1. 1 Forms of Life Barry Smith http://ifomis.org

2. 2

3. 3 DNA Protein Organelle Cell Tissue Organ Organism 10 -5 m 10 -1 m Scales of anatomy 10 -9 m

4. 4 New Golden Age of Classification 30,000 genes in human 200,000 proteins 100s of cell types 100,000s of disease types 1,000,000s of biochemical pathways (including disease pathways) … legacy of Human Genome Project

5. 5 FUNCTIONAL GENOMICS proteomics, reactomics, metabonomics, phenomics, behaviouromics, toxicopharmacogenomics …

6. 6 The problem is: each (chemical, clinical, pathological, immunological, toxicological, pharmacological, anatomical …) information system uses its own classification system How can we overcome the incompatibilities which become apparent when data from distinct sources is combined?

7. 7 Answer: “Ontology”

8. 8 Google hits (as of yesterday) ontology + philosophy 143K ontology + engineering145K ontology + information systems 217K ontology + software 252K ontology + database 279K

9. 9 IFOMIS Institute for Formal Ontology and Medical Information Science

10. 10 The problem of the unity of science The logical positivist solution to this problem addressed a world in which sciences are associated with printed texts What happens when sciences are associated with databases ?

11. 11 A Linnaean Species Hierarchy

12. 12 Medical Diagnostic Hierarchy a hierarchy in the realm of diseases

13. 13 Combining hierarchies OrganismsDiseases

14. 14 via Dependence Relations OrganismsDiseases

15. 15 A Window on Reality

16. 16 A Window on Reality OrganismsDiseases

17. 17 A Window on Reality

18. 18 The UMLS Unified Medical Language System contains information about over 1 million biomedical concepts and 2.8 million concept names from more than 100 controlled vocabularies and classifications

19. 19 UMLS Source Vocabularies SNOMED – Systematized Nomenclature of Medicine ICD International Classification of Diseases MeSH – Medical Subject Headings GO – Gene Ontology FMA – Foundational Model of Anatomy

20. 20 To reap the benefits of standardization we need to make ONE SYSTEM out of many different terminologies = UMLS “Semantic Network” nearest thing to an “ontology” of the UMLS 134 Nodes, 54 Relationship-Types between these Nodes, forming a graph with 6000 Edges

21. 21 Fragment of the UMLSemantic Network

22. 22

23. 23 UMLS Semantic Network entity event physical conceptual object entity organism

24. 24 conceptual entity Organism Attribute Finding Idea or Concept Occupation or Discipline Organization Group Group Attribute Intellectual Product Language

25. 25 Idea or Concept Functional Concept Qualitative Concept Quantitative Concept Spatial Concept Body Location or Region Body Space or Junction Geographic Area Molecular Sequence Amino Acid Sequence Carbohydrate Sequence Nucleotide Sequence

26. 26 Trattenbach is an Idea or Concept

27. 27 Idea or Concept Functional Concept Qualitative Concept Quantitative Concept Spatial Concept Body Location or Region Body Space or Junction Geographic Area Molecular Sequence Amino Acid Sequence Carbohydrate Sequence Nucleotide Sequence

28. 28 Problem: Confusion of concepts and entities in reality

29. 29 Blood Pressure Ontology The hydraulic equation: BP = CO*PVR arterial blood pressure (BP) is directly proportional to the product of blood flow (cardiac output, CO) and peripheral vascular resistance (PVR).

30. 30 UMLS-Semantic Types: blood pressure is an Organism Function, cardiac output is a Laboratory or Test Result or Diagnostic Procedure BP = CO*PVR thus asserts that blood pressure is proportional either to a laboratory or test result or to a diagnostic procedure

31. 31 Problem: Confusion of reality with our (ways of gaining) knowledge about reality

32. 32 What are the terms of ontologies in the ontological engineering sense Answer: Concepts

33. 33 ‘Concept’ Semantic Network Definition: Concept = def. An abstract concept, such as a social, religious, or philosophical concept UMLS Definition: Concept = def. A class of synonymous terms

34. 34 Trattenbach is_a class of synonymous terms

35. 35 UMLS Semantic Network entity physical conceptual object entity organism is_a

36. 36 is_a Concept A is_a Concept B is_a = def. If one item ‘is_a’ another item then the first item is more specific in meaning than the second item. (Italics added)

37. 37 fish is_a vertebrate enzyme is_a biologically active substance copulation is_a biological process

38. 38 Fragment of the UMLSemantic Network

39. 39

40. 40 How can concepts figure as relata of these relations? part_of = def. Composes, with one or more other physical units, some larger whole causes =def. Brings about a condition or an effect. contains =def. Holds or is the receptacle for fluids or other substances. This includes filled with, holds, and is occupied by

41. 41 embryonic structure part_of human –embryonic structures appear as parts of entities other than humans –humans have embryonic structures as parts only in certain phases of their existence

