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.

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