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Presented at the AI center of the Stanford Research Institute: chemical ontologies provide a chemical view into biological systems. Various challenges with modelling "active properties" (roles, ...

Presented at the AI center of the Stanford Research Institute: chemical ontologies provide a chemical view into biological systems. Various challenges with modelling "active properties" (roles, functions, dispositions) are discussed.

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  • The EBI Chemoinformatics and Metabolism Team led by Dr.Christoph Steinbeck (back, right)
  • ‘small molecules’ can be contrasted with those encoded by the genomeAlso, with chemical substancesChEBI was created as a unified resource for annotating small molecules in different kinds of biological information databases. This provides a unified chemical view into the biological processes that underlie life.
  • This is BFO terminology
  • Overview: Different kinds of roles of chemical entities. Modelling drugs (which don’t become drugs until they are prescribed as such). The difference between that and enzyme inhibitors (which can act as such even when it is not known that they are doing so). Granularity. Modelling treatments for headache – you need a whole organism to treat a headache. By contrast, you can describe treatment of brain tumours at the level of the organ. Biochemical—Cell(Pathway)—Tissue—Organ—Organism. Dispositions. Disposition realization. Under what conditions are dispositions realized? Chemical reaction roles; Rhea/MaCiE? Solvent etc. Biological roles such as hormone. Metabolites – not really a role. Conditional realization – probabilistic work.
  • We say active properties on purpose; we want to avoid saying roles at this stage.
  • Need to say more about what functions are in the general case here
  • And now more examples of how functions can co-evolve, or rather, how small molecules can have functions in the biological, evolutionary sense at all. Most functionally active molecules are either natural products or they are designed by humans. Natural product molecules are the output of biological processes (usually metabolic) BUT they can have specific functions (such as antibiotic activity). We harvest many natural product molecules from plants in order to serve as precursors to the drugs we create. Also include a list of functions from ChEBI.
  • This has the opposite relationship to time as dispositions, in a way.
  • Granularity also affects the processes that are going on at the different levels and the participants that are ascribed. A challenge in producing a whole-systems integrated perspective is being able to consistently map one level of description down to the lower level of detail and back up to the higher level of detail together with the emergent properties.
  • We have done some work on using OWL concrete domains to represent this type of information, but variability poses a big problem.
  • Actually it is called acetaminophenhere in the US isn’t it?

A chemical view into biological systems A chemical view into biological systems Presentation Transcript

  • A chemicalview into biological systemsJanna Hastings, EBI Chemoinformatics and MetabolismStanford Research Institute, 20 September 2011
  • Thank you!
    ChEBI ontology
    21.09.2011
    2
  • “Small” molecules are involved in all the processes of life
    ChEBI ontology
    21.09.2011
    3
    REACTOME: PEPTIDE HORMONE BIOSYNTHESIS
  • Fundamentally different properties
    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 asa strong acid
    21.09.2011
    4
  • “Realizable”
    Properties that we ascribe to things because of what can happen under certain circumstances (future-pointing) we call realizable
    The processes (events) in which they display those properties are called realizations
    (the property, however, exists all the time)
    21.09.2011
    5
  • How do chemical entities act?
    They react (strong)
    Covalent (polar covalent, aromatic, coordinate)
    Ionic
    Metallic
    or they interact (weak)
    Hydrogen
    van der Waals
    21.09.2011
    6
    Changed categorical type as a result
    No change to chemicaltype, but may changeshape (conformation)
  • Chemical entities – as actors
    Static (monadic) properties: shape, mass, size, elemental composition
    Active (relational, realizable) properties: the disposition to donate a hydrogen or attract electrons; taste and smell; the effect when ingested in a biological system; the effect in solution with a mix of other chemicals
    Photo credit: Hamachidori
  • 21.09.2011
    8
    What are the different kinds ofactive properties of chemical entities in a biological context?
    In what kinds of processes are those active properties realized?
    What are the necessary aspects of a full formal description thereof?
    Batchelor, Hastings, Steinbeck. Ontological Dependence, Dispositions and Institutional Reality in Chemistry. Proceedings of FOIS2010
  • The ChEBI Ontology
    21.09.2011
    9
    ChEBI Ontology
    chemical entity
    role
    biological role
    chemical substance
    molecular entity
    application
    chemical role
    group
    carbonyl compound
    pharmaceutical
    solvent
    carboxy group
    carboxylic acid
    antibacterial drug
    cyclooxygenaseinhibitor
    has part
    has role
    de Matos, P., Alcántara, R., Dekker, A., Ennis, M., Hastings, J., Haug, K., Spiteri, I., Turner, S., and Steinbeck, C. (2009). Chemical entities of biological interest: an update.Nucl. Acids Res. 2010 38: D249-D254.
