VR http ifomis de Formal Principles for Biomedical

VR http: // ifomis. de

Formal Principles for Biomedical Ontologies Barry Smith http: //ifomis. de http: // ifomis. de

Three levels of ontology http: // ifomis. de 3

Three levels of ontology 1) formal (top-level) ontology dealing with categories employed in every domain: 2) object, event, whole, part, instance, class 3) 2) domain ontology, applies top-level system to a particular domain cell, gene, drug, disease, therapy 3) terminology-based ontology large, lower-level system Dupuytren’s disease of palm, nodules with no contracture http: // ifomis. de 4

Three levels of ontology 1) formal (top-level) ontology dealing with categories employed in every domain: 2) object, event, whole, part, instance, class 3) 2) domain ontology, applies top-level system to a particular domain cell, gene, drug, disease, therapy 3) terminology-based ontology large, lower-level system Dupuytren’s disease of palm, nodules with no contracture http: // ifomis. de 5

Three levels of ontology 1) formal (top-level) ontology dealing with categories employed in every domain: 2) object, event, whole, part, instance, class 3) 2) domain ontology, applies top-level system to a particular domain cell, gene, drug, disease, therapy 3) terminology-based ontology large, lower-level system Dupuytren’s disease of palm, nodules with no contracture http: // ifomis. de 6

Compare: 1) pure mathematics (re-usable theories of structures such as order, set, function, mapping) 2) applied mathematics, applications of these theories = re-using the same definitions, theorems, proofs in new application domains 3) physical chemistry, biophysics, etc. = adding detail http: // ifomis. de 7

Three levels of biomedical ontology 1) formal (top-level) ontology = ? ? ? 2) medical ontology has nothing like the technology of re-usable definitions, theorems and proofs provided by pure mathematics 2) domain ontology = UMLS Semantic Network, GALEN CORE 3) terminology-based ontology = UMLS, SNOMED-CT, GALEN, FMA http: // ifomis. de 8

Description Logic , Protégé, and other tools for supporting automatic reasoning do not fill this gap they do not provide theories of classes, functions, processes, etc. rather: successful coding in a DL-framework presupposes that such theories have already been applied in the very construction of the terminology-based ontology http: // ifomis. de 9

IFOMIS Institute for Formal Ontology and Medical Information Science, mission: use basic principles of philosophical ontology, traditional theories of classification and definition for quality assurance and alignment of biomedical ontologies http: // ifomis. de 10

Strategy Part 1: Survey of GO Part 2: Provide principles for building biomedical ontologies derived from formal (top-level) ontology, and illustrate how they can help in quality assurance of terminologybased ontologies like GO Part 3: Show it can be done right http: // ifomis. de 11

Part One Survey of GO http: // ifomis. de 12

GO is three ontologies cellular components molecular functions biological processes December 16, 2003: 1372 component terms 7271 function terms 8069 process terms http: // ifomis. de 13

GO an impressive achievement used by over 20 genome database and many other groups in academia and industry successful methodology, much imitated now part of OBO (open biological ontologies) consortium Here I focus on problems / errors GO here is just an example http: // ifomis. de 14

Primary aim of GO not rigorous definition and principled classification but rather: providing a practically useful framework for keeping track of the biological annotations that are applied to gene products http: // ifomis. de 15

Each of GO’s ontologies is organized in a graph-theoretical structure involving two sorts of links or edges: is-a (epithelial cell differentiation is-a cell differentiation) part-of (axonemal microtubule part-of axoneme) http: // ifomis. de 16

This graph-theoretic architecture to designed to help humans, who can use the graphs to locate the features and attributes they are addressing in their work and thus to determine the designated terms for these features and attributes within GO’s ‘controlled vocabulary. ’ http: // ifomis. de 17

GO’s three ontologies When a gene is identified, three important types of questions need to be addressed: Where is it located in the cell? What functions does it have on the molecular level? And to what biological processes do these functions contribute? http: // ifomis. de 18

GO’s three ontologies biological processes molecular functions cellular constituents http: // ifomis. de 19

The Cellular Component Ontology (counterpart of anatomy) consists of terms such as flagellum, chromosome, ferritin, extracellular matrix and virion Cellular components are physical and measurable entities. They are, in the terminology of philosophical ontology, objects or things (independent continuants). They endure selfidentically through time while undergoing changes of various sorts Cellular component embraces also the extracellular environment of cells and cells themselves http: // ifomis. de 20

