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