what is systems biology? from genes to function and back

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Systems BiologySystems Biology

Hans V. Westerhoff Hans V. Westerhoff BioCentrum Amsterdam and Manchester Interdisciplinary BioCentrum Amsterdam and Manchester Interdisciplinary BiocentreBiocentre

Westerhoff , Amsterdam, 20060529Westerhoff , Amsterdam, 20060529Westerhoff , Amsterdam, 20060529 Methodologies of Systems BiologyMethodologies of Systems Biology

Philosophy of Systems Biology

Henk de Regt: Reductionism and physicsArno Wouters: Antireductionism and biologyHans Westerhoff: Systems BiologyFred Boogerd: Emergent mechanismsFrank Bruggeman: Theory of mechanistic explanation

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What I want you to learn:What I want you to learn:

Molecular Cell Biology does not satisfy classical Molecular Cell Biology does not satisfy classical requirements, neither of Physics nor of Biologyrequirements, neither of Physics nor of BiologyWhy genomics is not enoughWhy genomics is not enoughSystems Biology: about interactions leading to Systems Biology: about interactions leading to emergent functional propertiesemergent functional propertiesDifferent types of Systems BiologyDifferent types of Systems BiologySystems Biology aimsSystems Biology aimsSystems Biology: systems properties, lawsSystems Biology: systems properties, lawsSilicon cell as experimental tool for philosophySilicon cell as experimental tool for philosophy


Why the philosophy of SystemsSystems Biology?

Systems Biology holds the promise of being the synthesis of reductionism and holismSystems Biology is happening NOW!Philosophy of science before the facts!Unification of the sciences (and the arts)

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Philosophy of Biology

‘All science is either Physics or stamp collecting’ (Rutherford)Is Biology physics?

Stamp collectingBased in physical chemistry

It is neither (or both??)It is neither (or both??)


Philosophy of SystemsBiology

Is Biology physics?‘All science is either Physics or stamp collecting’ (Rutherford)Is Biology physics?

Stamp collectingBased in physical chemistry

Systems Biology is physics Systems Biology is physics andandstamp collectingstamp collecting

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The methodologies of the The methodologies of the various sciencesvarious sciences

PhysicsPhysicsLaws induced from empirical findingsLaws induced from empirical findingsThen deduce from underlying principlesThen deduce from underlying principlesVerify, falsifyVerify, falsify

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Science ….. (according to physics)

DefinitionsDefinitions

Principles/lawsPrinciples/laws

ValidationValidation


Philosophical foundations of physics (the classics)

Laws (theories, hypotheses) are Laws (theories, hypotheses) are inducedinduced from from empirical findingsempirical findingsConsequences deduced by combining hypotheses with Consequences deduced by combining hypotheses with established underlying principles are examined established underlying principles are examined experimentally to experimentally to test the new hypothesestest the new hypothesesGiven sufficient positive testing they are transformed Given sufficient positive testing they are transformed to underlying principlesto underlying principles through theorization. through theorization. For better testing, theories better be For better testing, theories better be quantitativequantitativeLaws and theories should be Laws and theories should be reducedreduced to underlying to underlying theoriestheories of greater validity and generality. of greater validity and generality.

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The methodologies of the The methodologies of the various sciencesvarious sciences

BiologyBiologyLargely observationalLargely observationalNo immutable laws; lots of exceptionsNo immutable laws; lots of exceptionsPredictions with 80 % success ratePredictions with 80 % success rate

Hence Biology is not a science?Hence Biology is not a science?But Life and Health are of major interest!But Life and Health are of major interest!


Hence Biology is not a Hence Biology is not a science?science?

Two solutions:Two solutions:

Physics is unfit: adjust physicsPhysics is unfit: adjust physicsE.g. mechanistic non equilibrium thermodynamicsE.g. mechanistic non equilibrium thermodynamics

Biology is unfit: adjust biology:Biology is unfit: adjust biology:Biochemistry and Molecular biologyBiochemistry and Molecular biology

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Molecular biology and biochemistry

Single molecules well understoodSingle molecules well understoodGene sequencing: sequence Gene sequencing: sequence knownknownProperties determinedProperties determined


Rate equation for enzymeRate equation for enzyme

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Life (Biology) adapted to physics

Living organism reduced to its moleculesStructure and activity of every molecule determinedAll of this verifiable, falsifiable science:

Biology turned physics Or ??? Not quite:


Molecular biology and biochemistry

Single molecules well understoodSingle molecules well understoodGenomics: sequences knownGenomics: sequences knownProperties determinedProperties determined

But they are not reducedBut they are not reducedNot always testedNot always testedNot verifiable/falsifiableNot verifiable/falsifiableNot quantitativeNot quantitativeBut who cared? Does this matter?But who cared? Does this matter?