No organisms GO does not include terms for specific organisms, not even for single-celled organisms http: // ifomis. de 21

The Molecular Function Ontology molecular function = the action characteristic of a gene product. Actions such as ice nucleation or protein stabilization do not endure but rather occur. http: // ifomis. de 22

The Molecular Function Ontology Originally included terms such as anticoagulant (defined as: ‘a substance that retards or prevents coagulation’) and enzyme (defined as: ‘a substance … that catalyzes’) These refer neither to functions nor to actions but rather to components. http: // ifomis. de 23

The Molecular Activity Ontology Confusion remedied to a degree by policy change of March 2003: ‘All GO molecular function term names [with the exception of the parent term molecular function and of the whole node binding] are to be appended with the word “activity”. ’ http: // ifomis. de 24

‘Function’ = ‘Activity’ Thus the term ‘structural molecule, ’ which is defined as meaning: ‘the action of a molecule that contributes to structural integrity, ’ is amended to ‘structural molecule activity’ http: // ifomis. de 25

still problem’s with GO Molecular Function Definitions anti-coagulant activity (defined as: “a substance that retards or prevents coagulation”) enzyme activity (defined as: “a substance that catalyzes”) http: // ifomis. de 26

… and there are still problems with Molecular Function terms GO: 0005199: structural constituent of cell wall http: // ifomis. de 27

structural constituent of cell wall Definition: The action of a molecule that contributes to the structural integrity of a cell wall. confuses actions, which GO includes in its function ontology, with constituents, which GO includes in its cellular component ontology http: // ifomis. de 28

extracellular matrix structural constituent puparial glue (sensu Diptera) structural constituent of bone structural constituent of chorion (sensu Insecta) structural constituent of chromatin structural constituent of cuticle structural constituent of cytoskeleton structural constituent of epidermis structural constituent of eye lens structural constituent of muscle structural constituent of myelin sheath structural constituent of nuclear pore structural constituent of peritrophic membrane (sensu Insecta) structural constituent of ribosome structural constituent of tooth enamel structural constituent of vitelline membrane (sensu Insecta) http: // ifomis. de 29

The Biological Process Ontology biological process: ‘A phenomenon marked by changes that lead to a particular result, mediated by one or more gene products. ’ Examples: glycolysis, death, adult walking behavior response to blue light http: // ifomis. de 30

Occurrents Both molecular activity and biological process terms refer to what philosophical ontologists call occurrents = entities which do not endure through time but rather unfold themselves in successive temporal phases. Occurrents can be segmented into parts along the temporal dimension. Continuants exist in toto in every instant at which they exist at all. http: // ifomis. de 31

Molecular functions and biological processes are closely interrelated E. g. the process anti-apoptosis involves the molecular function apoptosis inhibitor activity. How can GO express such relations? http: // ifomis. de 32

Are they a matter of granularity? ‘A biological process is accomplished via one or more ordered assemblies of molecular functions. ’ ? ? ? Molecular activities = building blocks of biologica processes ? ? ? So: Functions are parts of processes But no: http: // ifomis. de 33

GO’s three ontologies are separate biological processes molecular functions cellular constituents No links or edges defined between them http: // ifomis. de 34

Question: How understand granularity if not in terms of parthood? http: // ifomis. de 35

Molecular functions renamed ‘activities’, because ‘activity’ unlike ‘process’, connotes agency ? but molecules are not agents hypothesis: the term ‘function’ was used for the molecular function ontology because the activities in question are functional in relation to the pertinent organism. http: // ifomis. de 36

Functions A function is functional = beneficial to the organism If an organism-part has a function, this is because the functioning of this organismpart is beneficial to the organism The function of the heart is to pump blood Not: the function of the hip is to financially support hip-replacement surgeons http: // ifomis. de 37

Some processes are functionings E. g. pumping blood http: // ifomis. de 38

Two sorts of processes 1. Functionings (realizations of functions = beneficial to the organism) 2. Other processes (e. g. the result of external interventions) 3. Cf. difference between physiology and pathology http: // ifomis. de 39

GO not clear about this distinction transport: The directed movement of substances (such as … ions) into, out of, or within a cell growth and/or maintenance: Any process required for the survival and growth of a cell Synonym: cell physiology transport is-a cell growth and/or maintenance but (GO: 0019060) viral intracellular protein transport is-a transport http: // ifomis. de 40

