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A chemical view into biological systems

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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?
  • Transcript

    • 1. A chemicalview into biological systemsJanna Hastings, EBI Chemoinformatics and MetabolismStanford Research Institute, 20 September 2011
    • 2. Thank you!
      ChEBI ontology
      21.09.2011
      2
    • 3. “Small” molecules are involved in all the processes of life
      ChEBI ontology
      21.09.2011
      3
      REACTOME: PEPTIDE HORMONE BIOSYNTHESIS
    • 4. 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
    • 5. “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
    • 6. 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)
    • 7. 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
    • 8. 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
    • 9. 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.
    • 10. 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’
    • 11. What are the different kinds of active properties of chemical entities relevantin a biological context?
      21.09.2011
      11
    • 12. Dispositions
      Image credit: kylemay on flickr
    • 13. 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
    • 14. 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
    • 15. Mutual dispositions
      Image credit: kelehen on flickr
    • 16. 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.
    • 17. 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
    • 18. 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
    • 19. Functions
      Image credit: Hans GodoFrabel
    • 20. 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
    • 21. 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
    • 22. 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
    • 23. Roles
      Image credit: gramachree on flickr
    • 24. 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.
    • 25. 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
    • 26. 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
    • 27. 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)
    • 28. 21.09.2011
      28
      In what kinds of processesare those active properties realized?
    • 29. 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
    • 30. 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)
    • 31. 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
    • 32. 21.09.2011
      32
      What are the necessary elementsin afull formal description
      of active properties?
    • 33. 33
      Granularity
      Bulk
      has role
      analgesic
      portion of paracetamol
      has grain
      has grain
      paracetamol molecule
      COX-3 inhibitor
      has role
      Molecular
    • 34. 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
    • 35. 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/
    • 36. 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/
    • 37. 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
    • 38. 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
    • 39. 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
    • 40. 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
    • 41. 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
      ?
    • 42. 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)
    • 43. 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
    • 44. 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
    • 45. Thank you for your attention!
      Janna Hastings -- hastings@ebi.ac.uk

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