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But who cared? Does this But who cared? Does this matter?matter?

Well, we donWell, we don’’t know yet;t know yet;We did not yet understand We did not yet understand LifeLife

Cell Biology

Understand LifeBy doing the Molecular Biology of the cell (??)

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SOS

P

TF

P

Translocationto the nucleus

MEK

PP

EGFEGFEGFREGFR

GRB2RasGDP

cell membraneRas

P Raf

P

P ERK

P

P ERK

P

GTP

TF Gene transcription DNA

RNA

cyclin D1 Mitosiscdk

Rb otherfactors

E2F

P RbP

P

PKC

MKP-1MKP-2

MKP-3

MEK

ERK

Raf

ERK

PP2A

VHR

PLA2

AA

PMA

And cell biology: Mitogen-activated protein kinase cascade


The maps of cell biology

Metabolic pathwaysGene expression hierarchySignal transductionSpatial organization

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SOS

P

TF

P

Translocationto the nucleus

MEK

PP

EGFEGFEGFREGFR

GRB2RasGDP

cell membraneRas

P Raf

P

P ERK

P

P ERK

P

GTP

TF Gene transcription DNA

RNA

cyclin D1 Mitosiscdk

Rb otherfactors

E2F

P RbP

P

PKC

MKP-1MKP-2

MKP-3

MEK

ERK

Raf

ERK

PP2A

VHR

PLA2

AA

PMA

And intracellular: Mitogen-activated protein kinase cascade


Limitations to the scientific status of biochemistry and molecular biology

InaccuracyInaccuracy: no quantitative, : no quantitative, i.e.i.e. accurate accurate testingtesting of of hypotheseshypothesesInabilityInability to deal with emergent propertiesto deal with emergent propertiesIrreducibilityIrreducibility: biochemistry and molecular biology : biochemistry and molecular biology theories cannot be reduced to physical chemical theories cannot be reduced to physical chemical theoriestheoriesImpotencyImpotency, , i.e.i.e. inability to address Life itself and lack of inability to address Life itself and lack of connection to connection to organismalorganismal BiologyBiologyUndefinednessUndefinedness:: not all factors that play important roles not all factors that play important roles are known and consequently hypotheses cannot be are known and consequently hypotheses cannot be testedtestedInaccessibilityInaccessibility to experimentation: the systems under to experimentation: the systems under study cannot be experimented on through a sufficient study cannot be experimented on through a sufficient number of degrees of freedomnumber of degrees of freedomLack of Lack of analyzabilityanalyzability

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Molecular Cell Biology does not satisfy classical Molecular Cell Biology does not satisfy classical requirements, neither of Physics nor of Biologyrequirements, neither of Physics nor of BiologyWhy genomics is not enoughWhy genomics is not enoughSystems Biology: about interactions leading to Systems Biology: about interactions leading to Systems Biology: about interactions leading to emergent functional propertiesemergent functional propertiesemergent functional propertiesDifferent types of Systems BiologyDifferent types of Systems BiologyDifferent types of Systems BiologySystems Biology aimsSystems Biology aimsSystems Biology aimsSystems Biology: systems properties, lawsSystems Biology: systems properties, lawsSystems Biology: systems properties, lawsSilicon cell as experimental tool for philosophySilicon cell as experimental tool for philosophySilicon cell as experimental tool for philosophy

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Limitations to the scientific status of biochemistry and molecular biology

InaccuracyInaccuracy: no quantitative, : no quantitative, i.e.i.e. accurate accurate testingtesting of of hypotheseshypothesesInabilityInability to deal with emergent propertiesto deal with emergent propertiesIrreducibilityIrreducibility: biochemistry and molecular biology : biochemistry and molecular biology theories cannot be reduced to physical chemical theories cannot be reduced to physical chemical theoriestheoriesImpotencyImpotency, , i.e.i.e. inability to address Life itself and lack of inability to address Life itself and lack of connection to connection to organismalorganismal BiologyBiologyUndefinednessUndefinedness:: not all factors that play important roles not all factors that play important roles are known and consequently hypotheses cannot be are known and consequently hypotheses cannot be testedtestedInaccessibilityInaccessibility to experimentation: the systems under to experimentation: the systems under study cannot be experimented on through a sufficient study cannot be experimented on through a sufficient number of degrees of freedomnumber of degrees of freedomLack of Lack of analyzabilityanalyzability

Genomics…

The elixir

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But now!, here we are But now!, here we are !!!!………………………………....

