From chemicals to minds: Integrated ontologies in the search for scientific understanding
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From Chemicals to Minds:
Integrated ontologies in the search for scientific understanding
Janna Hastings1,2
1 Cheminformatics and Metabolism, European Bioinformatics Institute, UK
2 Swiss Center for Affective Sciences, University of Geneva, Switzerland
InterOntology @ Tokyo, February 2012
Wednesday, April 12, 2023 2
Oxytocin is believed to play a role in various behaviors, including orgasm, social recognition, pair bonding, anxiety … it is sometimes referred to as the "love hormone".
The inability to secrete oxytocin and feel empathy is linked to sociopathy, psychopathy, narcissism and general manipulativeness.
I want…
I think…
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Bio-ontologies serve many purposesStandards … for automated data exchange in rapidly changing scientific environments
Categorisation of entities in the domain … for data-driven research such as functional analysis of gene transcription
Facilitating interdisciplinary research through enabling comparison of results across disciplines
Representing what we know about science
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ChEBI is an ontology of small molecules
ChEBI Ontology
chemical entity role
carboxylic acid
application
antibacterial drug
cefpodoxime (CHEBI:606443)
pharmaceutical
biological role
chemical role
chemical substance
molecular entitygroup
carbonyl compoundsolvent
has role
cyclooxygenaseinhibitor
carboxy group
has part
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Why do people want their chemicals annotated in ChEBI?
ChEBI is the only freely available chemical database with high-quality manual curation
ChEBI IDs are stable and maintained
ChEBI ontology allows automatic traversal and retrieval of chemical knowledge
e.g. for metabolic network reconstructione.g. for scaffold hopping in drug discovery
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Pathways and metabolic network reconstructions encode dynamic biochemical knowledge
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ChEBI and Metabolic Network Reconstruction
1.Fuzzy merging between different models for integrated view on patchy knowledge , uses nearest shared ancestor
2.Protonation state of metabolites important for charge balancing, uses conjugate base / acid relationships
3.Proper treatment of biomass reactions (searches for “is a” lipid relationship
[Swainston et al, Manchester]
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ChEBI is manually maintained by a team of chemists
Jan-08
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ChEBI growth: no. of entriesLong wishlist
from users
Classification practices in chemistry lead to massive multiple inheritance
ChEBI ontology
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Desiderata for structure-based automated classification
Class definitions should be expressed in a language or formalism which is accessible to domain experts (chemists);
It should be possible to combine different elementary features into sophisticated class definitions using compositionality;
The specification of class definitions should allow automatic arrangement of those classes into a hierarchy
Mid-level groupings should be semantic, i.e. they should make sense to chemists and be named;
Logical definitions enable automatic classification
hydrocarbon equivalentTo molecule and has_atom only
(carbon atom or hydrogen atom)
peptide cation equivalentTo peptide and has_charge some double
[>, 0.0]
ChEBI ontology
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Value restriction
Data range restriction
ChEBI ontology
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tricarboxylic acid equivalentTo molecule and has_functional_group exactly 3
carboxy group Cardinality restriction (but in practice: use data value restriction)
Beyond OWL
Structured object representation & reasoning (Magka et al., Oxford)
Hybrid reasoning with second-order features of symmetric graphs such as fullerenes (Kutz et al., Bremen)
What about non-structural classes?
All sulphuric acid molecules have a sulphur atom and four oxygen atoms arranged in a certain bonding pattern at all times that they exist.
But any given molecule may or may not ever be involved in acting as a strong acid
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ChEBI ‘roles’ represent how chemicals act
Subatomic particle: parts of atoms
Chemical entity:parts and structural features of molecules
Role ontology:active properties of chemical entities
‘Has role’
ChEBI ‘roles’ are BFO realizables (mostly)
Properties that we ascribe to things because of what can happen under certain circumstances (future-pointing) are called realizable entities
The processes (/events) in which they display those properties are called realizations
(the property, however, exists all the time)
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Examples of chemical dispositions
• Buffer • Catalyst• Hydrogen donor /
acceptor• Acid / base
• Surfactant• Antioxidant• Detergent• De-aminating agent• Radical scavenger
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Biological functionsChEBI functions are the ‘other side’ of the GO molecular functions (which have protein bearers)
Both functions are realized in the same process
• Epitope• Mitogen• Hormone• Growth regulator• Toxin• Nutrient• COX inhibitor• Cholinesterase
reactivator
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Artefactual functions
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•Label•Fragrance•Pesticide•Fuel•Dye•Detergent•Probe•Reagent •Agrochemical
Chemicals are designed synthetically or selected by chemists in order to perform certain functions outside of biological evolution
But what about drugs, e.g. for treatment of headaches?
Thalidomide is not a drug for treating morning sickness
(anymore)
Originally introduced as a sedative and hypnotic for treatment of morning sickness in 1957, thalidomide was withdrawn from use in the early 1960s after it was shown to produce severe teratogenic effects. It was subsequently found that the (R)-enantiomer is effective against morning sickness, whereas the (S)-enantiomer is teratogenic. However, as the enantiomers can interconvert in vivo, administering only the (R)-enantomer would not prevent the teratogenic effect.
Image credit: Hildeenmikey
A harmless metabolite in one organism is food to another and toxin to a third
Paracetamol treats pain and fever in humans and is safe enough to give to babies,
but it kills cats22
Bridging from chemistry to biologySome ChEBI roles are realized in biological processes
but beware: NOT toxin realized_in ‘response to toxin’
Life cycle of an organism: insecticide realized_in process ‘death’ and has_organism some ‘insect’ (a kind of participation)
GO:0051610The directed movement of serotonin into a cell
ChEBI is now the (behind-the-scenes) chemical representationof all the chemical biologyin GO(to be published soon!)