42. 42 Acquired Abnormality affects Fish Experimental Model of Disease affects Fungus Food causes Experimental Model of Disease Biomedical or Dental Material causes Mental or Behavioral Dysfunction Manufactured Object causes Disease or Syndrome Vitamin causes Injury or Poisoning Tissue location_of Mental or Behavioral Dysfunction

43. 43 Fragment of the UMLSemantic Network

44. 44 The Concept Orientation Work on biomedical ontologies grew out of work on medical dictionaries and nomenclatures Has focused almost exclusively on ‘concepts’ conceived (sometimes called ‘classes’, sometimes confused with terms/descriptions). Concept-orientation also common in KR, has led to the entrenchment of an assumption according to which all that need be said about classes can be said without appeal to time or instances. This, however, has fostered an impoverished regime of definitions in which the use of identical terms (like ‘part’) in different systems has been allowed to mask underlying incompatibilities.

45. 45 Belnap “it’s a good thing logicians were around before computer scientists; “if computer scientists had got there first, then we wouldn’t have numbers because arithmetic is undecidable”

46. 46 INSTANcES ARE SINGLETONS

47. 47 Belnap Hilbert's formalism is Kantianism (Cabalah) reference is one address writing to another addresses molecules have their parts rigidly 10 Billion Pounds for SNOMED Influence of GO Bad things in GO Ontologies in BIO generally (google) Functions, processes Pancreas gene story inhibition/function/regulation/plasticity/redundancy/death Evolution is opportunistic (= opportunistic infections) = good for bacteria etc. against Millikan -- cell death life plan = physiology = changes in qualities of parts growth - getting bigger development = new kinds of things getting formed aging = involution death

48. 48 Aristotle-Linnaeus Theory of Species and Instances

49. 49 siamese mammal cat organism substance species, genera animal instances frog

50. 50 Husserl’s Science of Pure Logic

51. 51 siamese is P mammal is P cat is P S is P judgment species, genera animal is P instances ……………… a stands in R to something a stands in R to b

52. 52 siamese is P mammal is P cat is P S is P judgment species, genera animal is P a stands in R to something a stands in R to b LAWS OF LOGIC = LAWS OF ESSENCE GOVERNING STRUCTURES/COMBINATIONS OF JUDGMENT

53. 53 The historical epistemology of the sciences life-world physics medicine molecular biology granularity

54. 54 Different scientific cultures/terminologies immunology genetics cell biology

55. 55 (Quine) an ‘ontology’ is a systematic representation of the ontological commitments of a given scientific discipline, culture, commercial enterprise … children’s ontology Buddhist ontology wine ontology

56. 56 Ontologies as hierarchies of ‘concepts’ “Concepts, also known as classes, are used in a broad sense. They can be abstract or concrete, elementary or composite, real or fictious. In short, a concept can be anything about which something is said, and, therefore, could also be the description of a task, function, action, strategy, reasoning process, etc.” Confusion of concept / object / description

57. 57 Semantic Web Ontology-based unification = REDUCE EVERYTHING TO SYNTACTIC STRINGS IN SOME ‘Ontology Web Language’ and STIR VIGOROUSLY The Crisis of Bioinformatic Sciences

58. 58 An alternative research programme for ontology based on philosophical principles Department of Biological Structure (Seattle) Ontek Corporation (Buffalo) Laboratory for Applied Ontology (Trento/Rome)

59. 59 Basic Formal Ontology (counterpart of pure mathematics) BFO

60. 60 A Network of Domain Ontologies Material (Regional) Ontologies Basic Formal Ontology

61. 61 A Network of Domain Ontologies BFO

62. 62 A Network of Domain Ontologies BFO ChemOPhysiOAROGOPsychO

63. 63 Part Three ARO: The Anatomy Reference Ontology

64. 64 Anatomy Reference Ontology = theoretical framework surrounding the Digital Anatomist Foundational Model of Anatomy of Department of Biological Structure, University of Washington, Seattle

65. 65

66. 66 A Linnaean Hierarchy

67. 67 at every level of granularity

68. 68 Anatomy Reference Ontology “Rather than stating the meanings of terms, definitions should state the essence of anatomical entities in terms of their characteristics... Paraphrasing Aristotle, the essence of an entity is constituted by … the genus, necessary to assign an entity to a class and … the differentiae, necessary to distinguish the entity from other entities also assigned to the class.”

69. 69 The Anatomy Reference Ontology is organized in a graph-theoretical structure involving two sorts of links or edges: is-a (= is a subtype of ) (auditory ossicle is-a bone) part-of (cervical vertebra part-of vertebral column)

70. 70 Part Four GO: The Gene Ontology

71. 71 GO is three ontologies cellular components molecular functions biological processes December 16, 2003: 1372 component terms 7271 function terms 8069 process terms

72. 72 GO product of Open Biological Ontologies consortium Fungal Ontology Plant Ontology Yeast Ontology Disease Ontology...