12 068 12 068 kbpkbp, a few , a few transcriptomestranscriptomes, an , an interactomeinteractome(?), parts of the metabolome (?), parts of the metabolome further further ……. and . and …………. . ……………………


The ‘omes’

Genome

Transcriptome

Proteome

Metabolome

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Transcriptome: hybridization array


Proteome

OK for prokaryotes

Not for mammals (too many genes)

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GenomicsGenomics

All molecules can be measured / will All molecules can be measured / will become measurablebecome measurable

Hence:Hence:Biology is understood?Biology is understood?


Everything is known

Has Biology become physics at last?Has Biology become physics at last?

Well, the boomerang strikes back:Well, the boomerang strikes back:This is the Physics of stamp collectingThis is the Physics of stamp collectingUnderstanding all the parts and how they Understanding all the parts and how they work individuallywork individually

This is just observingThis is just observing

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Genomics: the Biology of Genomics: the Biology of systemssystems

0. Make a picture of all the leaves0. Make a picture of all the leavesIndividuallyIndividually


GenomicsGenomicsAll molecules can be measured / will become All molecules can be measured / will become measurablemeasurable

Hence:Hence:Biology is understood?Biology is understood?No: we still do notNo: we still do not

Understand what Life isUnderstand what Life isCure diseaseCure diseaseHave green/white biotechnologyHave green/white biotechnology

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Limitations to the scientific (physics) status of biochemistry and molecular biology; solved by genomics??InaccuracyInaccuracy: no quantitative, : no quantitative, i.e.i.e. accurate accurate testingtesting of of hypotheseshypotheses

InabilityInability to deal with emergent properties to deal with emergent properties --IrreducibilityIrreducibility: biochemistry and molecular biology theories : biochemistry and molecular biology theories cannot be reduced to physical chemical theories cannot be reduced to physical chemical theories --ImpotencyImpotency, , i.e.i.e. inability to address Life itself and lack of inability to address Life itself and lack of connection to connection to organismalorganismal Biology Biology --UndefinednessUndefinedness:: not all factors that play important roles are not all factors that play important roles are known and consequently hypotheses cannot be testedknown and consequently hypotheses cannot be testedInaccessibilityInaccessibility to experimentation: the systems under study to experimentation: the systems under study cannot be experimented on through a sufficient number of cannot be experimented on through a sufficient number of degrees of freedomdegrees of freedomLack of Lack of analyzabilityanalyzability




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What is missing; Systems BiologyWhat is missing; Systems Biology

2020


Jan SteenJan Steen

What is missing?What is missing?


Life arises not just in the isolated Life arises not just in the isolated molecules but in their communicationmolecules but in their communication

Jan SteenJan Steen

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But we’d better explain….

What is systems biology?What is systems biology?


Methodologies of systems biology

The face of biology has been The face of biology has been changing:changing:Biology: focus on whole butterfliesBiology: focus on whole butterfliesMolecular Biology: focus on single Molecular Biology: focus on single moleculesmoleculesGenomics: focus on all moleculesGenomics: focus on all moleculesSystems Biology: focus on what Systems Biology: focus on what comes from their interrelationscomes from their interrelations

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Systems Biology is

ScienceSciencedeciphers how properties that are deciphers how properties that are functional functional biologicallybiologicallyarise in the interactionsarise in the interactions between components of between components of living organisms. living organisms. studies the studies the gap between (gap between (‘‘deaddead’’) molecules and ) molecules and LifeLife. . complements Genomics , which would otherwise complements Genomics , which would otherwise not lead to the understanding of the living cell, not lead to the understanding of the living cell, hence of Life.hence of Life.




