The Music of LifeA new paradigm for biology

Denis NobleUniversity of Oxford

iSEI, CSEP, MCISBManchester University

Wednesday 25 November 2009

NOBLE, D The Music of Life, OUP 2006.

Paperback 2008

www.musicoflife.co.uk

Synthesis between Darwinian natural selection, particulate

(Mendelian) genetics, and Weissman‘s barrier

(separation of germ cells and soma cells)

Often called neo-Darwinism

Popularised by The Selfish Gene, Dawkins 1976

Evolution: The modern synthesis(Julian Huxley 1942)

Gene-centred view of natural selection (random mutations)

Impossibility of inheritance of acquired characteristics

(‗Larmarckism‘)

Distinction between replicator (genes) and vehicle (phenotype)

Buttressed by The Central Dogma of Molecular Biology (Crick)

Evolution: the modern synthesis

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

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

Some principles of Systems Biology

So, the ‗central dogma‘ of biology is insufficient or even incorrect!(Shapiro, J. A. 2009 Revisiting the Central Dogma in the 21st Century.

Annals of the New York Academy of Sciences 1178, 6-28)

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

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

Cardiac Cell Model Construction

INa

IClIK1 IKIto

ICa

Channels

I Na/K

I NaCaNa/H Na/HCO3 Cl/OH

Cl/HCO3

Carriers

Ca

pH

ATP

Glucose

Fatty Acids

Amino Acids

H/Lactate

SubstratesAng II1

2

NO

ßM

Receptors

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

Model of sinus node – ibNa & if

Example of ‗gene knock-out‘

Em

If

IbNa

20% 40% 60% 80% 100%

Noble, D., J. C. Denyer, H.F. Brown. & D DiFrancesco (1992). Proc Royal Society B 250: 199-207.

The solution to the ‗genetic differential effect problem‘

Reverse engineering of genetically buffered

knockouts and mutations

Noble, D. (2008) Genes and Causation. Phil Trans Roy Soc series A 366 3001-3015

First if blocker developed by Servier (France)

Ivabradine (Procoralan)

November 2005

Procoralan (ivabradine, Servier), the first selective and specific

If inhibitor, has received marketing authorization in 27 European

countries from the European Medicines Evaluation Agency

(EMEA) for the symptomatic treatment of chronic stable angina

pectoris in patients with normal sinus rhythm who have a

contraindication or intolerance to beta-blockers.

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, 143-145

Jablonka & Lamb (1995) Epigenetic inheritance and Evolution (OUP)

Third principle

DNA is NOT the sole transmitter of inheritance

The two main

components o

DNA methylationMethyl markers added to certain

DNA bases repress gene activity

Histone modificationChemical tags can attach to histone tails

which then modify gene activity

The two main

components of

Epigenetic marking

Jane Qiu (Nature,2006)

The Guardian, 14 February 2007

Weaver et al

The Journal of Neuroscience, February 14,

2007 • 27(7):1756 –1768

Inheritance of epigenetic information

Anway, M. D., Leathers, C. & Skinner, M. K. 2006

Endocrine disruptor vinclozolin induced epigenetic

transgenerational adult-onset disease. Endocrinology 147, 5515-5523.

The observations demonstrate that an environmental

compound (an endocrine disruptor) can induce transgenerational

(four generations were followed) disease states or

abnormalities, and this suggests a potential epigenetic

etiology and molecular basis of adult onset disease.

Inheritance of epigenetic information

Carp 33

Goldfish 26

Carp nucleus in Goldfish egg ?

Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y.

(2005) Cytoplasmic Impact on Cross-Genus Cloned Fish

Derived from Transgenic Common Carp (Cyprinus carpio)

Nuclei and Goldfish (Carassius auratus) Enucleated Eggs.

Biology of Reproduction 72, 510-515.

28

Inheritance of epigenetic information

X-ray photographs showed that the vertebral number of six cloned fish was of the

enucleated egg providing goldfish type, ranging from 26 to 28. In contrast, the

vertebral number of nuclear-donor common carp was 33–36. These data suggest

that the goldfish egg cytoplasm plays an important role in regulating the somite

development and vertebral number in the nuclear transplants.

Goldfish 26

Carp 33 Carp nucleus in Goldfish egg 28

Sun, Y. H., Chen, S. P., Wang, Y. P., Hu, W. & Zhu, Z. Y.

(2005) Cytoplasmic Impact on Cross-Genus Cloned Fish

Derived from Transgenic Common Carp (Cyprinus carpio)

Nuclei and Goldfish (Carassius auratus) Enucleated Eggs.

Biology of Reproduction 72, 510-515.

OUP 1995 MIT Press, 2005

If the central dogma is insecure, how safe is neo-Darwinism?

Jablonka & Lamb, 1995, 2005

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

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?

Fifth principle

Gene 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)

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!

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. Ramachandran

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. Ramachandran

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

Some principles of Systems and

Computational Biology

The theory of biology does not yet exist.

That is the challenge for Systems Biology

Tenth principle

There are many more to be discovered!

Concluding remarks

Molecular genetics takes us from genes to proteins but no further

(Noble D (2008), Genes and Causation, Phil Trans Roy Soc A, 366 3001-3015)

The protein interactions we observe are a tiny fraction of those theoretically possible

(Feytmans, Noble & Peitsch (2005), Trans Comp Sys Biol 1, 44-49)

Mere computation, even spectacularly successful, is not in itself 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.‖

www.MusicofLife.co.uk

Noble, 1960Nature 188, 495-497