73. 73 When a gene is identified three important types of questions need to be addressed: 1. Where is it located in the cell? 2. What functions does it have on the molecular level? 3. To what biological processes do these functions contribute?

74. 74 GO’s three ontologies molecular functions cellular components biological processes

75. 75 The Cellular Component Ontology (counterpart of anatomy) flagellum chromosome membrane cell wall nucleus

76. 76 The Molecular Function Ontology ice nucleation protein stabilization kinase activity binding The Molecular Function ontology is (roughly) an ontology of actions on the molecular level of granularity

77. 77 Biological Process Ontology Examples: glycolysis death adult walking behavior response to blue light = occurrents on the level of granularity of cells, organs and whole organisms

78. 78 the universals of GO are species- independent an ontology of the unchanging universal building blocks of life (substances and processes) and of the structures they form

79. 79 but: GO built by biologists compare: the Gene Statistic

80. 80 hemolysis Definition The cause of hemolysis …

81. 81 Molecular Function Definition: An activity or task performed by a gene product. It often corresponds to something (such as a catalytic activity) that can be measured in vitro.

82. 82 Biological Process Definition: A biological process is a biological goal that requires more than one function. Mutant phenotypes often reflect disruptions in biological processes.

83. 83 Each of GO’s ontologies is organized in a graph-theoretical structure involving two sorts of links or edges: is-a (= is a subtype of ) (copulation is-a biological process) part-of (cell wall part-of cell)

84. 84

85. 85 GO has only sentences of the form A is_a B and A part_of B no way to express ‘not’ and no way to express ‘is localized at’ and no way to express ‘I don’t know’: Holliday junction helicase complex is-a unlocalized

86. 86 GO:0008372 cellular component unknown cellular component unknown is-a cellular component

87. 87 Is biological classification Linnaean?

88. 88 Principle of Single Inheritance no class in a true (Linnaean) hierarchy should have more than one parent on the immediate higher level no diamonds:

89. 89 Problems with multiple inheritance B C is-a 1 is-a 2 A ‘is-a’ no longer univocal

90. 90 ‘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 they also serve as obstacles to integration with neighbouring ontologies

91. 91 ‘within’ lytic vacuole within a protein storage vacuole 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

92. 92 ‘extrinsic to’ extrinsic to membrane extrinsic to membrane part-of membrane

93. 93 GO’s three ontologies are separate No links or edges defined between them molecular functions cellular components biological processes

94. 94 Three granularities: Molecular (for functions) Cellular (for components) Whole organism (for processes)

95. 95 GO does not include molecules or organisms within any of its three ontologies The only continuant entities within the scope of GO are cellular components (including cells themselves)

96. 96 Are the relations between functions and processes a matter of granularity? Molecular activities are the building blocks of biological processes ? But they cannot be represented in GO as parts of biological processes

97. 97 GO does not recognize parthood relations between entities on its three distinct levels of granularity Compare: this wheel is part of the car this molecule is part of the car

98. 98

99. 99 Part Five Extending GO to make a full ontology by adding relations of dependence

100. 100 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

101. 101 Principle of Dependence If an ontology recognizes a dependent entity then it (or a linked ontology) should recognize also the relevant class of bearers

102. 102 Linking to external ontologies can also help to link together GO’s own three separate parts

103. 103 GO’s three ontologies molecular functions cellular components biological processes  dependent   independent

104. 104 GO’s three ontologies molecular functions cellular components organism- level biological processes cellular processes

105. 105 molecular functions molecule complexe s cellular processes cellular components organism- level biological processes organisms ‘part-of’; ‘is dependent on’

106. 106 molecule complexe s cellular component s molecular function s cellular functions organism- level biological functions organisms molecular processe s cellular processes organism- level biological processes

107. 107 molecule complexe s cellular component s molecular function s cellular functions organism- level biological functions organisms molecular processe s cellular processes organism- level biological processes functionings junk processes

108. 108 Basic Formal Ontology –theory of part and whole –theory of dependence –theory of boundary, continuity and contact –(Aristotelian) theory of species, instances and lowest specific differences (first edition of LU) –theory of continuants and occurrents –theory of functions –theory of granularity

109. 109 The End

110. 110 The problem About 30,000 genes in a human Probably 100-200,000 proteins Individual variation in most genes 100s of cell types 100,000s of disease types

111. 111 DNA Protein Organelle Cell Tissue Organ Organism Muscle tissue Nerve tissue Connective tissue Epithelial tissue Blood Musculo-skeletal system Circulatory system Respiratory system Digestive system Nervous system Urinary system Reproductive system Endocrine system Lymphoidal system Mitochondria Nucleus Endoplasmic reticulum Cell membrane

112. 112 The Challenge Each (clinical, pathological, genetic, proteomic, pharmacological …) information system uses its own terminology and category system biomedical research demands the ability to navigate through all such information systems How can we overcome the incompatibilities which become apparent when data from distinct sources is combined?

