Gene-Pharmaco Ontology - Functionality Ontology - Sumi Yoshikawa [email protected] Oct 28 2005 Workshop on bio-ontologies 205 Alfiero Center @University

Gene-Pharmaco OntologyGene-Pharmaco Ontology- Functionality Ontology -- Functionality Ontology -

Sumi YoshikawaSumi [email protected]@gsc.riken.jp

Oct 28 2005 Oct 28 2005 Workshop on bio-ontologiesWorkshop on bio-ontologies

205 Alfiero Center205 Alfiero Center@University at Buffalo North Campus@University at Buffalo North Campus

22

Drug-GO-DiseaseDrug-GO-Disease

GO:Function

GO

FunctionFunction

ProcessProcess

Drug Disease

How ? How ?

Indication, adverse reactions etc.How ?

33

TopicsTopics

Relations between molecular function anRelations between molecular function and processd process Determinant of “functionality” (functioning Determinant of “functionality” (functioning power) power) Integration of pharmacokinetics and pharIntegration of pharmacokinetics and pharmacodynamics in the context of relations omacodynamics in the context of relations of functionalityf functionality Drug-GO relations employing functionality Drug-GO relations employing functionality relations and disease-GO relationsrelations and disease-GO relations

44

Why Ontology ? Why Ontology ?

図を入れる

Simulation Result Interpretation

Data Input for Simulation

Link with Public Resources / Mining

Drug Interaction Knowledge BaseInference System

Human intelligible

Risk Communication

Drug InteractionSimulation

55

Why Biologists Talk about Function Why Biologists Talk about Function ??

Hypothesis driven approachHypothesis driven approach

Encountering withEncountering with “interesting Phenomenon” “interesting Phenomenon” eg. resistance to multiple drugseg. resistance to multiple drugs

ComparisonComparison with resistant patient (cell) and with resistant patient (cell) and sensitive patient (cell)sensitive patient (cell)

Identification of new molecule Identification of new molecule whichwhich was found was found only or much higher extentonly or much higher extent in resistant in resistant patient (cell)patient (cell)

The molecule was first called “multi-drug resistant protein”. The molecule was first called “multi-drug resistant protein”. Multi-drug resistance was regarded as its Multi-drug resistance was regarded as its functionfunction..

66

Why Biologists Talk about Function Why Biologists Talk about Function ??

In Genomics era: sequence to function In Genomics era: sequence to function approachapproach

Obtained dozens of Obtained dozens of sequence datasequence data

The Interest is “in which The Interest is “in which biological processbiological process is it is it responsible ? responsible ? = what is the= what is the function function ? ?

Prediction of function from homology Prediction of function from homology search etc. search etc.

How can we verify ? KO etc.How can we verify ? KO etc.

77

Gene – Gene Product – GOGene – Gene Product – GOAnnotated GO terms are mainly about the gene product Annotated GO terms are mainly about the gene product

Gene

GO: Molecular FunctionGO: Biological Process GO: Cellular Component

Gene Product (eg. Protein, RNA)

ANNOTATION TO GO TERMS

88

Biological Entities Are Multi-functionalBiological Entities Are Multi-functionalOne to many relationshipOne to many relationship::

a gene - gene products a gene - gene products a gene product - functionsa gene product - functionsa gene product - processesa gene product - processes

GO: Process I

Protein A

Protein B Protein C

GO:Function1

GO:Function2

GO:Function3

GO: Process II

GO: Process III

GO: Process IV

Protein D

Gene X’ products

Gene X

Drug

How ?

1010

Relations between GO: Function Relations between GO: Function and GO: Processand GO: Process

GO:Function

GO

FunctionFunction

ProcessProcess

How ?

How ?

1111

Function to Process (1)Function to Process (1)

RelationsRelations ExampleExample

Function(ing) Function(ing) enablesenables process process (type 1)(type 1)

Functioning of Transporter Functioning of Transporter activity activity enablesenables transportationtransportation

Functioning of A Enables Process B : Functionality or Functioning of A is necessary for execution of process B.Without functioning of A, execution of process B is incomplete or none.