  • Active properties are ChEBI ‘roles’
    Subatomic particle: parts of atoms
    Chemical entity:parts and structural features of molecules
    Role ontology:active properties of chemical entities
    ‘Has role’
  • What are the different kinds of active properties of chemical entities relevantin a biological context?
    21.09.2011
    11
  • Dispositions
    Image credit: kylemay on flickr
  • Dispositions
    Dispositions specifically depend on their bearers solely by virtue of the sort of things they are.
    Examples: fragility, malleability, ductility.
    Functions are “good” (selected) dispositions … but more on that later
  • Examples of chemical dispositions
    Buffer
    Catalyst
    Hydrogen donor / acceptor
    Solvent
    Acid / base
    Surfactant
    Antioxidant
    Detergent
    De-aminating agent
    Fuel additive
    Radical scavenger
    21.09.2011
    14
  • Mutual dispositions
    Image credit: kelehen on flickr
  • Mutual dispositions
    Many dispositions come in pairs. The bearer of one disposition, or the realization of that disposition, is part of the circumstances for the other.
    General examples: locks and keys, hosts and parasites.
  • Mutual dispositions in chemistry
    Chemical examples: acids and bases, ligands and binding sites, donors and acceptors.
    In ChEBI: some relationships allow representation of mutual dependence (conjugate base/acid);
    representation in role ontology does not (yet!) contain explicit formalisation of this mutuality
    For all (X realization-of some AcidRole) there exists some (Y realization-of some BaseRole) such that (X, Y process-part-of P)
    21.09.2011
    17
  • 21.09.2011
    18
    Chemical dispositions
    Acid/base, proton donor/acceptor, solvent, buffer, antioxidant
    All of these are
    - mind/institution/purpose independent
    - depend on the structure of the chemical entity
    - realization results in fundamental changein structure
  • Functions
    Image credit: Hans GodoFrabel
  • ChEBI ontology
    21.09.2011
    20
    Functions
    Biological function
    Co-evolution of small molecules and protein receptors: enzyme inhibitor, activator
    Ascription of function by natural selection, evolution
    Artefactual function
    Design or selection of chemical entity for purpose e.g. fluorochrome, pesticide.
    Ascription of function by design
  • Biological functions
    Like mutual dispositions, ChEBI functions are the ‘other side’ (mutually dependent) 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
    21.09.2011
    21
  • Artefactual functions
    21.09.2011
    22
    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?
    Label
    Fragrance
    Pesticide
    Fuel
    Dye
    Detergent
    Probe
    Reagent
    Agrochemical
  • Roles
    Image credit: gramachree on flickr
  • Roles
    Roles, by contrast, not only depend for their existence on the sort of thing their bearers are (pigs cannot graduate),
    but onsocial conventions, and speech acts that bring them into being.
  • Thalidomide is not a drug for treating morning sickness(anymore)
    21.09.2011
    25
    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
  • What is a drug?
    a tablet with a certain active ingredient?
    recreational substance of dubious and illegal composition?
    a healthy diet of beetroot and potatoes?
    echinaceae drops?
    beer?
    all of these can count as drugs
  • 21.09.2011
    27
    Chemical roles
    Modelling drug roles requires representing a complex interplay of social reality and biological function
    A chemical acts as a drug when it is prescribed by a professional with the relevant institutional status(doctor, pharmacist) in the course of a particular treatment
    A drug role can be groundedin a biological function (analgesic – COX inhibitor) or it may not (placebo)
  • 21.09.2011
    28
    In what kinds of processesare those active properties realized?
  • Examples
    the disposition to bind is realized in the process of binding
    the disposition to shatter is realized in the process of shattering
    the disposition to treat cancer is realized in a process of cancer treatment
  • Process ontologies
    Gene Ontology Biological Process
    ‘provitamin’ realized_in ‘vitamin biosynthetic process’
    but beware: NOT toxin realized_in ‘response to toxin’
    Molecular process ontology (MOP)
    ‘proton donor’ and ‘proton acceptor’ both realized in process ‘proton transfer’
    Life cycle of an organism insecticide realized_in process ‘death’ and has_organism some ‘insect’ (a kind of participation)
  • 21.09.2011
    31
    A problem area
    Natural products, metabolites, xenobiotics
    A chemical entity is a metabolite by virtue of being the outputof some biological process in some organism (xenobiotic -> NOT)
    A chemical entity is a natural product by virtue of being the output of some biological process and not occurring spontaneously in nature
  • 21.09.2011
    32
    What are the necessary elementsin afull formal description
    of active properties?