GO and ChEBI are (nearly)FULLY ALIGNED!
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A very interesting class of molecules: those that alter mental functioning
Mental Functioning Ontology (MFO)
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BFO:Entity
BFO:Continuant BFO:Occurrent
BFO:Process
Organism
BFO:Independent Continuant
BFOMFO
BFO:Dependent Continuant
Behaviour inducing state
Mental Functioning Related Anatomical
Structure
Cognitive Representation
BFO:Quality
Affective Representation
Mental Process
Bodily ProcessBFO:Disposition
How does mental functioning actually work?
Biology
Neuroscience
Chemistry
Psychology
Psychiatry
PhysicsHuman
Mouse
fMRI
Gene expression
analysis
Self-reportsMetabolic analysis
Genetic profiling
EEG
Questionnaires
Theories of mental functioning
Abducted! Replaced!
Capgras delusion: a disorder in which a person holds a delusion that a friend, spouse, parent, or other close family member has been replaced by an identical-looking impostor.
Faulty perception? Normal perception, faulty reasoning? Faulty emotional reaction to perception? Overactive imagination?
TESTABLE IMPLICATIONS
Existing vocabulariesdon’t include
computable definitions
BFO:Entity
BFO:Continuant BFO:Occurrent
BFO:ProcessBFO:Independent
Continuant
BFOMFO
BFO:Dependent Continuant
Cognitive Representation
Affective Representation
Mental Process
Bodily ProcessBFO:Disposition
MFO-EM
Emotion Occurrent
Organism
Emotional Action Tendencies
Appraisal
Subjective Emotional Feeling
Physiological Response to
Emotion Process
inheres_in
is_output_of
Emotional Behavioural Process
Appraisal Process
has_part
agent_of
The Emotion Ontology (MFO-EM)
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Types of emotion
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To define the characteristics of different emotions start with canonical emotions
Emotion types (such as fear) show enormous variance across instancesJust as do anatomical types, e.g. human bodies
Ontology expresses what is always true… But aims to say something useful for representation of domain knowledge.
Solution: encode such knowledge in ‘canonical’ types
canonical fear
appraisal process
Appraisal of dangerousness
Has part Has output
Canonical fear results from an appraisal of dangerousness
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Canonical fear
The Emotion Ontology (ICBO 2011)
canonical fear
fear
EMOTION COMPONENT CHARACTERISTIC FOR FEARAction tendency Fight-or-flightSubjective emotional feeling Negative, tense, powerlessBehavioural response Characteristic fearful facial
expressionCharacteristic appraisal Something is dangerous to me
subtype
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Canonical and non-canonical fear
Canonical fear gives rise to action tendencies that are conformant to the perceived danger
Phobia = disposition giving rise to non-canonical fear
laridaphobia : intense fear of seagulls
Cognitive Neuroscience of Emotion
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Task Classification in MFO/MFOEM
Recognition of gender in emotional facial expressions
Visual perception of emotional facial expressions (subClassOf perception)
Recall of personal emotional memories with instructions to try re-create feeling
Memory of emotional episodes (subClassOf memory)
Listening to emotional sounds (e.g. grunts of disgust)
Auditory perception of emotional stimuli (subClassOf perception)
Viewing emotional film extracts Visual and auditory perception of emotional stimuli (subClassOf perception)
Paradigms selected based on study of random sample ofpapers from BrainMap database. Conclusion…Cognitive Neuroscience does not usually study canonical emotions! The link from perception of emotional fear in facial expressions to canonical fear is subject to empirical research
(Part of) the biochemical basis of emotion is in ChEBI
Emotions are effected in part by neurotransmitters such as dopamine, tryptophan
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dopamine(CHEBI:25375)
molecular entity (CHEBI:25375)
biological role (CHEBI:24432)
neurotransmitter(CHEBI:25512)
has role
neurotransmitter receptor activity
(GO:0030594)
Molecular function (GO:0003674)
realized in
happiness(MFOEM:42)
part of
emotion(MFOEM:1)
subtype
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Disorders of affectSome mental diseases involve altered emotional functioning. (E.g. depression, bipolar disorder)
emotion
non-canonical sadness
ProcessDisposition
depression
mental disease
realized in
down-regulation of dopaminergic
system (GO:0032227)
has part
biological processMechanism of
action: complex
disturbances in underlying
systems
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Interlinked ontologies accelerate the search for scientific understanding
Linking diseases to mechanisms of action to treatment drugs and biomarkers to genetic factors giving rise to predispositions …
Different disciplines and methods – one reality being investigated
Different types of data – one ontology
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Good ontology design facilitates interlinking
Successfully interlinking ontologies depends on interoperability of the underlying ontologies:
shared technological platform; common upper level; non-overlapping content; agreed bridging relationships; …
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ConclusionsBio-ontology is inescapably interdisciplinary
It needs to be guided by the experts in each domain
The collective goal is to build an interlinked framework of ontologies which describe the best of what is known across the sciences
… in order to provide a knowledge-based backbone for increasingly intelligent and sophisticated computational data analysis and processing techniques
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AcknowledgementsMental Functioning and Emotion Ontologies:
Kevin Mulligan (UNIGE), Barry Smith & Werner Ceusters (Buffalo)
ChEBI: Paula de Matos, Christoph Steinbeck, Colin Batchelor
(RSC), Stefan Schulz (Graz)
FundingBBSRC (UK), NSF (CH), EU-OPENSCREEN