1212Enabling Place

ThreeThree components for molecular i components for molecular interaction: eg. Drug X, inside celll nteraction: eg. Drug X, inside celll ((triggertrigger), biomolecule Y – trans m), biomolecule Y – trans membrane (embrane (situated objectsituated object), drug X ), drug X outside cell (outside cell (outputoutput) ) are participanare participants ofts of mol. interaction of X&Y mol. interaction of X&YDrug X-inside cell, biomolecule Y Drug X-inside cell, biomolecule Y - membrane - membrane are enabling participaare enabling participants ofnts of mol. interaction of X&Y mol. interaction of X&Ydrug X outside cell drug X outside cell is a resultant pis a resultant participant ofarticipant of mol. interaction XY = mol. interaction XY = emergence of drug X is resultant pemergence of drug X is resultant phenomenon of mol. Interaction of henomenon of mol. Interaction of X&YX&Y

Molecular Interaction as ProcessMolecular Interaction as ProcessModel in Drug Interaction Ontology (DIO)Model in Drug Interaction Ontology (DIO)

Drug X, inside cell

Drug X, outside cell

Biomolecule Y

(Transporter)

1313

Molecular Interaction and PathwayMolecular Interaction and PathwayTriadic relations of molecules are pathway Triadic relations of molecules are pathway (process) building blocks. Emergence of resultant (process) building blocks. Emergence of resultant participant participant triggerstriggers next molecular interactions. next molecular interactions.

Process 1 Process 2

1414

1515

Function to Process (2)Function to Process (2)RelationsRelations ExampleExample

Functioning Functioning enablesenables process process (type2)(type2)

Functioning of Functioning of Thymidilate synthaThymidilate synthase activityse activity enablesenables dTMP biosyntdTMP biosynthesishesis (one of other enablers)(one of other enablers)

Thymidilate synthaseThymidilate synthase activityactivity enaenablesbles Pyrimidine biosynthesisPyrimidine biosynthesis (one o(one of other enablers)f other enablers)

1616

Thymidylate synthase

dTMP

dUMP

dUDP

UDP

UMP

1717

Function to Process (2)Function to Process (2)RelationsRelations ExampleExample

Functioning Functioning enablesenables process process (type2)(type2)

Functioning of Functioning of Thymidilate synthaThymidilate synthase activityse activity enablesenables dTMP biosyntdTMP biosynthesishesis (one of other enablers)(one of other enablers)

Thymidilate synthaseThymidilate synthase activityactivity enaenablesbles Pyrimidine biosynthesisPyrimidine biosynthesis (one o(one of other enablers)f other enablers)

1818

Function to Process (3)Function to Process (3)RelationsRelations ExampleExampleFunctioning Functioning enablesenables process process (type3)(type3)

Functioning of Functioning of Thymidilate synthaThymidilate synthase activityse activity enables enables DNA replicatioDNA replicationn

1919

Process to ProcessProcess to Process

RelationsRelations ExampleExample

Process Process enablesenables process (type 2)process (type 2)

dTMP biosynthesisdTMP biosynthesis enablesenables nucleotide biosynthesisnucleotide biosynthesis ( sub process)( sub process)

Process Process enablesenables process (type 3)process (type 3)

nucleotide biosynthesisnucleotide biosynthesis enablesenables DNA replicationDNA replication

(linked process)(linked process)

Process A Enables Process B : Execution of process A is necessary for execution of process B.

Without execution of A, execution of process B is incomplete or none.

2020

Mini Summary:Mini Summary: Relations to Process Relations to ProcessProcess - process relations (non is_a relation)Process - process relations (non is_a relation)

Enables as participant(type 2)

Enables as participant

Enables as (participant of) Linked Process (type3)

Enables as participant relation (type 1 one-to-one)

“enables” could be included in larger context:

Influence / affects on ….

2121

Enablers and ParticipantEnablers and ParticipantEnablers and Participants of process BEnablers and Participants of process B

(some) Linked process(eg. Process A)

Participants of BEnablers of B

Participants of (some) Linked process(eg. Participants ofProcess A)

Resultant continuant participant(output continuant participant)

2222

Influence on what ?Influence on what ?

Efficiency of Process: Efficiency of Process:

Relative increase or decrease of Relative increase or decrease of resultant phenomenaresultant phenomena

Quality of Process: Quality of Process:

If the process occurs or notIf the process occurs or not

Erroneous resultant phenomena Erroneous resultant phenomena (erroneous output)(erroneous output)

Termination at mid stream Termination at mid stream

2323

Process to FunctionProcess to Function

Process A Enables Functioning of B :

its meaning is :

Execution of process A is necessary for functioning of B.

Without execution of A, functioning of B is incomplete or none.

What is functioningWhat is functioning ？？What would influence on functioning ? What would influence on functioning ?

And how ?And how ?

Generalization of this question would apply to ontoGeneralization of this question would apply to onto

logy of drug action. logy of drug action.

Because effect of drug is achieved through modifiBecause effect of drug is achieved through modification of functioning (functionality) of biomoleculecation of functioning (functionality) of biomolecule

s.s.

2525

2727

What would possibly influence on What would possibly influence on efficiency of functioning ?efficiency of functioning ?