Why do these problems arise? GO has no clear understanding of the role of temporal relations in organizing an ontology (thus also no clear understanding of the difference between a function and the activity which is the realization of a function) http: // ifomis. de 41

GO excludes organisms from its scope (they are of the wrong granularity) Yet each process or function requires some bearer or bearers which it is the process or function of. Processes are dependent on their bearers (Theory of dependence vs. independence part of formal ontology) (Theory of continuants vs. occurrents part of formal ontology) http: // ifomis. de 42

Some formal ontology Components are independent continuants Functions are dependent continuants (the function of an object exists continuously in time, just like the object which has the function; and it exists even when it is not being exercised) Processes are (dependent) occurrents http: // ifomis. de 43

More generally: Continuants can be divided into independent (objects, things, components) and dependent (features, attributes, conditions, functions, roles, qualities …) All occurrents are dependent entities. Every occurrent is dependent for its existence on one or more continuants. A change is always a change in some continuant object. http: // ifomis. de 44

http: // ifomis. de 45

Part Two Principles of Biomedical Ontologies and their use in quality assurance of terminology-based ontologies http: // ifomis. de 46

Principle of Temporal Coherence An ontology should rigorously distinguish continuants from occurrents. (Anatomy is a science of continuants) http: // ifomis. de 47

Principle of Dependence If an ontology recognizes a dependent entity then it (or a linked ontology) should recognize also the relevant class of bearers Part of our aim here is to lay down principles which can support such linkability http: // ifomis. de 48

Linking to external ontologies can also help to link together GO’s own three separate parts http: // ifomis. de 49

GO’s three ontologies molecular functions dependent cellular constituents http: // ifomis. de biological processes independent 50

GO’s three ontologies molecular functions cellular processes organismlevel biological processes cellular constituents http: // ifomis. de 51

molecular functions molecule complexe s http: // ifomis. de cellular processes organismlevel biological processes cellular constituents organisms 52

molecular functions molecule complexe s http: // ifomis. de cellular processes organismlevel biological processes cellular constituents organisms 53

molecular processe s molecular function s molecule complexe s http: // ifomis. de cellular processes cellular functions cellular constituent s organismlevel biological processes organismlevel biological functions organisms 54

molecular processe s functionings molecular function s molecule complexe s http: // ifomis. de cellular processes organismlevel biological processes functionings cellular functions cellular constituent s organismlevel biological functions organisms 55

GO must be linked with other, neighboring ontologies GO has: adult walking behavior but not adult GO has: eye pigmentation but not eye GO has: response to blue light but not light (or blue) 94% of words used in GO terms are not GO terms Part of the solution “Medical Fact. Net” (NLM, 10 am tomorrow) http: // ifomis. de 56

GO taking steps in this direction Linking to a good external ontology of organism types (to solve some of the problems with sensu) It needs to link further to a good external ontology of anatomy, to solve the location problem and to a good external ontology of coarsegrained reality, to solve the adult walking behavior problem Human beings know what ‘walking’ means http: // ifomis. de 57

Human beings know what adults are older than embryos GO needs to be linked to ontology of development and in general to resources for reasoning about time and change http: // ifomis. de 58

but such linkages are possible only if GO itself has a coherent formal architecture http: // ifomis. de 59

Principle of Univocity univocity: terms should have the same meanings (and thus point to the same referents) on every occasion of use UMLS-Semantic Network: ‘organization’ = body plan (anatomy) ‘organization’ = social organization http: // ifomis. de 60

Polysemy of GO’s part-of – membrane part-of cell, intended to mean “a membrane is a part-of any cell” – flagellum part-of cell, intended to mean “a flagellum is part-of some cells” – replication fork part-of cell cycle, intended to mean: “a replication fork is part-of the nucleoplasm only during certain times of the cell cycle” http: // ifomis. de 61

Three meanings of ‘part-of ’ ‘part-of’ = ‘can be part of’ (flagellum part-of cell) ‘part-of’ = ‘is sometimes part of’ (replication fork part-of the nucleoplasm) ‘part-of’ = ‘is included as a sublist in’ http: // ifomis. de 62