113. 113 Answer: “Ontology”

114. 114 Three senses of ontology 1.Philosophical sense: an inventory of the types of entities and relations in reality 2.Knowledge engineering sense: an ontology as a consensus representation of the concepts used in a given domain 3.GO/OBO sense: a controlled vocabulary

115. 115 Ontology as a branch of philosophy seeks to establish the basic formal-ontological structures the kinds and structures of objects, properties, events, processes and relations in each material domain of reality

116. 116 Formal ontology an analogue of pure mathematics Can be applied to different domains

117. 117 Material ontology a kind of generalized chemistry or zoology (Aristotle’s ontology grew out of biological classification)

118. 118 Aristotle world’s first ontologist

119. 119 World‘s first ontology ( from Porphyry’s Commentary on Aristotle’s Categories)

120. 120 Linnaean Ontology

121. 121 Formal Ontology –theory of part and whole –theory of dependence / unity –theory of boundary, continuity and contact –theory of universals and instances –theory of continuants and occurrents (objects and processes) –theory of functions and functioning –theory of granularity

122. 122 Formal Ontology the theory of those ontological structures (such as part-whole, universal-particular) which apply to all domains whatsoever

123. 123 Formal Ontology vs. Formal Logic Formal ontology deals with the interconnections of things with objects and properties, parts and wholes, relations and collectives Formal logic deals with the interconnections of truths with consistency and validity, or and not

124. 124 Formal Ontology vs. Formal Logic Formal ontology deals with formal ontological structures Formal logic deals with formal logical structures (Epistemology deals with ways of gaining knowledge)

125. 125 Formal-Ontological Categories substance process function unity plurality site dependent part independent part are able to form complex structures in non- arbitrary ways joined by relations such as part, dependence, location.

126. 126 Example of a Formal-Ontological Structure D E AB C

127. 127 Ontological Structure D E AB C two-sided mutual dependence one-sided dependence

128. 128 Ontological Structure D E AB C part-whole relation F

129. 129 A Network of Domain Ontologies Material (Regional) Ontologies Basic Formal Ontology

130. 130 In formal ontology as in formal logic, we can grasp the properties of given structures in such a way as to establish in one go the properties of all formally similar structures

131. 131 Material Ontology of Social Interaction oblig- ation claim promiser promisee act of speaking act of registering content

132. 132 A Window on Reality oblig- ation claim promiser promisee act of speaking act of registering content

133. 133 Universals oblig- ation claim promiser promisee act of speaking act of registering content

134. 134 Instances oblig- ation claim promiser promisee act of speaking act of registering content

135. 135 A Window on Reality

136. 136 Medical Diagnostic Hierarchy a hierarchy in the realm of diseases

137. 137 Dependence Relations OrganismsDiseases

138. 138 A Window on Reality OrganismsDiseases

139. 139 A Window on Reality

140. 140 siamese mammal cat organism substance universals animal instances frog

141. 141

142. 142

143. 143 Many current standard ‘ontologies’ ramshackle because they have no counterpart of formal ontology The Universal Medical Language System (UMLS) a compendium of source vocabularies including: HL7 RIM SNOMED International Classification of Diseases MeSH – Medical Subject Headings Gene Ontology

144. 144 Problem: The different source vocabularies are incompatible with each other

145. 145 Problem: They contain bad coding which often derives from failure to pay attention to simple logical or ontological principles or from principles of good definitions

146. 146 Bad Coding Plant roots is-a Plant Plant leaves is-a Plant Pollen is-a Plant Both testes is a testis Both uterii is a uterus

147. 147 Bad definitions Heptolysis = def the cause of heptolysis Biological process = def a biological goal that requires more than one function

148. 148 is-a Standard definition: A is-a B =def every instance of A is an instance of B = standard definition of computer science adult is-a child animal owned by the Emperor is-a animal mammal is-a object weighing less than 200 kg

149. 149 correct reading of is-a 1.A and B are natural kinds, 2.there are times at which instances of A exist, 3.at all such times these instances are necessarily (of their very nature) also instances of B 1. eukaryotic cell is-a cell 2. mammal is-a animal 3. death is-a biological process

150. 150 Ontologies Here A and B are universals (= natural kinds, types …, roughly analogous to biological species) Universals have instances (you and me, your headache, my coughing)

151. 151 Instances are elite individuals they are those which instantiate universals (entering into biological laws)

152. 152 Linnaean Ontology

153. 153 Confusion of Ontology and Epistemology Physical Object Substance Food Chemical Body Substance

154. 154 Confusion of Ontology and Epistemology Chemical Viewed Structurally Functionally

155. 155 Chemical Viewed Structurally Functionally Inorganic Organic Enzyme Biomedical or Chemical Chemical Dental Material

156. 156 Chemical Viewed Structurally Functionally Inorganic Organic Biomedical or Chemical Chemical Dental Material Enzyme

157. 157 Is biological classification Linnaean?

