The principles of Systems Biologyillustrated using the virtual heart

Denis NobleUniversity of Oxford

ECCS 2007 DresdenWednesday 3rd October 2007

NOBLE, D The Music of Life, OUP 2006.NOBLE, D La Musique de la Vie, Seuil, 2007

? Systems Biology ?

What is it?

Who invented it?

Who’s doing it?

Who pays?

1865Publication of Claude Bernard’s classic

Introduction à l’étude de la médecine expérimentale

Highest systems property:

“The living organism does not really exist in the milieu extérieur but in the liquid

milieu intérieur ….. a complex organismshould be looked upon as an assemblageof simple organisms …. that live in the

liquid milieu intérieur.”

L’être vivant n’existe pas vraiment au milieu extérieur, mais dans le liquide du milieu intérieur. Un organisme complexe doit être vu comme un assemblage d’organismes simples qui vivent dans le

milieu intérieur.

On mathematics

“The most useful path for physiology andmedicine to follow now is to seek to

discover new facts instead of trying toreduce to equations the facts which science

already possesses”

BUT“the application of mathematics to natural phenomena is the aim of

all science, because the expression of the lawsof phenomena should always be mathematical.”

Cette application des mathématiques aux phénomènes naturels est le but de toute science, parce que l’expression 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 qu’on connaît complètement les conditions des phénomènes entre lesquels on

veut établir une équation.

The problem we face today bothresembles 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 Bernard’s time.

Some principles of Systems Biology

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 principleBiological functionality is multi-level

Consider the number of combinations of r objects taken out of n objects. ThennPr = n(n-1)(n-2) …… (n-r+1) = n !/(n-r) !

(Feytmans, Noble & Peitsch, 2005, Transactions on Computational Systems Biology, 1, 44-49).

Illustrative calculation

Assume each function depends on 2 genes(absurd, but still instructive)

Total number of possible ‘functions’ would be0.5 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); for all combinations (~ 2 e166713)

10289

1072403 !

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).

Some principles of Systems Biology

So, the ‘central dogma’ of biology is insufficient or even incorrect!

There is ‘downward causation’ from all levelsThis 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

Second principleTransmission of information is NOT one-way

The reductionist causal chain

organism organtissue

cellular sub-cellularpathwaysprotein

gene

They [genes] created us body and mind

Richard Dawkins, The Selfish Gene

Well, no, they didn’t!

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

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 rationalefor our existence.” Dawkins, The Selfish Gene, 1976, pp 19-20

“[readers] .. Should imbibe the fundamental truth that an organismis a tool of DNA rather than the other way round” Dawkins, The Extended Phenotype p 159

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.

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

(Our joy not theirs!)

NOBLE, D (2002) Nature Reviews Molecular Cell Biology 3, 460-463.

Unravelling complexityNeed to work in an integrative way at all levels:

organism organtissue

cellular sub-cellularpathwaysprotein

gene

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

Systems leveltriggers ofcell signalling Systems level

controls ofgene expression

Protein machineryreads 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

If

All 3 protein levels up-regulated

Some principles of Systems Biology

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, 143-145Jablonka & Lamb (1995) Epigenetic inheritance and Evolution (OUP)

Third principleDNA is NOT the sole transmitter of inheritance

Jane Qiu (2006) Unfinished Symphony, Nature, 441, 143-145

The two main components of Epigenetic marking

DNA methylationMethyl markers added to certainDNA bases repress gene activity

Histone modificationChemical tags can attach to histone tailswhich then modify gene activity

The two main components of Epigenetic marking

Qiu (2006)

The Guardian, 14 February 2007

Weaver et al The Journal of Neuroscience, February 14, 2007 • 27(7):1756 –1768

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

Fourth principleTheory of (biological) Relativity

Some principles of Systems Biology

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 commonAnalogy with the evolution of language

What then is a gene? A stretch of DNA? A protein code? A function?

Fifth principleGene ontology will fail without higher-level insight

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)

Gabriel Dover: We don’t 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

Sixth principleThere is no ‘genetic program’

Peter Hunter – the Aucklandmodel ventricle

Spread of excitation wave in whole ventricle model

Model – Smith et al

Impact-induced arrhythmia Li, Kohl & Trayanova, 2004

Bi-domain modelling with full ionic cell modelsincluding stretch-activated channels

Breakdown of re-entrant arrhythmia into fibrillationSimulation – Panfilov,

Experiment – Witkowsky

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

Re-entrant arrhythmia inhuman model

TEN TUSSCHER & PANFILOV (2004).

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 principleThere are no programs at any other level

Thomas Lemberger, EMBO Reports, 7, 12, 1200 (2006)

Some principles of Systems Biology

The MUSIC of LIFE, chapter 9.

Eighth principleNo programs at any level – including the brain!

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. Ramachanran

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. Ramachanran

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 principleThe self is an integrative process

not an object or substance

Some principles of Systems Biology

The theor(y/ies) of biology do/es not yet exist.

That is the challenge for Systems Biology

Tenth principleThere are many more to be discovered!

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.”