THE GOAL IS: not to impose basic principles of classification and definition on biologists – All the principles presented here should be conceived not as iron requirements but rather as rules of thumb – deviation from which is often marked by characteristic families of coding errors http: // ifomis. de 63

example [GO: 0030430] host cell cytoplasm, defined as: The cytoplasm of a host cell [GO: 0018995] host, defined as: Any organism in which another organism, especially a parasite or symbiont, spends part or all of its life cycle and from which it obtains nourishment and/or protection http: // ifomis. de 64

Why is this an error? because organisms do not fall within the scope of GO An organism is not a cellular component, and it is not a molecular function, and not a biological process, either http: // ifomis. de 65

host cell cytoplasm part-of host breaks GO’s own granularity constraints http: // ifomis. de 66

Why univocity? 1. humans are good at disambiguating ambiguous expressions, machines not 2. quality assurance and ontology maintenance 3. GO, SNOMED, etc. , are designed to constitute ‘controlled vocabularies’ http: // ifomis. de 67

Quality assurance and ontology maintenance must be automated As GO increases in size and scope it will “be increasingly difficult to maintain the semantic consistency we desire without software tools that perform consistency checks and controlled updates”. The addition of each new term will require the curator to understand the entire structure of GO in order to avoid redundancy and to ensure that all appropriate linkages are made with other terms. http: // ifomis. de 68

The purpose of a ‘controlled vocabulary’ = to ensure that the same terms are used by different research groups with the same meanings this has implications also for the syntax of GO terms (= the way terms are compounded together out of other terms) http: // ifomis. de 69

Univocity and syntax The story of ‘/’ http: // ifomis. de 70

/ GO: 0008608 microtubule/kinetochore interaction =df Physical interaction between microtubules and chromatin via proteins making up the kinetochore complex http: // ifomis. de 71

/ GO: 0001539 ciliary/flagellar motility =df Locomotion due to movement of cilia or flagella. http: // ifomis. de 72

/ GO: 0045798 negative regulation of chromatin assembly/disassembly =df Any process that stops, prevents or reduces the rate of chromatin assembly and/or disassembly http: // ifomis. de 73

/ GO: 0000082 G 1/S transition of mitotic cell cycle defined as: Progression from G 1 phase to S phase of the standard mitotic cell cycle. http: // ifomis. de 74

/ GO: 0001559 interpretation of nuclear/cytoplasmic to regulate cell growth =df The process where the size of the nucleus with respect to its cytoplasm signals the cell to grow or stop growing. http: // ifomis. de 75

/ GO: 0015539 hexuronate (glucuronate/galacturonate) porter activity =df Catalysis of the reaction: hexuronate(out) + cation(out) = hexuronate(in) + cation(in) http: // ifomis. de 76

Problems with GO’s compositionality http: // ifomis. de / (slash) : (semi-colon) 286 177 , (comma) 1206 and 180 77

comma cytokinesis, site selection http: // ifomis. de 78

plurals biological process physiological processes cellular process cell growth and/or maintenance http: // ifomis. de 79

specification formation; forming determination; determinacy 39 142 complex regulator; regulatory; regulated; regulation 563 1326 56 acting on 146 with 54 constituting 35 from 141 constituent; constitutive 29 51 164 182 469 in via http: // ifomis. de dependent sensu 80

Questions regarding operators How does ‘constituent’ relate to ‘component’ If A within B then is A part-of B or included-in -the-interior-of B ? Does via mean by means of or along the path of ? How is ‘un-’ related to ‘not’ (how is ‘unlocalized’ related to ‘not localized’) http: // ifomis. de 81

‘involved in’ term-forming operator (reflection of GO’s limited resources for expressing relations): hydrolase activity, acting on acid anhydrides, involved in cellular and subcellular movement asymmetric protein localization involved in cell fate commitment cell-cell signaling involved in cell fate commitment protein secretion involved in cell fate commitment http: // ifomis. de 82

‘involved in’ hydrolase activity, acting on acid anhydrides, involved in cellular and subcellular movement This is a term because GO does not have the resources to express ‘is-involved-in’ as a relation between terms note problems with commas http: // ifomis. de 83

‘involved in’ hydrolase activity, acting on acid anhydrides, involved in cellular and subcellular movement is-a hydrolase activity, acting on acid anhydrides http: // ifomis. de 84

‘involved in’ hydrolase activity, acting on acid anhydrides, involved in cellular and subcellular movement is-a hydrolase activity, acting on acid anhydrides is ok: hydrolase activity, acting on anhydrides can but need not be involved in cellular and subcellular movement http: // ifomis. de 85