158. 158 Principle of Single Inheritance (rule of thumb) no class in a classificatory hierarchy should have more than one parent

159. 159 The Problem of Multiple Inheritance cars Buicks blue cars blue Buicks

160. 160 Principle of Taxonomic Levels

161. 161 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

162. 162 Principle of Exhaustiveness the classes on any given level should exhaust the domain of the classificatory hierarchy.

163. 163 Single Inheritance + Exhaustiveness = JEPD 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

164. 164 Problems with multiple inheritance B C is-a 1 is-a 2 A E D ‘sibling’ is no longer determinate

165. 165 Problems with multiple inheritance B C is-a 1 is-a 2 A E D ‘is_a’ is no longer univocal

166. 166 when ‘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 they also serve as obstacles to integration with neighboring ontologies

167. 167 How are universals and instances related together?

168. 168 Entities

169. 169 Entities universals (classes, types, taxa, …) particulars (individuals, tokens, instances …) Axiom: Nothing is both a universal and a particular

170. 170 Two Kinds of Elite Entities classes, within the realm of universals instances within the realm of particulars

171. 171 Entities classes

172. 172 Entities classes* *natural, biological

173. 173 Entities classes of objects, substances need modified axioms for classes of functions, processes, pathways, reactions, etc.

174. 174 Entities classes instances

175. 175 Classes are natural kinds Instances are natural exemplars of natural kinds (problem of non-standard instances) Not all individuals are instances of classes

176. 176 Entities classes instances penumbra of borderline cases

177. 177 Entities classes instances junk example of junk: beachball-desk

178. 178 Primitive relations: inst and part inst(Jane, human being) part(Jane’s heart, Jane’s body) A class is anything that is instantiated An instance as anything (any individual) that instantiates some class

179. 179 Entities human Jane inst

180. 180 Entities human Jane’s heart part Jane

181. 181 part as a relation between individuals subject to the usual axioms of mereology

182. 182 Two primitive relations: inst and part inst(Jane, human being) part(Jane’s heart, Jane’s body) A universal is anything that is instantiated An instance is anything (any individual) that instantiates some class

183. 183 Two primitive relations: inst and part Axioms governing inst : (1) it holds in every case between an instance and a class, in that order; (2) that nothing can be both an instance and a class. Axioms governing part (= ‘proper part’) (1) it is irreflexive (2) it is asymmetric (3) it is transitive (4) it holds only between individuals (usual mereological axioms)

184. 184 Part_for and Has_Part A part_for B = def given any x, if inst(x, A) then there is some y such that inst(y, B) and part(x, y) B has_part A = def given any y, if inst(y, B) then there is some x such that inst(x, A) and part(x, y) human testis part_for human being, But not: human being has_part human testis. human being has_part heart, But not: heart part_for human being.

185. 185 The usual part_of relation as a relation between universals A part_of B = def A part_for B & B has_part A As exist only as parts of Bs and Bs are structurally organized in such a way that As must appear in them as parts.

186. 186 Analogous problems for nearly all foundational relations of ontologies and semantic networks: A causes B A is associated with B A is located in B etc. Reference to instances is necessary to clear up these problems

187. 187 if they can be cleared up at all …

188. 188 Fragment of the UMLSemantic Network

189. 189

190. 190 Mental Process precedes Molecular Function Mental Process precedes Genetic Function Experimental Model of Disease precedes Cell or Molecular Dysfunction Acquired Abnormality affects Bird Experimental Model of Disease affects Fungus Physiologic Function affects Reptile Antibiotic causes Experimental Model of Disease Biomedical or Dental Material causes Mental or Behavioral Dysfunction Manufactured Object causes Disease or Syndrome Vitamin causes Injury or Poisoning Fungus location_of Vitamin Organization location_of Diagnostic Procedure

191. 191 What are universals? invariants in reality satisfying biological laws (there are truths about universals in biological textbooks)

192. 192 Universals are Not Sums Universals are distinguished by granularity: they divide up the corresponding domain into whole units or members, whose interior parts and structure are traced over. The universal human being is instantiated only by human beings as single, whole units. A mereological sum is not granular in this sense (molecules are parts of the mereological sum of human beings)

193. 193 Universals are Not Sets Both universals and sets are marked by granularity – but universals are timeless Both a universal and a set is laid across reality like a grid consisting (1) of a number of slots or pigeonholes each (2) occupied by some member. But a set is determined by its members. This means that it is (1) associated with a specific number of slots, each of which (2) must be occupied by some specific member. A universal survives the turnover in its instances: it is specified neither (1) what the number of associated slots should be nor (2) what individuals should occupy these slots. Both may vary with time.