Gene expression

Maturation/Activation

LocatingMigration

ExcretionDegradation

Execution

Meta LevelRegulation

2828

Analogy : Key’s functionAnalogy : Key’s function

EmbodimentMaturation(Activation) Locating Execution

Elimination/DegradationMeta Level

Regulation

Not applicable to inanimate system

2929

Determinant on Functionality of Gene ProductDeterminant on Functionality of Gene ProductFunctionality is influenced by

Functionality of participantExternal Influencers

enabling placeenabling place

Effect on Functioning

Functionality of participant

trigger participanttrigger participant

situated participantsituated participant

transient participanttransient participant





Gene Expression

Maturation

Locating

Elimination

Meta levelRegulation

Effect onExternal

Influencers

3030

Influence on Functioning / ProcessInfluence on Functioning / Process

A affects BA affects B

Upward direction(positive direction)

Non +/- modulation

Enables

Downward direction(negative direction)

Non-Enables

increase

decrease

3131

Determinant on Functionality of DrugDeterminant on Functionality of DrugFunctionality is influenced by

Functionality of Drug




transient participanttransient participant






Pharmaco-Dynamics

(Effect on Functioning

Pharmaco-Kinetics

(Effect onExternal

Influencers)

Absorption(Embodiment)

Metabolism(Maturation)

Distribution(Locating)

Excretion(Elimination)


3232

Determinant on Functionality of DrugDeterminant on Functionality of DrugFunctionality (functioning efficiency /quality) is influenced by

Drug Affecting Process




transient participanttransient participantPharmaco-Dynamics

(Effect on Functioning

PK






Embodiment

Maturation

Locating

EliminationMeta levelRegulation

Absorption

Metabolism

Distribution

Excretion


3333

Determinant of Drug EfficacyDeterminant of Drug Efficacy

PKAbsorption

Metabolism

Distribution

Excretion


Drug Affecting ProcessPharmaco-Dynamics(Effect on

FunctioningEmbodiment

Maturation

Locating

Elimination


Gene Expression

Maturation

Locating

Elimination


Effect onExternal

Influencers

Effect on Functioning

Functionality of participant

3434

Gene-Gene Product-Drug-GOGene-Gene Product-Drug-GO

Protein B1

Protein B2 Protein B3

GO:Function1

GO:Function2

GO:Function3

Protein B4

Gene X’ product

Drug A1

A1 A1 affects_affects_GO:Function 2 GO:Function 2 by_modulating_gene_by_modulating_gene_expression_process_ofexpression_process_of Gene X to B2 Gene X to B2

Gene X

3535

Gene-Gene Product-Drug-GO Gene-Gene Product-Drug-GO [Example][Example]

LDL receptor gene

GO: LDL receptor activity

LDL receptors

cholestyramine

cholestyramine cholestyramine affects_affects_GO: LDL receptor activity (hepaGO: LDL receptor activity (hepatic) tic) by_enhancing_gene_expression_process_oby_enhancing_gene_expression_process_of f LDL receptor gene to hepatic LDL receptorLDL receptor gene to hepatic LDL receptor

Hepatic LDL receptor

3636

Gene-Gene Product-Drug-GOGene-Gene Product-Drug-GO

Protein B1

Protein B2 Protein B3

GO:Function1

GO:Function2

GO:Function3

Protein B4

Gene X’ product

A2 A2 affects_GOaffects_GO:Function3 :Function3 by_direct_interaction_withby_direct_interaction_with B1, B2, and BB1, B2, and B33..

Drug A2

3737

Gene-Gene Product-Drug-GO [5]Gene-Gene Product-Drug-GO [5]

Protein B1Protein B2

Protein B3

GO:Function1

GO:Function2

GO:Function3

Protein B4

Gene X’ product

A3 affects_GOA3 affects_GO: Function3 : Function3 by_modulating_activation_process_ofby_modulating_activation_process_of B B3.3.

Drug A3

3838

QuestionQuestionTask scope :Task scope : looking through “mechanism of drug action” looking through “mechanism of drug action”

GO:Function

GO?

FunctionFunction

ProcessProcess

Drug Disease

Interaction of Functionality

？

Treatment / adverse events etc.

3939

DiseaseDisease

A definite A definite pathologic processpathologic process with a with a characteristic set of signs and symptoms. characteristic set of signs and symptoms. (mesh) (mesh)

A disease is any A disease is any abnormal condition ofabnormal condition of the the body or mind that causes discomfort, body or mind that causes discomfort, dysfunction, or distress to the person dysfunction, or distress to the person affected or those in contact with the affected or those in contact with the person. (NCI thesaurus)person. (NCI thesaurus)

4040

Normal State vs. Disease StateNormal State vs. Disease State

Disease Disease statestate is characterized as deviations is characterized as deviations from “normal” from “normal” statestate. . Various phenomena (symptoms etc.) as a Various phenomena (symptoms etc.) as a result of result of altered processesaltered processes & specific & specific process profiles are observed.process profiles are observed.

