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, 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

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

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