194. 194 A universal is not determined by its instances as a state is not determined by its citizens A universal may vary with time as an organism may vary with time (by gaining and losing molecules)

195. 195 Universals are Not Sets A set is an abstract structure, existing outside time and space. The set of Romans timelessly has Julius Caesar as a member. Universals exist in time.

196. 196

197. 197 Two Questions 1. What does “Functional” mean in expressions like “Functional Genomics” ? 2. How can we use the answer to this question to help us understand notions fundamental to medicine such as “health” and “disease” ?

198. 198 Towards an Tri-Categorial Ontology of Structures, Functions and Processes

199. 199 Definition of Function in UMLS Semantic Network Functional Concept = df A concept which is of interest because it pertains to the carrying out of a process or activity. Function  Functional Concept Function  Realization of a Function

200. 200 What do the kidneys do? Your entire blood volume flows through your kidneys every few minutes, leaving behind excess water, solutes and waste materials The Kidney From Andrew Lonie, University of Melbourne

201. 201 How does a kidney work? Essentially a massively parallel filter composed of 10 5 to 10 6 nephrons The nephron is the functional unit of the kidney Each nephron is a very convoluted, long, thin tube lined with biochemical pumps

202. 202 Nephron Functions 10 functional segments 15 different cell types

203. 203 Qualitative functional ontology Normal Physiology Disease States Genetics/Mutations Species Differences Structural ontology Kidney Renal architecture Tubule section/ Glomerulus Cell = ANATOMY AT DIFFERENT LEVELS OF GRANULARITY Structural and functional representation process ontology (molecular, cellular, organ-level …)

204. 204 UMLS Semantic Network entity event physical conceptual object entity organism

205. 205 Tri-Categorial Ontology present also in GO: The Gene Ontology 3 ‘ontologies’ (large telephone directories) of standardized designations for gene functions and products

206. 206 RUMLS Semantic Network entity event structures functions processes

207. 207 GO’s three disjoint term hierarchies the cellular component (structure) ontology, e.g. flagellum, chromosome, cell the biological process ontology, e.g. glycolysis, death the molecular function ontology, e.g. ice nucleation, binding, protein stabilization

208. 208 RUMLS Semantic Network entity event structures functions processes

209. 209 Functional Genomics What does “Functional“ mean?

210. 210 The Problem The tumor developed in John’s lung over 25 years

211. 211 The Problem ____ developed in _____ over 25 years process

212. 212 The Problem The tumor developed in the lung over 25 years substances things objects continuants

213. 213 The Problem The tumor developed in John’s lung over 25 years PARTHOOD NOT DETERMINATE

214. 214 The Problem The tumor developed in the lung over 25 years substances GLUING THESE TOGETHER YIELDS ONTOLOGICAL MONSTERS processes

215. 215 Substances and processes exist in time in different ways substance t i m e process

216. 216 SNAP vs SPAN Endurants vs perdurants Continuants vs occurrents In preparing an inventory of reality we keep track of these two different kinds of entities in two different ways

217. 217 Fourdimensionalism – only processes exist – time is just another dimension, analogous to the three spatial dimensions – substances are analyzed away as worms/fibers within the four-dimensional plenum

218. 218 There are no substances Bill Clinton does not exist Rather: there exists within the four- dimensional plenum a continuous succession of processes which are similar in a Billclintonizing way

219. 219 Fourdimensionalism (the SPAN perspective) is right in everything it says But incomplete

220. 220 Need for Two Orthogonal, Complementary Perspectives SNAP and SPAN

221. 221 Snapshot Video ontology ontology substance t i m e process

222. 222 SNAP and SPAN stocks and flows commodities and services product and process anatomy and physiology

223. 223 SNAP and SPAN SNAP entities - have continuous existence in time - preserve their identity through change - exist in toto if they exist at all SPAN entities - have temporal parts - unfold themselves phase by phase - exist only in their phases/stages

224. 224 You are a substance Your life is a process You are 3-dimensional Your life is 4-dimensional

225. 225 Many SNAP Ontologies t1t1 t3t3 t2t2 here time exists outside the ontology, as an index or time-stamp

226. 226 each SNAP i section through reality includes everything which exists (present tense)

227. 227 mereology works without restriction (parthood is everywhere determinate) in every SNAP i ontology

228. 228 Three kinds of SNAP entities 1.SNAP Independent Entities (you and me) 2.SNAP Dependent Entities 3.Spatial regions

229. 229 SNAP dependent entities States, powers, qualities, functions, dispositions, plans, shapes, liabilities, propensities…

230. 230 SNAP dependent entities: one-place: your temperature, color, height my knowledge of French the whiteness of this cheese the warmth of this stone the fragility of this glass

231. 231 relational SNAP dependent entities John Mary love stand in relations of one-sided dependence to a plurality of substances simultaneously one-sided dependence