‘involved in’ asymmetric protein localization involved in cell fate commitment is-a cell fate commitment should be a part-of relation (compare: breathing involved in running is a running) http: // ifomis. de 86

‘involved in’ cell-cell signaling involved in cell fate commitment is-a cell fate commitment ditto: should be a part-of relation http: // ifomis. de 87

these, though, are good: asymmetric protein localization involved in cell fate commitment is-a asymmetric protein localization cell-cell signaling involved in cell fate commitment is-a cell-cell signaling http: // ifomis. de 88

‘involved in’ protein secretion involved in cell fate commitment synonym of protein secretion are there instances of protein secretion not involved in cell fate commitment? … Problems with GO’s peculiar use of ‘synonym’ http: // ifomis. de 89

Consequences of inconsistent and/or indeterminate use of operators there are 29. 42% distinct terms within GO which contain one or more polysemous operators but these terms receive only 13. 96% of the annotations present within GO Hypothesis: This lower percentage of annotations reflects the fact that poorly defined operators are not well understood by annotators, who thus avoid the corresponding terms http: // ifomis. de 90

Principle of Compositionality The meanings of compound terms should be determined 1. by the meanings of constituent terms together with 2. the rules governing the syntactic operators http: // ifomis. de 91

Principle of Objectivity which classes exist is not a function of our biological knowledge. (Terms such as ‘unclassified’ or ‘unknown ligand’ or ‘not otherwise classified as peptides’ do not designate biological natural kinds. ) http: // ifomis. de 92

GO: 0008372 cellular component unknown is-a cellular component unlocalized is-a cellular component Holliday junction helicase complex is-a unlocalized http: // ifomis. de 93

GO’s excuse ‘unlocalized’ is used as a placeholder only but automatic information retrieval systems cannot distinguish it from other, genuine class names formal tools exist which can deal with the addition of knowledge into a classification system without the need to create fake classes (Theory of Granular Partitions) http: // ifomis. de 94

Principle of Positivity Class names should be positive. Logical complements of classes are not themselves classes. (Terms such as ‘non-mammal’ or ‘nonmembrane’ or ‘invertebrate’ or do not designate natural kinds. ) http: // ifomis. de 95

Terms such as ‘Veterinary proprietary drug AND/OR biological’ * do not designate natural kinds. (Which biological classes exist is not a matter of logic. ) *has 2532 children in SNOMED-CT http: // ifomis. de 96

Principle of Explicitness if a link between two classes holds only under certain specific restrictions, then this restriction should be made explicit in the statement of the corresponding link-axiom cf. GO’s sensu http: // ifomis. de 97

GO can in practice be used only by trained biologists (with know how) whether a GO-term truly stands in the is_a relation depends e. g. on the type of organism involved glycosome is part-of cytoplasm only for Kinetoplastidae Computers have no counterpart of such context-dependent know-how http: // ifomis. de 98

Principle of Single Inheritance no class in a classificatory hierarchy should have more than one parent on the immediate higher level http: // ifomis. de 99

Principle of Taxonomic Levels the terms in a classificatory hierarchy should be divided into predetermined levels (analogous to the levels of kingdom, phylum, class, order, etc. , in traditional biology). depth in GO’s hierarchies not determinate because of multiple inheritance http: // ifomis. de 100

Principle of Partonomic Levels Terms in a partonomic hierarchy should be divided into predetermined granularity levels, for example: organism, organ, cell, molecule, etc. ) (GO is about to break physiological process into 'cell physiological process' and 'organism physiological process'. ) = take granularity seriously http: // ifomis. de 101

Principle of Exhaustiveness the classes on any given level should exhaust the domain of the classificatory hierarchy. http: // ifomis. de 102

Single Inheritance + Exhaustiveness = JEPD for: Jointly Exhaustive and Pairwise Disjoint Exhaustiveness often difficult to satisfy in the realm of biological phenomena; but its acceptance as an ideal is presupposed as a goal by every scientist. Single inheritance accepted in all traditional (species-genus) classifications, now under threat because multiple inheritances is a computationally useful device (allows one to avoid certain kinds of combinatory explosion). http: // ifomis. de 103

Problems with multiple inheritance B C is-a 1 is-a 2 A ‘is-a’ no longer univocal http: // ifomis. de 104

