy not theirs!
17
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
Systems level triggers of cell signalling
Systems level controls of gene expression
Epigenetic marking by all levels
Protein machinery reads genes
There are feed-downs as well as upward between
all these levels
18
Example of protein interaction in a cell model
Reconstructing the hearts pacemaker
Sinus rhythm generated by ion channel interaction
Acceleration of sinus rhythm by adrenaline
Rhythm abolished when interaction prevented
All 3 protein levels up-regulated
If is example of fail-safe redundancy
19
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,
143-145 Jablonka Lamb (1995) Epigenetic
inheritance and Evolution (OUP)
20
Jane Qiu (2006) Unfinished Symphony, Nature, 441,
143-145
21
The two main components of Epigenetic marking
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
Qiu (2006)
22
The Guardian, 14 February 2007
Weaver et al The Journal of Neuroscience,
February 14, 2007 27(7)1756 1768
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
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) Gabriel Dover We dont have a theory
of interactions and until we do we cannot have a
theory of development or a theory of
evolution. There are no genes for
interactions (Dear Mr Darwin, Weidenfeld
Nicolson, 2000) Denis Noble (2006) The MUSIC of
LIFE (OUP), chapter 4
26
Peter Hunter the Auckland model ventricle
27
Spread of excitation wave in whole ventricle model
Model Smith et al
28
Spread of excitation wave in whole ventricle model
Experiment Nash et al
29
Impact-induced arrhythmia Li, Kohl Trayanova,
2004 Bi-domain modelling with full ionic cell
models including stretch-activated channels
30
Breakdown of re-entrant arrhythmia into
fibrillation Simulation Panfilov, Experiment
Witkowsky
31
Human cell model
TEN TUSSCHER, NOBLE, D., NOBLE, P. J. PANFILOV
(2004). A model of the human ventricular
myocyte. American Journal of Physiology 286,
H1573-1589.

Detailed channel, transporter and SR
equations, but computationally very efficient
32
Human ventricular cell model Class III induced EAD
iKr blocked by 90
mV
Ko reduced
seconds
Ko reduced from 5.4 mM to 2.7 mM Then iKr
blocked by 90
33
Re-entrant arrhythmia in human model
TEN TUSSCHER PANFILOV (2004).
34
Some principles of Systems Biology
Seventh principle There are no programs at any
other level
With thanks to the Japanese Paper Artist ????
Hideharu Naito
The music of lifedoes not have a conductor
Thomas Lemberger, EMBO Reports, 7, 12, 1200 (2006)
35
Some principles of Systems Biology
Eighth principle No programs at any level
including the brain!
The MUSIC of LIFE, chapter 9.
36
We are poised for the greatest revolution of
allunderstanding consciousnessunderstanding 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
ambitionseven  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
moleculeseverything else is sociology"). THE
ASTONISHING FRANCIS CRICK by V.S. Ramachanran
37
As I was leaving he said Rama, I think the
secret of consciousness lies in the
claustrumdon'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. Ramachanran
38
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 ??, Buddhists??) were right
(???
non-dualism)
39
Some principles of Systems Biology
Tenth principle There are many more to be
discovered!
The theor(y/ies) of biology do/es not yet exist.
That is the challenge for Systems Biology
40
Concluding remarks Molecular genetics takes us
from genes to proteins but no further (no genes
for interactions) The protein interactions we
observe are a tiny fraction of those
theoretically possible Mere computation, even
spectacularly successful, is not 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.