232. 232 A Window on Reality oblig- ation claim promiser promisee act of speaking act of registering content

233. 233 Spatial regions + sites (contexts, niches, environments) Organism species evolve into environments Domesticated spatial regions: rooms, nostrils, your alimentary tract Fiat spatial regions: JFK designated airspace

234. 234 SNAP: Entities existing in toto at a time http://ontology.buffalo.edu/bfo

235. 235 The SPAN Ontology t i m e

236. 236 here time exists as part of the domain of the ontology The SPAN ontology

237. 237 mereology works without restriction everywhere here t i m e clinical trial

238. 238 mereology works without restriction everywhere here t i m e course of a disease

239. 239 Processes, too, are dependent on substances One-place vs. relational processes One-place processes: your getting warmer your getting hungrier

240. 240 Relational processes kissings, thumpings, conversations, dancings, promisings, infectings, bindings join their carriers together into collectives of greater or lesser duration

241. 241 SPAN: Entities extended in time http://ontology.buffalo.edu/bfo

242. 242 Two kinds of SPAN entities 1.Processes (including events: process-boundaries, settings) 2.Spatio-temporal regions

243. 243 How do you know whether an entity is SNAP or SPAN?

244. 244 problem cases forest fire hurricane Maria traffic jam ocean wave disease anthrax epidemic

245. 245 forest fire: a process a pack of monkeys jumping from tree to tree and eating up the trees as they go the Olympic flame: a process or a thing? (anthrax spores are little monkeys)

246. 246 A disease The course/history of a disease

247. 247 The Epidemic (SNAP) The Spread of an Epidemic (SPAN)

248. 248 Material examples: performance of a symphony projection of a film expression of an emotion utterance of a sentence application of a therapy increase of temperature

249. 249 The Tri-Categorial Ontology SNAP SPAN structures functions processes = independent = dependent continants continuants

250. 250 The Tri-Categorial Ontology continuants occurrents structures functions processes = independent = dependent continants continuants

251. 251 A Window on Reality continuants occurrents structures functions processes = independent = dependent continants continuants Entities in all three categories exist both as universals and as instances (as tokens and as types) The function of your heart is: to pump blood The function of my heart is: to pump blood

252. 252 Functions are continuants The function of your heart begins to exist with the beginning to exist of your heart, and continues to exist, self-identically, until (roughly) your heart ceases to be able to respond if stimulated by your sympathetic and parasympathetic nervous systems

253. 253 Functions have bearers The bearer of the function of your heart is: your heart. Functions are dependent continuants. The bearers of functions are independent continuants (hearts, screwdrivers …)

254. 254 Functions are realized in special sorts of processes called functionings The processes taking place in or involving entities which are bearers of functions can be divided into two types: those which are realizations of their functions (also called functionings) and processes of other types (junk processes)

255. 255 Functions can exist even when they are not being realized

256. 256 Processes (realizations) are causal-energetic time

257. 257 Functions are historical (they exist in time) but they are also quasi-Platonic time

258. 258 Compare the relation between temperature, which is quasi-Platonic and Brownian motion, which is causal-energetic Your temperature at t vs. the value of your temperature at t

259. 259 Your temperature is quasi-Platonic Your temperature as a determinable is identical from one moment of your existence to the next This determinable takes on different values at different times

260. 260 Biological functions are always constituent functions If X has a biological function then there is some Y of which X is a part and X’s functioning is in the service of / for the benefit of Y

261. 261 Functions are beneficial If an organism has a constituent part X, and if X is the bearer of a function Z, then those processes which are the realizations of the function Z are (in normal circumstances) beneficial to the organism (  such as to sustain the organism in existence)

262. 262 Functional Genomics = study of what the genes contribute to the organism in the way of survival (Bad genes do not have functions) Every oncogene is a proto-oncogene There is functioning, poor functioning, malfunctioning There is not having a function at all (and this can be either neutral in the stakes of beneficiality or also positively malignant)

263. 263 Does this sense of ‘function’ correspond to the way biologists talk?

264. 264 Clinical vs. biological sense of ‘function’ Biologists sometimes talk about biological structures ‘gaining function’ (= being switched on) even where their functioning is not beneficial Are all functions associated with malfunctionings?

265. 265 Health – Disease – Illness Diseased organ = organ predisposed to malfunction Its functioning is defective

266. 266

267. 267 Part Four: Definitions of Health World Health Organization: Health is the state of psychological and physical well-being of humans

268. 268 Biostatistical Theory Christopher Boorse Health is conformity to normal species design (as statistically determined). Abnormally healthy people are therefore in fact sick ( ?)

269. 269 The Vital Goal Theory Lennart Nordenfelt Health is the bodily and mental state of a person which is such that he or she has an ability to realize vital goals, given standard or otherwise accepted circumstances. Disease is a state or process of a person’s body or mind that tends to cause ill health in the bearer.