GO’s ‘is-a’ is pressed into service to mean a variety of different things the resulting ambiguities make the rules for correct coding difficult to communicate to human curators in terms of generally intelligible principles they also serve as obstacles to integration with neighboring ontologies http: // ifomis. de 105

Problems with multiple inheritance B C is-a 1 is-a 2 A E D ‘sibling’ is no longer determinate Principle of levels is violated http: // ifomis. de 106

http: // ifomis. de 107

http: // ifomis. de 108

A storage vacuole is not a special kind of vacuole a box used for storage is not a special kind of box http: // ifomis. de 109

http: // ifomis. de 110

Another term-forming operator lytic vacuole within a protein storage vacuole is -a protein storage vacuole time-out within a baseball game is-a baseball game embryo within a uterus is-a uterus http: // ifomis. de 111

Problems with Location is-located-at / is-located-in and similar relations need to be expressed in GO via some combination of ‘is-a’ and ‘part-of’ … is-a unlocalized is-a site of … within … … in … http: // ifomis. de 112

Problems with location extrinsic to membrane part-of membrane extrinsic to plasma membrane part-of plasma membrane extrinsic to vacuolar membrane part-of vacuolar membrane http: // ifomis. de 113

Differentiation and Development development cellular process cell differentiation http: // ifomis. de 114

Cell differentation is-a development But according to GO’s own definitions the agent or subject of differentiation is the cell, while the agent or subject of development is the whole organism (again: GO has problems in keeping track of entities on differerent levels of granularity) http: // ifomis. de 115

cell differentiation is-a development but: hemocyte differentiation part-of hemocyte development http: // ifomis. de 116

GO: 0007514: garland cell differentiation Definition: Development of garland cells, a small group of nephrocytes which take up waste materials from the hemolymph by endocytosis. (Illustrates GO’s problems with definitions) http: // ifomis. de 117

http: // ifomis. de 118

Part Three How to do things right so far only scratched the surface: sensu synonyms GO’s definitions GO’s ‘logical relationships’ http: // ifomis. de 119

Principles for GO terms Temporal coherence Dependence Univocity Compositionality Objectivity Positivity Explicitness Taxonomic Levels Partonomic Levels Single Inheritance Exhaustiveness http: // ifomis. de 120

Should these principles be satisfied? Michael Ashburner: GO’s philosophy from the beginning was ‘just in time’ - that is, we made no great attempt to ‘complete’ the ontologies …. If you try and ‘complete’ an ontology, or worse: try and ‘get it right, ’ then you will fail … http: // ifomis. de 121

Can these principles be satisfied? Compare GO with Foundational Model of Anatomy (FMA) http: // ifomis. de 122

http: // ifomis. de Principle GO FMA Temporal coherence No N/A Dependence No N/A Univocity No Yes Compositionality No Yes Objectivity No Yes Positivity No Yes Explicitness No N/A Taxonomic Levels No Yes Partonomic Levels No Yes Single Inheritance No Yes Exhaustiveness No No 123

The End http: // ifomis. de Principle GO FMA Temporal coherence No N/A Dependence No N/A Univocity No Yes Compositionality No Yes Objectivity No Yes Positivity No Yes Explicitness No N/A Taxonomic Levels No Yes Partonomic Levels No Yes Single Inheritance No Yes Exhaustiveness No No 124

Is GO an ontology GO a controlled vocabulary = (ramshackle) syntactic regimentation but because is-a and part-of are not given uniform readings, this does NOT mean the sort of semantic regimentation which would amount to an ontology in the proper sense of the word http: // ifomis. de 125

rules for definitions intelligibility: the terms used in a definition should be simpler (more intelligible) than the term to be defined definitions: do not confuse definitions with the communication of new knowledge http: // ifomis. de 126

Principle of Substitutability in all so-called extensional contexts a defined term should be substitutable by its definition in such a way that the result is both grammatically correct and has the same truth-value as the sentence with which we begin GO: 0015070: toxin activity Definition: Acts as to cause injury to other living organisms. http: // ifomis. de 127

substitutability There is toxin activity here There is acts as to cause injury to other living organisms here http: // ifomis. de 128

Defining is-a A is-a B = every instance of A is an instance of B A is-a B = A and B are natural kinds and every instance of A is as a matter of necessity an instance of B http: // ifomis. de 129

Solutions to these problems ‘part_of’ should mean: part_of http: // ifomis. de 130