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Systems Biology has various modes

Top down versus bottom-up; analytic versus synthetic; data driven versus hypothesis driven

Historical: molecular biology versus mathematical biology

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Top downTop down Systems BiologySystems Biology

1. Mathematical analysis: 1. Mathematical analysis: the phenomena; top downthe phenomena; top downDiagnosis; pattern recognition;Diagnosis; pattern recognition;Data driven hypothesis generationData driven hypothesis generation


bottombottom--upup Systems BiologySystems Biology

2. Get to the roots; bottom up;2. Get to the roots; bottom up;Understanding of the specialUnderstanding of the specialSystem properties/principles;System properties/principles;Hypothesis drivenHypothesis driven

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Top downTop down andand bottombottom--upupSystems BiologySystems Biology

1. Mathematical analysis: 1. Mathematical analysis: the phenomena; top downthe phenomena; top downDiagnosis; pattern recognition;Diagnosis; pattern recognition;Data driven hypothesis generationData driven hypothesis generation2. Get to the roots; bottom up;2. Get to the roots; bottom up;Understanding of the specialUnderstanding of the specialSystem properties/principles;System properties/principles;Hypothesis drivenHypothesis driven


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NET (1931), selfNET (1931), self--organization organization (1952),feed back regulation in (1952),feed back regulation in metabolism (1957) metabolism (1957)

Systems biologySystems biology

Molecular biology grows rapidly, Molecular biology grows rapidly, hybridization, restriction enzymes, hybridization, restriction enzymes, cloning (1960s &70s)cloning (1960s &70s)

HighHigh--throughputthroughputsequencing (1980s)sequencing (1980s)

Genome sequences, GenomeGenome sequences, Genome--wide wide expression analysis; bioinformatics expression analysis; bioinformatics ‘‘90s)90s)

Large scale simulators of metabolic Large scale simulators of metabolic networks, dissipative structures, networks, dissipative structures, energy coupling, MCA, BST (1970s)energy coupling, MCA, BST (1970s)

Data poor Data poor in silicoin silico biology, models of biology, models of viruses, red blood cell (1980viruses, red blood cell (1980’’s & s & early 1990early 1990’’s)s)

GenomeGenome--scale models and analysis, scale models and analysis, EE--cells, silicon cell (late 90cells, silicon cell (late 90’’s)s)

Analog simulation, bioenergetics, Lac Analog simulation, bioenergetics, Lac operonoperon (early 1960s)(early 1960s)DNA structure DNA structure

(1953)(1953)

The future: Integrative Systems Biology:The future: Integrative Systems Biology:GenomeGenome--Scale, Emergence of function from interactions, Quest for princScale, Emergence of function from interactions, Quest for principles/laws, Connection to iples/laws, Connection to

fundamental sciences,Teamwork: multi site infrastructure, Theoryfundamental sciences,Teamwork: multi site infrastructure, Theory--experiment integrationexperiment integrationNew curricula, trainingNew curricula, training




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The goals of Systems Biology

Understand more general principles underlying Understand more general principles underlying Life (Life (‘‘lawslaws’’))Mechanistic understanding of living systems Mechanistic understanding of living systems ((‘‘detailsdetails’’))PredictionsPredictionsBiotechnology, therapyBiotechnology, therapyUnderstand Life in molecular terms:Understand Life in molecular terms:

Complete the non Complete the non vitalistvitalist claimclaimUnderstand emergenceUnderstand emergenceDebunk Debunk ‘‘intelligent designintelligent design’’

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Systems

System Property

Does an enzyme control the Does an enzyme control the rate at which it functions? rate at which it functions?

??

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No No


Why would Why would aldolasealdolase NOT NOT determine its own flux?determine its own flux?

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The The enzymesenzymes controlcontrol the flux the flux togethertogether

VagueVague statementstatement

3232

Systems

Even molecular function in situ isis a System Property


No No But how to deal with this?But how to deal with this?

Find a good way to find outFind a good way to find out

Find general principlesFind general principles

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Science …..





How to measure whether an enzyme How to measure whether an enzyme determines its fluxdetermines its flux

Flux versus enzyme activity

0

0.5

1

0 0.5 1 1.5 2 2.5

Enzyme is not limitingEnzyme is not limiting

Enzyme activity

Flux

Enzyme Enzyme isis limitinglimiting

The slope matters, i.e. dJ/de

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Definition flux-control coefficient

% change in flux caused by 1 % specific % change in flux caused by 1 % specific modulation of an enzyme, at steady statemodulation of an enzyme, at steady state

ii

istatesteadyi

Je de

dJ

ede

JdJ

edJdC

i %1'''%

ln||ln

==⎟⎟⎠

⎞⎜⎜⎝

⎛=


Science …..