270. 270 The Ordinary Action Theory K.W.M. Fulford Health is being able to do what one ordinarily does in the absence of obstruction or opposition. Illness is failing to do what one ordinarily does in the absence of obstruction or opposition.

271. 271 The Abnormality Theory Lawrie Reznek Disease is a state of a person which issues in abnormal behavior; something is an abnormal bodily or mental process if it does standard members of the human species some harm in standard circumstances; something does a person harm if it makes the person less able to live a good or worthwhile life.

272. 272 Problems with standard definitions 1.Circularity 2.Make health a social construction 3.Make health a Cambridge property 4.Confuse state and process, disposition and realization, potentiality and actuality 5.Do not apply to organisms other than humans

273. 273 Circularity Health is... well-being Health is... being able to live a good or worthwhile life Disease is a state … that tends to cause ill health in the bearer

274. 274 Health a social construction Health is …the ability to realize vital goals, given standard or otherwise accepted circumstances Illness = what the insurance company will pay to treat

275. 275 Health a Cambridge Property Health is conformity to normal species design (as statistically determined). If everyone in society becomes sicker and you remain the same, then you are the person who becomes unhealthy

276. 276 Ontology of Disease Diseases are, like functions, dependent continuants They are states or conditions which endure for a certain time and have a course or history, which is an occurrent Disease tokens, like roles and functions, do not change through their existence over time

277. 277 Diseases are both historical and quasi-Platonic time

278. 278 Functions This is a screwdriver This is a good screwdriver This is a broken screwdriver This is a heart This is a healthy heart This is an unhealthy heart

279. 279 Functions are associated with certain characteristic process shapes Screwdriver: rotates and simultaneously moves forward simultaneously transferring torque from hand and arm to screw Heart: performs a contracting movement inwards and an expanding movement outwards simultaneously transferring hydraulic pressure to the blood stored within its chambers

280. 280 For each function there is an associated family of (four- dimensional) process shapes, organized around a core of prototypical process shapes representing good functioning The prototypes play a role analogous to the standard meter rule in the organization of those one-dimensional shapes we call lengths

281. 281

282. 282 Outside the core are process shapes which are not instances of functioning at all

283. 283

284. 284

285. 285 Normal functioning = functioning (realizing a four-dimensional shape) at or close to the prototype

286. 286 Prototypes good functioning

287. 287 Prototypes reasonable functioning

288. 288 Poor functioning poor functioning

289. 289 Malfunctioning malfunctioning

290. 290 Death? not functioning at all

291. 291 Not functioning at all leads to death modulo internal factors: plasticity redundancy (2 kidneys) criticality of the system involved external factors: prosthesis (dialysis machines, oxygen tent) special environments assistance from other organisms

292. 292 Relevance of Millikan Prototypical functioning = exercising what Millikan calls ‘proper function’ (defined historically) X is the proper function of Y means: 1) Y performs X and 2) Y exists because its predecessors’ performing the function X is responsible for my existing It is not the function of the nose to hold up spectacles because this was not selected for

293. 293 Millikan = backward looking, focused on whole species This account = forward looking, focused on single organism X has a function = (1) X’s functioning is beneficial to the organism of which X is a part

294. 294 Boorse’s Internal Impairment Theory Disease is an internal state which is an impairment or limitation of normal functional ability.

295. 295 Disease

296. 296 Disease = remoteness from prototypical functioning disease

297. 297 Disease = remoteness from prototypical functioning disease 1 2 3 1 = not functioning at all 2 = malfunctioning 3 = functioning poorly

298. 298 Not functioning at all = death modulo: criticality of the system involved

299. 299 Biological entities have biological functions only as parts of organisms An organic entity functions in the service of the organism of which it is a part There are immediate parts of the organism – the bodily systems – which function directly in the service of the organism. And there are mediate (= smaller) parts of the organism – cells, tissues, organs … -- which function in the service of larger parts

300. 300 Immediate parts of the organism are more critical

301. 301 Bodily Systems respiratory digestive skeletal circulatory musculatory immune

302. 302 ENDOCRINE SYSTEM

303. 303 What do the kidneys do? KIDNEY

304. 304 How does a kidney work? NEPHRON

305. 305 Nephron Functions FUNCTIONAL SEGMENTS

306. 306 DNA Protein Organelle Cell Tissue Organ Organism

307. 307 Coda on ‘Normal’ Normal functioning of the pancreas Normal functioning of the sexual organs On the several senses of ‘normal’ in biology

308. 308 Problem: The Sexual Organs do not have Biological Functions A constituent part of an organism has a function = its functioning is beneficial to the survival of the host organism – this does not hold for the reproductive system and its parts

309. 309 Hence the sexual organs do not have functions Alternatively they have functions in relation to some larger whole (the family, the dynasty …) Compare the role of worker bees in bee colonies …

310. 310 The End