  • 33
    Granularity
    Bulk
    has role
    analgesic
    portion of paracetamol
    has grain
    has grain
    paracetamol molecule
    COX-3 inhibitor
    has role
    Molecular
  • 34
    Bulk granularity
    portion of wine
    has_part
    has_participant
    has_participant
    portion of water
    portion of ethanol
    water–hydroxide +
    proton equilibrium
    ethanol–ethoxide ion +
    proton equilibrium
    has_grain
    hydrogen atom
    water
    CHEBI:15377
    ethanol
    CHEBI:16236
    hydroxide
    CHEBI:16234
    proton
    CHEBI:24636
    ethoxide
    CHEBI:52092
    icao
    icao
    has_part
    icbo
    icbo
    oxygen atom
    has_participant
    proton transfer
    from ethanol
    to ethoxide
    Molecular granularity
    proton transfer
    from ethoxide
    to ethanol
  • 21.09.2011
    35
    Context
    Oxygen transport in the body depends on the disposition of heme tobindoxygen
    and the disposition to releaseoxygen
    depending on the surrounding
    concentration
    Image credit: gassama.myweb.uga.edu/
  • 21.09.2011
    36
    Concentrations
    Concentrations are system propertiesa concentration is always a concentration of something in something
    e.g. the concentration of alcohol in bloodhere shown in the Blood Alcohol Chart
    Image credit: http://www.boat-ed.com/images/drawings/
  • 21.09.2011
    37
    Active concentrations
    Consider aspirin as treatment for a headache
    Too few individual molecules will have no effectToo many tablets will have unpleasant additional effects
    Image credit: tell.fll.purdue.edu
  • Sufficient concentration?
    21.09.2011
    38
    PortionOfParacetamol ⊑ ∃ bearerOf. (Disposition ⊓ ∀ hasRealization. (Treating ⊓ ∃ hasParticipant.Pain ⊓ ∃ hasTrigger. SufficientConcentration))
    Depends on body size, metabolism, susceptibility, genetic factors…
    Hastings, Steinbeck, Jansen, Schulz: Substance concentrations as conditions for the realization of dispositions. Proceedings of Bio-ontologies 2010
  • Different perspectives
    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 cats
    21.09.2011
    39
  • 21.09.2011
    40
    Reasoning with OWL data ranges
    Can we automatically differentiate normal from abnormal concentrations?
    4440 uM (normal adult)
    7000 uM (adult with diabetes)
    D-glucosein blood
    measured value(abnormal)
    measured value(normal)
    threshold
    metaboliteconcentration
    abnormal
  • 21.09.2011
    41
    Uncertainty
    Individual differences mean that we can’t straightforwardly associate an abnormal metabolite concentration with a disorder
    Rather, we want to infer the likelihood (risk) that a patient has a given disorder, given their metabolite concentration value
    ?
  • 21.09.2011
    42
    A probabilistic extension to OWL
    Probabilistic DLs extend traditional DLs with the ability to associate with each axiom in the ontology a probability valuewhich represents the degree of certainty of the axiom.
    Pronto is a probabilistic, non-monotonic extension to Pellet
    Accepts probabilistic axioms of the form
    X subClassOf Y [l, u]
    (as annotations: pronto:certainty)
  • 21.09.2011
    43
    Reasoning with probabilities
    2
    what is the likelihood that this person has this disorder? (reasoning based on probabilistic constraints)
    Low risk
    0.00—0.24
    Disorder
    Medium risk
    concentration
    in blood
    0.25—0.54
    High risk
    0.55—1.00
    1
    what risk category is this concentration? (reasoning based on data restrictions)
    Hastings, Jansen, Steinbeck, Schulz: Metabolite concentrations as evidence for disorders OWLED2011
  • Conclusions
    Formalising active properties in an ontology requires representing the conditionsunder which the properties are realized, the processesin which they are realized, and the perspectiveunder which they apply (granularity, organism etc.)
    The ChEBI effort is still in progress…
    21.09.2011
    44
  • Thank you for your attention!
    Janna Hastings -- hastings@ebi.ac.uk