Standard (normal) state

Disease State

Aggravated State

Alleviated State

4141

Processes associated with diseaseProcesses associated with disease

Treatment Treatment motivated viewmotivated view Processes in a

current disease State

Processes contributed for emergence of current disease state

Processes for cure / alleviation

Processes for aggravation

4242

Processes as Treatment TargetProcesses as Treatment Target

Treatment target is not only noticeable Treatment target is not only noticeable processes but also causal, aggravating, processes but also causal, aggravating, alleviating, compensational ones. alleviating, compensational ones.

Molecular level of such processes can be Molecular level of such processes can be called “disease associated pathways called “disease associated pathways (process)” or “(process)” or “disease pathwaysdisease pathways””

Disease pathways include not only distinct Disease pathways include not only distinct disease specific pathways, but also disease specific pathways, but also deregulated normal processes. deregulated normal processes.

4343

Disease State and Disease State and Medication StateMedication State

Medication specific biological response Medication specific biological response appearsappears

Normal state

Disease State

Medication State

Alleviated State

Medication associated aggravating response

Medication associated alleviating response

4444

Disease – GO relationDisease – GO relation

Observation based process

In Disease A, Process / Events B is ..

Part of causal process of observed symptom

Disease associationevidence

need treatment

No need treatment

unknown

Alleviationprocess if

Aggravatingprocess if

Participated indisease development

as

Risk events if

Contributed for protection

Contributed as diseaseestablishment

Other deregulation

Increased than normalDecreased than normal

Other deregulation


Other deregulation


Other modulation


Other deregulation


Other deregulation


Other modulation


4545

ExampleExampleCancer drug 5FU and Colorectal CancerCancer drug 5FU and Colorectal Cancer

GO:Function

GO

FunctionFunction

ProcessProcess

5FU Colorectal Cancer

4646

Example: 5FUExample: 5FU

Colorectal Cancer

.DPYD

Gene / GPeg. TYMS / Thymidilate

Synthetase

Thymidilate synthetase activity GOFGOF

Nucleotide biosynthesis GOPGOP

DNA replication GOPGOP

affects as participating enabler

Thymidilate synthetase biosynthesis GOPGOP

(functioning) affects as participating enabler

affects as upstream process enabler

Disease association with evidence

Increased than normal



Aggravating process if

Participated in disease development



4747

Example: 5FUExample: 5FU

5FU & metabolites

.DPYD

Gene / GPeg. TYMS / Thymidilate

Synthetase

Thymidilate synthetase activity GOFGOF

Nucleotide biosynthesis GOPGOP

DNA replicationGOPGOP

affects as participating enabler

Thymidilate synthetase biosynthesis GOPGOP

(functioning) affects as participating enabler

affects as upstream processdecreases process efficiency by decreasing upstream process*

decreases functionality by direct interaction (inhibit by direct interaction)

decreases process efficiency by direct interaction with one of situated enabling continuant

participant

Inhibits (non-enables) by competing with

(normal) participantsby drug specific pathway that generate erronous analog

4848

Example: 5FU & CancerExample: 5FU & Cancer

5FU & metabolites

DNA replication GOPGOP

Decrease process efficiency by decreasing upstream process*

Inhibits (non-enables) by competing with normal participants

Disease association with evidence




Colorectal Cancer

Downward effect

includes cancer treatment

effect is against observed symptom,

aggravating effect ..

Aggravating process if

Participated in disease development



4949

Example: Cholestyramine & HyperlExample: Cholestyramine & Hyperlipidemiaipidemia

Cholestyramine (questra

n)

LDL receptor activity

Increase functionalityby

increasing gene expression

(hepatic)


Hyper Lipidemia

Upward effect is on

alleviation process

(treatment is for

enhancement of alleviation)

Alleviatingprocess if

GOFGOF

5050

Overall summaryOverall summary

Potentiality of functionality relations as Potentiality of functionality relations as generic one in biomedical domain.generic one in biomedical domain.

Integration of PK and PD by functionality Integration of PK and PD by functionality relations. Schematized PD.relations. Schematized PD.

Merging drug functionalities and disease Merging drug functionalities and disease process by GO as bridgeprocess by GO as bridge

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Documents

Gene-Pharmaco Ontology - Functionality Ontology - Sumi Yoshikawa [email protected] Oct 28 2005 Workshop on bio-ontologies 205 Alfiero Center @University