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The first law of Systems Biology:The first law of Systems Biology:summation law for flux controlsummation law for flux control

Implication: steadyImplication: steady--state flux control need not be in state flux control need not be in single step; single step; can be distributedcan be distributed, but must sum to 1, but must sum to 1

1.........321

=++++ Je

Je

Je

Je n

CCCC


trypanosome:trypanosome:


0

0.5

1

0 0.5 1 1.5 2 2.5

ii

istatesteadyi

Ji de

dJ

ede

JdJ

edJdC

%1'''%

ln||ln

==⎟⎟⎠

⎞⎜⎜⎝

⎛=

Flux versus Flux versus enzyme/gene enzyme/gene dosagedosage

3636







3737


Silicon cells: the ultimate systems biology?

ReductionistHolistSynthesis:

The computer replica of reality


The essence of System Biology:The essence of System Biology:From interactions to life; repeatedlyFrom interactions to life; repeatedly

cf. cf. www.systembiology.netwww.systembiology.net

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Where to Where to target drugs?target drugs?

?

The The ‘‘pacepace--maker maker PFKPFK’’??

Example of Example of implicationsimplications

3939


Silicon trypanosome: PFK lousy target; most Silicon trypanosome: PFK lousy target; most control in glucose transporter; control in glucose transporter;


0

0.5

1

0 0.5 1 1.5 2 2.5

ii

istatesteadyi

Ji de

dJ

ede

JdJ

edJdC

%1'''%

ln||ln

==⎟⎟⎠

⎞⎜⎜⎝

⎛=

Flux versus Flux versus enzyme/gene enzyme/gene dosagedosage


Very low Very low [glucose][glucose]

Physiological Physiological [glucose][glucose]

Experimental: control by Experimental: control by transport approximately 0.5transport approximately 0.5

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Where to Where to target drugs?target drugs?

The glucose The glucose transportertransporter


Limitations to the scientific status of systems biology

InaccuracyInaccuracy: no quantitative, : no quantitative, i.e.i.e. accurate accurate testingtestingof of hypotheseshypotheses

InabilityInability to deal with emergent properties to deal with emergent properties ??IrreducibilityIrreducibility: biochemistry and molecular : biochemistry and molecular biology theories cannot be reduced to physical biology theories cannot be reduced to physical chemical theories chemical theories ??ImpotencyImpotency, , i.e.i.e. inability to address Life itself and inability to address Life itself and lack of connection to lack of connection to organismalorganismal BiologyBiologyUndefinednessUndefinedness:: not all factors that play not all factors that play important roles are known and consequently important roles are known and consequently hypotheses cannot be testedhypotheses cannot be testedInaccessibilityInaccessibility to experimentation: the systems to experimentation: the systems under study cannot be experimented on through under study cannot be experimented on through a sufficient number of degrees of freedoma sufficient number of degrees of freedomLack of Lack of analyzabilityanalyzability

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Limitations to the scientific status of systems biology: removed!

InaccuracyInaccuracy: no quantitative, : no quantitative, i.e.i.e. accurate accurate testingtestingof of hypotheseshypothesesInabilityInability to deal with emergent propertiesto deal with emergent propertiesIrreducibilityIrreducibility: biochemistry and molecular : biochemistry and molecular biology theories cannot be reduced to physical biology theories cannot be reduced to physical chemical theorieschemical theoriesImpotencyImpotency, , i.e.i.e. inability to address Life itself and inability to address Life itself and lack of connection to lack of connection to organismalorganismal BiologyBiologyUndefinednessUndefinedness:: not all factors that play not all factors that play important roles are known and consequently important roles are known and consequently hypotheses cannot be testedhypotheses cannot be testedInaccessibilityInaccessibility to experimentation: the systems to experimentation: the systems under study cannot be experimented on through under study cannot be experimented on through a sufficient number of degrees of freedoma sufficient number of degrees of freedomLack of Lack of analyzabilityanalyzability

Silicon cell is replica

Then any emergence can be calculated (??)…..See Fred Boogerd later today

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what is systems biology? from genes to function and back

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