The Music of Life - MCISB · (Mendelian) genetics, and Weissman‘s barrier (separation of germ...
Transcript of The Music of Life - MCISB · (Mendelian) genetics, and Weissman‘s barrier (separation of germ...
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
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